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2016 update WHO treatment guidelines for drug- resistant tuberculosis OCTOBER 2016 REVISION

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ISBN: 978-92-4-154963-9

2016 update

WHO treatment guidelines for drug-resistant tuberculosis

OCTOBER 2016 REVISION

WHO treatment guidelines for drug-

resistant tuberculosis2016 update

OCTOBER 2016 REVISION

These guidelines were developed in compliance with the process for evidence gathering, assessment and formulation of recommendations, as outlined in the WHO Handbook for Guideline Development (version March 2014; available at http://www.who.int/kms/handbook_2nd_ed.pdf ).

WHO Library Cataloguing-in-Publication Data

WHO treatment guidelines for drug-resistant tuberculosis, 2016 update. October 2016 revision.

Contents: Web Annex 4: GRADE tables – Web Annex 5: Evidence to decision tables – Web Annex 6: Summaries of unpublished data used for the recommendations

1.Tuberculosis, Multidrug-Resistant – drug therapy. 2.Antitubercular Agents. 3.Guideline. I.World Health Organization.

ISBN 978 92 4 154963 9 (NLM classification: WF 310)

© World Health Organization 2016

All rights reserved. Publications of the World Health Organization are available on the WHO website (http://www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; email: [email protected]).

Requests for permission to reproduce or translate WHO publications –whether for sale or for non-commercial distribution– should be addressed to WHO Press through the WHO website (http://www.who.int/about/licensing/copyright_form/index.html).

The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement.

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.

All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.

Printed by the WHO Document Production Services, Geneva, Switzerland

Design by Inis Communication – www.iniscommunication.com

WHO/HTM/TB/2016.04

Contents

Abbreviations & acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv

Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Declarations of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Executive summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

WHO policy recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Annex 1. Agenda for the Guideline Development Group meeting on the WHO treatment guidelines for drug-resistant TB, 2016 update, 9–11 November 2015 . . . . . . . 46

Annex 2. Experts involved in the development of the WHO treatment guidelines for drug-resistant TB, 2016 update . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Annex 3. PICO questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Annex 4. GRADE tables

Annex 5. Evidence to decision tables

Annex 6. Summaries of unpublished data used for the recommendations

Annexes 4, 5 and 6 are only available online at: www.who.int/entity/tb/areas-of-work/drug-resistant-tb/treatment/resources/en/

iv

Abbreviations & acronyms1

aDSM active TB drug safety monitoring and managementaOR adjusted odds ratioAIDS acquired immunodeficiency syndromeaIPD adult individual patient dataCDC United States Centers for Disease Control and PreventionCL confidence limitsCNS central nervous systemCPTR Critical Path to TB Drug RegimensDSMB Data and Safety Monitoring BoardDST drug susceptibility testingEBA early bactericidal activityERG External Review GroupGDF Global Drug FacilityGDG Guideline Development GroupGRADE Grading of Recommendations Assessment, Development and EvaluationGRC WHO Guideline Review CommitteeGTB WHO Global TB ProgrammeHIV human immunodeficiency virusIPD individual patient dataKNCV KNCV Tuberculosis FoundationLSHTM London School of Hygiene and Tropical MedicineLTBI latent TB infectionMDR-TB multidrug-resistant tuberculosisMIC minimum inhibitory concentrationMSF Médecins sans FrontièresMTBDRsl GenoType Mycobacterium tuberculosis drug-resistant second-line assayNTM non-tuberculous mycobacteriaOR odds ratioPICO Patients, Intervention, Comparator and OutcomespIPD paediatric individual patient dataRCT randomized controlled trialRR-TB rifampicin-resistant TBSAE serious adverse eventSIAPS Systems for Improved Access to Pharmaceuticals and ServicesTAG Treatment Action GroupTB tuberculosisTB-PRACTECAL Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment

Regimen(s)UNION International Union Against Tuberculosis and Lung DiseaseUSAID United States Agency for International DevelopmentWHO World Health OrganizationXDR-TB extensively drug-resistant tuberculosis

1 See also page 23 for the abbreviations of the names of TB medicines.

1

Acknowledgements

The recommendations and remarks contained in this document resulted from the discussions of an ad hoc Guideline Development Group (GDG) convened by the Global TB Programme (GTB) of the World Health Organization (WHO) in Geneva, Switzerland from 9 to 11 November 2015 (Annex 1). WHO gratefully acknowledges the contributions made by this Group ahead of, during and after this meeting by its members, namely Holger Schünemann (Chair and GRADE methodologist) and Charles L Daley (Co-Chair) and other experts: Farhana Amanullah, José A Caminero, Tsira Chakhaia, Daniela Cirillo, Kelly Dooley, Luis Gustavo do Valle Bastos, Michel Gasana, Agnes Gebhard, Armen Hayrapetyan, Antonia Kwiecien, Sundari Mase, Lindsay McKenna, Nguyen Viet Nhung, Maria Rodriguez, James Seddon, Tom Shinnick, Alena Skrahina, and Carlos Torres-Duque (Annex 2). The experts on the External Review Group (ERG) who provided comments in preparation of the meeting and on the draft document before its finalization – Chen-Yuan Chiang, Dalene von Delft, Vaira Leimane, Guy Marks, Norbert Ndjeka, Lee Reichman and Rohit Sarin – are also acknowledged.

The writing of these guidelines was coordinated by Dennis Falzon and Elizabeth Harausz (Consultant), under the guidance and supervision of Ernesto Jaramillo and Karin Weyer, and the overall direction of Mario Raviglione, Director of the GTB. The authors acknowledge the contribution of other WHO staff in the production of these guidelines making up the WHO Guideline Steering Committee, namely Nathan Ford, Giuliano Gargioni, Haileyesus Getahun, Malgorzata Grzemska, Avinash Kanchar, Soleil Labelle, Christian Lienhardt, Knut Lönnroth, Fuad Mirzayev, Linh Nhat Nguyen, Marco Antonio Vitoria, Fraser Wares, Diana Weil and Matteo Zignol. The following WHO staff from the regional offices received a final draft of the guideline document for review: Masoud Dara (Europe), Mirtha del Granado (Americas), Daniel Kibuga (Africa), Hyder Khursid (South-East Asia), Mohammed Abdel Aziz (Eastern Mediterranean) and Nobuyuki Nishikiori (Western Pacific). The document was finalized following an iteration of comments in early 2016 from members of the GDG, the ERG, and the the WHO Guideline Steering Committee, ahead of submission to the WHO Guideline Review Committee (GRC) in March 2016 following the WHO internal clearance process.

The funding for the update of the guidelines was made available by the United States Agency for International Development (USAID), through the USAID–WHO Consolidated Grant No. GHA-G-00–09–00003/US-2014–735.

2

Declarations of interest

Guideline Development Group (GDG) 

The scope of the guidelines update, and the composition of the GDG, including their biographies, were made public for comment ahead of the meeting in line with WHO’s conflict of interest policy. All GDG members completed the WHO Declaration of Interest forms. The WHO Guideline Steering Committee in preparation for the update of the guidelines and the GDG meeting reviewed the completed forms.

The following GDG members declared no interests: Luis Gustavo do Valle Bastos, José A Caminero, Tsira Chakhaia, Michel Gasana, Armen Hayrapetyan, Antonia Kwiecien, Sundari Mase, Nguyen Viet Nhung, Maria Rodriguez, Holger Schünemann, James Seddon and Alena Skrahina.

The following GDG members declared interests that were judged not to be in conflict with the objectives of the meeting: 

Farhana Amanullah declared having received funding for consultancies (US$500/day) and travel from WHO; and grants from the Global Fund and TB-REACH to cover her salary (10% full time equivalent).

Daniela Cirillo declared having received funding from FIND to conduct evaluation of drug susceptibility testing (DST) for new drugs (US$16 000), and from Otsuka to evaluate DST for delamanid (US$25 000). She also declared being the head of a supranational TB reference laboratory in Italy involved in country capacity building in DST technologies for second-line drugs and new diagnostics for drug-resistant TB; and being a member of the Italian national committee for the use of bedaquiline.

Charles L Daley declared having received funding from Otsuka to serve as chair of the data monitoring committee for trials of delamanid (US$47 000 over 7 years–current).

Kelly Dooley declared having received funding to provide expert advice on a trial design for TB/HIV (US$2000/year paid to the university/employer); she also declared the following activities and roles: co-chair AIDS Clinical Trials Group (ACTG) study assessing bedaquiline and delamanid; principal investigator for adjuvant paclitaxel and trastuzumab (APT) trial assessing pretomanid (PA-824); and investigator in trials assessing high-dose isoniazid for MDR-TB, rifapentine for pregnant women and children with latent TB infection (LTBI), high-dose rifampicin and levofloxacin for paediatric TB meningitis, as well as bedaquiline and delamanid for children with MDR-TB and HIV infection.

3

Declarations of interest

Agnes Gebhard declared that she works for the KNCV TB Foundation, which has two projects funded by the Eli Lilly and Company Foundation: (i) engaging the private sector in diagnosis and treatment of TB and MDR-TB with quality assured second-line TB drugs, and (ii) the roll-out of QuanTB (a drug forecasting tool) in countries not supported by the Systems for Improved Access to Pharmaceuticals and Services  (SIAPS) implemented by Management Sciences for Health. In addition, she declared that the KNCV TB Foundation has a collaborative project with Cepheid in two countries (Nigeria, Viet Nam) with KCNV providing services for the installation and initial training on the use of GeneXpert machines.

Carlos Torres-Duque declared having received honoraria from Janssen Pharmaceuticals for presentations on TB prevention and WHO policy on bedaquiline at a Latin American Meeting on MDR-TB held in 2014 (US$2000).

Tom Shinnick declared being an employee of the United States Centers for Disease Control and Prevention (CDC). CDC supports his travel and research related to his work on laboratory services needed for TB control. He declared having often represented CDC’s position on laboratory services needed for TB diagnosis, treatment and control. As part of his official duties for CDC, he served on the Data and Safety Monitoring Board (DSMB) organized by Otsuka for the clinical trial of delamanid. He did not receive any remuneration for serving on the DSMB nor for travel expenses (CDC paid for all travel expenses related to serving on the DSMB). The DSMB has completed its work for the trial.

The following GDG members declared interests that were judged to be in conflict with some of the objectives of the meeting and were thus recused from some of the discussions: 

Lindsay McKenna declared non-commercial support to Treatment Action Group (TAG), her employer, from Stop TB Partnership; Bill & Melinda Gates Foundation; the US Department of Veteran Affairs (on behalf of CDC); Janssen Therapeutics for Hepatitis C and HIV projects and the Global Alliance for TB Drug Development (a public-private entity developing new drugs and regimens for TB treatment). She was thus recused from participating in the 9 November 2015 meeting session on Patients, Intervention, Comparator and Outcomes (PICO) question 1 on MDR-TB regimen composition for adults and children.

José A Caminero stated in his biosketch that he is a staff consultant of the International Union Against Tuberculosis and Lung Disease (UNION), an agency directly involved in the implementation and evaluation of programmes using shorter MDR-TB regimens. He was therefore recused from the 10 November 2015 meeting session on PICO question 3 on shorter regimens for MDR-TB.

4

WHO TREATMENT GUIDELINES FOR DRUG-RESISTANT TUBERCULOSIS, 2016 UPDATE

External Review Group (ERG)

The following ERG members declared no interest related to the objects of this meeting: Chen-Yuan Chiang, Celine Garfin, Michael Kimerling, Vaira Leimane, Gao Mengqiu, Norbert Ndjeka, Ejaz Qadeer, Lee Reichman, Rohit Sarin and Irina Vasilyeva.

The following two ERG members declared interests which were judged not to be in conflict with the objects of the guidelines development.

Guy Marks declared research support from AERAS (US$450 000) related to the evaluation of latent TB infection and the rate of recurrence of TB after initial treatment in Viet Nam. He also declared being the Vice-President (and a board member) of the UNION and Editor-in-Chief of the International Journal of Tuberculosis and Lung Disease (for which he receives an honorarium).

Dalene von Delft declared having received support from TAG, USAID, UNITAID, Janssen Pharmaceuticals, Critical Path to TB Drug Regimens (CPTR) and AERAS to cover travel costs and accommodation to give presentations/speeches on drug-resistant TB. She declared that in 2011 she received bedaquiline as part of her MDR-TB treatment through a compassionate use access programme.

Evidence reviewers

The researchers who undertook the systematic reviews of evidence for this revision were the following (Annex 2):

McGill University, Montréal, Canada [Mayara Bastos, Gregory J Fox, Faiz Ahmad Khan, Richard (Dick) Menzies]

London School of Hygiene and Tropical Medicine (LSHTM), London, UK [Katherine Fielding, Rebecca Harris, Mishal Khan, David Moore]

Stellenbosch University, Cape Town, South Africa [Anneke Hesseling]

The evidence reviewers did not participate in the formulation of the policy recommendations.

The following reviewers declared no interest related to the objectives of this meeting: Mayara Bastos, Faiz Ahmad Khan, Richard (Dick) Menzies and Mishal Khan.

The following reviewers declared interests that were judged not to be in conflict with the objectives of the meeting:

Gregory J Fox declared having received research and non-monetary support from the UNION (sponsored by Otsuka) valued at about US$5000 to attend the 2015 International Union Conference and to receive the Young Innovator Award (he declares no work for Otsuka nor any relationship of this award with any commercial or research activities with Otsuka).

5

Declarations of interest

Katherine Fielding declared that her employer (LSHTM) was a recipient of an award from Médecins Sans Frontières (MSF) (GB£26 890) for the period February–December 2015 to provide statistical support for the TB-PRACTECAL study on which she is a co-investigator. The study is a Phase II-III randomized controlled trial (RCT) to evaluate the efficacy and safety of shorter MDR-TB regimens for adults.

Rebecca Harris declared she is consulting for a clinical research organization (Cromsource) working for GlaxoSmithKline (GSK) vaccines (~GB£90 000 in 2013); and on GSK vaccines not related to TB (~GB£10 000 since 2013) for Manpower Solutions.

David Moore declared receiving research support from the Wellcome Trust Research Training Fellowship Programme to supervise a PhD student to study MDR-TB in Peru (GB£ 207 056 in 2014).

Anneke Hesseling declared that her employer (Stellenbosch University) is a recipient of an award from Otsuka Pharmaceutical (~US$70 000 to date) for her work on the Phase III delamanid clinical trials in children.

6

Executive summary

In November 2015, the World Health Organization (WHO) convened a meeting of a Guideline Development Group (GDG) for the update of policy recommendations on the treatment of drug-resistant TB. The GDG was composed of a multidisciplinary group of tuberculosis (TB) and drug-resistant TB experts external to WHO. Before the meeting, the members of the GDG and the WHO Guideline Steering Committee had decided upon the priority questions in the treatment and care of patients with drug-resistant TB to be considered for the update of the guidelines. The scope of the 2016 update comprised the following:

i. The optimal combination of medicines and approach towards regimen design for TB patients (both adults and children) with isoniazid-resistant, rifampicin-resistant (RR-TB), multidrug-resistant (MDR-TB), and extensively drug-resistant (XDR-TB) forms of TB, as well as for patients with M. bovis disease.

ii. The effectiveness and safety of standardized regimens lasting up to 12 months for the treatment of patients with MDR-TB (“shorter regimens”) when compared with longer treatment.

iii. The effect of delay in starting treatment on treatment outcomes for patients with drug-resistant TB.

iv. The effect of surgical interventions on treatment outcomes for patients with drug-resistant TB.

The scope of the WHO treatment guidelines for drug-resistant tuberculosis, 2016 update thus differed from the one that guided the previous update of the WHO policy recommendations on the programmatic management of drug-resistant TB in 2011 (1). It did not cover aspects of policy guidance on the programmatic management of drug-resistant TB that were of lesser priority or for which no new evidence has emerged since the 2011 revision. These included questions relating to the use of rapid diagnostics for RR-TB, the monitoring of response to treatment, the duration of longer (“conventional”) MDR-TB regimens, the delay in starting antiretroviral therapy in MDR-TB patients with human immunodeficiency virus (HIV) and models of care. The GDG considered that the 2011 recommendations relating to these areas would continue to apply until future evidence reviews show a need for revision of current WHO policy.

In preparation for the GDG meeting, systematic reviews were conducted to answer questions formulated in PICO format (Patients, Intervention, Comparator and Outcomes) that addressed all domains of the guidelines scope. The treatment regimen recommendations for adults in the 2016 update were based in part on individual patient data meta-analysis (of 9153 patients who were mostly adults) that informed the 2011 guidance, supplemented with additional evidence published until August 2015, which was summarized in a study-level meta-analysis. Treatment regimen recommendations for children were based on a paediatric individual patient data

7

executive summary

(pIPD) meta-analysis, which included data on 974 children in cohorts and studies published until September 2014. The data for shorter MDR-TB treatment regimens (up to 12 months) were from an analysis of individual patient data and aggregated data from observational studies conducted in Asia and Africa. Surgical recommendations for MDR-TB patients were based on individual patient data analysis and a study-level meta-analysis.

The evidence available on the treatment of isoniazid-resistant TB and on the delay in starting MDR-TB treatment could not address the respective PICO questions. There were very few published studies on the treatment of M. bovis and the regimens differed too much, precluding any attempt at formulating recommendations of clinical use.

The recommendations that address the other PICO questions are summarized below.

1. Shorter MDR-TB regimen for adults and childrenIn patients with RR-TB or MDR-TB who were not previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents was excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9–12 months may be used instead of the longer regimens (conditional recommendation, very low certainty in the evidence).

2. Longer MDR-TB regimens for adults and children2a) In patients with RR-TB or MDR-TB, a regimen with at least five effective TB medicines during the intensive phase is recommended, including pyrazinamide and four core second-line TB medicines – one chosen from Group A, one from Group B, and at least two from Group C2 (conditional recommendation, very low certainty in the evidence). If the minimum number of effective TB medicines cannot be composed as given above, an agent from Group D2 and other agents from Group D3 may be added to bring the total to five.3

2b) In patients with RR-TB or MDR-TB, it is recommended that the regimen be further strengthened with high-dose isoniazid and/or ethambutol (conditional recommendation, very low certainty in the evidence).

It is recommended that any patient – child or adult – with RR-TB in whom isoniazid resistance is absent or unknown be treated with a recommended MDR-TB regimen. It could either be a shorter MDR-TB regimen, or a longer MDR-TB regimen to which isoniazid is added.

As a result of the update, the grouping of medicines used in the treatment of MDR/RR-TB has been revised from the one used in the last guidance to reflect the updated evidence on the efficacy and safety of the different agents. This reclassification of medicines has a bearing on the choice of medicines when users design longer, individualized regimens for patients with

2 Group A=levofloxacin, moxifloxacin, gatifloxacin; Group B=amikacin, capreomycin, kanamycin, (streptomycin); Group C= ethionamide (or prothionamide), cycloserine (or terizidone), linezolid, clofazimine; in children with non-severe disease Group B medicines may be excluded (see guidelines text for how disease severity was assessed).

3 Group D2=bedaquiline, delamanid; Group D3=p-aminosalicylic acid, imipenem–cilastatin, meropenem, amoxicillin clavulanate, (thioacetazone). Bedaquiline is only recommended for adults; delamanid may also be used in patients aged 6–17 years.

8

WHO TREATMENT GUIDELINES FOR DRUG-RESISTANT TUBERCULOSIS, 2016 UPDATE

drug-resistant TB. There is no change in the recommended use of bedaquiline and delamanid from those defined by the WHO interim guidance. These two new medicines now occupy a unique subgroup within the add-on agents used to treat MDR/RR-TB.

3. Surgical interventions in patients with MDR-TBIn patients with RR-TB or MDR-TB patients, elective partial lung resection (lobectomy or wedge resection) may be used alongside a recommended MDR-TB regimen (conditional recommendation, very low certainty in the evidence).

MAIN CHANGES TO THE WHO POLICY RECOMMENDATIONS FOR THE TREATMENT OF DRUG-RESISTANT TB

These guidelines update the previous evidence-informed recommendations on the treatment of drug-resistant TB issued by the World Health Organization (WHO) in 2011. The current priorities in the management of drug-resistant TB have been reflected in the scope of the current guidance. For the 2016 update, the Guideline Development Group convened to update the guidelines proposed priority questions focused on the composition of treatment regimens for rifampicin-resistant (RR-TB) and multidrug-resistant TB (MDR-TB), the effectiveness and safety of shorter MDR-TB regimens, the treatment of isoniazid-resistant and M. bovis TB, the role of surgery, and the impact of delays in starting treatment for RR-TB. In contrast to the 2011 recommendations the current guidance did not update the policy on the use of rapid diagnostics for RR-TB, the monitoring of response to treatment, the duration of longer MDR-TB regimens, the delay in starting antiretroviral therapy in MDR-TB patients with HIV infection and models of care. For these aspects of the programmatic management of drug-resistant TB, the 2011 recommendations continue to apply until future evidence reviews conducted for the purpose of updating WHO policy show a need for revision.

The main changes in the 2016 recommendations are as follows:

� A shorter MDR-TB treatment regimen is recommended under specific conditions.

� Medicines used in the design of longer MDR-TB treatment regimens are now regrouped differently based upon current evidence on their effectiveness and safety. Clofazimine and linezolid are now recommended as core second-line medicines in the MDR-TB regimen while p-aminosalicylic acid is an add-on agent.

� MDR-TB treatment is recommended for all patients with RR-TB, regardless of confirmation of isoniazid resistance.

� Specific recommendations are made on the treatment of children with RR-TB or MDR-TB.

� Clarithromycin and other macrolides are no longer included among the medicines to be used for the treatment of MDR/RR-TB.

� Evidence-informed recommendations on the role of surgery are now included.

Bedaquiline and delamanid have now been assigned to a specific subgroup of add-on agents. In October 2016, WHO published its new policy on delamanid. Delamanid may now also be used alongside longer MDR-TB regimens in patients aged 6–17 years. Bedaquiline is still only recommended for adults.

9

Introduction

The WHO treatment guidelines for drug-resistant tuberculosis, 2016 update aims to support health professionals worldwide to respond to the continued challenge posed by multidrug-resistant and extensively drug-resistant tuberculosis in the post-2015 period of the End TB Strategy (2). It includes important policy changes made following a review of the latest available evidence on the medical and surgical treatment of both adults and children. This revision updates several of the evidence-informed recommendations released by WHO in 2011 (1). Until such time as future evidence reviews conducted for the purpose of updating WHO policy guidance show a need for further revision, the previous recommendations which were not revised in the 2016 update continue to apply (see also Table 1).

Methods

Preparation for revisionThe WHO Guideline Steering Committee met regularly from November 2014 through November 2015 to draft the scope and the corresponding PICO (Patients, Intervention, Comparator and Outcomes) questions, and to follow up the development of the guidelines. An application for the revision of the guidelines was submitted to the WHO Guideline Review Committee (GRC) in August 2015 that received final approval in September 2015.

Seven webinars (using WebEx) were held between May and November 2015 (on May 20, July 17, August 7, August 28, September 16, October 6, and November 5) to discuss with the GDG members the scoping, the PICO questions, the scoring of the outcomes, and progress with the evidence reviews ahead of the meeting. For certain sessions, the groups assessing the evidence were invited to these discussions in their capacity as resource persons. In between the webinars, discussions were continued via email. Two WebEx discussions were also held in 2015 with the External Review Group (ERG) members (on 7 September and 29 October), during which they were briefed about their roles and expectations as peer-reviewers.

10

WHO TREATMENT GUIDELINES FOR DRUG-RESISTANT TUBERCULOSIS, 2016 UPDATE

Tabl

e 1. Sum

mar

y of

cha

nges

in t

he e

vide

nce

base

d re

com

men

dati

ons

betw

een

the

20

11

(1)

and

20

16

gui

delin

esa

2011 G

UID

ELIN

ES (

1)

2016 G

UID

ELIN

ES

Use

of

rap

id d

iagn

osti

cs f

or r

ifa

mp

icin

re

sist

an

ce

Rap

id d

rug

susc

eptib

ility

tes

ting

(DS

T) o

f is

onia

zid

and

rifam

pici

n or

of rif

ampi

cin

alon

e is

rec

omm

ende

d ov

er c

onve

ntio

nal t

estin

g or

no

test

ing

at t

he t

ime

of T

B

diag

nosi

s, s

ubje

ct t

o av

aila

ble

reso

urce

s (c

ondi

tiona

l rec

omm

enda

tion,

ver

y lo

w

qual

ity e

vide

nce)

.

UPD

ATED

[fr

om (

3)]

Rap

id D

ST

of a

t le

ast

rifam

pici

n is

rec

omm

ende

d in

adu

lts a

nd

child

ren

over

con

vent

iona

l tes

ting

or n

o te

stin

g at

the

tim

e of

TB

dia

gnos

is (st

rong

rec

omm

enda

tion,

hig

h ce

rtai

nty

in t

he

evid

ence

).

Use

of

sput

um-s

mea

r m

icro

scop

y a

nd c

ultu

re t

o m

onit

or r

espo

nse

to t

rea

tmen

t

The

use

of s

putu

m-s

mea

r m

icro

scop

y an

d cu

lture

rat

her

than

spu

tum

-sm

ear

mic

rosc

opy

alon

e is

rec

omm

ende

d fo

r th

e m

onito

ring

of p

atie

nts

with

MD

R-T

B

durin

g tr

eatm

ent

(con

ditio

nal r

ecom

men

datio

n, v

ery

low

qua

lity

evid

ence

).

REM

AIN

S V

ALID

b

Use

of

a s

hor

ter

MD

R-T

B t

rea

tme

nt

regi

me

n

NO

SPE

CIF

IC R

ECO

MM

END

ATIO

N

In p

atie

nts

with

RR

-TB

or

MD

R-T

B w

ho w

ere

not

prev

ious

ly

trea

ted

with

sec

ond-

line

drug

s an

d in

who

m r

esis

tanc

e to

flu

oroq

uino

lone

s an

d se

cond

-line

inje

ctab

le a

gent

s w

as e

xclu

ded

or is

con

side

red

high

ly u

nlik

ely, a

sho

rter

MD

R-T

B r

egim

en o

f 9–1

2

mon

ths

may

be

used

inst

ead

of t

he lo

nger

reg

imen

s (c

ondi

tiona

l re

com

men

datio

n, v

ery

low

cer

tain

ty in

the

evi

denc

e).c

Com

pos

itio

n o

f lo

nge

r M

DR

-TB

tre

atm

en

t re

gim

en

s

In t

he t

reat

men

t of

pat

ient

s w

ith M

DR

-TB

, a fl

uoro

quin

olon

e sh

ould

be

used

(st

rong

re

com

men

datio

n, v

ery

low

qua

lity

evid

ence

).

In t

he t

reat

men

t of

pat

ient

s w

ith M

DR

-TB

, a la

ter-g

ener

atio

n flu

oroq

uino

lone

ra

ther

tha

n an

ear

lier-g

ener

atio

n flu

oroq

uino

lone

sho

uld

be u

sed

(con

ditio

nal

reco

mm

enda

tion,

ver

y lo

w q

ualit

y ev

iden

ce).

In t

he t

reat

men

t of

pat

ient

s w

ith M

DR

-TB

, eth

iona

mid

e (o

r pr

othi

onam

ide)

sho

uld

be u

sed

(str

ong

reco

mm

enda

tion,

ver

y lo

w q

ualit

y ev

iden

ce).

In t

he t

reat

men

t of

pat

ient

s w

ith M

DR

-TB

, reg

imen

s sh

ould

incl

ude

at

leas

t py

razi

nam

ide,

a fl

uoro

quin

olon

e, a

par

ente

ral a

gent

, eth

iona

mid

e (o

r pr

othi

onam

ide)

, and

eith

er c

yclo

serin

e or

p-a

min

osal

icyl

ic a

cid

(PAS

) if

cycl

oser

ine

cann

ot b

e us

ed (co

nditi

onal

rec

omm

enda

tion,

ver

y lo

w q

ualit

y ev

iden

ce).

In t

he t

reat

men

t of

pat

ient

s w

ith M

DR

-TB

, fou

r se

cond

-line

ant

i-tub

ercu

losi

s dr

ugs

likel

y to

be

effe

ctiv

e (in

clud

ing

a pa

rent

eral

age

nt),

as w

ell a

s py

razi

nam

ide,

sho

uld

be in

clud

ed in

the

inte

nsiv

e ph

ase

(con

ditio

nal r

ecom

men

datio

n, v

ery

low

qua

lity

evid

ence

).

UPD

ATED

d

In p

atie

nts

with

RR

-TB

or

MD

R-T

B, a

reg

imen

with

at

leas

t fiv

e ef

fect

ive

TB m

edic

ines

dur

ing

the

inte

nsiv

e ph

ase

is

reco

mm

ende

d, in

clud

ing

pyra

zina

mid

e an

d fo

ur c

ore

seco

nd-li

ne

TB m

edic

ines

– o

ne c

hose

n fr

om G

roup

A, o

ne fro

m G

roup

B, a

nd

at le

ast

two

from

Gro

up C

e (c

ondi

tiona

l rec

omm

enda

tion,

ver

y lo

w

cert

aint

y in

the

evi

denc

e). If

the

min

imum

num

ber

of e

ffec

tive

TB

med

icin

es c

anno

t be

com

pose

d as

giv

en a

bove

, an

agen

t fr

om

Gro

up D

2 a

nd o

ther

age

nts

from

Gro

up D

3 m

ay b

e ad

ded

to b

ring

the

tota

l to

five.

f

In p

atie

nts

with

RR

-TB

or

MD

R-T

B, i

t is

rec

omm

ende

d th

at t

he

regi

men

be

furt

her

stre

ngth

ened

with

hig

h-do

se is

onia

zid

and/

or

etha

mbu

tol (

cond

ition

al r

ecom

men

datio

n, v

ery

low

cer

tain

ty in

the

ev

iden

ce).

11

methoDs

2011 G

UID

ELIN

ES (

1)

2016 G

UID

ELIN

ES

Tre

atm

en

t of

pa

tie

nts

wit

h R

R-T

B

NO

SPE

CIF

IC R

ECO

MM

END

ATIO

N

It is

rec

omm

ende

d th

at a

ny p

atie

nt –

chi

ld o

r ad

ult

– w

ith R

R-T

B in

w

hom

ison

iazi

d re

sist

ance

is a

bsen

t or

unk

now

n be

tre

ated

with

a

reco

mm

ende

d M

DR

-TB

reg

imen

, eith

er a

sho

rter

MD

R-T

B r

egim

en,

or if

thi

s ca

nnot

be

used

, a lo

nger

MD

R-T

B r

egim

en t

o w

hich

is

onia

zid

is a

dded

.

Du

rati

on o

f lo

nge

r M

DR

-TB

tre

atm

en

t re

gim

en

s

In t

he t

reat

men

t of

pat

ient

s w

ith M

DR

-TB

, an

inte

nsiv

e ph

ase

of e

ight

mon

ths

is

sugg

este

d fo

r m

ost

patie

nts;

the

dur

atio

n m

ay b

e m

odifi

ed a

ccor

ding

to

the

patie

nt’s

re

spon

se t

o th

erap

y (c

ondi

tiona

l rec

omm

enda

tion,

ver

y lo

w q

ualit

y ev

iden

ce).

In t

he t

reat

men

t of

pat

ient

s ne

wly

dia

gnos

ed w

ith M

DR

-TB

(i.e

. no

t pr

evio

usly

tr

eate

d fo

r M

DR

-TB

), a

tota

l tre

atm

ent

dura

tion

of 2

0 m

onth

s is

sug

gest

ed for

m

ost;

the

dur

atio

n m

ay b

e m

odifi

ed a

ccor

ding

to

the

patie

nt’s

res

pons

e to

the

rapy

(c

ondi

tiona

l rec

omm

enda

tion,

ver

y lo

w q

ualit

y ev

iden

ce).

REM

AIN

S V

ALID

b

Sta

rt o

f a

nti

retr

ovir

al t

he

rapy

wit

h M

DR

-TB

tre

atm

en

t

Antir

etro

vira

l the

rapy

is r

ecom

men

ded

for

all p

atie

nts

with

HIV

and

dru

g-re

sist

ant

TB

requ

iring

sec

ond-

line

anti-

tube

rcul

osis

dru

gs, i

rres

pect

ive

of C

D4 c

ell-c

ount

, as

early

as

pos

sibl

e (w

ithin

the

firs

t ei

ght

wee

ks) fo

llow

ing

initi

atio

n of

ant

i-tub

ercu

losi

s tr

eatm

ent

(str

ong

reco

mm

enda

tion,

ver

y lo

w q

ualit

y ev

iden

ce).

REM

AIN

S V

ALID

b

Use

of

surg

ery

as

pa

rt o

f M

DR

-TB

tre

atm

en

t

NO

SPE

CIF

IC R

ECO

MM

END

ATIO

N

In p

atie

nts

with

RR

-TB

or

MD

R-T

B, e

lect

ive

part

ial l

ung

rese

ctio

n (lo

bect

omy

or w

edge

res

ectio

n) m

ay b

e us

ed a

long

side

a

reco

mm

ende

d M

DR

-TB

reg

imen

(co

nditi

onal

rec

omm

enda

tion,

ver

y lo

w c

erta

inty

in t

he e

vide

nce)

.

Mod

els

of

MD

R-T

B c

are

(a

mb

ula

tory

/hos

pit

ali

zati

on)

Patie

nts

with

MD

R-T

B s

houl

d be

tre

ated

usi

ng m

ainl

y am

bula

tory

car

e ra

ther

tha

n m

odel

s of

car

e ba

sed

prin

cipa

lly o

n ho

spita

lizat

ion

(con

ditio

nal r

ecom

men

datio

n,

very

low

qua

lity

evid

ence

).

REM

AIN

S V

ALID

b

a Th

ese

reco

mm

enda

tions

nee

d to

be

read

alo

ng w

ith the

acc

ompa

nyin

g re

mar

ks in

the

rel

evan

t se

ctio

ns o

f thi

s do

cum

ent,

whi

ch a

re c

ritic

al to

thei

r pr

oper

impl

emen

tatio

n.b

This

rec

omm

enda

tion

cont

inue

s to

app

ly. It

will

be

revi

sed

if a

futu

re e

vide

nce

revi

ew c

ondu

cted

for

the

pur

pose

of

upda

ting

WH

O p

olic

y gu

idan

ce s

how

s su

ch a

nee

d.c

See

tex

t fo

r th

e de

finiti

on o

f th

e sh

orte

r M

DR

-TB

tre

atm

ent

regi

men

, and

for

oth

er c

ondi

tions

tha

t ap

ply

whe

n im

plem

entin

g th

is r

ecom

men

datio

n.d

No

chan

ges

to t

he W

HO

inte

rim p

olic

ies

on t

he u

se o

f be

daqu

iline

and

del

aman

id in

the

May

2016 u

pdat

e (4

,5).

In O

ctob

er 2

01

6, W

HO

pub

lishe

d its

rev

ised

pol

icy

on

dela

man

id. D

elam

anid

may

now

als

o be

use

d al

ongs

ide

long

er M

DR

-TB

reg

imen

s in

pat

ient

s ag

ed 6

–17 y

ears

(6

). B

edaq

uilin

e is

onl

y re

com

men

ded

for

adul

ts.

e G

roup

A=

levo

floxa

cin,

mox

iflox

acin

, gat

iflox

acin

; G

roup

B=am

ikac

in, c

apre

omyc

in, k

anam

ycin

, (st

rept

omyc

in);

Gro

up C

=et

hion

amid

e (o

r pr

othi

onam

ide)

, cyc

lose

rine

(or

teriz

idon

e), l

inez

olid

, clo

fazi

min

e; in

chi

ldre

n w

ith n

on-s

ever

e di

seas

e G

roup

B m

edic

ines

may

be

excl

uded

(se

e gu

idel

ines

tex

t fo

r ho

w d

isea

se s

ever

ity w

as a

sses

sed)

.f

Gro

up D

2=

beda

quili

ne, d

elam

anid

; G

roup

D3=

p-am

inos

alic

ylic

aci

d, im

ipen

em–c

ilast

atin

, mer

open

em, a

mox

icill

in–c

lavu

lana

te, (

thio

acet

azon

e).

12

WHO TREATMENT GUIDELINES FOR DRUG-RESISTANT TUBERCULOSIS, 2016 UPDATE

ScopeThe 2016 update of the WHO treatment guidelines for drug-resistant tuberculosis, 2016 update aimed to revise the previous evidence-informed policy recommendations from 2011 (1). The scope of the current guidelines differed from that of the 2011 guidance in a number of ways. In 2011, the scope of the guidelines was broader and included programmatic aspects, such as rapid diagnostics for RR-TB, patient monitoring with culture and sputum microscopy during treatment, length of the intensive phase and total duration of treatment in longer (“conventional”) regimens, use of antiretroviral therapy and ambulatory/inpatient models of care. In deciding the scope of the 2016 update, the GDG and the WHO Guideline Steering Committee considered priority questions at the time of the update (2014–2015). The scope did not cover other aspects of policy guidance on the programmatic management of drug-resistant TB for which no new evidence has been published since the 2011 revision.

The GDG agreed to limit the scope of these guidelines to the following priority areas within the current debates on the treatment and care of patients with drug-resistant TB:

i. The optimal combination of medicines and approach towards regimen design for TB patients with isoniazid-resistant, rifampicin-resistant (RR-TB), multidrug-resistant (MDR-TB), and extensively drug-resistant (XDR-TB) forms of TB as well as for patients with M. bovis disease.

ii. The effectiveness and safety of standardized regimens lasting up to 12 months for the treatment of patients with MDR-TB (“shorter regimens”) when compared with longer treatment.

iii. The effect of delay in starting treatment on treatment outcomes for patients with drug-resistant TB.

iv. The effect of surgical interventions on treatment outcomes for patients with drug-resistant TB.

As far as possible and where evidence exists, the guidelines also aimed to formulate recommendations which would be relevant to patients of all ages as well as individuals with key comorbidities (e.g. HIV, diabetes).

The target audience of the guidelines includes staff and medical practitioners working in prevention and care of TB, managers implementing the programmatic management of drug-resistant TB within their centres and national programmes, and organizations providing technical and financial support for drug-resistant TB. Although primarily intended for use in resource-limited countries, the recommendations are also applicable in other settings.

Key questionsThe PICO questions were grouped into four sets (see full versions in Annex 3). PICO questions 1 and 2 were devoted to the first area of the guidelines scope (see i above). PICO question 3 was devoted entirely to the second area (see ii above) and PICO question 4 covered both the third and fourth areas (see iii and iv above).

The outcomes were defined and scored by the GDG (Table 2). The mean scores for the nine responses received were all in the “Critical” range (7–9 points).

13

methoDs

Table 2. Scoring of outcomes considered relevant by the GDG for evidence reviews related to the WHO treatment guidelines for drug-resistant TB 2016 updatea

OUTCOMES MEAN SCORE

Adherence to TB treatment (treatment interruption due to non-adherence) 6.8

Avoiding adverse reactions from TB medicines 7.0

Avoiding the acquisition or amplification of drug resistance 7.9

Cure or successful completion by the end of treatment 9.0

Culture conversion by month six 7.4

Death (survival) by the end of projected treatment 8.1

Treatment failure 8.7

Relapse 7.7

a Relative importance was rated on an incremental scale:1–3 points: Not important for making recommendations on the treatment of drug-resistant TB.4–6 points: Important but not critical for making recommendations on the treatment of drug-resistant TB.7–9 points: Critical for making recommendations on the treatment of drug-resistant TB.

Certainty of evidence and strength of recommendationsThe recommendations in these guidelines qualify their strength as well as the certainty of evidence on which they are based. The text of the recommendation itself should be read along with the accompanying remarks that summarize the evidence upon which the recommendation was made, the anticipated desirable and undesirable effects of the interventions to assess the balance of expected benefits to risks, and other considerations which are important for the implementation of the policy. The GDG also made a statement about research priorities within the different dimensions covered by each of the PICO questions (see Section E below).

The certainty of evidence is categorized into four levels (Table  3). The criteria used by the evidence reviewers to qualify the quality of available evidence are summarized in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tables annexed to these guidelines (online Annex 4). A number of factors may increase or decrease the certainty of evidence (see Figure 9.1 of (7)). The highest rating is usually assigned to data from randomized controlled trials (RCT) while evidence from observational studies is usually assigned a low or very low quality value at the start.

14

WHO TREATMENT GUIDELINES FOR DRUG-RESISTANT TUBERCULOSIS, 2016 UPDATE

Table 3. Certainty of evidence and definitions (8)

CERTAINTY OF EVIDENCE DEFINITION

High ( ) Further research is very unlikely to change our confidence in the estimate of effect.

Moderate ( ) Further research is likely to have an important impact on our confidence in the effect and may change the estimate.

Low ( ) Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low ( ) Any estimate of effect is very uncertain.

A recommendation may be strong or conditional. Apart from the quality of evidence, the strength of a recommendation is determined by the balance between desirable and undesirable effects, values and preferences, and costs or resource allocation (online Annex 5; (8)). For strong recommendations, the GDG is confident that the desirable effects of adherence to the recommendation outweigh the undesirable effects. For conditional recommendations, the GDG considers that desirable effects probably outweigh the undesirable effects. The strength of a recommendation has different implications for the individuals affected by these guidelines (Table 4).

Table 4. Implications of the strength of a recommendation for different users (adapted from (8))

PERSPECTIVE STRONG RECOMMENDATION CONDITIONAL RECOMMENDATION

For patients Most individuals in this situation would want the recommended course of action and only a small proportion would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.

The majority of individuals in this situation would want the suggested course of action, but many would not.

For clinicians Most individuals should receive the intervention. Adherence to this recommendation according to the guidelines could be used as a quality criterion or performance indicator.

Recognize that different choices will be appropriate for individual patients, and that patients must be helped to arrive at a management decision consistent with their values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their values and preferences.

For policy-makers The recommendation can be adopted as policy in most situations.

Policy-making will require substantial debate and involvement of various stakeholders.

15

methoDs

DefinitionsRifampicin-resistant TB (RR-TB) refers to TB strains that are considered eligible for treatment with MDR-TB regimens (9). Rifampicin-resistant TB strains may be susceptible to isoniazid, or resistant to isoniazid (i.e. MDR-TB), or resistant to other medicines from the first-line group (poly-resistant) or from the second-line medicine group (e.g. XDR-TB) (10).

Drug-susceptibility testing (DST) refers to in vitro testing using either phenotypic methods to determine susceptibility or molecular techniques to detect resistance-conferring mutations to a particular medicine. New policy guidance on the use of line probe assay for the detection of resistance to second-line anti-TB drugs are now available (11).

A second-line TB medicine (drug or agent) is used to treat drug-resistant TB (see also Section B under WHO policy recommendations in these guidelines). For the treatment of RR-TB and MDR-TB, streptomycin is included as a substitute for second-line injectable agents when aminoglycosides or capreomycin cannot be used and susceptibility is highly likely. The core second-line TB medicines (or agents) refer to those in Groups A, B or C.

A shorter MDR-TB regimen refers to a course of treatment for RR-TB or MDR-TB lasting 9–12 months, which is largely standardized, and whose composition and duration follows closely the one for which there is documented evidence from different settings (12–14). The features and indications of this regimen are further elaborated in Section  A under WHO policy recommendations in these guidelines.

Longer MDR-TB regimens are treatments for RR-TB or MDR-TB which last 18 months or more and which may be standardized or individualized. These regimens are usually designed to include a minimum number of second-line TB medicines considered to be effective based on patient history or drug-resistance patterns (1,9). These regimens were previously qualified as “conventional”, having been the mainstay of MDR-TB treatment before the 2016 update. The features and indications of longer regimens are further elaborated in Section B of the current document.

The treatment outcome categories used in these guidelines and the term relapse were applied according to the definitions agreed for use by TB programmes, unless otherwise specified (10,15).

For the purposes of the reviews conducted for these guidelines, a serious adverse event (SAE) is defined as one which was classified as Grade 3 (severe) or Grade 4 (life-threatening or disabling) (16), or which led to the medicine being stopped permanently.

Assessment of evidence and its gradingTeams of experts were commissioned to assess the evidence for the PICO questions and their outcomes through systematic literature reviews following a standard methodology (17). Evidence reviewers are listed in Annex 2; more details on the methods used in unpublished studies are presented in Annex 6 (online) and in published studies referenced under the respective sections. Titles, abstracts and full text of potentially relevant literature were screened using key subject words and text words. Authors in the field and members of the GDG were

16

WHO TREATMENT GUIDELINES FOR DRUG-RESISTANT TUBERCULOSIS, 2016 UPDATE

contacted to identify missing studies or studies in progress. Individual patient-level data were used to address PICO 1 (adults (18) and children; see also Section B), for PICO 3 (shorter MDR-TB regimens; see Section A) and PICO 4 (use of surgery (19); see Section D).

Relative effects (relative risks or odds ratios of an event) were calculated from pooled data in individual or aggregated formats from the included studies. Absolute effects and risk differences were used to express the magnitude of an effect or difference between the intervention and comparator groups. Where possible, adjustments were made to reduce risk of bias and confounding. More details are provided in the notes on the GRADE evidence profiles that were used to summarize the results of systematic reviews done for each question (online Annex 4). The evidence profiles were prepared using GRADEPro software – an online tool to create guideline materials (see http://gdt.guidelinedevelopment.org). The certainty of the evidence was assessed using the following criteria: study design, limitations in the studies (risk of bias), imprecision, inconsistency, indirectness, publication bias, magnitude of effect, dose–effect relations and residual confounding (7).

The GDG membership represented a broad cross-section of future users of the guidelines as well as affected persons (including the patient). Ahead of the GDG meeting held at the WHO headquarters in Geneva, Switzerland, between 9 and 11 November 2015, one or more discussants were identified from among the GDG members to assess the evidence for each of the PICO questions and to present his or her perspective on the implications of the findings during the meeting. Drafts of the review reports were shared with the GDG members ahead of the meeting (Annexes 4 and 6). During the days of the meeting and in the following weeks additional analyses were shared with the group upon their demand. The GRADE evidence profiles were discussed by the GDG ahead of formulating the recommendations. The group used the “Evidence to Decision” tables via the GRADEPro interface to capture the content of the discussions, make judgements, annotate the different considerations, develop the wording and strength of the recommendations, and add the remarks that accompany each recommendation (online Annex 5).

Apart from the quality of evidence, the strength of a recommendation was determined by assessing the balance between desirable and undesirable effects, values and preferences, considerations on equity, resource use and feasibility. In the preparation of PICO questions and outcomes, and in the discussions of the evidence before, during and after the meeting, the GDG members paid particular attention to the spectrum of values and preferences attached to the recommendations by the different users. One important factor that lowered the strength of all recommendations made in these guidelines was the variability in values and preferences of those affected by these policies as perceived by the GDG members. Resource use was not assessed by means of formal cost-effectiveness studies, and the GDG assessed it from the perspective of the patient and the health services, in terms of feasibility and opportunity cost. Decisions on the certainty of evidence and on the wording of a recommendation and of its strength were largely made through moderated discussion. Any disagreements were resolved by a group decision on an acceptable position. For the recommendation on surgery (part of PICO 4), the final wording was agreed through voting. None of the recommendations for these guidelines were strong and all the certainty in the evidence was rated as very low.

17

methoDs

External reviewThe ERG commented on the questions during their formulation (in mid-2015) and on a draft text of the guidelines, including the recommendations, following comments from the GDG (in February 2016). Six reviewers provided substantive comments on the draft of the guidelines.

Publication, implementation, evaluation and expiryThese guidelines were published on the World Health Organization Global TB Programme (WHO/GTB) website (http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/resources/en/) as freely downloadable pdf files from 13 May 2016. The main text of the guidelines (without Annexes 4, 5 and 6) will also be made available in print version in late 2016. The evidence reviews as well as the recommendations are also being published separately in peer-reviewed journals to improve the dissemination of the main messages. The changes to the policy guidance will also be reflected in a forthcoming revision of the WHO implementation handbook for programmatic management of drug-resistant TB planned later in 2016 (9).

WHO will work closely with its regional and country offices, as well as technical and funding agencies and partners, to ensure wide communication of the updated guidance in technical meetings and training activities. WHO/GTB will review and update these guidelines within four to five years after their publication, or earlier if new evidence becomes available (e.g. on bedaquiline and delamanid use). These changes will also be reflected in a forthcoming revision of the implementation handbook (9).

18

WHO policy recommendations

A. The effectiveness and safety of standardized regimens lasting up to 12 months for the treatment of patients with MDR-TB when compared with longer treatment

Recommendation

In patients with RR-TB or MDR-TB who were not previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents was excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9–12 months may be used instead of the longer regimens (conditional recommendation, very low certainty in the evidence).

Justification

The interest in reducing the duration of treatment for MDR-TB has motivated a number of initiatives to treat patients with shorter regimens under programmatic as well as trial conditions. Experience and data on the effect of shorter MDR-TB regimens was limited until recently and before the 2016 update of the guidelines WHO advised that shorter regimens were to be used only under operational research conditions and with close monitoring for effectiveness and safety during and after the end of treatment. In the past few years, results from three studies of MDR-TB patients on shorter regimens have been published and other observational studies as well as a randomized controlled trial in different settings have begun (12–14, 20). Early results from observational studies in Bangladesh, Cameroon and Niger using regimens lasting 12 months or less have shown much higher likelihood of treatment success compared with longer regimens when treating patients with specific inclusion criteria (such as lack of previous exposure to second-line anti-TB medications). Given the published data and potential impact of shorter regimens on treatment cost and affordability, WHO proceeded with the evidence assessment. A PICO question was developed to assess the effectiveness of the shorter MDR-TB treatment regimens lasting up to 12 months and to inform a possible policy change with respect to their use and application (Annex 3; Question 3).

The evidence reviewed for this question compared the treatment outcomes for confirmed RR-TB or MDR-TB patients treated with these regimens with those of patients treated with longer regimens (online Annex 4; Section 1). The shorter MDR-TB treatment regimens were standardized in content and duration and split into two distinct parts. The first was an intensive phase of four months (extended up to a maximum of six months in case of lack of sputum smear conversion) and included the following drugs: gatifloxacin (or moxifloxacin), kanamycin, prothionamide, clofazimine, high-dose isoniazid, pyrazinamide and ethambutol. This was followed by a continuation phase of five months with the following medicines:

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gatifloxacin (or moxifloxacin), clofazimine, pyrazinamide and ethambutol (prothionamide was kept in the continuation phase in earlier studies). In the studies, patients were placed on these regimens based on a set of criteria, and individuals who had prior exposure to second-line TB drugs were excluded from the analysis. No modifications were made to the shorter MDR-TB regimen if previously unknown drug resistance was detected after start of treatment. The recommendation made on the shorter MDR-TB regimen applies only to a regimen profile with similar characteristics of the ones studied. This is because the substitution or exclusion of one or more of the medicines of this regimen may affect its overall performance which is not possible to predict given the lack of evidence of the impact of such modifications (see “Implementation considerations” below).

All data used to assess the shorter MDR-TB treatment regimens were derived from observational studies (see online Annex 6 for background, methods and summary of findings). Individual patient data from Bangladesh (n=493; supported by the Damien Foundation), Uzbekistan (n=65; supported by Médecins sans Frontières (MSF)) and Swaziland (n=24; MSF) as well as aggregated data from Cameroon (n=150) (13), Niger (n=65) (14) and seven sub-Saharan African countries (n=408; supported by the International Union Against Tuberculosis and Lung Disease (UNION)) were included in the analysis (total number of observations=1205, of whom 89 cases were lost to follow-up and were therefore excluded in certain analyses). These were compared with the outcomes of patients without previous exposure to second-line TB drugs who were included in the adult individual patient data (aIPD) analysis (n=7665) (18) (see also Section B below for more details on the aIPD). The standard outcomes used in the intervention and comparator arms largely complied with the standardized outcomes used by TB programmes (10,15,21).

The analyses performed for the evidence assessment showed that patients who met specific inclusion criteria for receiving the shorter MDR-TB treatment regimens had a statistically significant higher likelihood of treatment success than those who received longer regimens – 90% versus 78% when success was compared with treatment failure/relapse/death (Table 5) and 84% versus 62% when compared with treatment failure/relapse/death/loss to follow-up (see also online Annex 4). The number of relapses was very low, although this may be due to the relatively small number of patients followed up. As expected, treatment success was lower among patients with additional resistance to pyrazinamide and/or fluoroquinolones on shorter MDR-TB regimens, even if in general it remained high and exceeded that in the patients on longer regimens (although the differences were not statistically significant).

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Table 5. Treatment success in patients treated with a shorter MDR-TB regimen vs longer MDR-TB regimensa

RESISTANCE PATTERN SHORTER MDR-TB REGIMEN LONGER MDR-TB REGIMEN

N % (95% CL) N % (95% CL)

All cases regardless of pyrazinamide and fluoroquinolone susceptibility

1008/1116 90.3% (87.8%– 92.4%)

4033/5850 78.3% (71.2%–84%)

Pyrazinamide resistant; fluoroquinolone resistant

19/28 67.9% (47.6%–84.1%)

81/137 59.1% (50.6%–67.1%)

Pyrazinamide resistant; fluoroquinolone susceptible

90/100 88.8% (47.3%–98.6%)

840/1075 81.4% (71.6%–88.4%)

Pyrazinamide susceptible; fluoroquinolone resistant

12/15 80.0% (50.0%–94.1%)

72/120 64.4% (49.6%–76.9%)

Pyrazinamide susceptible; fluoroquinolone susceptible

121/125 96.8% (77.3%–99.6%)

890/1119 83.5% (75.7%–89.2%)

a Treatment success (cured or treatment completed (10,15)) versus treatment failure/relapse/death in patients not previously treated with second-line TB medications; percentages shown have been adjusted where possible (see also online Annex 4; Section 1 for more details).

Until more evidence is available, WHO recommends that the shorter MDR-TB regimen not be used in patients who have been previously treated with second-line drugs for more than one month or who have documented or are likely to have strains resistant to medicines in the regimen. Preferably, resistance to at least fluoroquinolones and the injectable agent used in the regimen is excluded before starting treatment by in vitro testing. In the absence of such testing, patients who are highly unlikely to be infected with resistant strains based on history of exposure, use of second-line medicines at country level or recent representative surveillance data may also be eligible for the shorter MDR-TB regimen (see “Implementation considerations” below).

Subgroup considerations

Rifampicin-resistant TB (RR-TB) without MDR-TB. All patients – children or adult – with RR-TB in whom isoniazid resistance is not confirmed may be treated with the shorter MDR-TB treatment regimen.

Resistance additional to MDR-TB. For patients infected with strains known or strongly suspected of being resistant to one or more drugs in the shorter MDR-TB treatment regimen (e.g. pyrazinamide) it is recommended not to use the shorter regimen until more evidence becomes available about its performance in such a situation.

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People living with HIV need to be given the same consideration for treatment with the shorter MDR-TB treatment regimen as people who are HIV seronegative.

Children were generally excluded from studies of shorter MDR-TB treatment regimens. However, given that the same medicines have been in use in paediatric MDR-TB regimens for many years, there is no plausible biological reason to believe that these regimens are less effective or safe in children than in adults. As a result, it is recommended that children with confirmed RR-TB or MDR-TB be given the same consideration for treatment with a shorter MDR-TB treatment regimen as adults.

Pregnancy was an exclusion criterion for the shorter MDR-TB treatment regimen studies. Two of the core components of the shorter MDR-TB regimens – the injectable agent and ethionamide (or prothionamide) – are usually contraindicated in pregnancy (9). Withholding these medicines from the shorter MDR-TB treatment regimen could seriously compromise its effectiveness. Thus for pregnant women, it is recommended that a longer individualized regimen be used which can allow the inclusion of four or more effective second-line TB medicines with no known teratogenic properties (see Section B below).

Extrapulmonary disease. The findings from studies of shorter MDR-TB regimen were limited to patients with pulmonary disease, and they cannot be extrapolated directly to extrapulmonary TB cases. No recommendation is thus possible at this stage to use the shorter regimen in patients with extrapulmonary MDR-TB.

Implementation considerations

In order to reproduce the high cure rates achieved by the studies included in the reviews for this guidance, all efforts need to be made to avoid the acquisition of additional resistance, by ensuring careful selection of patients to be enrolled, and effective patient support to enable full adherence to treatment. It is recommended that patients be tested for susceptibility or resistance to fluoroquinolones and to second-line injectable agents used in the regimen before being started on a shorter MDR-TB regimen. Patients with strains resistant to any of the two groups of medicines are to be transferred to a longer MDR-TB regimen (see Section B below).

The availability of reliable and rapid tests would be valuable in deciding (within a few days) which patients would be eligible for the shorter MDR-TB regimen, and what modifications to longer, individualized MDR-TB regimens are necessary based on the resistance detected. In patients with confirmed RR-TB or MDR-TB, WHO now recommends that the GenoType M. tuberculosis drug-resistant second-line assay (MTBDRsl) be used as an initial direct test, instead of phenotypic culture-based DST, to detect resistance to fluoroquinolones and second-line injectable drugs (conditional recommendation; certainty of evidence low to moderate (11),(22)). This applies to testing in both children and adults. While resistance-conferring mutations to fluoroquinolones detected by the MTBDRsl assay are highly correlated with phenotypic resistance to ofloxacin and levofloxacin, the correlation with moxifloxacin and gatifloxacin is less clear and the inclusion of moxifloxacin or gatifloxacin in a MDR-TB regimen is best guided by phenotypic DST results.

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In settings in which laboratory capacity for DST to fluoroquinolones and injectable agents is not yet available, treatment decisions would need to be guided by the likelihood of resistance to these medicines, informed by the patient’s clinical history and recent representative surveillance data.

The evidence for the effectiveness and safety of the shorter MDR-TB regimen derives from studies where treatment was administered under fairly standardized conditions with relatively little variation in the content and duration, and with close monitoring. Thus, the recommendation for the shorter MDR-TB regimen is premised on the use of a regimen similar in composition and duration to those used in observational studies. Any replacement of medicines or any changes to the duration are only to be considered within the parameters applied in these studies (e.g. gatifloxacin replaced by moxifloxacin; prothionamide replaced by ethionamide; intensive phase is prolonged up to six months in case of no sputum conversion).

Two staples of the regimen, clofazimine and high-dose isoniazid may be difficult to procure in some countries. Moreover, there are no good paediatric formulations of clofazimine and dividing the capsule into smaller doses is almost impossible, making dosing in children uncertain. Given the global shortage in the supply of quality-assured gatifloxacin in recent years, the sites where observational studies have been conducted have had to substitute this agent with moxifloxacin. This led to an increase in the overall price of the regimen, although the costs for quality-assured moxifloxacin have since declined. The implementation of these guidelines at the national level needs to ensure that sufficient quantities of these medicines are available to meet the demand and that no stock-outs occur.

Monitoring and evaluation

Patients who receive a shorter MDR-TB treatment regimen need to be monitored during treatment and after completion of treatment using schedules of relevant clinical and laboratory testing which have been successfully applied in the studies under field conditions. The WHO framework for active TB drug-safety monitoring and management (aDSM) needs to be applied to ensure appropriate action to monitor and respond promptly to adverse events (23,24). This could be conducted alongside the routine programme monitoring for patient response and for treatment outcomes that has been conducted worldwide for many years (10,25).

Continued efforts to reduce MDR-TB treatment duration, both under observational and trial conditions, is ongoing and is expected to increase the knowledge base for the effectiveness/efficacy and safety of the regimens under different field conditions, patient subgroups and composition – including new medicines.

B. The optimal combination of medicines and approach towards regimen design for TB patients with RR-TB and MDR-TB

As part of the GDG discussion on the design of MDR-TB regimens for adults and children, a regrouping of TB medicines from that being formerly used is proposed (1,9). These include medicines used in first-line TB treatment that may also have a role in strengthening MDR-TB

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regimens (Table  6). When reclassifying these medicines, the GDG assessed the available evidence and the associated level of certainty, as well as other considerations relating to the balance between anticipated desirable and undesirable effects, and feasibility of implementation. WHO considers that currently only the medicines shown in Table 6 have a role in MDR-TB treatment under programmatic conditions.4

Table 6. Medicines recommended for the treatment of RR-TB and MDR-TBa

Group A. Fluoroquinolonesb Levofloxacin

Moxifloxacin

Gatifloxacin

Lfx

Mfx

Gfx

Group B. Second-line injectable agents Amikacin

Capreomycin

Kanamycin

(Streptomycin)c

Am

Cm

Km

(S)

Group C. Other core second-line agentsb Ethionamide / prothionamide

Cycloserine / terizidone

Linezolid

Clofazimine

Eto / Pto

Cs / Trd

Lzd

Cfz

Group D. Add-on agents (not part of the core MDR-TB regimen)

D1 Pyrazinamide

Ethambutol

High-dose isoniazid

Z

E

Hh

D2 Bedaquiline

Delamanid

Bdq

Dlm

D3 p-aminosalicylic acid

Imipenem–cilastatind

Meropenemd

Amoxicillin-clavulanated

(Thioacetazone)e

PAS

Ipm

Mpm

Amx-Clv

(T)

a This regrouping is intended to guide the design of longer regimens; the composition of the recommended shorter MDR-TB regimen is standardized (see Section A).

b Medicines in Groups A and C are shown by decreasing order of usual preference for use (subject to other considerations; see text).

c Refer to the text for the conditions under which streptomycin may substitute other injectable agents. Resistance to streptomycin alone does not qualify for the definition of XDR-TB (26).

d Carbapenems and clavulanate are meant to be used together; clavulanate is only available in formulations combined with amoxicillin.

e HIV-status must be confirmed to be negative before thioacetazone is started.

4 Other medicines than those in Table 6 are currently being investigated for use in TB (see Figure 8.3 of reference (25)).

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B1. Longer treatment regimens for RR-TBThe recommendations in this section cover all forms of RR-TB, including also patients with strains susceptible to isoniazid, or with additional resistance to isoniazid (i.e. MDR-TB), or resistant to other medicines from the first-line group (poly-resistant) or from the second-line group (e.g. XDR-TB) (online Annex 4; Section 2).

Recommendations5

• In patients with RR-TB or MDR-TB, a regimen with at least five effective TB medicines during the intensive phase is recommended, including pyrazinamide and four core second-line TB medicines – one chosen from Group A, one from Group B, and at least two from Group C6 (conditional recommendation, very low certainty in the evidence). If the minimum number of effective TB medicines cannot be composed as given above, an agent from Group D2 and other agents from Group D3 may be added to bring the total to five.7

• In patients with RR-TB or MDR-TB, it is recommended that the regimen be further strengthened with high-dose isoniazid and/or ethambutol (conditional recommendation, very low certainty in the evidence).

Justification

Treatment of MDR-TB in adults and children with longer second-line regimens has been known to increase the likelihood of cure and lower the risk of chronicity and death (18,27). This section refers to MDR-TB treatment regimens that are of longer duration than the shorter MDR-TB regimen described in Section A. The composition and duration of longer regimens are based on a number of factors, including the combination of sufficient agents considered to be effective, the balance of expected benefits to harms, and the response or reactions to treatment in the individual patient. Recommendations for the design of these regimens have been issued for a number of years and have been implemented in many countries worldwide.

The evidence base for the effectiveness of many of the medicines used in MDR-TB regimens relies heavily on observational studies with only a few having been studied under randomized controlled conditions. As a result, the overall quality of the evidence is graded as low or very low.

Adults. The evidence that informed the adult treatment recommendations is based on two main sources (see GRADE tables in online Annex 4; Section 2): (i) an IPD meta-analysis including data on 9153 mostly adult patients (only 76 were under <15 years) from studies that incorporated three systematic reviews of MDR-TB treatment outcomes published until 2010 (18); and (ii) additional evidence published until August 2015 that summarized a study-level meta-analysis conducted expressly for the revision of the current guidelines (see online Annex 6 for background, methods and summary of findings). All studies included had to

5 See (6) for the new recommendation on the use of delamanid in patients aged 6-17 years.6 Group A=levofloxacin, moxifloxacin, gatifloxacin; Group B=amikacin, capreomycin, kanamycin, (streptomycin); Group

C=ethionamide (or prothionamide), cycloserine (or terizidone), linezolid, clofazimine; in children with non-severe disease Group B medicines may be excluded.

7 Group D2=bedaquiline, delamanid; Group D3=p-aminosalicylic acid, imipenem-cilastatin, meropenem, amoxicillin-clavulanate, (thioacetazone). Bedaquiline is only recommended for adults. Following the revised WHO policy published in October 2016, delamanid may now also be used in patients aged 6–17 years.

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report treatment outcomes, have less than 10% extrapulmonary cases (unless pulmonary and extrapulmonary cases were reported separately), and include at least 25 adult patients with bacteriologically confirmed MDR-TB.

The best available evidence has been used to construct recommendations for a regimen that has high relapse-free cure rates, reduced likelihood of death and low emergence of additional resistance while minimizing SAEs. In the case of high-dose isoniazid, the results from a separate, paediatric individual patient data (pIPD) meta-analysis were extrapolated to adults.

Children. These treatment regimen recommendations are based on the pIPD meta-analysis that included both published and unpublished data on 974 children up until September 30, 2014 (see GRADE tables in online Annex 4 Section 3; and online Annex 6, Section 3 for background, methods and summary of findings). Datasets were eligible if they included a minimum of three children (aged <15 years) within a defined treatment cohort who were treated for clinically diagnosed or bacteriologically confirmed pulmonary or extrapulmonary MDR-TB, and for whom treatment outcomes were reported, using standard WHO TB case definitions. Eligible study designs included controlled and uncontrolled retrospective and prospective studies and case series. No randomized control trials were included (or known to exist) and as a result the overall certainty of the evidence is very low.

Children with XDR-TB were excluded from the analysis (n=36) as their treatment regimens were not considered to be comparable with those of other MDR-TB patients and their numbers were too low to analyse independently. For analysis, children were split in two different cohorts: (i) those who were bacteriologically confirmed as having MDR-TB, and (ii) those who were clinically diagnosed with MDR-TB. When making treatment recommendations, preference was given to the results in the bacteriologically confirmed cohort, as this group had a higher certainty of diagnosis. The children with bacteriologically confirmed MDR-TB were more likely to have severe disease; they had statistically significant higher levels of malnutrition, severe disease on chest radiography, severe extrapulmonary disease and were more likely to be HIV positive. Children without these features were considered to have milder forms of disease.

Where data on children were unavailable, evidence from adults was extrapolated to children. The best available evidence was used to construct recommendations for a regimen that has high relapse-free cure rates, reduces the likelihood of death and of the emergence of additional resistance while minimizing SAEs.

Remarks

Based on the evidence reviews, it is recommended that the MDR-TB regimen be composed of at least five drugs that are likely to be effective, i.e. four core second-line drugs plus pyrazinamide. If a minimum of four core second-line TB medicines cannot be reached by using agents from Groups A to C alone, drugs from Group D2 (in adults; delamanid may also be used in patients aged 6–17 years) or, if not possible, from Group D3 are added. Pyrazinamide is added routinely unless there is confirmed resistance from reliable DST, or well-founded reasons to believe that the strain is resistant, or there is risk of significant toxicity. If pyrazinamide is compromised or cannot be used, the regimen may also be strengthened with an additional agent from Groups

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C or D (preferably D2, or if not possible, from D3). Other agents from Group D1 are included if they are considered to add benefit (e.g. high-dose isoniazid in patients without high-level isoniazid resistance). The total number of TB medicines to include in the regimen needs to balance expected benefit with risk of harms and non-adherence when the pill-burden is high.

The recommendations for children are mostly identical to those of adults. However, in children with mild forms of disease, the harms associated with Group B medications (second-line injectable agents) outweigh potential benefits and therefore Group B medications may be excluded in this group of children. The GDG based this decision on the observation that treatment success in children with clinically diagnosed disease (which was associated with less severe clinical or radiological manifestations) was high and not significantly different in patients treated with and without a Group B medication (93.5% versus 98.1%; n=219; see online Annex 4). In October 2016, WHO published its revised policy on the use of delamanid in patients aged 6–17 years following the advice of a separate Guideline Development Group convened expressly to review evidence for its effectiveness and safety in children and adolescents (6). Delamanid is now conditionally recommended for use in these age-groups as an add-on agent to a longer MDR-TB regimen. Lack of data at this stage on the use of bedaquiline in children precludes a recommendation in patients aged under 18 years.

WHO recommends that all TB patients – children or adult – diagnosed with strains shown to be resistant to rifampicin be placed on a MDR-TB treatment regimen. In such cases, isoniazid is added alongside the rest of the MDR-TB regimen until susceptibility results are confirmed. If isoniazid susceptibility cannot be tested, isoniazid may still be added to the regimen unless there are well-founded grounds to consider the drug ineffective.

Desirable and undesirable effects

Group A. FluoroquinolonesBased on the evidence reviews, the GDG concluded that treatment with later-generation fluoroquinolones (defined for these guidelines as high-dose levofloxacin,8 moxifloxacin, and gatifloxacin) significantly improves treatment outcomes in adults with RR-TB and MDR-TB. This group of medicines is considered to be the most important component of the core MDR-TB regimen and the benefits from their use outweigh potential risks. They should therefore always be included unless there is evidence for absolute contraindication for their use. The order of preference for the inclusion of later-generation fluoroquinolones in longer MDR-TB regimens is: high-dose levofloxacin, moxifloxacin and gatifloxacin. It is recommended that ofloxacin be phased out from MDR-TB regimens and ciprofloxacin never used due to the limited evidence of their effectiveness. Although the pIPD had high levels of confounding and insufficient numbers to discern the treatment effect of high-dose levofloxacin, moxifloxacin and gatifloxacin, data from adults with MDR-TB show a treatment benefit. Therefore these recommendations have been extrapolated to children.

8 For levofloxacin, high-dose is usually defined as 750 mg/day or more. The definition of high-dose will be the subject of discussion of another WHO consultation planned in early 2017.

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Fluoroquinolones in general have a good safety profile and considering the seriousness of RR-TB and MDR-TB, the potential for drug-related harms is offset by the benefits from their use. Although adverse events were poorly recorded, in the study-level meta-analysis the frequency of SAEs attributed to fluoroquinolones was low (1.2%–2.8%; Table 7). Moxifloxacin and other fluoroquinolones carry a risk of QT prolongation, which is a cause for concern when used in combination with medications that have a similar effect, such as bedaquiline, delamanid and clofazimine.

Table 7. Serious adverse events (SAEs) in patients on MDR-TB treatment regimens

MEDICINE COHORTS USING THE DRUG AND

REPORTING SAEs (N)

PATIENTS RECEIVING MEDICINE

(N)

SAEs ATTRIBUTED TO INDIVIDUAL MEDICINE

N PATIENTS % (95%CL)a

Pyrazinamide 19 2023 56 2.8% (2.1%–3.7%)

Ethambutol 16 1325 6 0.5% (0.2%–1.1%)

Second-line injectable agent

19 2538 184 7.3% (6.2%–8.4%)

Ofloxacin or ciprofloxacin

9 1408 40 2.8% (1.9%–4.1%)

Other fluoroquinolones 13 827 10 1.2% (0.6%–2.4%)

Ethionamide/prothionamide

17 2106 173 8.2% (7.0%–9.6%)

Cycloserine 16 2140 96 4.5% (3.6%–5.5%)

p-aminosalicylic acid 16 1706 208 12.2% (10.6%–13.9%)

Linezolid 8 190 28 14.7% (10.0%–20.6%)

a values from fixed effects meta-analysis.

Source: study-level meta-analysis (Bastos M, Lan Z, Menzies R. An updated systematic review and meta-analysis for treatment of multidrug-resistant tuberculosis, 2016. [under review, 25 July 2016]); 43/73 studies reported adverse events, but only 5/43 studies reported Grade 3–4 adverse events, and 28/43 studies reported TB drugs being stopped due to adverse events; for linezolid estimate is based on an aggregated analysis of eight observational studies (28–35) (see also online Annex 4; Section 2 for the respective GRADE tables).

Concerns about dysglycaemia reported in 2006 in patients treated with gatifloxacin for conditions other than TB led the parent company to stop manufacturing the medicine (36), and a global shortage in quality-assured formulations of this drug ensued. A trial of a four-month standardized regimen for drug-susceptible TB which included gatifloxacin (400 mg once daily) published in 2014 reported no significant risk of hyperglycaemia associated with exposure to gatifloxacin (37). Although in general adverse events were poorly recorded in the studies assessed for this review, the data showed that there was a lower risk of SAEs in patients taking gatifloxacin than in those who did not, including those receiving no fluoroquinolones (3.6% vs 8%, not statistically significant; see online Annex 4; Section 2). The frequency of SAEs

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associated with gatifloxacin was thus comparable to the one associated with fluoroquinolones in the study-level meta-analysis (Table 7).

Group B. Second-line injectable agentsBased on the available evidence, second-line injectable agents were associated with an increased likelihood of treatment success when included in a longer MDR-TB treatment regimen (the small size of the population not receiving an injectable agent in the aIPD limited the power to quantify the impact of this class of agents). It is therefore recommended that adults with RR-TB or MDR-TB always receive a second-line injectable agent as part of their regimen unless there is an important contraindication. In children with mild forms of disease, however, the harms associated with this group of medications may outweigh potential benefits and therefore injectable agents may be excluded for children. The GDG based this decision upon the observation that in children with clinically-diagnosed disease  – which was associated with less severe clinical manifestations – treatment success was in general high and did not differ significantly between patients who received Group B medication and those who did not (see above and online Annex 4; Section 3). For children with additional resistance to fluoroquinolones, Group B medications are best retained.

The choice from among amikacin, capreomycin or kanamycin would be determined by the likelihood of effectiveness and implementation considerations. While streptomycin is not usually included with the second-line drugs it can be used as the injectable agent of the core MDR-TB regimen if none of the other three agents can be used and if the strain is unlikely to be resistant to it. Streptomycin resistance by itself does not qualify to define XDR-TB (26) and DST methods for it are not considered accurate or reproducible (38).

Adverse events need to be carefully monitored while using second-line injectable agents. Hearing loss and nephrotoxicity are the most frequent and serious adverse reactions. However, skin rash, hypersensitivity and peripheral nephropathy may also occur. The risk of adverse reactions increases with the total cumulative dose of second-line injectable agents, so particular caution should be given to people who have previously received these medications, including streptomycin as part of a regimen for drug-susceptible TB. In children especially, hearing loss can have a profound impact on their quality of life, affecting acquisition of language and the ability to learn at school.

Although adverse events are poorly reported, the data for this review found that 7.3% of adult patients (10.1% in children) had SAEs attributed to second-line injectable agents (Table 7). In a study focused on hearing loss in children with TB (30% of the children were HIV-infected), 24% of children treated for MDR-TB with an injectable agent had hearing loss and 64% of children had progression of hearing loss after completing the treatment (39).

Group C. Other core second-line agentsWhen designing the core MDR-TB treatment regimen, two or more of the following four medicines are to be included: ethionamide (or prothionamide), cycloserine (or terizidone), linezolid and clofazimine, usually in this order of preference, unless the balance of benefits-to-harms for the individual patient demands otherwise. Group C agents are included to bring the total number of effective second-line TB medicines in the core regimen to at least four during

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the intensive phase. If pyrazinamide cannot be included or counted upon, another agent is added. Ethionamide can be used interchangeably with prothionamide, and terizidone can be used instead of cycloserine.

Given the lack of reliable DST for drugs in Group C, the choice of which ones to include is determined by the balance of desirable to undesirable effects and implementation considerations. The aIPD and pIPD meta-analyses showed an increase in the likelihood of treatment success when MDR-TB treatment regimens included cycloserine (marginally statistically significant) and ethionamide/prothionamide (statistically significant only in adults). In the pIPD, the vast majority of children received ethionamide or prothionamide and significance testing was therefore not always possible for want of sufficient number of controls. In contrast to cycloserine/terizidone and ethionamide/prothionamide, RCT data from a few recent studies are now available for clofazimine and linezolid (32,40,40). Linezolid has shown a statistically significant treatment benefit in both RCT and in cohort studies in adult patients, with this benefit being most pronounced in patients with additional resistance to fluoroquinolones and with XDR-TB (41). Both the aIPD and pIPD showed no significant increase in treatment success associated with the use of clofazimine, while linezolid was used too sparingly in the cohorts included to allow a conclusive analysis (18).

Ethionamide and prothionamide cause gastrointestinal disturbance, in particular vomiting, which can limit tolerability. Hypothyroidism may occur, especially in combination with PAS, but is reversible upon cessation of drugs. This review found that 8.2% of patients had SAEs due to ethionamide or prothionamide, although adverse events were poorly reported across the individual studies (Table 7).

Cycloserine has a well-established association with neuropsychiatric adverse reactions. However, the aIPD meta-analysis in adults revealed low levels of SAEs (4.5% in the study-level meta-analysis conducted for this update). A meta-analysis published in 2013 comparing the adverse effects of cycloserine with terizidone found that terizidone had no to little benefit over cycloserine with regard to adverse reactions (42).

Adverse reactions of linezolid include lactic acidosis, thrombocytopenia and anaemia. These can be severe and life threatening, although they are reversible with cessation of the drug or on some occasions by lowering its dose (usually from 600 mg daily to 300 mg daily) (9). Haematologic toxicities are less common with current strategies of once-daily dosing. Peripheral neuropathy may or may not improve with cessation of the drug. Optic neuropathy should be treated as a medical emergency. Given the potential seriousness of the adverse reactions associated with linezolid the decision to use it must balance its risks and benefits, and the availability of other TB medicines. Its use needs to be accompanied by close monitoring for adverse events. Where this is not possible, linezolid would best be reserved for MDR-TB patients who have additional drug resistance, or XDR-TB patients, or those who are intolerant to other components of the core regimen.

Clofazimine probably contributes to the sterilizing function of MDR-TB regimens where pyrazinamide is not effective. Although the single published for clofazimine use in MDR-TB had serious methodological concerns, it showed a statistically significant treatment

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benefit associated with clofazimine use (40). However, much of the evidence for the effect of clofazimine in MDR-TB is based upon observational studies, which showed conflicting or inconclusive findings (43). One of the main adverse effects of clofazimine is skin discoloration/darkening, which may be distressing to patients. In the RCT, the adverse events reported were mostly limited to skin conditions and discoloration, and did not lead to discontinuation in the use of the drug. Overall, small rates of adverse events were noted in the observational studies and SAEs appear to be relatively uncommon. Clofazimine may prolong the QT interval, so caution is advised when using this medication in combination with other drugs also known to have the same effect.

Group D. Add-on agentsThis group of medicines includes drugs that do not form part of the core second-line agents. It is split into three subgroups:

Group D1 consists of pyrazinamide, ethambutol and high-dose isoniazid. These agents are usually added to core second-line medications, unless confirmed resistance, pill burden, intolerance or drug–drug interaction outweigh their potential benefits.

The aIPD showed improved likelihood of success (versus treatment failure, relapse or death combined) in patients who had pyrazinamide included in their regimens. This effect was significant both statistically and in absolute terms. The pIPD did not show a significant treatment effect with use of pyrazinamide. In many settings, RR-TB strains frequently have additional resistance to pyrazinamide. While it would be desirable to avoid giving pyrazinamide to patients whose strains are resistant to the drug, it is acknowledged that reliable DST for pyrazinamide is very often unavailable in resource-constrained settings. Although adverse events were poorly reported, data from the study-level meta-analysis showed that 2.8% of patients who received pyrazinamide had SAEs (Table 7). The balance of desirable to undesirable effects favours the addition of pyrazinamide to the core second-line MDR-TB regimen by default, unless there is confirmed resistance from reliable DST, or well-founded reasons to believe that the strain is resistant, or there are other contraindications for its use, particularly risk of significant toxicity. As for the drugs from the core regimen, if pyrazinamide is compromised or cannot be used, more agents from Group C and subsequently Group D are added until at least five effective medicines are available in the intensive phase.

The recommendation for the inclusion of isoniazid9 in adult MDR-TB regimens is largely based on evidence from the analysis of pIPD. This analysis showed a statistically significant increased likelihood of treatment success (versus treatment failure, relapse or death combined) in children with bacteriologically confirmed MDR-TB, even after adjustment for age, HIV status, sex, TB disease severity and treatment centre (treatment with high-dose isoniazid was almost exclusively done in South African sites). An RCT of high-dose isoniazid therapy for MDR-TB in adults found no increased risk of hepatotoxicity (44). Additionally, high-dose isoniazid was very well tolerated in children with drug susceptible tuberculous meningitis in a large cohort study from the Western Cape (45).

9 For isoniazid, the definition of high-dose will be the subject of discussion of another WHO consultation planned in early 2017.

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Isoniazid is recommended alongside a full MDR-TB regimen in patients with rifampicin-resistant strains confirmed or suspected to be susceptible to isoniazid. High-dose isoniazid is one of the core components of the shorter MDR-TB treatment regimen (see Section A above). Strains bearing mutations in the promoter region of the inhA gene may have a minimum inhibitory concentration (MIC) to isoniazid that is low enough to be overcome by high-dose isoniazid. In such settings the drug may still add benefit (46). However, this mutation has been associated with high-level ethionamide resistance (47) and therefore, if present, ethionamide (or prothionamide) may have to be replaced in the regimen. In settings with elevated prevalence of high-level isoniazid resistance associated with katG mutations, high-dose isoniazid may be less effective and therefore its routine use may not be warranted. In such a situation the susceptibility to ethionamide (or prothionamide) is not affected and it can be used in combination with high-dose isoniazid.

The aIPD did not show any statistically significant association between the use of ethambutol and likelihood of treatment success. Ethambutol may cause ocular toxicity, which can be difficult to diagnose in young children, although this risk is reduced if the dose does not exceed recommended limits. SAEs were reportedly associated in 0.5% of cases in the meta-analysis conducted for this review although the reporting of adverse events data was incomplete (Table 7). Special care is needed when renal function is compromised. RR-TB and MDR-TB strains may also be resistant to ethambutol, particularly in those patients who have been treated with this drug previously. However, DST for this drug is not considered reliable and reproducible (38). The potential benefit that ethambutol may add to a core MDR-TB regimen needs to be balanced carefully with the inconvenience of adding another medicine to the regimen and the risks of associated harms.

Group D2 is made up of two new drugs released in recent years – bedaquiline and delamanid. WHO issued an interim policy on the use of these medicines in 2013 and 2014 (4,5). In October 2016, WHO published its revised policy on delamanid following the advice of a separate GDG which reviewed its use in children and adolescents (6) (see also above). At this point, bedaquiline remains only recommended for use in adults. When the results from ongoing studies and the Phase III trials become available the evidence for the effectiveness of these two new drugs will be re-evaluated with respect to the other medicines making up the MDR-TB regimen.

Group D3 consists of p-aminosalicylic acid (PAS), imipenem–cilastatin, meropenem, clavulanate and thioacetazone. These drugs are only to be used when a MDR-TB regimen with at least five effective drugs in the intensive phase (i.e. four core second-line medicines plus pyrazinamide) cannot be otherwise composed.

The aIPD (18), as well as the study-level meta-analysis conducted for the current guidelines revision, found no significant effect of PAS on treatment success. PAS use is associated with a high frequency of adverse reactions (12.2% SAEs in the meta-analysis undertaken for this study) and is thus reserved for situations when there is no option to use other drugs.

Carbapenems (imipenem–cilastin or meropenem) appear to be hydrolyzed more slowly by M. tuberculosis when combined with clavulanic acid (48,49). Amoxicillin-clavulanate has

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shown poor results in in vitro studies and in early bactericidal activity (EBA) studies (50–52). The aIPD showed that patients treated with amoxicillin- clavulanate were more likely to have poor treatment outcomes, although this may be due to confounding by the higher likelihood that patients receiving this drug tended to have more severe disease (not all confounding could be adjusted for in the analysis). WHO recommends that whenever amoxicillin-clavulanate and carbapenems are included in regimens they are always to be used together. Clavulanate is only available as a combination preparation containing amoxicillin. The spectrum of adverse reactions associated with amoxicillin-clavulanate and carbapenems is to a large extent identical to that associated with penicillins (53).

Thioacetazone has been used extensively in the past as part of first-line combination therapy for TB, based on RCT evidence of effectiveness (54). Use of the drug in TB treatment has however been restricted since the early 1990s due to the severe skin reactions it causes (including Stevens–Johnson syndrome and toxic epidermal necrolysis that can lead to death, especially in people living with HIV (55)), as well as the widespread availability of safer, affordable alternatives for combination TB regimens. If thioacetazone is being considered as part of a MDR-TB treatment regimen, close monitoring for severe skin reactions is required and it is imperative that the patient be tested for HIV, and the drug not used if the patient is HIV seropositive.

M. tuberculosis is intrinsically resistant to the macrolide class of antibiotics (56). The evidence reviews for the current guidelines did not show any effectiveness of drugs of this class (clarithromycin, azithromycin) (57), which have at times been included in MDR-TB regimens in both adults and children. In addition, the aIPD showed an increased risk – although not statistically significant – for poor outcomes in patients receiving macrolides although macrolides appeared to be safe during prolonged use. Macrolides are associated with QT prolongation (58), which would be of particular concern if patients are receiving other TB drugs with a similar risk, such as moxifloxacin, clofazimine, bedaquiline or delamanid. WHO therefore no longer recommends the use of clarithromycin or azithromycin as part of regimens for the treatment of MDR/RR-TB.

Adverse reactions linked to PAS include gastrointestinal disturbance and hypothyroidism (in particular when given in combination with ethionamide/prothionamide). Hypothyroidism is reversible upon cessation of drugs. Although adverse events were poorly reported in studies assessed, the data for this review found that 12.2% of patients had SAEs attributed to PAS (Table 7). The pIPD showed the possibility of harm associated with the use of PAS (not statistically significant). However, PAS is frequently given to children when few other treatment options remain, and therefore this effect may be due to confounding by indication (sites that had poorer outcomes with PAS also had significantly higher rates of children who were HIV seropositive and malnourished, as well as with severe pulmonary disease, and additional resistance to fluoroquinolones and second-line injectable medicines).

Subgroup considerations

Rifampicin-resistant TB/MDR-TB with additional resistance to fluoroquinolones, second-line injectable agents and XDR-TB. In patients with RR-TB and MDR-TB, if there is confirmed or well-founded belief of resistance to medications from Group A (fluoroquinolones) or Group

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B (second-line injectable agents), the medicines in the regimen that belong to these classes are substituted as detailed in the beginning of section B1. If any of the components of the regimen – the four core second-line medicines and pyrazinamide – is not considered to be effective, additional agents from Groups D2 or D3 are added. This is almost always necessary when resistance to both Groups A and B drugs (i.e. XDR-TB) is present. Analysis of additional individual patient data collected for the update of the WHO drug-resistant TB treatment guidelines of 2011 concluded that regimens containing more drugs were associated with the highest odds of success for MDR-TB patients who had additional resistance to fluoroquinolones and/or second-line injectable agents (59). The current WHO advice continues to apply when designing regimens for patients with resistance to fluoroquinolones and second-line injectable medications, as well as those with XDR-TB (9).

Access to rapid diagnostic testing, which could reliably identify resistance to Group A or Group B agents, would help clinicians decide on how to modify longer MDR-TB regimens. The Genotype MTBDRsl line probe assay (22) may now be used as an initial test, over phenotypic culture-based DST, to detect resistance to fluoroquinolones and to the second-line injectable drugs among patients with MDR/RR-TB (conditional recommendation; certainty of evidence low to moderate for direct testing (12)). Genotype MTBDRsl can be used in both children and adults and as a direct and indirect test (it could thus be used on extrapulmonary samples). While resistance-conferring mutations to fluoroquinolones detected by the MTBDRsl assay are highly correlated with phenotypic resistance to ofloxacin and levofloxacin, the correlation with moxifloxacin and gatifloxacin is less clear and the inclusion of moxifloxacin or gatifloxacin in a MDR-TB regimen is best guided by phenotypic DST results.

TB of the central nervous system. The treatment of tuberculous meningitis related to rifampicin-resistant or MDR strains is best guided by drug susceptibility results and the known properties of TB drugs to penetrate the central nervous system (CNS) (9). In patients with MDR/RR-TB meningitis, it is recommended that medications selected for the regimen have good CNS penetration properties.

The fluoroquinolones recommended by these guidelines have good CNS penetration (60), as do ethionamide (or prothionamide), cycloserine (or terizidone) and linezolid (61,62). Pyrazinamide has good CNS penetration, although caution should be exercised, as a large percentage of MDR-TB strains may be resistant. Isoniazid penetrates the CNS very well, with higher doses reaching adequate MICs in the cerebrospinal fluid. Due to its good CNS penetration, high-dose isoniazid is recommended as part of the treatment regimen unless high-level resistance is known to exist.

PAS and ethambutol do not penetrate the CNS well and should not be counted on as effective drugs to treat MDR-TB meningitis. Kanamycin, amikacin and streptomycin only penetrate the cerebrospinal fluid in the presence of meningeal inflammation. There are little data on the CNS penetration of capreomycin, clofazimine, bedaquiline or delamanid.

People living with HIV. The composition of the treatment regimen for MDR-TB does not differ for people living with HIV. However, thioacetazone should not be given to patients who

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are HIV positive. If it is being considered as part of a treatment regimen, then HIV infection needs to be reliably excluded in the patient.

Implementation considerations

The implementation of MDR-TB chemotherapy is feasible under programmatic conditions, as has been amply shown by the global expansion in the use of MDR-TB regimens worldwide, particularly in the past decade (25,63). Changes made by the current revision to the grouping of medicines and composition of longer MDR-TB regimens are not expected to have a major impact on their continued use. Most of the fluoroquinolones and injectable agents are readily available as are the majority of the Group C and Group D agents. The latest WHO Model Lists of Essential Medicines (August 2015) include most of the agents in Table 6 except for gatifloxacin and thioacetazone (64,65). However, clofazimine, meropenem, imipenem–cilastatin and amoxicillin-clavulanate are listed for indications other than TB, while bedaquiline and delamanid are only included in the adult list. Other specific factors important for implementation are discussed in the respective sections below.

Where possible a patient’s rifampicin-resistant or MDR-TB strain needs to be tested for susceptibility to medicines planned for inclusion in the regimen. The availability of reliable, rapid tests for susceptibility to fluoroquinolones and second-line injectable drugs which would give results within a few days is valuable to ensure that longer MDR-TB regimens are strengthened as necessary (11,38). Where reliable DST is not an option, proof of the effectiveness of a medicine needs to be based on careful clinical history of the patient’s previous exposure to the medicine, of significant contact with another MDR/RR-TB patient whose antibiogramme is documented, and knowledge of the prevalent resistance patterns based on representative drug-resistance surveillance. Both the DST and the individual clinical history should be considered when constructing a treatment regimen. The only reliable laboratory tests for TB drug susceptibility (or resistance) which are widely used today are those for isoniazid, rifampicin, fluoroquinolones and second-line injectable agents.

The recommendations made by the current guidelines envisage a more widespread application of the shorter MDR-TB regimen among MDR/RR-TB patients. This implies that a larger proportion of the patients to whom longer MDR-TB regimens will be given would have additional resistance to core second-line medications than is the case today. For this reason additional care will need to be taken to ensure that regimens are adequately strengthened to ensure the best possible outcomes for these patients.

The current revision of the guidelines did not re-analyse the optimal duration of treatment (intensive and continuation phases). Thus the recommendations from the 2011 guidelines which were based on the aIPD meta-analysis continue to apply (1,18). The 2011 guidelines conditionally recommended an intensive phase of eight months for most MDR-TB patients and total treatment duration of 20 months in patients who had not been previously treated. The duration may need to be modified according to the patient’s response to therapy (9). The association between treatment success and the total length of treatment was less clear in patients who had been previously treated compared with those who had not, although the likelihood of treatment success appeared to peak between 27.6 and 30.5 months. The number

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of observations was also far fewer than for those who had no previous MDR-TB treatment. As a result no recommendation on total duration was made in the 2011 revision for previously-treated patients. Many of the MDR/RR-TB patients who will be ineligible for the shorter MDR-TB regimen and referred for treatment with longer regimens would have been treated with second-line medication in the past. In these patients, uncertainties will remain on the optimal duration of treatment and therefore the duration of therapy would need to be guided primarily by their response to therapy.

Group A. Fluoroquinolones. Both levofloxacin and moxifloxacin are commonly used to treat MDR-TB. Levofloxacin is more widely available than moxifloxacin, which is more expensive although a reduction in its price is expected in the coming years.

Gatifloxacin is an affordable drug that was commonly used by TB treatment programmes until the concerns about its dysglycaemic effects led to a global shortage in its supplies. If manufacture of quality-assured formulations of the drug restarts, it could provide more options for regimen design and could lower the costs of regimens by substituting more expensive fluoroquinolones.

Moxifloxacin is relatively easy to administer to older children. However, the tablet must be split to accommodate dosing in younger children and it is highly unpalatable once split or crushed. Levofloxacin is available as a suspension.

Group B. Second-line injectable agents. These agents present problems to administer intramuscularly or intravenously on a daily basis for several months, often necessitating hospitalization. Giving injections to children and underweight adults is particularly unpleasant and unwelcome.

Group C. Other core second-line agents. Ethionamide and prothionamide are inexpensive, readily available worldwide and easily administered.

Cycloserine has been one of the standard inexpensive drugs for the treatment of MDR-TB for several years and therefore experience in its use is widespread. Terizidone is less widely used but is available on the Global Drug Facility (GDF) Products List.

Clofazimine is relatively inexpensive but it can be difficult to procure. The implementation of the recommendation on the shorter MDR-TB regimen, of which this medicine is an irreplaceable core component, needs to ensure that sufficient quantities of this medicine are available to meet the demand and that no stock-outs occur.

When linezolid is used, there needs to be close monitoring for adverse effects, particularly anaemia, thrombocytopenia, lactic acidosis, peripheral neuropathy and optic neuropathy, as these can be severe and life threatening. Historically linezolid has been very expensive, however, it has recently come off patent and the availability of generic products has hugely reduced its market price and it may become even more affordable in future.

Group D. Add-on agents. Pyrazinamide is inexpensive, readily available and easy to administer. Isoniazid is inexpensive. It is important to consider the epidemiology of high-level versus low-level isoniazid resistance in a population before standard treatment regimens including

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high-dose isoniazid are recommended. Ethambutol is inexpensive and readily available. All of these three medicines are core components of first-line regimens for drug-susceptible TB.

PAS may be difficult to obtain although it is available through the GDF. Otherwise it is relatively inexpensive and easy to administer.

Amoxicillin-clavulanate is inexpensive and easily obtainable. However, the carbapenems are expensive and are difficult to administer as they must be given two or three times per day via an intravenous line.

Thioacetazone is inexpensive but it has limited availability and is not currently available through the GDF.

Monitoring and evaluation

Patients on longer MDR-TB treatment regimens need to be monitored for response to treatment and for safety using reasonable schedules of relevant clinical and laboratory testing (9,24). Frameworks for the surveillance of bacteriological status, drug-resistance and outcomes have been fairly standardized over the past decade. The systematic monitoring of adverse events during and after the end of treatment is a recent introduction in TB programmes and experience in their implementation is still developing in many countries. Its rationale is largely defined by frequent use of new and re-purposed medications in MDR-TB treatment regimens in the world, at times in combinations for which there has been very limited experience of use.

B2. Treatment regimens for isoniazid-resistant TB and M. bovisIn the review for isoniazid-resistant TB, no cohorts or RCTs were found which included fluoroquinolones as part of standardized combination TB regimens intended primarily for isoniazid-resistant TB. Fluoroquinolones, when used, were individualized and introduced at varying points in a patient’s regimen. These studies thus did not allow meaningful pooling. In three recent RCTs that investigated the potential for fluoroquinolones to shorten first-line TB regimens (37,66,67) over 240 patients with non-MDR, isoniazid-resistant strains were placed on fluoroquinolone-containing regimens. Data for 66 of these patients enrolled in one of these RCTs showed similar levels of unfavourable outcome (treatment failure/relapse/death/loss to follow-up) in patients on fluoroquinolone-containing four-month regimens (20.7%) compared with the standard 2HRZE/4HR10 regimen (21.6%) (37) (personal communication, Merle C). In a second trial, success rates in patients treated with four-month fluoroquinolone-containing regimens were similar in subgroups with isoniazid-resistant strains and those with fully susceptible strains (66) (personal communication, Gillespie SH). In conclusion, the evidence reviews of published studies on isoniazid-resistant TB could not address the PICO question.

Only eight studies identified by the literature search provided information on treatment and treatment outcomes of patients with confirmed M. bovis disease. Of these only three studies

10 2HRZE/4HR = two months of isoniazid, rifampicin, pyrazinamide and ethambutol followed with four months of rifampicin and isoniazid.

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included 20 or more subjects – a minimum criterion for the review. In the three case series retained, treatment regimens were very different and tended to be individualized. It was thus impossible to group the different case series for pooled analysis.

Owing to the lack of data to address the questions directly, no clinically useful recommendations could be made for these two forms of TB.

C. The effect of delay in starting treatment on treatment outcomes for patients with drug-resistant TB

Global monitoring of the response to MDR/RR-TB shows that several countries have successfully expanded diagnostic services for RR-TB without matching it with complementary capacity to enrol patients on adequate treatment (63,69). This has led to patients with confirmed drug-resistant TB waiting for months or even years to initiate treatment. It is widely held, based largely upon findings from TB patients without drug-resistant disease, that prolonging the time to initiate treatment in TB patients is undesirable and predisposes to unfavourable clinical and public health consequences, such as increased disease progression with higher bacillary load in sputum, more lung damage and continued transmission. A PICO question was thus developed to inform any policy recommendation to be made in support of earlier start of treatment (see Annex 3; PICO 4). Evidence was reviewed to assess whether starting an adequate treatment regimen within four weeks of diagnosis, or a strong presumption of MDR/RR-TB, was associated with positive outcome, and to quantify any such effect.

An initial search of the literature yielded 1978 references of which 64 underwent full text review (70). None of these articles fulfilled the inclusion criteria. A supplementary full text review of the 64 references was undertaken with the explicit aim of determining whether any articles described treatment outcomes in MDR-TB patients stratified by delay to initiation of treatment. The original parameters were subsequently broadened from those in the PICO question to allow for the use of other time delay categorizations and to look for other relevant outcomes such as culture conversion. Sixteen articles were identified from which scant data could be abstracted. None of these articles addressed the independent effect of delay in start of treatment upon treatment outcomes with a meaningful comparator group.

A major obstacle to finding published evidence to support the assumption that shorter delays lead to better outcomes is the lack of studies reporting outcome in which treatment delay could be analysed as a dependent variable in groups which were otherwise comparable or in which other covariates could be adjusted for.

Differences in time to treatment initiation rarely occur in isolation. Programmatic changes related to delivery of care and modifications in drug regimen are common in the literature reviewed. Attribution of variations in delay to treatment outcomes is thus a significant challenge. Even if such data were available, an additional constraint is that the interval from RR-TB or MDR-TB diagnosis to start of treatment does not account for any delay in diagnosis, the magnitude of which may dominate overall delay and overshadow any benefits that could accrue from reducing the time to start treatment once the disease is diagnosed.

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Despite the absence of a discrete evidence base, it is reasonable to advise national programmes to adhere to the general standard of TB care which promotes an early start of appropriate therapy when MDR/RR-TB are diagnosed or strongly suspected (71). Studies to address this question are not a priority and intentionally withholding or delaying treatment presents ethical concerns. Nonetheless, this should not preclude from attempts to quantify the effect of delay using data from studies – observational or otherwise – mounted to answer other questions.

D. The effect of surgical interventions on treatment outcomes for patients with drug-resistant TB

Recommendation

In patients with RR-TB or MDR-TB, elective partial lung resection (lobectomy or wedge resection) may be used alongside a recommended MDR-TB regimen (conditional recommendation, very low certainty in the evidence).

Justification

Surgery has been employed in treating TB patients since before the advent of chemotherapy. In many countries it remains one of the treatment options for TB. With the challenging prospect in many settings of inadequate regimens to treat MDR-/XDR-TB, and the risk for serious sequelae, the role of pulmonary surgery is being re-evaluated as a means to reduce the amount of lung tissue with intractable pathology, to reduce bacterial load and thus improve prognosis.

The review for this question was based on both an individual patient-level meta-analysis to evaluate the effectiveness of different forms of elective surgery as an adjunct to combination medical therapy for MDR-TB (19), as well as a systematic review and study-level meta-analysis (72) (online Annex 4; Section 4). Demographic, clinical, bacteriological, surgical and outcome data of MDR-TB patients on treatment were obtained from the authors of 26 cohort studies participating in the aIPD (18). The analyses summarized in the GRADE tables consist of three strata comparing treatment success (cure and completion) with different combinations of treatment failure, relapse, death and loss to follow-up. Two sets of such tables were prepared for (i) partial pulmonary resection, and (ii) pneumonectomy.

In the study-level meta-analysis that examined all forms of surgery together, there was a statistically significant improvement in cure and successful treatment outcomes among patients who received surgery. However, when the aIPD meta-analysis examined patients who underwent partial lung resection and those who had a more radical pneumonectomy, versus patients who did not undergo surgery, those who underwent partial lung resection had statistically significantly higher rates of treatment success. Those patients who underwent pneumonectomy did not have better outcomes than those who did not undergo surgery. Prognosis appeared to be better when partial lung resection was performed after culture conversion. This effect was not observed in patients who underwent pneumonectomy.

There are several important caveats to these data. Substantial bias is likely to be present given that only patients judged to be fit for surgery would have been operated upon. No patient

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with HIV co-infection in the aIPD underwent lung resection surgery. Therefore the effects of surgery among HIV-infected patients with MDR-TB could not be evaluated.

Rates of death did not differ significantly between those who underwent surgery versus those who received medical treatment only. However, the outcomes could be biased because the risk of death could have been much higher among patients in whom surgery was prescribed had they not been operated upon.

Subgroup consideration

The relative benefits of surgery are expected to depend substantially on the population subgroups that are targeted. The analysis could not provide a refined differentiation of the type of patient who would be best suited to benefit from the intervention or the type of intervention that would bear most benefit. The effect is expected to be moderate in the average patient considered appropriate for surgery.

The odds of success for patients with XDR-TB were statistically significantly lower when they underwent surgery compared with other patients (adjusted OR 0.4, 0.2–0.9). This effect is likely to be biased given that patients who underwent surgery would have had other factors predisposing to poor outcomes, which could not be adjusted for.

Implementation considerations

Partial lung resection for patients with MDR-TB is only to be considered under conditions of good surgical facilities, trained and experienced surgeons and with careful selection of candidates.

Monitoring and evaluation

The rates of death in the IPD for surgical outcomes did not differ significantly between patients who underwent surgery and those who received medical treatment only.

There were not enough data on adverse events, surgical complications or long term sequelae – some of which may be fatal – to allow a meaningful analysis.

Despite the unknown magnitude of perioperative complications the GDG assumed that overall there is a net benefit from surgery.

E. Research priorities

In addition to summarizing the available evidence, the reviews undertaken for this update revealed a number of gaps in current knowledge about critical areas for the treatment for MDR/RR-TB. Where evidence was available it was usually assigned a very low quality rating. This was one of the main reasons why all the recommendations made in this guidelines revision are conditional.

The GDG discussed research priorities and highlighted a number of them. They identified some problem areas which had already been singled out by earlier efforts to define research priorities for MDR-TB treatment, such as preventive therapy for MDR-TB and improving evidence on reduction of regimen duration (1,73,74).

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The optimal combination of medicines and approach towards regimen-design for patients (both adults and children) with isoniazid-resistant TB, RR-TB, MDR-TB and XDR-TB, as well as for patients with M. bovis disease.

• More randomized controlled trials, especially involving the new drugs and regimens, but also for patients with isoniazid-resistant forms of TB who are placed on fluoroquinolone-containing regimens.

• Inclusion and separate reporting of outcomes for key subgroups, especially children and HIV-positive individuals on treatment, in randomized controlled studies.

• Complete recording of adverse events and standardized data recording on organ class, seriousness, severity, and certainty of association, to allow reliable comparison of the association between adverse events and exposure to different medicines.

• Identification of factors that determine the optimal duration of treatment (e.g. previous treatment history, baseline resistance patterns, site of disease, child/adult).

• Determination of the minimum number of drugs and treatment duration (especially in patients previously treated for MDR-TB).

• Determination of conditions under which injectable-sparing regimens can be used in both children and adults (e.g. surrogates for severity / extent of disease, alternative medication).

• Pharmacokinetic studies to determine optimal drug dosing and safety (especially in pregnancy).• Improved diagnostics and drug-susceptibility testing methods (e.g. which test for

pyrazinamide).• Randomized controlled trials to define the benefits and harms of chemoprophylaxis for

child and adult contacts of MDR/RR-TB (with and without additional resistance patterns) (9,75). The composition, dosages and duration of the latent TB infection (LTBI) regimen for MDR-TB needs to be optimized and the potential role of newer drugs with good sterilization properties investigated. Studies are needed to examine the adverse reactions of the long-term use of fluoroquinolones in preventive treatment.

• Palliative and end-of-life care in patients with very advanced resistance patterns.

The effectiveness and safety of standardized regimens lasting up to 12 months for the treatment of patients with MDR-TB (“shorter regimens”) when compared with longer treatment

• Future research needs to include the effectiveness/safety of the shorter MDR-TB treatment regimen in subgroups which have been systematically excluded from study protocols (e.g. children, patients with different forms of extrapulmonary TB) and in settings where background resistance to drugs other than fluoroquinolones and second-line injectable agents is high (e.g. pyrazinamide or high-level isoniazid resistance).

• Implementation research on the introduction of the shorter MDR-TB regimen.• More studies on cost effectiveness and health-related quality of life.

The effect of surgical interventions on treatment outcomes for patients with drug-resistant TB

• Better definition of the role of surgery (i.e. decisions about when to operate and the type of surgical intervention, drug-resistance patterns), needs to be better examined.

• Improved collection, reporting, standardization of data on surgery including long-term survival post surgery.

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Who policy recommenDations

References1. Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 Update. (WHO/

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32. Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, et al. Linezolid for Treatment of Chronic Extensively Drug-Resistant Tuberculosis. N Engl J Med. 2012;367(16):1508–18.

43

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36. Park-Wyllie LY, Juurlink DN, Kopp A, Shah BR, Stukel TA, Stumpo C, et al. Outpatient gatifloxacin therapy and dysglycemia in older adults. N Engl J Med. 2006;354(13):1352–61.

37. Merle CS, Fielding K, Sow OB, Gninafon M, Lo MB, Mthiyane T, et al. A four-month gatifloxacin-containing regimen for treating tuberculosis. N Engl J Med. 2014;371(17):1588–98.

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39. Seddon JA, Thee S, Jacobs K, Ebrahim A, Hesseling AC, Schaaf HS. Hearing loss in children treated for multidrug-resistant tuberculosis. J Infect. 2013;66(4):320–9.

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41. Tang S, Yao L, Hao X, Zhang X, Liu G, Liu X, et al. Efficacy, safety and tolerability of linezolid for the treatment of XDR-TB: a study in China. Eur Respir J. 2015;45(1):161–70.

42. Hwang TJ, Wares DF, Jafarov A, Jakubowiak W, Nunn P, Keshavjee S. Safety of cycloserine and terizidone for the treatment of drug-resistant tuberculosis: a meta-analysis. Int J Tuberc Lung Dis. 2013;17(10):1257–66.

43. Hwang TJ, Dotsenko S, Jafarov A, Weyer K, Falzon D, Lunte K, et al. Safety and availability of clofazimine in the treatment of multidrug and extensively drug-resistant tuberculosis: analysis of published guidance and meta-analysis of cohort studies. BMJ Open. 2014;4(1):e004143.

44. Katiyar SK, Bihari S, Prakash S, Mamtani M, Kulkarni H. A randomised controlled trial of high-dose isoniazid adjuvant therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2008;12(2):139–45.

45. van Toorn R, Schaaf HS, Laubscher JA, van Elsland SL, Donald PR, Schoeman JF. Short intensified treatment in children with drug-susceptible tuberculous meningitis. Pediatr Infect Dis J. 2014;33(3):248–52.

46. Niehaus AJ, Mlisana K, Gandhi NR, Mathema B, Brust JCM. High prevalence of inhA promoter mutations among patients with drug-resistant tuberculosis in KwaZulu-Natal, South Africa. PLoS One. 2015;10(9):e0135003.

47. Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, et al. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science. 1994;263(5144):227–30.

48. Hugonnet J-E, Blanchard JS. Irreversible inhibition of the Mycobacterium tuberculosis beta-lactamase by clavulanate. Biochemistry (Mosc). 2007;46(43):11998–2004.

49. Solapure S, Dinesh N, Shandil R, Ramachandran V, Sharma S, Bhattacharjee D, et al. In vitro and in vivo efficacy of β-lactams against replicating and slowly growing/nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2013;57(6):2506–10.

50. Chambers HF, Kocagöz T, Sipit T, Turner J, Hopewell PC. Activity of amoxicillin/clavulanate in patients with tuberculosis. Clin Infect Dis. 1998;26(4):874–7.

51. Donald PR, Sirgel FA, Venter A, Parkin DP, Van de Wal BW, Barendse A, et al. Early bactericidal activity of amoxicillin in combination with clavulanic acid in patients with sputum smear-positive pulmonary tuberculosis. Scand J Infect Dis. 2001;33(6):466–9.

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52. Gonzalo X, Drobniewski F. Is there a place for β-lactams in the treatment of multidrug-resistant/extensively drug-resistant tuberculosis? Synergy between meropenem and amoxicillin/clavulanate. J Antimicrob Chemother. 2013;68(2):366–9.

53. Prescott, Jr. WA, DePestel DD, Ellis JJ, Regal RE. Incidence of carbapenem-associated allergic-type reactions among patients with versus patients without a reported penicillin allergy. Clin Infect Dis. 2004;38(8):1102–7.

54. Isoniazid with thiacetazone (thioacetazone) in the treatment of pulmonary tuberculosis in East Africa–fifth investigation. A co-operative study in East African hospitals, clinics and laboratories with the collaboration of the East African and British Medical Research Councils. Tubercle. 1970;51(2):123–51.

55. Nunn P, Kibuga D, Gathua S, Brindle R, Imalingat A, Wasunna K, et al. Cutaneous hypersensitivity reactions due to thiacetazone in HIV-1 seropositive patients treated for tuberculosis. Lancet. 1991;337(8742):627–30.

56. Andini N, Nash KA. Intrinsic macrolide resistance of the Mycobacterium tuberculosis complex is inducible. Antimicrob Agents Chemother. 2006;50(7):2560–2.

57. Winters N, Butler-Laporte G, Menzies D. Efficacy and safety of World Health Organization group 5 drugs for multidrug-resistant tuberculosis treatment. Eur Respir J. 2015;46(5):1461–70.

58. Iannini PB. Cardiotoxicity of macrolides, ketolides and fluoroquinolones that prolong the QTc interval. Expert Opin Drug Saf. 2002;1(2):121–8.

59. Falzon D, Gandhi N, Migliori GB, Sotgiu G, Cox H, Holtz TH, et al. Resistance to fluoroquinolones and second-line injectable drugs: impact on MDR-TB outcomes. Eur Respir J. 2013;42(1):156–68.

60. Thwaites GE, Bhavnani SM, Chau TTH, Hammel JP, Torok ME, Van Wart SA, et al. Randomized pharmacokinetic and pharmacodynamic comparison of fluoroquinolones for tuberculous meningitis. Antimicrob Agents Chemother. 2011;55(7):3244–53.

61. Donald PR. The chemotherapy of tuberculous meningitis in children and adults. Tuberculosis. 2010;90(6):375–92.

62. Sun F, Ruan Q, Wang J, Chen S, Jin J, Shao L, et al. Linezolid manifests a rapid and dramatic therapeutic effect for patients with life-threatening tuberculous meningitis. Antimicrob Agents Chemother. 2014;58(10):6297–301.

63. Falzon D, Mirzayev F, Wares F, Baena IG, Zignol M, Linh N, et al. Multidrug-resistant tuberculosis around the world: what progress has been made? Eur Respir J. 2015;45(1):150–60.

64. WHO Model List of Essential Medicines. 19th list. Geneva: World Health Organization; 2015 (http://www.who.int/selection_medicines/committees/expert/20/EML_2015_FINAL_amended_AUG2015.pdf, accessed 13 May 2016).

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66. Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 2014;371(17):1577–87.

67. Jawahar MS, Banurekha VV, Paramasivan CN, Rahman F, Ramachandran R, Venkatesan P, et al. Randomized clinical trial of thrice-weekly 4-month moxifloxacin or gatifloxacin containing regimens in the treatment of new sputum positive pulmonary tuberculosis patients. PloS One. 2013;8(7):e67030.

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69. Virenfeldt J, Rudolf F, Camara C, Furtado A, Gomes V, Aaby P, et al. Treatment delay affects clinical severity of tuberculosis: a longitudinal cohort study. BMJ Open. 2014 Jun 1;4(6):e004818.

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70. Harris RC, Grandjean L, Martin LJ, Miller AJP, Nkang J-EN, Allen V, et al. The effect of early versus late treatment initiation after diagnosis on the outcomes of patients treated for multidrug-resistant tuberculosis: a systematic review. BMC Infectious Diseases 2016 Dec;16(1). (http://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-016-1524-0, accessed 19 July 2016).

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74. Mitnick CD, Rodriguez CA, Hatton ML, Brigden G, Cobelens F, Grobusch MP, et al. Programmatic Management of Drug-Resistant Tuberculosis: An Updated Research Agenda. PLOS ONE. 2016 May 25;11(5):e0155968. (http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155968, accessed 26 July 2016).

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46

Annex 1. Agenda for the Guideline Development Group meeting on the WHO treatment guidelines for drug-resistant TB, 2016

update, 9–11 November 2015

Chair: Holger Schünemann | Co-chair: Charles L Daley

Day 18:30–9:00 Registration

9:00–9:15 Welcome and introductions Karin Weyer

9:15–9:30 Meeting objectives and expected outcomes, agenda and working methods

Declarations of interest

Ernesto Jaramillo

Dennis Falzon

9:30–10:00 WHO requirements for evidence-based guidelines, GRADE methodology

Holger Schünemann

10:00–10:45 Plenary – Presentation of draft GRADE tables

PICO 1: MDR-TB REGIMEN COMPOSITION – SYSTEMATIC REVIEWS OF INDIVIDUAL DRUGS

Dick Menzies, Mayara Bastos

10:45–11:00 Coffee break

11:00–11:30 Plenary – Presentation of draft GRADE tables

PICO 1: MDR-TB REGIMEN COMPOSITION – PAEDIATRIC IPD

Anneke Hesseling

11:30–11:40 Plenary – Discussants present their perspectives on the implications of the findings for the approach to the composition and duration of MDR-TB regimens in adults and children.

Discussants: Charles L Daley (adults), Farhana Amanullah (children)

11:40–13:00 Plenary – Development of decision tables to formulate draft recommendations based on quality of the evidence, and other considerations (balance between desirable and undesir-able effects, resources, feasibility, values and preferences).

Facilitated discussion

13:00–14:00 Lunch break

14:00–15:30 Continued – Development of decision tables to formulate draft recommendations based on quality of the evidence, and other considerations (balance between desirable and undesirable effects, resources, feasibility, values and preferences).

Facilitated discussion

15:30–15:45 Coffee break

15:45–17:45 Continued – Finalization of draft recommendations Facilitated discussion

17:45–18:00 Summary of the day Chair

47

annex 1

Day 28:30–9:15 Plenary – Presentation of draft GRADE tables

PICO 2: REGIMENS FOR ISONIAZID RESISTANCE and M. bovis

Dick Menzies, Mayara Bastos

9:15–9:30 Plenary – Discussants present their perspectives on the implications of the findings for the approach to the composition and duration of regimens in adults and children.

Discussants:

Daniela Cirillo; Carlos Torres (isoniazid-resistant); Jose Caminero; Agnes Gebhard (M.bovis)

9:30–10:45 Plenary – Development of decision tables to formulate draft recommendations based on quality of the evidence, and other considerations (balance between desirable and undesirable effects, resources, feasibility, values and preferences).

Facilitated discussion

10:45–11:00 Coffee break

11:00–13:00 Continued – Finalization of draft recommendations Facilitated discussion

13:00–14:00 Lunch break

14:00–14:45 Plenary – Presentation of GRADE tables

PICO 3: SHORTER REGIMENS FOR MDR-TB

Dick Menzies,

Faiz A Khan

14:45–15:00 Plenary – Discussants present their perspectives on the implications of the findings for the treatment of MDR-TB using shorter regimens.

Discussants:

Sundari Mase, Tsira Chakhaia, Michel Gasana

15:00–16:00 Plenary – Development of decision tables to formulate draft recommendations based on quality of the evidence, and other considerations (balance between desirable and undesirable effects, resources, feasibility, values and preferences).

Facilitated discussion

16:00–16:15 Coffee break

16:15–17:00 Continued – Finalization of draft recommendations Facilitated discussion

17:00–17:45 Implications of the findings from reviews of PICO 1 and PICO 3 for the approach to the composition and duration of MDR-TB regimens.

Facilitated discussion

17:45–18:00 Wrap-up and summary of the day Chair

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WHO TREATMENT GUIDELINES FOR DRUG-RESISTANT TUBERCULOSIS, 2016 UPDATE

Day 38:30–9:30 Plenary – Presentation of draft GRADE tables

PICO 4: DELAYS IN STARTING MDR TREATMENT, THE ROLE OF SURGERY

Mishal Khan,

Rebecca Harris,

Greg Fox

9:30–9:40 Plenary – Discussant presents perspectives on the implications of the findings for the approach to the management of MDR-TB.

Discussant :

Armen Hayrapetyan (role of surgery)

9:40–10:45 Plenary – Development of decision tables to formulate draft recommendations based on quality of the evidence, and other considerations (balance between desirable and undesirable effects, resources, feasibility, values and preferences).

Facilitated discussion

10:45–11:00 Coffee break

11.00–11.30 Levels of resistance to pyrazinamide and fluoroquinolones Matteo Zignol

11:30–13:00 Review of the recommendations for the four PICOs combined (continued)

Facilitated discussion

13:00–14:00 Lunch break

14:00–15:00 Research priorities on treatment of drug-resistant TB Dick Menzies

Christian Lienhardt

15:00–15:30 Next steps and closure Chair &

Karin Weyer

49

Annex 2. Experts involved in the development of the WHO treatment guidelines for drug-

resistant TB, 2016 update

GUIDELINE DEVELOPMENT GROUP MEMBERS

Dr Farhana AmanullahAssociate DirectorPediatric TB ProgramIndus HospitalKarachiPakistan

Dr Tsira ChakhaiaACSM Advisor, Civil Society University Research Co., LLCTbilisiGeorgia

Dr Daniela Maria CirilloHeadEmerging Bacterial Pathogens UnitSan Raffaele del Monte Tabor Foundation (hSR)San Raffaele Scientific InstituteMilanoItaly

Dr Charles L Daley (Co-Chair)ChiefDivision of Mycobacterial and Respiratory InfectionsNational Jewish HealthDenver, COUSA

Dr Luis Gustavo do Valle BastosSenior Technical AdvisorCenter for Pharmaceutical ManagementManagement Sciences for HealthArlington, VAUSA

Dr Kelly DooleyAssociate Professor of MedicinePharmacology & Molecular Science Divisions of Clinical Pharmacology & Infectious DiseasesJohns Hopkins University School of MedicineCenter for Tuberculosis ResearchBaltimore, MDUSA

Dr Carlos A Torres DuqueDirectorTuberculosis DepartmentLatin American Thoracic SocietyBogotáColombia

Dr Michel GasanaManagerNational TB & Other Respiratory Communicable Diseases DivisionMinistry of HealthKigaliRwanda

Dr Agnes GebhardSenior ConsultantTeam Leader of ACCESS TeamTechnical DivisionKNCV Tuberculosis FoundationThe HagueNetherlands

Dr Armen HayrapetyanDirectorNational TB Control CentreMinistry of HealthAbovyan cityArmenia

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WHO TREATMENT GUIDELINES FOR DRUG-RESISTANT TUBERCULOSIS, 2016 UPDATE

Dr Antonia KwiecienSenior Technical AdvisorSystems for Improved Access toPharmaceuticals and Services Program (SIAPS)Management Sciences for Health (MSH)Arlington, VAUSA

Dr José A Caminero LunaCoordinatorMDR-TB Unit, International Union Against Tuberculosis & Lung Disease (UNION)General Hospital of Gran Canaria “Dr. Negrin”Las Palmas de Gran CanariaSpain

Dr Sundari MaseMedical Team LeadField Services and Evaluation Branch Division of Tuberculosis Elimination National Center for HIV, Hepatitis, STD and TB PreventionCenters for Disease Control and PreventionAtlanta, GAUSA

Dr Lindsay McKennaTB/HIV Project OfficerTreatment Action GroupNew York, NYUSA

Dr Nguyen Viet NhungDirectorNational Tuberculosis Control ProgrammeHanoiViet Nam

Dr Maria RodriguezCoordinatorMDR-TB National Technical UnitMinistry of HealthSanto DomingoDominican Republic

Dr Holger Schünemann (Chair)Chair and ProfessorDepartments of Clinical Epidemiology & Biostatistics and of MedicineMcMaster UniversityHamilton, ONCanada

Dr James SeddonClinical LecturerDepartment of PaediatricsImperial CollegeLondonUnited Kingdom

Dr Thomas ShinnickAssociate DirectorGlobal Laboratory Activities Mycobacteriology Laboratory Branch, Division of Tuberculosis Elimination Centers for Disease Control and PreventionAtlanta, GAUSA

Dr Alena SkrahinaScientific DirectorRepublican Scientific & Practical Centre for Pulmonology & TuberculosisBelarus Research Institute of Pulmonology and TuberculosisMinskBelarus

51

OBSERVERS (at the GDG Meeting in Geneva in November 2015)

Dr J Peter CegielskiTeam LeaderMDR TB International Programs and Research Branch, Division of Tuberculosis EliminationCenters for Disease Control & Prevention (CDC)Atlanta, GAUSA

Mrs Janet Kristen GinnardTechnical Officer Strategy & ResultsUNITAIDGenevaSwitzerland

Dr Giovanni Battista MiglioriDirectorWHO Collaborating Centre for Tuberculosis and Lung DiseasesFondazione Salvatore MaugeriTradate, VAItaly

Dr Payam NahidProfessor of MedicineUniversity of California, San FranciscoSan Francisco General Hospital Division of Pulmonary and Critical Care MedicineSan Francisco, CAUSA

Dr Nobuyuki NishikioriRegional Adviser, TBWHO Western Pacific Regional OfficeManilaThe Philippines

Dr Thomas W PiggottResident PhysicianMcMaster UniversityHamilton ONCanada

Dr Anna ScardigliDisease Advisor, TuberculosisTechnical Advice and PartnershipThe Global Fund to Fight AIDS, Tuberculosis and MalariaGenevaSwitzerland

Dr Barbara SeaworthProfessor of MedicineDirector Heartland National TB CenterUniversity of Texas Health Science Center, TylerSan Antonio, TXUSA

Dr Mohammed YassinTechnical Advisor, TuberculosisThe Global Fund to Fight AIDS, Tuberculosis and MalariaGenevaSwitzerland

Dr Ya Diul MukadiSenior TB Technical AdvisorInfectious Disease Division, Global Health BureauUS Agency for International Development (USAID)Washington, DCUSA

RESOURCE PERSONS (at the GDG Meeting in Geneva in November 2015)

Dr Philipp Du CrosTB AdvisorMédecins sans Frontières (MSF)LondonUnited Kingdom

Dr Michael L RichMedical OfficerPartners in HealthHarvard Medical SchoolBoston, MAUSA

annex 2

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WHO TREATMENT GUIDELINES FOR DRUG-RESISTANT TUBERCULOSIS, 2016 UPDATE

Dr Abdul Hamid SalimAdvisor, NTP BangladeshTB Gate, Leprosy hospital Compound MohakhaliDhakaBangladesh

Dr Valérie SchwoebelMedical OfficerInternational Union Against Tuberculosis & Lung Disease (UNION)ParisFrance

Dr Francis VaraineInternational Medical CoordinatorMédecins sans Frontières (MSF)ParisFrance

Dr Askar B. YedilbayevMedical OfficerPartners in HealthBoston, MAUSA

EXTERNAL REVIEW GROUP

Dr Chen-Yuan ChiangInternational Union Against Tuberculosis and Lung Disease (UNION)ParisFrance

Dr Celine GarfinInfectious Diseases for Prevention and Control DivisionDisease Prevention and Control BureauDepartment of HealthManilaThe Philippines

Dr Michael KimerlingKNCV Tuberculosis FoundationThe HagueNetherlands

Dr Vaira LeimaneNational TB ProgrammeMinistry of HealthRigaLatvia

Dr Guy MarksInternational Union Against Tuberculosis and Lung Disease (UNION)ParisFrance

Dr Gao MengqiuBeijing Chest HospitalCapital Medical University, Beijing Tuberculosis and Thoracic Tumor Research InstituteBeijingChina

Dr Norbert NdjekaDrug Resistant TB, TB & HIVDepartment of HealthPretoriaSouth Africa

Dr Ejaz QadeerNational TB ProgrammeMinistry of HealthIslamabadPakistan

Dr Lee ReichmanRutgers UniversityNew Jersey, NJUSA

Dr Rohit SarinLRS Institute of TB and Respiratory DiseasesDelhiIndia

Dr Irina VasilyevaCentral Tuberculosis Research Institute (CTRI)MoscowRussian Federation

Dr Dalene von DelftTB ProofSouth Africa

53

EVIDENCE REVIEWERS (at the GDG Meeting in Geneva in November 2015)

Dr Mayara Lisboa Soares de BastosMcGill UniversityMontreal, QcCanada

Dr Gregory J Fox* University of SydneySpit Junction, NSWAustralia

Ms Rebecca HarrisLondon School of Hygiene and Tropical MedicineLondonUnited Kingdom

Dr Anneke HesselingPaediatric TB Research ProgrammeDesmond Tutu TB Centre Department of Paediatrics and Child HealthFaculty of Medicine and Health SciencesStellenbosch UniversityCape TownSouth Africa

Dr Faiz KhanFaculty of Medicine, McGill UniversityMontreal Chest InstituteMcGill University Health CentreMontreal, QcCanada

Dr Mishal KhanLondon School of Hygiene and Tropical MedicineLondonUnited Kingdom

Dr Dick MenziesMontreal Chest InstituteMcGill University Health CentreMontreal, QcCanada

WHO GUIDELINE STEERING COMMITTEE

Dr Dennis Falzon, LDR/GTBDr Nathan Ford, TAC/HIVDr Giuliano Gargioni, TSC/GTBDr Haileyesus Getahun, THC/GTBDr Malgorzata Grzemska, TSC/GTBDr Ernesto Jaramillo, LDR/GTBDr Avinash Kanchar, THC/GTBMs Soleil Labelle, TSC/GTBDr Christian Lienhardt, PSI/GTB

Dr Knut Lönnroth, PSI/GTBDr Alberto Matteelli, THC/GTBDr Fuad Mirzayev, LDR/GTBDr Linh Nhat Nguyen, LDR/GTBDr Marco Antonio Vitoria, TAC/HIVDr Fraser Wares, LDR/GTBMrs Diana Weil, PSI/GTBDr Karin Weyer, LDR/GTBDr Matteo Zignol, TME/GTB

WHO CONSULTANT

Dr Elizabeth Harausz

annex 2

* Affiliated with McGill University for the evidence reviews done for these guidelines

54

Ann

ex 3

. P

ICO

que

stio

nsa

Q1

. In

patie

nts

with

RR

-TB

or

MD

R-T

B, w

hat

indi

vidu

al d

rugs

in the

reg

imen

s ar

e lik

ely

to le

ad to

the

out

com

es

liste

d be

low

?

PO

PU

LATI

ON

INTE

RVEN

TIO

N

CO

MPA

RAT

OR

OU

TCO

MES

Rifa

mpi

cin-

resi

stan

t TB

onl

y

MD

R-T

B w

ithou

t re

sist

ance

or

seve

re

into

lera

nce

to t

he s

econ

d-lin

e dr

ugs

MD

R-T

B w

ith r

esis

tanc

e or

sev

ere

into

lera

nce

to a. F

luor

oqui

nolo

nes

b. S

econ

d-lin

e in

ject

able

dru

gs, b

oth

clas

ses

c. P

yraz

inam

ide

d. 2

or

3 G

roup

4 d

rugs

b

e. F

luor

oqui

nolo

nes

+ s

econ

d-lin

e in

ject

able

s (i.

e. X

DR

-TB

+/-

oth

er r

esis

tanc

e)

Chi

ldre

n (0

–4, 5

–14 y

ears

), pe

rson

s w

ith H

IV,

preg

nant

wom

en, p

erso

ns w

ith d

iabe

tes

A se

cond

-line

reg

imen

c whi

ch IN

CLU

DES

:• C

ured

/com

plet

ed b

y en

d of

tre

atm

ent

• C

ultu

re c

onve

rsio

n by

si

x m

onth

s

• Fa

ilure

• R

elap

se

• S

urvi

val (

or d

eath

)

• Ad

vers

e re

actio

ns

(sev

erity

, typ

e, o

rgan

cl

ass)

–pyr

azin

amid

e –n

o py

razi

nam

ide

–inj

ecta

ble

agen

ts (ka

nam

ycin

/am

ikac

in/c

apre

omyc

in)

–no

inje

ctab

le a

gent

s (k

anam

ycin

/am

ikac

in/c

apre

omyc

in)

–pro

thio

nam

ide/

ethi

onam

ide

–no

prot

hion

amid

e/et

hion

amid

e

–cyc

lose

rine

or t

eriz

idon

e –n

o cy

clos

erin

e or

ter

izid

one

–PAS

–no

PAS

–lat

er-g

ener

atio

n flu

oroq

uino

lone

d –n

o la

ter-g

ener

atio

n flu

oroq

uino

lone

d

–hig

h-do

se is

onia

zid

–no

high

-dos

e is

onia

zid

–clo

fazi

min

e –n

o cl

ofaz

imin

e

–lin

ezol

id –n

o lin

ezol

id

–bed

aqui

line

–no

beda

quili

ne

–del

aman

id –n

o de

lam

anid

–oth

er in

divi

dual

Gro

up 5

b dr

ugs

–no

othe

r in

divi

dual

Gro

up 5

b dr

ugs

a P

ICO

= P

opul

atio

n, In

terv

entio

n, C

ompa

rato

r, O

utco

mes

b G

roup

4 d

rugs

ref

er t

o: e

thio

nam

ide,

pro

thio

nam

ide,

cyc

lose

rine,

ter

izid

one,

PAS

. G

roup

5 d

rugs

ref

er t

o: a

mox

icill

in-c

lavu

lana

te, b

edaq

uilin

e, c

larit

hrom

ycin

, clo

fazi

min

e,

dela

man

id, h

igh-

dose

ison

iazi

d, im

ipen

em–c

ilast

atin

, lin

ezol

id, m

erop

enem

, thi

oace

tazo

ne.

For

beda

quili

ne a

nd d

elam

anid

, defi

nitiv

e re

com

men

datio

ns o

n th

eir

role

in

trea

tmen

t w

ill o

nly

be p

ossi

ble

once

the

res

ults

of

the

Phas

e III

tria

ls b

ecom

e av

aila

ble.

c D

ata

from

reg

imen

s la

stin

g up

to

12 m

onth

s w

ill n

ot b

e in

clud

ed in

thi

s qu

estio

n bu

t in

Que

stio

n 3.

d M

oxifl

oxac

in o

r ga

tiflox

acin

; hi

gh-d

ose

levo

floxa

cin

may

be

incl

uded

but

res

ults

to

be m

ade

avai

labl

e se

para

tely.

55

Ann

ex 3

. P

ICO

que

stio

nsa

Q1

. In

patie

nts

with

RR

-TB

or

MD

R-T

B, w

hat

indi

vidu

al d

rugs

in the

reg

imen

s ar

e lik

ely

to le

ad to

the

out

com

es

liste

d be

low

?

PO

PU

LATI

ON

INTE

RVEN

TIO

N

CO

MPA

RAT

OR

OU

TCO

MES

Rifa

mpi

cin-

resi

stan

t TB

onl

y

MD

R-T

B w

ithou

t re

sist

ance

or

seve

re

into

lera

nce

to t

he s

econ

d-lin

e dr

ugs

MD

R-T

B w

ith r

esis

tanc

e or

sev

ere

into

lera

nce

to a. F

luor

oqui

nolo

nes

b. S

econ

d-lin

e in

ject

able

dru

gs, b

oth

clas

ses

c. P

yraz

inam

ide

d. 2

or

3 G

roup

4 d

rugs

b

e. F

luor

oqui

nolo

nes

+ s

econ

d-lin

e in

ject

able

s (i.

e. X

DR

-TB

+/-

oth

er r

esis

tanc

e)

Chi

ldre

n (0

–4, 5

–14 y

ears

), pe

rson

s w

ith H

IV,

preg

nant

wom

en, p

erso

ns w

ith d

iabe

tes

A se

cond

-line

reg

imen

c whi

ch IN

CLU

DES

:• C

ured

/com

plet

ed b

y en

d of

tre

atm

ent

• C

ultu

re c

onve

rsio

n by

si

x m

onth

s

• Fa

ilure

• R

elap

se

• S

urvi

val (

or d

eath

)

• Ad

vers

e re

actio

ns

(sev

erity

, typ

e, o

rgan

cl

ass)

–pyr

azin

amid

e –n

o py

razi

nam

ide

–inj

ecta

ble

agen

ts (ka

nam

ycin

/am

ikac

in/c

apre

omyc

in)

–no

inje

ctab

le a

gent

s (k

anam

ycin

/am

ikac

in/c

apre

omyc

in)

–pro

thio

nam

ide/

ethi

onam

ide

–no

prot

hion

amid

e/et

hion

amid

e

–cyc

lose

rine

or t

eriz

idon

e –n

o cy

clos

erin

e or

ter

izid

one

–PAS

–no

PAS

–lat

er-g

ener

atio

n flu

oroq

uino

lone

d –n

o la

ter-g

ener

atio

n flu

oroq

uino

lone

d

–hig

h-do

se is

onia

zid

–no

high

-dos

e is

onia

zid

–clo

fazi

min

e –n

o cl

ofaz

imin

e

–lin

ezol

id –n

o lin

ezol

id

–bed

aqui

line

–no

beda

quili

ne

–del

aman

id –n

o de

lam

anid

–oth

er in

divi

dual

Gro

up 5

b dr

ugs

–no

othe

r in

divi

dual

Gro

up 5

b dr

ugs

a P

ICO

= P

opul

atio

n, In

terv

entio

n, C

ompa

rato

r, O

utco

mes

b G

roup

4 d

rugs

ref

er t

o: e

thio

nam

ide,

pro

thio

nam

ide,

cyc

lose

rine,

ter

izid

one,

PAS

. G

roup

5 d

rugs

ref

er t

o: a

mox

icill

in-c

lavu

lana

te, b

edaq

uilin

e, c

larit

hrom

ycin

, clo

fazi

min

e,

dela

man

id, h

igh-

dose

ison

iazi

d, im

ipen

em–c

ilast

atin

, lin

ezol

id, m

erop

enem

, thi

oace

tazo

ne.

For

beda

quili

ne a

nd d

elam

anid

, defi

nitiv

e re

com

men

datio

ns o

n th

eir

role

in

trea

tmen

t w

ill o

nly

be p

ossi

ble

once

the

res

ults

of

the

Phas

e III

tria

ls b

ecom

e av

aila

ble.

c D

ata

from

reg

imen

s la

stin

g up

to

12 m

onth

s w

ill n

ot b

e in

clud

ed in

thi

s qu

estio

n bu

t in

Que

stio

n 3.

d M

oxifl

oxac

in o

r ga

tiflox

acin

; hi

gh-d

ose

levo

floxa

cin

may

be

incl

uded

but

res

ults

to

be m

ade

avai

labl

e se

para

tely.

Q2

. In

TB p

atie

nts

with

dru

g-re

sist

ance

pat

tern

s ot

her

than

with

rifa

mpi

cin

resi

sita

nce

or m

ultid

rug

resi

stan

ce,

wha

t dr

ug r

egim

en c

ompo

sitio

n an

d du

ratio

n is

like

ly to

lead

to the

out

com

es li

sted

bel

ow?

PO

PU

LATI

ON

aIN

TER

VEN

TIO

Nb

CO

MPA

RAT

OR

OU

TCO

MES

Res

ista

nce

to

ison

iazi

dc

RZE

+ F

Qd fo

r 6–9

mon

ths

–HR

ZE for

6–9

mon

ths

–RZE

for

6–9

mon

ths

–8-m

onth

firs

t-lin

e dr

ug r

etre

atm

ent

regi

men

(“C

ateg

ory

2”)

–6-m

onth

firs

t-lin

e dr

ug t

reat

men

t re

gim

en

(“C

ateg

ory

1 o

r 3”)

–oth

er

• C

ured

/com

plet

ed b

y en

d of

tr

eatm

ent

• C

ultu

re c

onve

rsio

n by

6 m

onth

s

• Fa

ilure

• R

elap

se

• S

urvi

val (

or d

eath

)

• Ad

vers

e re

actio

ns (se

verit

y,

type

, org

an c

lass

)

• Ac

quis

ition

(am

plifi

catio

n) o

f ad

ditio

nal d

rug

resi

stan

ce

RZ

+ F

Qd fo

r 9–1

2 m

onth

s –8

-mon

th fi

rst-l

ine

drug

ret

reat

men

t re

gim

en (“C

ateg

ory

2”)

–6-m

onth

firs

t-lin

e dr

ug in

itial

tre

atm

ent

regi

men

(“

Cat

egor

y 1 o

r 3”)

–oth

er

Sec

ond-

line

inje

ctab

le/R

/Eto

/FQ

d fo

r 3 m

onth

s + R

/Eto

/FQ

d fo

r 15 m

onth

s

–8-m

onth

firs

t-lin

e dr

ug r

etre

atm

ent

regi

men

(“C

ateg

ory

2”)

–6-m

onth

firs

t-lin

e dr

ug in

itial

tre

atm

ent

regi

men

(“

Cat

egor

y 1 o

r 3”)

–oth

er

M. b

ovis

6- o

r 8-m

onth

firs

t-lin

e dr

ug t

reat

men

t re

gim

ens

(“C

ateg

ory

1, 2

or

3”)

–oth

er

–2H

RE/

7H

R

a If

dat

a ar

e av

aila

ble

the

effe

cts

will

be

stra

tified

by

key

subp

opul

atio

ns:

child

ren

(0–4

, 5–1

4 y

ears

), pe

rson

s w

ith H

IV, p

regn

ant

wom

en, a

nd p

eopl

e w

ith d

iabe

tes.

b T

he t

reat

men

t m

odal

ities

des

crib

ed in

the

MD

R-T

B t

reat

men

t ha

ndbo

ok (

8).

c In

clud

ing

case

s w

ith o

r w

ithou

t ad

ditio

nal r

esis

tanc

e to

eth

ambu

tol a

nd p

yraz

inam

ide.

The

ass

essm

ent

of e

vide

nce

and

reco

mm

enda

tions

on

thes

e re

sist

ance

pat

tern

s w

ill b

e co

nditi

oned

by

the

fact

tha

t D

ST

for

etha

mbu

tol a

nd p

yraz

inam

ide

is o

ften

unr

elia

ble

(alth

ough

rel

iabl

e D

ST

to p

yraz

inam

ide

may

be

avai

labl

e in

som

e se

ttin

gs),

but

whi

ch n

onet

hele

ss m

ay b

ring

abou

t th

e us

e of

fluo

roqu

inol

ones

, and

tha

t th

e ev

iden

ce m

ay b

e ba

sed

on e

xper

ienc

e fr

om p

atie

nts

who

may

hav

e be

en s

witc

hed

to

fluor

oqui

nolo

ne-c

onta

inin

g re

gim

ens

afte

r a

perio

d of

tim

e on

firs

t-lin

e re

gim

ens.

d If

dat

a ar

e av

aila

ble

the

effe

cts

will

be

stra

tified

by

the

type

of

fluor

oqui

nolo

ne (

early

ver

sus

late

r ge

nera

tion)

.

R =

rifa

mpi

cin

Z = p

yraz

inam

ide

E = e

tham

buto

l; FQ

= fl

uoro

quin

olon

e; E

to =

eth

iona

mid

e; H

= is

onia

zid.

annex 3

56

WHO TREATMENT GUIDELINES FOR DRUG-RESISTANT TUBERCULOSIS, 2016 UPDATEQ

3. I

n M

DR

-TB

pat

ient

s, a

re tre

atm

ent

regi

men

s la

stin

g up

to 1

2 m

onth

s lik

ely

to le

ad to

the

out

com

es li

sted

be

low

whe

n co

mpa

red

with

tho

se r

ecom

men

ded

in the

WH

O g

uide

lines

of 201

1?

PO

PU

LATI

ON

INTE

RVEN

TIO

Na

CO

MPA

RAT

OR

aO

UTC

OM

ES

MD

R-T

B p

atie

nts

Prev

ious

ly t

reat

ed w

ith s

econ

d-lin

e dr

ugs

or n

ot

Sev

erity

of di

seas

e (m

ild/e

xten

sive

ra

diog

raph

ic le

sion

s)

Dru

g re

sist

ance

pat

tern

s (for

firs

t-lin

e dr

ugs

and

seco

nd-li

ne d

rugs

)

His

tory

of pa

tient

use

of et

ham

buto

l or

pyra

zina

mid

e

Chi

ldre

n (0

–14 y

ears

) vs

adu

lts

Pers

ons

with

HIV

, pre

gnan

t w

omen

, and

peo

ple

with

dia

bete

s

Dur

atio

n of

9–1

2 m

onth

s

Inje

ctab

le a

gent

for

4–6

m

onth

s

Com

bina

tion

of d

rugs

(u

sual

ly 7

in t

he in

tens

ive

phas

e an

d 4–5

in t

he

cont

inua

tion)

Use

of at

leas

t 4 e

ffec

tive

seco

nd-

line

drug

s pl

us p

yraz

inam

ide

Inje

ctab

le a

gent

giv

en for

abo

ut

8 m

onth

s, a

t le

ast

4 m

onth

s af

ter

cultu

re c

onve

rsio

n

Tota

l tre

atm

ent

for

at le

ast

18

mon

ths

past

the

dat

e of

cul

ture

co

nver

sion

to

nega

tive

Inje

ctab

le a

gent

giv

en u

ntil

smea

r co

nver

sion

and

tot

al t

reat

men

t fo

r at

leas

t 12 m

onth

s af

ter

smea

r co

nver

sion

• C

ured

/com

plet

ed b

y en

d of

tr

eatm

ent

• C

ultu

re c

onve

rsio

n by

6 m

onth

s

• Fa

ilure

• R

elap

se

• S

urvi

val (

or d

eath

)

• Ad

vers

e re

actio

ns (se

verit

y,

type

, org

an c

lass

)

• Ac

quis

ition

(am

plifi

catio

n) o

f ad

ditio

nal d

rug

resi

stan

ce

• Ad

here

nce

to t

reat

men

t (o

r tr

eatm

ent

inte

rrup

tion

due

to

non-

adhe

renc

e)

a R

egim

ens

last

ing

>12 a

nd <

18 m

onth

s w

ill n

ot b

e in

clud

ed in

the

inte

rven

tion

or c

ompa

rato

r.

Q4. A

mon

g pa

tient

s on

MD

R-T

B tre

atm

ent, a

re the

follo

win

g tw

o in

terv

entio

ns (d

elay

in s

tart

of tr

eatm

ent

and

elec

tive

surg

ery)

like

ly to

lead

to the

out

com

es li

sted

bel

ow?

PO

PU

LATI

ON

aIN

TER

VEN

TIO

N

CO

MPA

RAT

OR

O

UTC

OM

E

Patie

nts

on M

DR

-TB

tre

atm

ent

Patie

nts

on X

DR

-TB

tre

atm

ent

Chi

ldre

n (0

–14 y

ears

) vs

adu

lts

Pers

ons

with

HIV

(on

ant

iretr

ovira

ls)

Preg

nant

wom

en, a

nd p

eopl

e w

ith

diab

etes

Sta

rt o

f ad

equa

te t

reat

men

t w

ithin

fo

ur w

eeks

of di

agno

sis

(or

stro

ng

pres

umpt

ion)

Trea

tmen

t st

arte

d be

yond

fou

r w

eeks

of di

agno

sis

(or

stro

ng

pres

umpt

ion)

• C

ured

/com

plet

ed b

y en

d of

tre

atm

ent

• C

ultu

re c

onve

rsio

n by

6 m

onth

s

• Fa

ilure

• R

elap

se

• S

urvi

val (

or d

eath

)

• Ad

vers

e re

actio

ns (se

verit

y, t

ype,

or

gan

clas

s)

• Ad

here

nce

to t

reat

men

t (o

r tr

eatm

ent

inte

rrup

tion

due

to n

on-a

dher

ence

)

Elec

tive

surg

ery

(diff

eren

t ty

pes

/ st

ages

of di

seas

e)N

o el

ectiv

e su

rger

y

a T

he p

opul

atio

ns a

re e

xpec

ted

to d

iffer

for

the

tw

o su

bque

stio

ns;

patie

nts

who

are

sur

gica

lly o

pera

ted

are

mor

e lik

ely

to b

e XD

R-T

B a

nd p

erso

ns w

ith H

IV w

ho a

re h

avin

g an

tiret

rovi

rals

wou

ld b

e pa

rtic

ular

ly im

port

ant

for

the

first

sub

ques

tion.

ISBN: 978-92-4-154963-9

2016 update

WHO treatment guidelines for drug-resistant tuberculosis

OCTOBER 2016 REVISION

2016 update

WHO treatment guidelines for drug-resistant tuberculosis

ISBN: 978-92-4-154963-9

Annexes 4, 5 and 6

WHO treatment guidelines for drug-

resistant tuberculosis2016 update

Annexes 4, 5 and 6

These guidelines were developed in compliance with the process for evidence gathering, assessment and formulation of recommendations, as outlined in the WHO Handbook for Guideline Development (version March 2014; available at http://www.who.int/kms/handbook_2nd_ed.pdf ).

WHO Library Cataloguing-in-Publication Data

WHO treatment guidelines for drug-resistant tuberculosis, 2016 update.

Contents: Web Annex 4: GRADE tables – Web Annex 5: Evidence to decision tables – Web Annex 6: Summaries of unpublished data used for the recommendations

1.Tuberculosis, Multidrug-Resistant – drug therapy. 2.Antitubercular Agents. 3.Guideline. I.World Health Organization.

ISBN 978 92 4 154963 9 (NLM classification: WF 310)

© World Health Organization 2016

All rights reserved. Publications of the World Health Organization are available on the WHO website (http://www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; email: [email protected]).

Requests for permission to reproduce or translate WHO publications –whether for sale or for non-commercial distribution– should be addressed to WHO Press through the WHO website (http://www.who.int/about/licensing/copyright_form/index.html).

The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement.

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.

All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.

Printed by the WHO Document Production Services, Geneva, Switzerland

Design by Inis Communication – www.iniscommunication.com

WHO/HTM/TB/2016.04

Contents

Annex 4. GRADE tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1. Shorter regimens for MDR-TB (PICO 3) . . . . . . . . . . . . . . . . . . . . . . . . . . 22. MDR-TB regimen composition – systematic reviews of individual medicines

in adults (PICO 1). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123. MDR-TB regimen composition – paediatric individual patient data

meta-analysis (PICO 1). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324. The role of surgery (PICO 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Annex 5. Evidence to decision tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

1. Standardized shorter regimens versus longer regimens for the treatment of MDR-TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

2. Regimens with individualized composition and duration for adults and children with MDR-TB in whom a shorter MDR-TB regimen cannot be used . . . . . . . . . 55

3. Elective partial lung resection versus no surgery for patients on treatment for MDR-TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Annex 6. Summaries of unpublished data used for the recommendations . . . . . . . . . . . 70

1. Short MDR-TB regimens: meta-analyses of data from published and unpublished studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

2. An updated systematic review and meta-analysis for treatment of multidrug-resistant tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

3. A systematic review and individual patient data meta-analysis of treatment and outcomes among children with multidrug- resistant tuberculosis . . . . . . . . . . . . 77

Appendix 6A. Search strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Appendix 6B. Table of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

1

AN

NE

X 4

GR

AD

E ta

bles

The G

RA

DE

tabl

es ar

e ord

ered

as fo

llow

s:1

1.

Shor

ter r

egim

ens f

or M

DR

-TB

(PIC

O 3

)

2.

MD

R-T

B re

gim

en co

mpo

sitio

n –

syst

emat

ic re

view

s of i

ndiv

idua

l med

icin

es in

adul

ts (P

ICO

1)

3.

MD

R-T

B re

gim

en co

mpo

sitio

n –

paed

iatr

ic in

divi

dual

pat

ient

dat

a met

a-an

alys

is (P

ICO

1)

4.

The r

ole o

f sur

gery

(PIC

O 4

)

1 Ev

iden

ce fr

om st

udie

s ide

ntifi

ed d

urin

g th

e rev

iew

s per

form

ed to

answ

er P

ICO

que

stion

2 (t

reat

men

t of i

soni

azid

-resis

tant

TB

and

Myc

obac

teriu

m b

ovis)

as w

ell a

s par

t of P

ICO

que

stion

4 (d

elay

in

star

ting M

DR

-TB

trea

tmen

t) co

uld

not b

e sum

mar

ized

as G

RA

DE

tabl

es an

d th

us ar

e not

incl

uded

her

e. Se

e also

Ann

ex 6

for a

sum

mar

y of fi

ndin

gs fr

om st

udie

s tha

t wer

e not

pub

lishe

d at

the

time o

f the

rele

ase o

f the

se g

uide

lines

.

2

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

1. S

hort

er r

egim

ens

for

MD

R-T

B (

PIC

O 3

)

Aut

hor(

s): A

hmad

Kha

n F,

Ham

id S

alim

MA

, Sch

woe

bel V

, Tré

bucq

A, D

uCro

s P, C

asas

E, F

alzo

n D

, Men

zies

D (1

0 N

ovem

ber 2

015)

Que

stio

n: S

tand

ardi

zed

shor

ter

regi

men

s co

mpa

red

to lo

nger

reg

imen

s fo

r th

e tr

eatm

ent

of M

DR

-TB

(all

case

s; re

gard

less

of

pyra

zina

mid

e or

flu

oroq

uino

lone

susc

eptib

ility

)

Sett

ing:

Am

ong

patie

nts w

ho h

ad n

o hi

stor

y of

pre

viou

s tre

atm

ent w

ith se

cond

-line

dru

gs; s

hort

er re

gim

ens r

efer

to th

ose

lasti

ng u

p to

12

mon

ths;

long

er re

gim

ens l

ast 1

8 m

onth

s or m

ore.

Not

e tha

t the

“lon

ger r

egim

ens”

gro

up p

ools

data

from

stud

ies t

hat d

iffer

in th

e com

bina

tion

and

num

ber o

f dr

ugs,

in th

e dur

atio

n of

trea

tmen

t, an

d in

the u

se o

f a st

anda

rdiz

ed ve

rsus

an in

divi

dual

ized

appr

oach

. Hen

ce th

e poo

led

estim

ates

do

not n

eces

saril

y re

flect

the

outc

omes

ass

ocia

ted

with

the

regi

men

reco

mm

ende

d in

the

2011

WH

O G

uide

lines

for t

he p

rogr

amm

atic

man

agem

ent o

f dru

g-re

sista

nt

tube

rcul

osis.

Bib

liogr

aphy

: Res

ults

for s

hort

er re

gim

ens f

rom

agg

rega

te m

eta-

anal

ysis

com

bini

ng p

relim

inar

y da

ta fr

om th

ree

serie

s (1–

3), w

ith d

ata

from

thre

e pu

blish

ed st

udie

s (4–

6). R

esul

ts fo

r lon

ger r

egim

ens f

rom

aggr

egat

e met

a-an

alys

is us

ing d

ata f

rom

31

stud

ies o

f lon

ger M

DR

regi

men

s (7)

.

(1) M

édec

ins S

ans F

ront

ière

s Sw

azila

nd, p

relim

inar

y ou

tcom

es, u

npub

lishe

d da

ta. (

2) M

édec

ins S

ans F

ront

ière

s Uzb

eksit

an, p

relim

inar

y ou

tcom

es,

unpu

blish

ed d

ata.

(3) T

rébu

cq A

, Sch

woe

bel V

, Ghi

slain

Kou

ra K

, Rog

gi A

, Rie

der H

L. O

bser

vatio

nal s

tudy

on

the

eval

uatio

n of

the

toler

ance

and

eff

ectiv

enes

s of a

shor

t 9 m

onth

s tre

atm

ent f

or m

ultid

rug

resis

tant

tube

rcul

osis

patie

nts:

prel

imin

ary

repo

rt fo

r the

Wor

ld H

ealth

Org

aniz

atio

n. Th

e In

tern

atio

nal U

nion

Aga

inst

Tub

ercu

losis

and

Lung

Dise

ases

(UN

ION

). O

ctob

er 1

6 20

15. (

4) A

ung

KJ,

Van

Deu

n A

, Dec

lercq

E, S

arke

r MR

, Das

PK

, Hos

sain

MA

, et a

l. Suc

cessf

ul ‘9

-mon

th B

angl

ades

h re

gim

en’ f

or m

ultid

rug-

resis

tant

tube

rcul

osis

amon

g ove

r 500

cons

ecut

ive p

atie

nts.

Int J

Tub

erc

Lung

Dis.

201

4;18

(10)

:118

0–7.

(5) P

iube

llo A

, Har

ouna

SH

, Sou

leym

ane M

B, B

ouka

ry I,

Mor

ou S

, Dao

uda M

, et a

l. Hig

h cu

re ra

te w

ith st

anda

rdise

d sh

ort-c

ours

e mul

tidru

g-re

sista

nt tu

berc

ulos

is tr

eatm

ent i

n N

iger

: no

rela

pses

. Int

J Tu

berc

Lun

g Dis.

201

4;18

(10)

:118

8–94

. (6)

Kua

ban

C, N

oesk

e J,

Rie

der H

L, A

ït-K

hale

d N

, Abe

na F

oe JL

, Tré

bucq

A. H

igh

effec

tiven

ess o

f a 1

2-m

onth

regi

men

for M

DR

-TB

patie

nts i

n C

amer

oon.

Int J

Tub

erc L

ung

Dis.

201

5;19

(5):5

17–2

4. (7

) Ahu

ja S

D, A

shki

n D

, Ave

ndan

o M

, Ban

erje

e R, B

auer

M, B

ayon

a JN

, et a

l. M

ultid

rug

resis

tant

pul

mon

ary

tube

rcul

osis

trea

tmen

t reg

imen

s and

pat

ient

out

com

es: a

n in

divi

dual

pat

ient

dat

a met

a-an

alys

is of

9,1

53 p

atie

nts.

PLoS

Med

. 201

2;9(

8):1

212.

33

ANNE

X 4:

GRA

DE tA

blEs

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

QU

ALI

TYIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

STAN

DARD

IZED

SH

ORTE

R RE

GIM

ENS

LONG

ER

REGI

MEN

SRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se (a

sses

sed

with

: ind

irect

com

paris

on o

f two

agg

rega

te d

ata

met

a-an

alys

es (o

ne o

f sho

rter r

egim

ens

and

one

of lo

nger

regi

men

s)a

37b

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

serio

us

stro

ng a

ssoc

iatio

n al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

the

dem

onst

rate

d ef

fect

1008

/103

3 (9

7.6%

)c40

33/4

639

(86.

9%)d

not

estim

able

e

e

VERY

lOW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

(ass

esse

d wi

th: i

ndire

ct c

ompa

rison

of t

wo a

ggre

gate

dat

a m

eta-

anal

yses

(one

of s

horte

r reg

imen

s an

d on

e of

long

er re

gim

ens)

a

37b

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

serio

us

stro

ng a

ssoc

iatio

n al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

the

dem

onst

rate

d ef

fect

1008

/111

6 (9

0.3%

)f40

33/5

850

(68.

9%)g

not

estim

able

e

e

VERY

lOW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

/los

s to

follo

w-up

(ass

esse

d wi

th: i

ndire

ct c

ompa

rison

of t

wo p

oole

d in

divi

dual

pat

ient

met

a-an

alys

es)a

37b

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

serio

us

stro

ng a

ssoc

iatio

n al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

the

dem

onst

rate

d ef

fect

1008

/120

5 (8

3.7%

)h40

33/7

665

(52.

6%)i

not

estim

able

e

e

VERY

lOW

CRIt

ICAl

Cls:

con

fiden

ce li

mits

; RE:

rand

om e

ffect

sa I

n th

e sh

orte

r reg

imen

met

a-an

alys

is, d

ata

on re

laps

e we

re o

nly

avai

labl

e fro

m th

e pu

blis

hed

stud

ies

(refe

renc

es 4

–6);

in th

e lo

nger

regi

men

stu

dies

rela

pse

was

asce

rtain

ed in

14

coho

rts o

vera

ll (re

fere

nce

7).

b six

stud

ies

of s

horte

r reg

imen

s, 3

1 st

udie

s of

long

er re

gim

ens.

c Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 97.

6% (9

5% C

ls: 9

2.4%

–99.

2%).

d Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 91.

2% (9

5% C

ls: 8

6.1%

–94.

6%).

e Due

to m

etho

dolo

gica

l diff

eren

ces

in th

e st

udie

s th

e re

lativ

e an

d ab

solu

te ri

sks

are

not s

hown

. the

sho

rter M

DR-t

b re

gim

ens

data

set c

onsi

sts

of re

cent

ly c

ondu

cted

stu

dies

– s

ome

ongo

ing

– in

whi

ch p

atie

nts

were

ca

refu

lly s

elec

ted,

and

all

data

wer

e pr

ospe

ctive

ly c

olle

cted

as

part

of a

rese

arch

pro

toco

l. Pa

tient

s we

re u

nifo

rmly

trea

ted

with

a s

tand

ardi

zed

regi

men

. In

cont

rast

, stu

dies

with

long

er re

gim

ens

data

set w

ere

on

aver

age

olde

r, an

d m

any

were

retro

spec

tive

serie

s, a

nd m

any

used

dat

a co

llect

ed fo

r clin

ical

pur

pose

s. th

e la

rge

maj

ority

of p

atie

nts

in th

e co

nven

tiona

l reg

imen

s gr

oup

rece

ived

indi

vidu

alize

d th

erap

y, wi

th m

any

regi

men

s th

at d

iffer

ed fr

om o

ne a

noth

er in

num

ber a

nd ty

pe o

f dru

gs u

sed,

and

the

dura

tion

of tr

eatm

ent.

f Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 90.

3% (9

5% C

ls: 8

7.8%

–92.

4%).

g Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 78.

3% (9

5% C

ls: 7

1.2%

–84%

).h U

nwei

ghte

d pr

opor

tion;

wei

ghte

d pr

opor

tion

from

RE

met

a-an

alys

is: 8

3.7%

(95%

Cls

: 79.

2%–8

7.4%

).i U

nwei

ghte

d pr

opor

tion;

wei

ghte

d pr

opor

tion

from

RE

met

a-an

alys

is: 6

1.7%

(95%

Cls

: 53.

1%–6

9.6%

).

4

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): A

hmad

Kha

n F,

Ham

id S

alim

MA

, Sch

woe

bel V

, Tré

bucq

A, D

uCro

s P, C

asas

E, F

alzo

n D

, Men

zies

D (1

0 N

ovem

ber 2

015)

Que

stio

n: S

tand

ardi

zed

shor

ter r

egim

ens c

ompa

red

to lo

nger

regi

men

s for

the

trea

tmen

t of M

DR

-TB

(pyr

azin

amid

e su

scep

tible

; fluo

roqu

inol

one

susc

eptib

le)

Sett

ing:

Am

ong

patie

nts w

ho h

ad n

o hi

stor

y of

pre

viou

s tre

atm

ent w

ith se

cond

-line

dru

gs; s

hort

er re

gim

ens r

efer

to th

ose

lasti

ng u

p to

12

mon

ths;

long

er re

gim

ens l

ast 1

8 m

onth

s or m

ore.

Not

e tha

t the

“lon

ger r

egim

ens”

grou

p po

ols d

ata f

rom

stud

ies t

hat d

iffer

ed in

the c

ombi

natio

n an

d nu

mbe

r of

drug

s, in

the d

urat

ion

of tr

eatm

ent,

and

in th

e use

of a

stan

dard

ized

vers

us an

indi

vidu

aliz

ed ap

proa

ch. H

ence

the p

oole

d es

timat

es d

o no

t nec

essa

rily

refle

ct th

e ou

tcom

es a

ssoc

iate

d w

ith th

e re

gim

en re

com

men

ded

in th

e 20

11 W

HO

Gui

delin

es fo

r the

pro

gram

mat

ic m

anag

emen

t of d

rug-

resis

tant

tu

berc

ulos

is.

Bib

liogr

aphy

: Res

ults

for s

hort

er re

gim

ens f

rom

indi

vidu

al p

atie

nt d

ata m

eta-

anal

ysis

of u

npub

lishe

d (1

,2) a

nd p

ublis

hed

(3) d

ata.

Res

ults

for l

onge

r re

gim

ens f

rom

indi

vidu

al p

atie

nt d

ata m

eta-

anal

ysis

usin

g dat

a fro

m st

udy (

4).

(1) M

édec

ins S

ans F

ront

ière

s Sw

azila

nd, p

relim

inar

y ou

tcom

es, u

npub

lishe

d da

ta. (

2) M

édec

ins S

ans F

ront

ière

s Uzb

eksit

an, p

relim

inar

y ou

tcom

es,

unpu

blish

ed d

ata.

(3)

Aun

g K

J, Va

n D

eun

A, D

ecler

cq E

, Sar

ker

MR

, Das

PK

, Hos

sain

MA

, et a

l. Su

cces

sful ‘

9-m

onth

Ban

glad

esh

regi

men

’ for

m

ultid

rug-

resis

tant

tube

rcul

osis

amon

g ove

r 500

cons

ecut

ive p

atie

nts.

Int J

Tub

erc L

ung D

is. 2

014;

18(1

0):1

180–

7. (4

) Ahu

ja S

D, A

shki

n D

, Ave

ndan

o M

, Ban

erje

e R, B

auer

M, B

ayon

a JN

, et a

l. M

ultid

rug r

esist

ant p

ulm

onar

y tub

ercu

losis

trea

tmen

t reg

imen

s and

pat

ient

out

com

es: a

n in

divi

dual

pat

ient

da

ta m

eta-

anal

ysis

of 9

,153

pat

ient

s. PL

oS M

ed. 2

012;

9(8)

:121

2.

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

STAN

DARD

IZED

SH

ORTE

R RE

GIM

ENS

LONG

ER

REGI

MEN

SRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se (a

sses

sed

with

: ind

irect

com

paris

on o

f two

poo

led

indi

vidu

al p

atie

nt d

ata

met

a-an

alys

es)a

26b

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

serio

us

stro

ng a

ssoc

iatio

n al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

th

e de

mon

-st

rate

d ef

fect

dos

e re

spon

se g

radi

entc

121/

121

(100

.0%

)d89

0/97

9 (9

0.9%

)eno

t es

timab

lef

f

VERY

lOW

CRIt

ICAl

55

ANNE

X 4:

GRA

DE tA

blEs

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

STAN

DARD

IZED

SH

ORTE

R RE

GIM

ENS

LONG

ER

REGI

MEN

SRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

(ass

esse

d wi

th: i

ndire

ct c

ompa

rison

of t

wo p

oole

d in

divi

dual

pat

ient

dat

a m

eta-

anal

yses

)a

26b

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

serio

us

stro

ng a

ssoc

iatio

n al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

th

e de

mon

-st

rate

d ef

fect

dos

e re

spon

se g

radi

entc

121/

125

(96.

8%)g

890/

1119

(7

9.5%

)hno

t es

timab

lef

f

VERY

lOW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

/los

s to

follo

w-up

(ass

esse

d wi

th: i

ndire

ct c

ompa

rison

of t

wo p

oole

d in

divi

dual

pat

ient

dat

a m

eta-

anal

yses

)a

26b

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

serio

us

stro

ng a

ssoc

iatio

n al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

th

e de

mon

-st

rate

d ef

fect

dos

e re

spon

se g

radi

entc

121/

132

(91.

7%)i

890/

1666

(5

3.4%

)jno

t es

timab

lef

f

VERY

lOW

CRIt

ICAl

Cl: c

onfid

ence

lim

its; R

E: ra

ndom

effe

cts

a In

the

shor

ter r

egim

en in

divi

dual

pat

ient

met

a-an

alys

is, d

ata

on re

laps

e we

re o

nly

avai

labl

e in

the

bang

lade

sh s

erie

s, in

whi

ch s

ix pa

tient

s ex

perie

nced

trea

tmen

t fai

lure

and

thre

e ot

hers

rela

psed

.b t

hree

stu

dies

of s

horte

r reg

imen

s; 2

3 st

udie

s of

long

er re

gim

ens.

c Dos

e-re

spon

se g

radi

ent r

efer

s to

the

inve

rse

rela

tions

hip

obse

rved

bet

ween

incr

easi

ng re

sist

ance

and

dec

reas

ing

effe

ctive

ness

of t

reat

men

t.d C

onfid

ence

lim

its c

ould

not

be

com

pute

d us

ing

met

a-an

alyt

ical

met

hods

. Exa

ct b

inom

ial 9

5%Cl

s: 9

7.0%

–100

%.

e Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 94.

5% (9

5% C

ls: 8

8.9%

–97.

4%).

f Due

to m

etho

dolo

gica

l diff

eren

ces

in th

e st

udie

s th

e re

lativ

e an

d ab

solu

te ri

sks

are

not s

hown

. the

sho

rter M

DR-t

b re

gim

ens

data

set c

onsi

sts

of re

cent

ly c

ondu

cted

stu

dies

– s

ome

ongo

ing

– in

whi

ch p

atie

nts

were

ca

refu

lly s

elec

ted,

and

all

data

wer

e pr

ospe

ctive

ly c

olle

cted

as

part

of a

rese

arch

pro

toco

l. Pa

tient

s we

re u

nifo

rmly

trea

ted

with

a s

tand

ardi

zed

regi

men

. In

cont

rast

, stu

dies

with

long

er re

gim

ens

data

set w

ere

on

aver

age

olde

r, an

d m

any

were

retro

spec

tive

serie

s, a

nd m

any

used

dat

a co

llect

ed fo

r clin

ical

pur

pose

s. th

e la

rge

maj

ority

of p

atie

nts

in th

e lo

nger

regi

men

s gr

oup

rece

ived

indi

vidu

alize

d th

erap

y, wi

th m

any

regi

men

s th

at d

iffer

ed fr

om o

ne a

noth

er in

num

ber a

nd ty

pe o

f dru

gs u

sed,

and

the

dura

tion

of tr

eatm

ent.

g Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 96.

8% (9

5% C

ls: 7

7.3%

–99.

6%).

h Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 83.

5% (9

5% C

ls: 7

5.7%

–89.

2%).

i Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 91.

7% (9

5% C

ls: 7

3.9%

–97.

7%).

j Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 68.

2% (9

5% C

ls: 5

6.2%

–78.

1%).

6

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): A

hmad

Kha

n F,

Ham

id S

alim

MA

, Sch

woe

bel V

, Tré

bucq

A, D

uCro

s P, C

asas

E, F

alzo

n D

, Men

zies

D (1

0 N

ovem

ber 2

015)

Que

stio

n: S

tand

ardi

zed

shor

ter r

egim

ens c

ompa

red

to lo

nger

regi

men

s for

the

trea

tmen

t of M

DR

-TB

(pyr

azin

amid

e su

scep

tible

; fluo

roqu

inol

one

resis

tant

)

Sett

ing:

Am

ong

patie

nts w

ho h

ad n

o hi

stor

y of

pre

viou

s tre

atm

ent w

ith se

cond

-line

dru

gs; s

hort

er re

gim

ens r

efer

to th

ose

lasti

ng u

p to

12

mon

ths;

long

er re

gim

ens l

ast 1

8 m

onth

s or m

ore.

Not

e tha

t the

“lon

ger r

egim

ens”

grou

p po

ols d

ata f

rom

stud

ies t

hat d

iffer

ed in

the c

ombi

natio

n an

d nu

mbe

r of

drug

s, in

the d

urat

ion

of tr

eatm

ent,

and

in th

e use

of a

stan

dard

ized

vers

us an

indi

vidu

aliz

ed ap

proa

ch. H

ence

the p

oole

d es

timat

es d

o no

t nec

essa

rily

refle

ct th

e ou

tcom

es a

ssoc

iate

d w

ith th

e re

gim

en re

com

men

ded

in th

e 20

11 W

HO

Gui

delin

es fo

r the

pro

gram

mat

ic m

anag

emen

t of d

rug-

resis

tant

tu

berc

ulos

is.

Bib

liogr

aphy

: Res

ults

for s

hort

er re

gim

ens f

rom

indi

vidu

al p

atie

nt d

ata

met

a-an

alys

is of

unp

ublis

hed

(1) a

nd p

ublis

hed

(2) d

ata.

Res

ults

for l

onge

r re

gim

ens f

rom

indi

vidu

al p

atie

nt d

ata m

eta-

anal

ysis

usin

g dat

a fro

m st

udy (

3).

(1) M

édec

ins S

ans F

ront

ière

s Sw

azila

nd, p

relim

inar

y out

com

es, u

npub

lishe

d da

ta. (

2) A

ung K

J, Va

n D

eun

A, D

ecler

cq E

, Sar

ker M

R, D

as P

K, H

ossa

in

MA

, et a

l. Su

cces

sful ‘

9-m

onth

Ban

glad

esh

regi

men

’ for

mul

tidru

g-re

sista

nt tu

berc

ulos

is am

ong o

ver 5

00 co

nsec

utiv

e pat

ient

s. In

t J T

uber

c Lun

g Dis.

20

14;1

8(10

):118

0–7.

(3) A

huja

SD

, Ash

kin

D, A

vend

ano

M, B

aner

jee

R, B

auer

M, B

ayon

a JN

, et a

l. M

ultid

rug

resis

tant

pul

mon

ary

tube

rcul

osis

trea

tmen

t reg

imen

s and

pat

ient

out

com

es: a

n in

divi

dual

pat

ient

dat

a met

a-an

alys

is of

9,1

53 p

atie

nts.

PLoS

Med

. 201

2;9(

8):1

212.

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

STAN

DARD

IZED

SH

ORTE

R RE

GIM

ENS

LONG

ER

REGI

MEN

SRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se (a

sses

sed

with

: ind

irect

com

paris

on o

f two

poo

led

indi

vidu

al p

atie

nt d

ata

met

a-an

alys

es)a

18b

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

serio

us

stro

ng a

ssoc

iatio

n al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

th

e de

mon

-st

rate

d ef

fect

do

se re

spon

se

grad

ient

c

12/1

4 (8

5.7%

)d72

/95

(75.

8%)e

not

estim

able

f

f

VERY

lOW

CRIt

ICAl

77

ANNE

X 4:

GRA

DE tA

blEs

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

STAN

DARD

IZED

SH

ORTE

R RE

GIM

ENS

LONG

ER

REGI

MEN

SRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

(ass

esse

d wi

th: i

ndire

ct c

ompa

rison

of t

wo p

oole

d in

divi

dual

pat

ient

dat

a m

eta-

anal

yses

)a

18b

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

serio

us

stro

ng a

ssoc

iatio

n al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

th

e de

mon

-st

rate

d ef

fect

dos

e re

spon

se g

radi

entc

12/1

5 (8

0.0%

)g72

/120

(6

0.0%

)hno

t es

timab

lef

f

VERY

lOW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

/los

s to

follo

w-up

(ass

esse

d wi

th: i

ndire

ct c

ompa

rison

of t

wo p

oole

d in

divi

dual

pat

ient

dat

a m

eta-

anal

yses

)a

18b

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

serio

us

stro

ng a

ssoc

iatio

n al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

th

e de

mon

-st

rate

d ef

fect

dos

e re

spon

se g

radi

entc

12/1

8 (6

6.7%

)i72

/155

(4

6.5%

)jno

t es

timab

lef

f

VERY

lOW

CRIt

ICAl

Cls:

con

fiden

ce li

mits

; RE:

rand

om e

ffect

sa F

luor

oqui

nolo

ne re

sist

ance

was

an

excl

usio

n cr

iterio

n fo

r enr

olm

ent i

nto

MsF

’s Uz

beki

stan

sho

rter r

egim

en c

ohor

t. In

the

abov

e in

divi

dual

pat

ient

met

a-an

alys

es fo

r the

sho

rter r

egim

ens,

eac

h gr

oup

cons

ists

of 1

pa

tient

from

the

swaz

iland

coh

ort w

ith th

e re

mai

nder

con

sist

ing

of p

atie

nts

from

the

bang

lade

sh s

tudy

(13

for s

ucce

ss v

ersu

s fa

ilure

; 14

for s

ucce

ss v

ersu

s fa

ilure

or d

eath

; and

17

for s

ucce

ss v

ersu

s fa

ilure

, dea

th,

or lo

ss to

follo

w-up

). In

the

shor

ter r

egim

en in

divi

dual

pat

ient

met

a-an

alys

is, d

ata

on re

laps

e we

re o

nly

avai

labl

e in

the

bang

lade

sh s

erie

s.b t

wo s

tudi

es o

f sho

rter r

egim

ens;

16

stud

ies

of lo

nger

regi

men

s.c D

ose-

resp

onse

gra

dien

t ref

ers

to th

e in

vers

e re

latio

nshi

p ob

serv

ed b

etwe

en in

crea

sing

resi

stan

ce a

nd d

ecre

asin

g ef

fect

ivene

ss o

f tre

atm

ent.

d Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m F

E m

eta-

anal

ysis

: 85.

7% (9

5% C

ls: 5

3.5%

-96.

9%).

e Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 55.

7% (9

5% C

ls: 4

0.8%

-69.

8%).

f Due

to m

etho

dolo

gica

l diff

eren

ces

in th

e st

udie

s th

e re

lativ

e an

d ab

solu

te ri

sks

are

not s

hown

. the

sho

rter M

DR-t

b re

gim

ens

data

set c

onsi

sts

of re

cent

ly c

ondu

cted

stu

dies

– s

ome

ongo

ing

– in

whi

ch p

atie

nts

were

ca

refu

lly s

elec

ted,

and

all

data

wer

e pr

ospe

ctive

ly c

olle

cted

as

part

of a

rese

arch

pro

toco

l. Pa

tient

s we

re u

nifo

rmly

trea

ted

with

a s

tand

ardi

zed

regi

men

. In

cont

rast

, stu

dies

with

long

er re

gim

ens

data

set w

ere

on

aver

age

olde

r, an

d m

any

were

retro

spec

tive

serie

s, a

nd m

any

used

dat

a co

llect

ed fo

r clin

ical

pur

pose

s. th

e la

rge

maj

ority

of p

atie

nts

in th

e lo

nger

regi

men

s gr

oup

rece

ived

indi

vidu

alize

d th

erap

y, wi

th m

any

regi

men

s th

at d

iffer

ed fr

om o

ne a

noth

er in

num

ber a

nd ty

pe o

f dru

gs u

sed,

and

the

dura

tion

of tr

eatm

ent.

g Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m F

E m

eta-

anal

ysis

: 80.

0% (9

5% C

ls: 5

0.0%

–94.

1%).

h Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 64.

4% (9

5% C

ls: 4

9.6%

–76.

9%).

i Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m F

E m

eta-

anal

ysis

: 66.

7% (9

5% C

ls: 4

1.1%

–85.

2%).

j Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 56.

1% (9

5% C

ls: 4

0.7%

–70.

4%).

8

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): A

hmad

Kha

n F,

Ham

id S

alim

MA

, Sch

woe

bel V

, Tré

bucq

A, D

uCro

s P, C

asas

E, F

alzo

n D

, Men

zies

D (1

0 N

ovem

ber 2

015)

Que

stio

n: S

tand

ardi

zed

shor

ter

regi

men

s co

mpa

red

to lo

nger

reg

imen

s fo

r th

e tr

eatm

ent

of M

DR

-TB

(pyr

azin

amid

e re

sista

nt; fl

uoro

quin

olon

e su

scep

tible

)

Sett

ing:

Am

ong

patie

nts w

ho h

ad n

o hi

stor

y of

pre

viou

s tre

atm

ent w

ith se

cond

-line

dru

gs; s

hort

er re

gim

ens r

efer

to th

ose

lasti

ng u

p to

12

mon

ths;

long

er re

gim

ens l

ast 1

8 m

onth

s or m

ore.

Not

e tha

t the

“lon

ger r

egim

ens”

grou

p po

ols d

ata f

rom

stud

ies t

hat d

iffer

ed in

the c

ombi

natio

n an

d nu

mbe

r of

drug

s, in

the d

urat

ion

of tr

eatm

ent,

and

in th

e use

of a

stan

dard

ized

vers

us an

indi

vidu

aliz

ed ap

proa

ch. H

ence

the p

oole

d es

timat

es d

o no

t nec

essa

rily

refle

ct th

e ou

tcom

es a

ssoc

iate

d w

ith th

e re

gim

en re

com

men

ded

in th

e 20

11 W

HO

Gui

delin

es fo

r the

pro

gram

mat

ic m

anag

emen

t of d

rug-

resis

tant

tu

berc

ulos

is.

Bib

liogr

aphy

: Res

ults

for s

hort

er re

gim

ens f

rom

indi

vidu

al p

atie

nt d

ata m

eta-

anal

ysis

of u

npub

lishe

d (1

,2) a

nd p

ublis

hed

(3) d

ata.

Res

ults

for l

onge

r re

gim

ens f

rom

indi

vidu

al p

atie

nt d

ata m

eta-

anal

ysis

usin

g dat

a fro

m st

udy (

4).

(1) M

édec

ins S

ans F

ront

ière

s Sw

azila

nd, p

relim

inar

y ou

tcom

es, u

npub

lishe

d da

ta. (

2) M

édec

ins S

ans F

ront

ière

s Uzb

eksit

an, p

relim

inar

y ou

tcom

es,

unpu

blish

ed d

ata.

(3)

Aun

g K

J, Va

n D

eun

A, D

ecler

cq E

, Sar

ker

MR

, Das

PK

, Hos

sain

MA

, et a

l. Su

cces

sful ‘

9-m

onth

Ban

glad

esh

regi

men

’ for

m

ultid

rug-

resis

tant

tube

rcul

osis

amon

g ove

r 500

cons

ecut

ive p

atie

nts.

Int J

Tub

erc L

ung D

is. 2

014;

18(1

0):1

180–

7. (4

) Ahu

ja S

D, A

shki

n D

, Ave

ndan

o M

, Ban

erje

e R, B

auer

M, B

ayon

a JN

, et a

l. M

ultid

rug r

esist

ant p

ulm

onar

y tub

ercu

losis

trea

tmen

t reg

imen

s and

pat

ient

out

com

es: a

n in

divi

dual

pat

ient

da

ta m

eta-

anal

ysis

of 9

,153

pat

ient

s. PL

oS M

ed. 2

012;

9(8)

:121

2.

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

STAN

DARD

IZED

SH

ORTE

R RE

GIM

ENS

LONG

ER

REGI

MEN

SRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se (a

sses

sed

with

: ind

irect

com

paris

on o

f two

poo

led

indi

vidu

al p

atie

nt d

ata

met

a-an

alys

es)a

26b

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

serio

us

stro

ng a

ssoc

iatio

n al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

th

e de

mon

-st

rate

d ef

fect

dos

e re

spon

se g

radi

entc

90/9

6 (9

3.8%

)d84

0/96

2 (8

7.3%

)eno

t es

timab

lef

f

VERY

lOW

CRIt

ICAl

99

ANNE

X 4:

GRA

DE tA

blEs

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

STAN

DARD

IZED

SH

ORTE

R RE

GIM

ENS

LONG

ER

REGI

MEN

SRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

s (a

sses

sed

with

: ind

irect

com

paris

on o

f two

poo

led

indi

vidu

al p

atie

nt d

ata

met

a-an

alys

es)a

26b

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

serio

us

stro

ng a

ssoc

iatio

n al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

th

e de

mon

-st

rate

d ef

fect

dos

e re

spon

se g

radi

entc

90/1

00

(90.

0%)g

840/

1075

(7

8.1%

)hno

t es

timab

lef

f

VERY

lOW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

s/lo

ss to

follo

w-up

(ass

esse

d wi

th: i

ndire

ct c

ompa

rison

of t

wo p

oole

d in

divi

dual

pat

ient

dat

a m

eta-

anal

yses

)a

26b

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

serio

us

stro

ng a

ssoc

iatio

n al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

th

e de

mon

-st

rate

d ef

fect

dos

e re

spon

se g

radi

ent3

90/1

07

(84.

1%)i

840/

1392

(6

0.3%

)jno

t es

timab

lef

f

VERY

lOW

CRIt

ICAl

Cls:

con

fiden

ce li

mits

; RE:

rand

om e

ffect

sa I

n th

e sh

orte

r reg

imen

indi

vidu

al p

atie

nt m

eta-

anal

ysis

, dat

a on

rela

pse

were

onl

y av

aila

ble

in th

e ba

ngla

desh

ser

ies.

b thr

ee s

tudi

es o

f sho

rter r

egim

ens;

23

stud

ies

of lo

nger

regi

men

s.c D

ose-

resp

onse

gra

dien

t ref

ers

to th

e in

vers

e re

latio

nshi

p ob

serv

ed b

etwe

en in

crea

sing

resi

stan

ce a

nd d

ecre

asin

g ef

fect

ivene

ss o

f tre

atm

ent.

d Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 93.

5% (9

5% C

ls: 4

0.4%

–99.

7%).

e Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 90.

1% (9

5% C

ls: 8

3.5%

–94.

2%).

f Due

to m

etho

dolo

gica

l diff

eren

ces

in th

e st

udie

s th

e re

lativ

e an

d ab

solu

te ri

sks

are

not s

hown

. the

sho

rter M

DR-t

b re

gim

ens

data

set c

onsi

sts

of re

cent

ly c

ondu

cted

stu

dies

– s

ome

ongo

ing

– in

whi

ch p

atie

nts

were

ca

refu

lly s

elec

ted,

and

all

data

wer

e pr

ospe

ctive

ly c

olle

cted

as

part

of a

rese

arch

pro

toco

l. Pa

tient

s we

re u

nifo

rmly

trea

ted

with

a s

tand

ardi

zed

regi

men

. In

cont

rast

, stu

dies

with

long

er re

gim

ens

data

set w

ere

on

aver

age

olde

r, an

d m

any

were

retro

spec

tive

serie

s, a

nd m

any

used

dat

a co

llect

ed fo

r clin

ical

pur

pose

s. th

e la

rge

maj

ority

of p

atie

nts

in th

e lo

nger

regi

men

s gr

oup

rece

ived

indi

vidu

alize

d th

erap

y, wi

th m

any

regi

men

s th

at d

iffer

ed fr

om o

ne a

noth

er in

num

ber a

nd ty

pe o

f dru

gs u

sed,

and

the

dura

tion

of tr

eatm

ent.

g Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 88.

8% (9

5% C

ls: 4

7.3%

–98.

6%).

h Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 81.

4% (9

5% C

ls: 7

1.6%

–88.

4%).

i Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 83.

3% (9

5% C

ls: 2

7.3%

–98.

5%).

j Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m R

E m

eta-

anal

ysis

: 64.

0% (9

5% C

ls: 5

3.0%

–73.

8%).

10

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): A

hmad

Kha

n F,

Ham

id S

alim

MA

, Sch

woe

bel V

, Tré

bucq

A, D

uCro

s P, C

asas

E, F

alzo

n D

, Men

zies

D (1

0 N

ovem

ber 2

015)

Que

stio

n: S

tand

ardi

zed

shor

ter

regi

men

s co

mpa

red

to lo

nger

reg

imen

s fo

r th

e tr

eatm

ent

of M

DR

-TB

(pyr

azin

amid

e re

sista

nt; fl

uoro

quin

olon

e re

sista

nt)

Sett

ing:

Am

ong

patie

nts w

ho h

ad n

o hi

stor

y of

pre

viou

s tre

atm

ent w

ith se

cond

-line

dru

gs; s

hort

er re

gim

ens r

efer

to th

ose

lasti

ng u

p to

12

mon

ths;

long

er re

gim

ens l

ast 1

8 m

onth

s or m

ore.

Not

e tha

t the

“lon

ger r

egim

ens”

grou

p po

ols d

ata f

rom

stud

ies t

hat d

iffer

ed in

the c

ombi

natio

n an

d nu

mbe

r of

drug

s, in

the d

urat

ion

of tr

eatm

ent,

and

in th

e use

of a

stan

dard

ized

vers

us an

indi

vidu

aliz

ed ap

proa

ch. H

ence

the p

oole

d es

timat

es d

o no

t nec

essa

rily

refle

ct th

e ou

tcom

es a

ssoc

iate

d w

ith th

e re

gim

en re

com

men

ded

in th

e 20

11 W

HO

Gui

delin

es fo

r the

pro

gram

mat

ic m

anag

emen

t of d

rug-

resis

tant

tu

berc

ulos

is.

Bib

liogr

aphy

: Res

ults

for s

hort

er re

gim

ens f

rom

one

pub

lishe

d st

udy (

1). R

esul

ts fo

r lon

ger r

egim

ens f

rom

indi

vidu

al p

atie

nt d

ata m

eta-

anal

ysis

usin

g da

ta fr

om st

udy (

2).

(1) A

ung K

J, Va

n D

eun

A, D

ecler

cq E

, Sar

ker M

R, D

as P

K, H

ossa

in M

A, R

iede

r HL.

Suc

cess

ful ‘9

-mon

th B

angl

ades

h re

gim

en’ f

or m

ultid

rug-

resis

tant

tu

berc

ulos

is am

ong

over

500

con

secu

tive

patie

nts.

Int J

Tub

erc

Lung

Dis.

201

4;18

(10)

:118

0–7.

(2) A

huja

SD

, Ash

kin

D, A

vend

ano

M, B

aner

jee

R,

Baue

r M, B

ayon

a JN

, et a

l. M

ultid

rug

resis

tant

pul

mon

ary

tube

rcul

osis

trea

tmen

t reg

imen

s and

pat

ient

out

com

es: a

n in

divi

dual

pat

ient

dat

a m

eta-

anal

ysis

of 9

,153

pat

ient

s. PL

oS M

ed. 2

012;

9(8)

:121

2.a

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

STAN

DARD

IZED

SH

ORTE

R RE

GIM

ENS

LONG

ER

REGI

MEN

SRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se (a

sses

sed

with

: ind

irect

com

paris

on o

f two

poo

led

indi

vidu

al p

atie

nt d

ata

met

a-an

alys

es)b

19c

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

very

ser

ious

dst

rong

ass

ocia

tion

all p

laus

ible

resi

d-ua

l con

foun

ding

wo

uld

redu

ce

the

dem

on-

stra

ted

effe

ct d

ose

resp

onse

gra

dien

te

19/2

6 (7

3.1%

)f81

/112

(7

2.3%

)gno

t es

timab

leh

h

VERY

lOW

CRIt

ICAl

1111

ANNE

X 4:

GRA

DE tA

blEs

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

STAN

DARD

IZED

SH

ORTE

R RE

GIM

ENS

LONG

ER

REGI

MEN

SRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

(ass

esse

d wi

th: i

ndire

ct c

ompa

rison

of t

wo p

oole

d in

divi

dual

pat

ient

dat

a m

eta-

anal

yses

)b

19c

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

very

ser

ious

dst

rong

ass

ocia

tion

all p

laus

ible

resi

d-ua

l con

foun

ding

wo

uld

redu

ce

the

dem

on-

stra

ted

effe

ct d

ose

resp

onse

gra

dien

te

19/2

8 (6

7.9%

)i81

/137

(5

9.1%

)jno

t es

timab

leh

h

VERY

lOW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

/los

s to

follo

w-up

(ass

esse

d wi

th: i

ndire

ct c

ompa

rison

of t

wo p

oole

d in

divi

dual

pat

ient

dat

a m

eta-

anal

yses

)b

19c

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

very

ser

ious

dst

rong

ass

ocia

tion

all p

laus

ible

resi

d-ua

l con

foun

ding

wo

uld

redu

ce

the

dem

on-

stra

ted

effe

ct d

ose

resp

onse

gra

dien

te

19/3

2 (5

9.4%

)k81

/193

(4

2.0%

)lno

t es

timab

leh

h

VERY

lOW

CRIt

ICAl

Cls:

con

fiden

ce li

mits

; RE:

rand

om e

ffect

sa I

n th

e st

udy

by A

ung,

et a

l. (1

) rep

ortin

g re

sults

from

the

sam

e ba

ngla

desh

coh

ort,

high

-leve

l gat

iflox

acin

-resi

stan

ce (d

efine

d as

MIC

≥2m

g/m

l) w

as a

ssoc

iate

d wi

th u

nsuc

cess

ful t

reat

men

t, bu

t not

low-

leve

l ga

tiflox

acin

-resi

stan

ce. I

n th

e ab

ove

tabl

e, a

ll pe

rson

s in

the

shor

t reg

imen

gro

up h

ad o

floxa

cin-

resi

stan

t MDR

-tb,

and

am

ongs

t the

se, h

igh-

leve

l gat

iflox

acin

resi

stan

ce w

as d

ocum

ente

d in

15;

low-

leve

l gat

iflox

acin

-re

sist

ance

in 1

3; a

nd g

atifl

oxac

in M

IC w

as n

ot m

easu

red

in 4

.b I

n th

e sh

orte

r reg

imen

indi

vidu

al p

atie

nt m

eta-

anal

ysis

, all

data

are

from

ban

glad

esh

(i.e.

no

patie

nts

from

swa

zilan

d or

Uzb

ekis

tan)

.c O

ne s

tudy

of s

horte

r reg

imen

s; 1

8 st

udie

s of

long

er re

gim

ens.

d Con

fiden

ce li

mits

are

wid

e fo

r sho

rter r

egim

en; a

ll sh

orte

r reg

imen

resu

lts a

re fr

om o

ne s

tudy

onl

y (A

ung,

et a

l.), a

nd fe

w pa

tient

s in

volve

d.e D

ose-

resp

onse

gra

dien

t ref

ers

to th

e in

vers

e re

latio

nshi

p ob

serv

ed b

etwe

en in

crea

sing

resi

stan

ce a

nd d

ecre

asin

g ef

fect

ivene

ss o

f tre

atm

ent.

f Unw

eigh

ted

prop

ortio

n; e

xact

bin

omia

l 95%

Cls

: 52.

2%–8

7.1%

.g U

nwei

ghte

d pr

opor

tion;

wei

ghte

d pr

opor

tion

from

RE

met

a-an

alys

is: 5

9.4%

(95%

Cls

: 41.

2%–7

5.3%

).h D

ue to

met

hodo

logi

cal d

iffer

ence

s in

the

stud

ies

the

rela

tive

and

abso

lute

risk

s ar

e no

t sho

wn. t

he s

horte

r MDR

-tb

regi

men

s da

tase

t con

sist

s of

rece

ntly

con

duct

ed s

tudi

es –

som

e on

goin

g –

in w

hich

pat

ient

s we

re

care

fully

sel

ecte

d, a

nd a

ll da

ta w

ere

pros

pect

ively

col

lect

ed a

s pa

rt of

a re

sear

ch p

roto

col.

Patie

nts

were

uni

form

ly tr

eate

d wi

th a

sta

ndar

dize

d re

gim

en. I

n co

ntra

st, s

tudi

es w

ith lo

nger

regi

men

s da

tase

t wer

e on

av

erag

e ol

der,

and

man

y we

re re

trosp

ectiv

e se

ries,

and

man

y us

ed d

ata

colle

cted

for c

linic

al p

urpo

ses.

the

larg

e m

ajor

ity o

f pat

ient

s in

the

long

er re

gim

ens

grou

p re

ceive

d in

divi

dual

ized

ther

apy,

with

man

y re

gim

ens

that

diff

ered

from

one

ano

ther

in n

umbe

r and

type

of d

rugs

use

d, a

nd th

e du

ratio

n of

trea

tmen

t.i U

nwei

ghte

d pr

opor

tion;

exa

ct b

inom

ial 9

5% C

ls: 4

7.6%

–84.

1%.

j Unw

eigh

ted

prop

ortio

n; w

eigh

ted

prop

ortio

n fro

m F

E m

eta-

anal

ysis

: 59.

1% (9

5% C

ls: 5

0.6%

–67.

1%).

k Unw

eigh

ted

prop

ortio

n; e

xact

bin

omia

l 95%

Cls

: 40.

6%–7

6.3%

.l U

nwei

ghte

d pr

opor

tion;

wei

ghte

d pr

opor

tion

from

RE

met

a-an

alys

is: 4

9.9%

(95%

Cls

: 30.

6%–6

9.2%

).

12

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

2. M

DR

-TB

reg

imen

com

posi

tion

– s

yste

mat

ic r

evie

ws

of in

divi

dual

med

icin

es in

adu

lts

(PIC

O 1

)

Aut

hor(

s): B

asto

s M, L

an Z

, Men

zies

R (1

1 N

ovem

ber 2

015)

Que

stio

n: A

late

r gen

erat

ion

fluor

oqui

nolo

ne co

mpa

red

to n

o la

ter g

ener

atio

n flu

oroq

uino

lone

for a

dults

with

rifa

mpi

cin-

resis

tant

TB

or M

DR

-TBa

Sett

ing:

Tre

atm

ent o

f adu

lts w

ith ri

fam

pici

n-re

sista

nt T

B/M

DR

-TB/

XD

R-T

B us

ing c

onve

ntio

nal r

egim

ens l

astin

g abo

ut 2

4 m

onth

s, in

low

and

high

re

sour

ce se

tting

s, w

ithin

hos

pita

l or a

mbu

lato

ry m

odel

s of c

are

Bib

liogr

aphy

: Ahu

ja S

D, A

shki

n D

, Ave

ndan

o M

, Ban

erje

e R

, Bau

er M

, Bay

ona

JN, e

t al.

Mul

tidru

g re

sista

nt p

ulm

onar

y tu

berc

ulos

is tr

eatm

ent

regi

men

s and

pat

ient

out

com

es: a

n in

divi

dual

pat

ient

dat

a met

a-an

alys

is of

9,1

53 p

atie

nts.

PLoS

Med

. 201

2;9(

8):1

212.

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

A LA

TER

GENE

RATI

ON

FLUO

ROQU

I-NO

LONE

NO L

ATER

GE

NERA

TION

FL

UORO

QUI-

NOLO

NERE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in p

atie

nts

on la

ter g

ener

atio

n flu

oroq

uino

lone

ver

sus

no fl

uoro

quin

olon

e, a

s pa

rt of

a M

DR-t

b re

gim

en (a

sses

sed

with

: ind

ivid

ual p

atie

nt d

ata

met

a-an

alys

is (A

huja

sD,

et a

l. Pl

Os M

ed. 2

012)

32

obse

rvat

iona

l st

udie

s se

rious

bno

t ser

ious

no

t ser

ious

no

t ser

ious

al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

the

dem

onst

rate

d ef

fect

691/

833

(83.

0%)

301/

678

(44.

4%)

OR 2

.5

(1.0

to

5.9)

c

390

mor

e pe

r 1,0

00

(from

30

fewe

r to

640

mor

e)

lO

W

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in p

atie

nts

on la

ter g

ener

atio

n flu

oroq

uino

lone

ver

sus

oflox

acin

, as

part

of a

MDR

-tb

regi

men

(ass

esse

d wi

th: i

ndiv

idua

l pat

ient

dat

a m

eta-

anal

ysis

(Ahu

ja

sD, e

t al.

PlOs

Med

. 201

2)

32

obse

rvat

iona

l st

udie

s se

rious

bno

t ser

ious

no

t ser

ious

no

t ser

ious

al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

the

dem

onst

rate

d ef

fect

691/

833

(83.

0%)

3386

/462

4 (7

3.2%

) OR

1.9

(1

.0 to

3.

6)c

100

mor

e pe

r 1,0

00

(from

15

fewe

r to

240

mor

e)

lO

W

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se in

pat

ient

s on

late

r gen

erat

ion

fluor

oqui

nolo

ne v

ersu

s no

fluo

roqu

inol

one

or c

ipro

floxa

cin

or o

floxa

cin,

as

part

of a

MDR

-tb

regi

men

(ass

esse

d wi

th: a

ggre

gate

d da

ta m

eta-

anal

ysis

201

5)d

48

obse

rvat

iona

l st

udie

s se

rious

eno

t ser

ious

no

t ser

ious

no

t ser

ious

no

ne

4270

/497

8 (8

5.8%

)f33

97/4

046

(84.

0%)g

10 fe

wer

pe

r 1,0

00

(from

78

fewe

r to

57 m

ore)

VE

RY l

OW

CRIt

ICAl

1313

ANNE

X 4:

GRA

DE tA

blEs

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

A LA

TER

GENE

RATI

ON

FLUO

ROQU

I-NO

LONE

NO L

ATER

GE

NERA

TION

FL

UORO

QUI-

NOLO

NERE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in p

atie

nts

on la

ter g

ener

atio

n flu

oroq

uino

lone

ver

sus

no fl

uoro

quin

olon

e or

cip

roflo

xaci

n or

oflo

xaci

n, a

s pa

rt of

a M

DR-t

b re

gim

en (a

sses

sed

with

: ag

greg

ated

dat

a m

eta-

anal

ysis

201

5)

47

obse

rvat

iona

l st

udie

s se

rious

eno

t ser

ious

no

t ser

ious

no

t ser

ious

no

ne

4270

/547

4 (7

8.0%

)h33

97/4

958

(68.

5%)i

23 m

ore

per 1

,000

(fr

om 6

0 fe

wer t

o 10

8 m

ore)

VE

RY l

OW

CRIt

ICAl

serio

us a

dver

se e

vent

s (G

rade

3 o

r 4, o

r dru

gs s

topp

ed d

ue to

adv

erse

eve

nts)

in p

atie

nts

on la

ter-g

ener

atio

n flu

oroq

uino

lone

13

obse

rvat

iona

l st

udie

s se

rious

no

t ser

ious

no

t ser

ious

no

t ser

ious

no

nej

10/8

27

(1.2

%)k

not

estim

able

j

VERY

lOW

CRIt

ICAl

serio

us a

dver

se e

vent

s (G

rade

3 o

r 4, o

r dru

gs s

topp

ed d

ue to

adv

erse

eve

nts)

in p

atie

nts

on o

floxa

cin

or c

ipro

floxa

cin

(ass

esse

d wi

th: a

ggre

gate

d da

ta m

eta-

anal

ysis

201

5)

9 ob

serv

atio

nal

stud

ies

serio

us

not s

erio

us

not s

erio

us

not s

erio

us

none

j40

1/14

08

(28.

5%)l

not

estim

able

j

VERY

lOW

CRIt

ICAl

Cls:

con

fiden

ce li

mits

; FE:

fixe

d ef

fect

s; O

R: o

dds

ratio

a Use

of l

ater

gen

erat

ion

fluor

oqui

nolo

nes

(mox

iflox

acin

, gat

iflox

acin

or l

evofl

oxac

in) i

s co

mpa

red

with

use

of o

floxa

cin

or n

o flu

oroq

uino

lone

alo

ngsi

de o

ther

dru

gs in

the

MDR

-tb

regi

men

; one

out

com

e re

late

d to

se

vere

adv

erse

eve

nts

of o

floxa

cin

also

incl

uded

in th

is ta

ble.

b In

the

indi

vidu

al p

atie

nt d

ata

anal

ysis

(Ahu

ja s

D, e

t al.)

, mos

t pat

ient

s re

ceive

d in

divi

dual

ized

treat

men

t, wi

th s

ubst

antia

l ris

k of

con

foun

ding

by

indi

catio

n (a

s we

ll as

sel

ectio

n bi

as).

c Odd

s ra

tio a

djus

ted

for a

ge, H

IV s

tatu

s, s

putu

m s

mea

r pos

itivi

ty, c

avita

tion

on c

hest

radi

ogra

ph, a

nd p

rior t

reat

men

t with

firs

t-lin

e an

d se

cond

-line

tb d

rugs

.d A

djus

tmen

t for

indi

vidu

al p

atie

nt c

hara

cter

istic

s no

t pos

sibl

e; th

e ad

just

ed v

alue

s of

the

pool

ed p

ropo

rtion

s (w

ith th

eir 9

5% C

l) s

hown

in fo

otno

tes

belo

w.e I

n 20

stu

dies

the

patie

nts

were

give

n st

anda

rdize

d re

gim

ens,

but

in th

e re

mai

ning

stu

dies

ther

apy

was

indi

vidu

alize

d, le

adin

g to

risk

of c

onfo

undi

ng b

y in

dica

tion.

f Adj

uste

d pr

opor

tion:

91%

(95%

Cl:

85%

–95%

).g A

djus

ted

prop

ortio

n: 9

2% (9

5% C

l: 8

7%–9

6%).

h Adj

uste

d pr

opor

tion:

80%

(95%

Cl:

74%

–85%

).i A

djus

ted

prop

ortio

n: 7

8% (9

5% C

l: 7

4%–8

5%).

j ser

ious

adv

erse

eve

nts

(sAE

s) re

porte

d in

pat

ient

s we

re a

ttrib

uted

to a

med

icin

e by

the

auth

ors

who

were

unb

linde

d an

d us

ed n

on-s

tand

ardi

zed

met

hods

to d

efine

, asc

erta

in a

nd re

port

sAEs

. No

valid

com

paris

ons

are

poss

ible

with

pat

ient

s no

t on

the

targ

et m

edic

ine,

bec

ause

sAE

s in

thes

e pa

tient

s co

uld

be d

ue to

oth

er d

rugs

rece

ived.

k Poo

led

prop

ortio

n: F

E 95

% C

l: 0

.6%

–2.4

%.

l Poo

led

prop

ortio

n: F

E 95

% C

l: 1

.9%

–4.1

%.

14

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): B

asto

s M, L

an Z

, Men

zies

R (1

1 N

ovem

ber 2

015)

Que

stio

n: G

atifl

oxac

in co

mpa

red

to n

o ga

tiflox

acin

for t

he tr

eatm

ent o

f adu

lts w

ith ri

fam

pici

n-re

sista

nt T

B or

MD

R-T

B

Sett

ing:

Tre

atm

ent o

f adu

lts w

ith r

ifam

pici

n-re

sista

nt T

B/M

DR

-TB/

XD

R-T

B us

ing

conv

entio

nal r

egim

ens l

astin

g ab

out 2

4 m

onth

s and

shor

ter

MD

R-T

B re

gim

ens,

in lo

w an

d hi

gh re

sour

ce se

tting

s, w

ithin

hos

pita

l or a

mbu

lato

ry m

odel

s of c

are

Bib

liogr

aphy

: (1)

Van

Deu

n A

, Mau

g A

KJ,

Salim

MA

H, D

as P

K, S

arke

r MR

, Dar

u P,

et a

l. Sh

ort,

high

ly e

ffect

ive,

and

inex

pens

ive

stand

ardi

zed

trea

tmen

t of m

ultid

rug-

resis

tant

tube

rcul

osis.

Am

J R

espi

r Crit

Car

e Med

. 201

0;18

2(5)

:684

–92.

(2) B

utov

DA

, Efre

men

ko Y

V, P

rihod

a ND

, Yur

chen

ko

LI, S

okol

enko

NI,

Arja

nova

OV,

et al

. Adj

unct

imm

une t

hera

py o

f firs

t-dia

gnos

ed T

B, re

laps

ed T

B, tr

eatm

ent-f

aile

d T

B, m

ultid

rug-

resis

tant

TB

and

TB/

HIV

. Im

mun

othe

rapy

201

2;4(

7):6

87–6

95. (

3) X

u H

B, Ji

ang R

H, X

iao

HP.

Clo

fazi

min

e in

the t

reat

men

t of m

ultid

rug-

resis

tant

tube

rcul

osis.

Clin

M

icro

biol

Infe

ct. 2

012;

18(1

1):1

104–

1110

. (4)

Xu

HB,

Jian

g RH

, Li L

, Xia

o H

P. L

inez

olid

in th

e tre

atm

ent o

f MD

R-T

B: a

retr

ospe

ctiv

e clin

ical

stud

y. In

t J T

uber

c Lun

g Dis.

201

2;16

(3):3

58–3

63. (

5) C

arro

ll M

W, L

ee M

, Cai

Y, H

alla

han

CW

, Sha

w P

A, M

in JH

, et a

l. Fr

eque

ncy o

f adv

erse

reac

tions

to

first-

and

seco

nd-li

ne an

ti-tu

berc

ulos

is ch

emot

hera

py in

a K

orea

n co

hort

. Int

J Tu

berc

Lun

g Dis.

201

2;16

(7):9

61–9

66. (

6) Ja

wah

ar M

S, B

anur

ekha

VV,

Pa

ram

asiv

an C

N, R

ahm

an F

, Ram

acha

ndra

n R

, Ven

kate

san

P, e

t al.

Ran

dom

ized

clin

ical

tria

l of t

hric

e-w

eekl

y 4-

mon

th m

oxifl

oxac

in o

r gat

iflox

acin

co

ntai

ning

regi

men

s in

the t

reat

men

t of n

ew sp

utum

pos

itive

pul

mon

ary t

uber

culo

sis p

atie

nts.

PLoS

One

201

3;8(

7):e

6703

0. (7

) Jo

KW

, Lee

SD

, Kim

W

S, K

im D

S, S

him

TS.

Tre

atm

ent o

utco

mes

and

mox

iflox

acin

susc

eptib

ility

in o

floxa

cin-

resis

tant

mul

tidru

g-re

sista

nt tu

berc

ulos

is. In

t J T

uber

c Lun

g D

is. 2

014:

18(1

):39–

43. (

8) R

usto

mje

e R, L

ienh

ardt

C, K

anyo

k T,

Dav

ies G

R, L

evin

J, M

thiy

ane T

, et a

l. A

Pha

se II

stud

y of t

he st

erili

sing a

ctiv

ities

of

oflox

acin

, gat

iflox

acin

and

mox

iflox

acin

in p

ulm

onar

y tub

ercu

losis

. Int

J Tu

berc

Lun

g Dis.

200

8;12

(2):1

28–1

38.

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

TC

ERTA

INTY

O

F EV

IDEN

CE

IMP

OR

TAN

CE

NO. O

F ST

UDIE

SST

UDY

DESI

GNRI

SK O

F BI

ASIN

CONS

ISTE

NCY

INDI

RECT

NESS

IMPR

ECIS

ION

OTHE

R CO

NSID

ERAT

IONS

GATI

FLOX

ACIN

NO

GATI

FLOX

ACIN

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

(ass

esse

d wi

th: V

an D

eun

2010

; but

ov 2

011;

Xu

2012

a, 2

012b

)a

4 ob

serv

atio

nal

stud

ies

very

se

rious

bse

rious

no

t ser

ious

se

rious

st

rong

ass

ocia

tion

189/

225

(84.

0%)

174/

268

(64.

9%)

191

mor

e pe

r 1,0

00

(116

mor

e to

265

m

ore)

VE

RY l

OW

CRIt

ICAl

Deat

h ve

rsus

all

othe

r out

com

es (a

sses

sed

with

: Van

Deu

n 20

10, b

utov

201

1, X

u 20

12a,

201

2b)a

4 ob

serv

atio

nal

stud

ies

very

se

rious

bse

rious

no

t ser

ious

se

rious

no

ne

6/22

5 (2

.7%

) 23

/268

(8.6

%)

59 fe

wer

pe

r 1,0

00

(20

fewe

r to

99

fewe

r)

VE

RY l

OW

CRIt

ICAl

1515

ANNE

X 4:

GRA

DE tA

blEs

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

TC

ERTA

INTY

O

F EV

IDEN

CE

IMP

OR

TAN

CE

NO. O

F ST

UDIE

SST

UDY

DESI

GNRI

SK O

F BI

ASIN

CONS

ISTE

NCY

INDI

RECT

NESS

IMPR

ECIS

ION

OTHE

R CO

NSID

ERAT

IONS

GATI

FLOX

ACIN

NO

GATI

FLOX

ACIN

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

serio

us a

dver

se e

vent

s (G

rade

3 o

r 4, o

r dru

gs s

topp

ed d

ue to

adv

erse

eve

nts)

in p

atie

nts

on g

atifl

oxac

in v

ersu

s no

gat

iflox

acin

(ass

esse

d wi

th: c

ompa

rativ

e ob

serv

atio

nal s

tudi

es: C

arol

l 201

2; Ja

waha

r 20

13; J

o 20

14; R

usto

mje

e 20

08; V

an D

eun

2010

)a

5 ob

serv

atio

nal

stud

ies

very

se

rious

se

rious

no

t ser

ious

se

rious

no

nec

15/4

22

(3.6

%)d

137/

1711

(8

.0%

)eno

t es

timab

lec

VE

RY l

OW

CRIt

ICAl

Cl: c

onfid

ence

lim

its; F

E: fi

xed

effe

cts

a In

the

no g

atifl

oxac

in g

roup

the

othe

r fluo

roqu

inol

one

used

was

eith

er o

floxa

cin,

levo

floxa

cin

or m

oxifl

oxac

in.

b sm

all o

bser

vatio

nal s

tudi

es u

sing

indi

vidu

alize

d re

gim

ens

with

sub

stan

tial p

oten

tial f

or b

ias;

in th

e Va

n De

un, e

t al.

stud

y ga

tiflox

acin

was

use

d as

par

t of s

horte

r MDR

-tb

regi

men

s re

serv

ed fo

r pat

ient

s se

lect

ed

upon

spe

cific

crit

eria

.c s

erio

us a

dver

se e

vent

s (s

AEs)

repo

rted

in p

atie

nts

were

attr

ibut

ed to

a m

edic

ine

by th

e au

thor

s wh

o we

re u

nblin

ded

and

used

non

-sta

ndar

dize

d m

etho

ds to

defi

ne, a

scer

tain

and

repo

rt sA

Es. N

o va

lid c

ompa

rison

s ar

e po

ssib

le w

ith p

atie

nts

not o

n th

e ta

rget

med

icin

e, b

ecau

se s

AEs

in th

ese

patie

nts

coul

d be

due

to o

ther

dru

gs re

ceive

d.d P

oole

d pr

opor

tion:

FE

95%

Cl:

2.0

%–5

.8%

.e P

oole

d pr

opor

tion:

FE

95%

Cl:

6.8

%–9

.4%

.

16

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): B

asto

s M, L

an Z

, Men

zies

R (1

1 N

ovem

ber 2

015)

Que

stio

n: A

seco

nd-li

ne in

ject

able

com

pare

d to

no

seco

nd li

ne in

ject

able

for a

dults

with

rifa

mpi

cin-

resis

tant

TB

or M

DR

-TBa

Sett

ing:

Tre

atm

ent o

f adu

lts w

ith r

ifam

pici

n-re

sista

nt T

B/M

DR

-TB/

XD

R-T

B us

ing

conv

entio

nal r

egim

ens l

astin

g ab

out 2

4 m

onth

s and

shor

ter

MD

R-T

B re

gim

ens,

in lo

w an

d hi

gh re

sour

ce se

tting

s, w

ithin

hos

pita

l or a

mbu

lato

ry m

odel

s of c

are

Bib

liogr

aphy

: (1)

Ahu

ja S

D, A

shki

n D

, Ave

ndan

o M

, Ban

erje

e R, B

auer

M, B

ayon

a JN

, et a

l. M

ultid

rug

resis

tant

pul

mon

ary

tube

rcul

osis

trea

tmen

t re

gim

ens a

nd p

atie

nt o

utco

mes

: an

indi

vidu

al p

atie

nt d

ata

met

a-an

alys

is of

9,1

53 p

atie

nts.

PLoS

Med

. 201

2;9(

8):e

1001

300.

(2) B

asto

s M, L

an Z

, M

enzi

es R

. An

upda

ted

syst

emat

ic re

view

and

met

a-an

alys

is fo

r tre

atm

ent o

f mul

tidru

g-re

sista

nt tu

berc

ulos

is, 2

016

(und

er re

view

, 28

May

201

6).

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

A SE

COND

-LIN

E IN

JECT

ABLE

NO S

ECON

D LI

NE

INJE

CTAB

LERE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in p

atie

nts

on k

anam

ycin

or a

mik

acin

, as

part

of a

MDR

-tb

regi

men

(ass

esse

d wi

th: i

ndivi

dual

pat

ient

dat

a m

eta-

anal

ysis

(Ahu

ja s

D, e

t al.

PlOs

Med

. 201

2)

32

obse

rvat

iona

l st

udie

s se

rious

bno

t ser

ious

no

t ser

ious

no

t ser

ious

al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

the

dem

onst

rate

d ef

fect

2572

/346

7 (7

4.2%

) 55

7/98

1 (5

6.8%

) aO

R 1.

6 (1

.2 to

2.

0)c

170

mor

e pe

r 1,0

00

(from

55

mor

e to

28

0 m

ore)

lO

W

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in p

atie

nts

on c

apre

omyc

in, a

s pa

rt of

a M

DR-t

b re

gim

en (a

sses

sed

with

: ind

ivid

ual p

atie

nt d

ata

met

a-an

alys

is (A

huja

sD,

et a

l. Pl

Os M

ed. 2

012)

32

obse

rvat

iona

l st

udie

s se

rious

bno

t ser

ious

no

t ser

ious

no

t ser

ious

al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

the

dem

onst

rate

d ef

fect

733/

1018

(7

2.0%

) 55

7/98

1 (5

6.8%

) aO

R 1.

3 (0

.5 to

3.

7)c

150

mor

e pe

r 1,0

00

(from

75

fewe

r to

310

mor

e)

lO

W

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se in

pat

ient

s on

kan

amyc

in o

r am

ikac

in, a

s pa

rt of

a M

DR-t

b re

gim

en (a

sses

sed

with

: agg

rega

ted

data

met

a-an

alys

is 2

015)

d

43

obse

rvat

iona

l st

udie

s se

rious

eno

t ser

ious

no

t ser

ious

no

t ser

ious

no

nef

3336

/393

5 (8

4.8%

)g,h

3378

/394

2 (8

5.7%

)g,i

not

estim

able

36 m

ore

per 1

,000

(fr

om 3

8 fe

wer t

o 11

0 m

ore)

VE

RY l

OW

CRIt

ICAl

1717

ANNE

X 4:

GRA

DE tA

blEs

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

A SE

COND

-LIN

E IN

JECT

ABLE

NO S

ECON

D LI

NE

INJE

CTAB

LERE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in p

atie

nts

on k

anam

ycin

or a

mik

acin

, as

part

of a

MDR

-tb

regi

men

(ass

esse

d wi

th: a

ggre

gate

d da

ta m

eta-

anal

ysis

201

5)

43

obse

rvat

iona

l st

udie

s se

rious

eno

t ser

ious

no

t ser

ious

no

t ser

ious

no

nef

3336

/474

1 (7

0.4%

)g,j

3378

/428

2 (7

8.9%

)g,k

not

estim

able

21 m

ore

per 1

,000

(fr

om 9

0 fe

wer t

o 13

1 m

ore)

VE

RY l

OW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se in

pat

ient

s on

cap

reom

ycin

ver

sus

no o

ther

sec

ond-

line

inje

ctab

le d

rug,

as

part

of a

MDR

-tb

regi

men

(ass

esse

d wi

th: a

ggre

gate

d da

ta m

eta-

anal

ysis

201

5)

43

obse

rvat

iona

l st

udie

s se

rious

eno

t ser

ious

no

t ser

ious

no

t ser

ious

no

nef

3960

/465

8 (8

5.0%

)l27

54/3

219

(85.

6%)m

not

estim

able

5 fe

wer

pe

r 1,0

00

(from

73

fewe

r to

62 m

ore)

VE

RY l

OW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in p

atie

nts

on c

apre

omyc

in v

ersu

s no

oth

er s

econ

d-lin

e in

ject

able

dru

g, a

s pa

rt of

a M

DR-t

b re

gim

en (a

sses

sed

with

: agg

rega

ted

data

met

a-an

alys

is 2

015)

43

obse

rvat

iona

l st

udie

s se

rious

eno

t ser

ious

no

t ser

ious

no

t ser

ious

no

nef

3960

/514

1 (7

7.0%

)n27

54/3

882

(70.

9%)o

not

estim

able

69 m

ore

per 1

,000

(fr

om 3

1 fe

wer t

o 16

8 m

ore)

VE

RY l

OW

CRIt

ICAl

serio

us a

dver

se e

vent

s (G

rade

3 o

r 4, o

r dru

gs s

topp

ed d

ue to

adv

erse

eve

nts)

in p

atie

nts

on a

mik

acin

, cap

rem

ycin

or k

anam

ycin

(ass

esse

d wi

th: a

ggre

gate

d da

ta m

eta-

anal

ysis

201

5)

19

obse

rvat

iona

l st

udie

s se

rious

fno

t ser

ious

no

t ser

ious

no

t ser

ious

no

nep

184/

2538

(7

.2%

)q-

not

estim

able

p-

VE

RY l

OW

CRIt

ICAl

Cls:

con

fiden

ce li

mits

; FE:

fixe

d ef

fect

sa I

n th

is a

naly

sis,

the

use

of a

spe

cific

inje

ctab

le a

gent

(am

ikac

in, k

anam

ycin

or c

apre

omyc

in) i

s co

mpa

red

with

no

use

of th

at p

artic

ular

age

nt, a

lthou

gh a

noth

er s

econ

d-lin

e in

ject

able

age

nt m

ay h

ave

been

use

d as

pa

rt of

the

MDR

-tb

regi

men

.b I

ndiv

idua

l pat

ient

dat

a ta

ken

from

32

obse

rvat

iona

l stu

dies

in w

hich

mos

t pat

ient

s re

ceive

d in

divi

dual

ized

treat

men

t. Ri

sk o

f sel

ectio

n bi

as, a

nd c

onfo

undi

ng b

y in

dica

tion.

c aOR

: Odd

s ra

tio a

djus

ted

for a

ge, H

IV, p

ositi

vity

on

sput

um-s

mea

r mic

rosc

opy,

ches

t rad

iogr

aph

cavi

tatio

n, a

nd p

rior t

reat

men

t with

firs

t-lin

e an

d se

cond

-line

tb d

rugs

.d I

n th

e ag

greg

ated

dat

a m

eta-

anal

ysis

pat

ient

s wi

th X

DR-t

b we

re e

xclu

ded

wher

e po

ssib

le.

e In

tota

l, 61

coh

orts

pro

vide

d en

d-of

-trea

tmen

t out

com

e in

form

atio

n: in

23

coho

rts th

e pa

tient

s we

re g

iven

stan

dard

ized

regi

men

s an

d in

38

coho

rts th

erap

y wa

s in

divi

dual

ized,

lead

ing

to ri

sk o

f con

foun

ding

by

indi

catio

n. O

f the

61

coho

rts, 1

8 co

horts

did

not

spe

cify

whi

ch s

econ

d-lin

e in

ject

able

age

nt w

as u

sed,

and

ther

efor

e on

ly th

e re

mai

ning

43

coho

rts w

ere

reta

ined

for t

his

anal

ysis

.f P

oten

tial c

onfo

undi

ng fr

om p

refe

rent

ial i

nclu

sion

of c

apre

omyc

in in

the

indi

vidu

alize

d re

gim

ens

of p

atie

nts

with

mor

e ad

vanc

ed re

sist

ance

pat

tern

s or

dis

ease

.g G

iven

that

am

ikac

in o

r kan

amyc

in w

ere

used

in a

lmos

t all

stud

ies,

the

com

paris

on is

mad

e be

twee

n st

udie

s in

whi

ch 7

2% –1

00%

of p

atie

nts

rece

ived

the

inje

ctab

le a

gent

(int

erve

ntio

n gr

oup)

ver

sus

a co

mpa

rato

r gr

oup

of s

tudi

es in

whi

ch 0

%–7

1% o

f pat

ient

s re

ceive

d on

e of

thes

e ag

ents

.h A

djus

ted

prop

ortio

n: 9

4% (9

5% C

l: 9

0%–9

7%).

i Adj

uste

d pr

opor

tion:

89%

(95%

Cl:

83%

–96%

).

18

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

j Adj

uste

d pr

opor

tion:

82%

(95%

Cl:

75%

–88%

).k A

djus

ted

prop

ortio

n: 7

8% (9

5% C

l: 7

0%–8

6%).

l Adj

uste

d pr

opor

tion:

92%

(95%

Cl:

87%

–97%

).m A

djus

ted

prop

ortio

n: 9

3% (9

5% C

l: 8

6%–9

7%).

n Adj

uste

d pr

opor

tion:

77%

(95%

Cl:

69%

–84%

).o A

djus

ted

prop

ortio

n: 8

3% (9

5% C

l: 7

6%–8

9%).

p ser

ious

adv

erse

eve

nts

(sAE

s) re

porte

d in

pat

ient

s we

re a

ttrib

uted

to a

med

icin

e by

the

auth

ors

who

were

unb

linde

d an

d us

ed n

on-s

tand

ardi

zed

met

hods

to d

efine

, asc

erta

in a

nd re

port

sAEs

. No

valid

com

paris

ons

are

poss

ible

with

pat

ient

s no

t on

the

targ

et m

edic

ine,

bec

ause

sAE

s in

thes

e pa

tient

s co

uld

be d

ue to

oth

er d

rugs

rece

ived.

q Poo

led

prop

ortio

n: F

E 95

% C

l: 6

.2%

–8.4

%.

1919

ANNE

X 4:

GRA

DE tA

blEs

Aut

hor(

s): M

enzi

es R

, Bas

tos M

, Lan

Z (1

1 N

ovem

ber 2

015)

Que

stio

n: E

thio

nam

ide/

prot

hion

amid

e com

pare

d to

no

ethi

onam

ide/

prot

hion

amid

e for

adul

ts w

ith ri

fam

pici

n-re

sista

nt T

B or

MD

R-T

B

Sett

ing:

Tre

atm

ent o

f adu

lts w

ith r

ifam

pici

n-re

sista

nt T

B/M

DR

-TB/

XD

R-T

B us

ing

conv

entio

nal r

egim

ens l

astin

g ab

out 2

4 m

onth

s and

shor

ter

MD

R-T

B re

gim

ens,

in lo

w an

d hi

gh re

sour

ce se

tting

s, w

ithin

hos

pita

l or a

mbu

lato

ry m

odel

s of c

are

Bib

liogr

aphy

: (1)

Ahu

ja S

D, A

shki

n D

, Ave

ndan

o M

, Ban

erje

e R, B

auer

M, B

ayon

a JN

, et a

l. M

ultid

rug

resis

tant

pul

mon

ary

tube

rcul

osis

trea

tmen

t re

gim

ens a

nd p

atie

nt o

utco

mes

: an

indi

vidu

al p

atie

nt d

ata

met

a-an

alys

is of

9,1

53 p

atie

nts.

PLoS

Med

. 201

2;9(

8):e

1001

300.

(2) B

asto

s M, L

an Z

, M

enzi

es R

. An

upda

ted

syst

emat

ic re

view

and

met

a-an

alys

is fo

r tre

atm

ent o

f mul

tidru

g-re

sista

nt tu

berc

ulos

is, 2

016

(und

er re

view

, 28

May

201

6).

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

ETHI

ONAM

IDE/

PR

OTHI

ONA-

MID

E

NO

ETHI

ONAM

IDE/

PR

OTHI

ONA-

MID

E RE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in p

atie

nts

on e

thio

nam

ide/

prot

hion

amid

e as

par

t of a

MDR

-tb

regi

men

(ass

esse

d wi

th: i

ndiv

idua

l pat

ient

dat

a m

eta-

anal

ysis

(Ahu

ja s

D, e

t al.

PlOs

M

ed. 2

012)

)a

32

obse

rvat

iona

l st

udie

s se

rious

bno

t ser

ious

no

t ser

ious

no

t ser

ious

al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

the

dem

onst

rate

d ef

fect

4101

/566

7 (7

2.4%

) 87

8/14

87

(59.

0%)

aOR

1.9

(1.5

to

2.3)

c

130

few

er

per 1

000

(from

65

mor

e to

18

5 m

ore)

lO

W

CRIt

ICAl

serio

us a

dver

se e

vent

s (G

rade

3 o

r 4, o

r dru

gs s

topp

ed d

ue to

adv

erse

eve

nts)

in p

atie

nts

on e

thio

nam

ide/

prot

hion

amid

e as

par

t of a

MDR

-tb

regi

men

(ass

esse

d wi

th: a

ggre

gate

d da

ta m

eta-

anal

ysis

201

5)

17

obse

rvat

iona

l st

udie

s se

rious

no

t ser

ious

no

t ser

ious

no

t ser

ious

no

ned

173/

2106

(8

.2%

)e-

not

estim

able

d

VERY

lOW

CRIt

ICAl

Cl: c

onfid

ence

lim

it; F

E: fi

xed

effe

cts

a In

this

ana

lysi

s, u

se o

f eth

iona

mid

e is

com

bine

d wi

th p

roth

iona

mid

e, a

nd c

ompa

red

to re

sults

in p

atie

nts

who

did

not g

et e

ither

of t

hese

dru

gs, b

ut re

ceive

d m

ultip

le o

ther

dru

gs.

b thi

s is

indi

vidu

al p

atie

nt d

ata

take

n fro

m 3

2 ob

serv

atio

nal s

tudi

es in

whi

ch m

ost p

atie

nts

rece

ived

indi

vidu

alize

d tre

atm

ent.

ther

e is

risk

of s

elec

tion

bias

and

con

foun

ding

by

indi

catio

n.c a

OR: O

dds

ratio

adj

uste

d fo

r age

, HIV

, aci

d fa

st b

acill

us s

mea

r, ch

est r

adio

grap

h ca

vita

tion,

and

prio

r tre

atm

ent w

ith fi

rst-l

ine,

and

sec

ond-

line

tb d

rugs

.d s

erio

us a

dver

se e

vent

s (s

AEs)

repo

rted

in p

atie

nts

were

attr

ibut

ed to

a m

edic

ine

by th

e au

thor

s wh

o we

re u

nblin

ded

and

used

non

-sta

ndar

dize

d m

etho

ds to

defi

ne, a

scer

tain

and

repo

rt sA

Es. N

o va

lid c

ompa

rison

s ar

e po

ssib

le w

ith p

atie

nts

not o

n th

e ta

rget

med

icin

e, b

ecau

se s

AEs

in th

ese

patie

nts

coul

d be

due

to o

ther

dru

gs re

ceive

d.e P

oole

d pr

opor

tion:

FE

95%

Cl:

7.0%

–9.6

%.

20

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): M

enzi

es R

, Bas

tos M

, Lan

Z (1

1 N

ovem

ber 2

015)

Que

stio

n: C

yclo

serin

e/te

rizid

one c

ompa

red

to n

o cy

clos

erin

e/te

rizid

one f

or ad

ults

with

rifa

mpi

cin-

resis

tant

TB

or M

DR

-TB

Sett

ing:

Tre

atm

ent o

f adu

lts w

ith M

DR

-TB

regi

men

s, in

low

and

high

reso

urce

sett

ings

, with

in h

ospi

tal o

r am

bula

tory

mod

els o

f car

e

Bib

liogr

aphy

: (1)

Ahu

ja S

D, A

shki

n D

, Ave

ndan

o M

, Ban

erje

e R, B

auer

M, B

ayon

a JN

, et a

l. M

ultid

rug

resis

tant

pul

mon

ary

tube

rcul

osis

trea

tmen

t re

gim

ens a

nd p

atie

nt o

utco

mes

: an

indi

vidu

al p

atie

nt d

ata m

eta-

anal

ysis

of 9

,153

pat

ient

s. PL

oS M

ed. 2

012;

9(8)

:e10

0130

0. (2

) Hw

ang T

J, W

ares

DF,

Ja

faro

v A, J

akub

owia

k W

, Nun

n P,

Kes

havj

ee S

. Saf

ety o

f cyc

lose

rine a

nd te

rizid

one f

or th

e tre

atm

ent o

f dru

g-re

sista

nt tu

berc

ulos

is: a

met

a-an

alys

is. In

t J

Tube

rc L

ung D

is. 2

013;

17(1

0):1

257–

66. (

3) B

asto

s M, L

an Z

, Men

zies

R. A

n up

date

d sy

stem

atic

revi

ew an

d m

eta-

anal

ysis

for t

reat

men

t of m

ultid

rug-

resis

tant

tube

rcul

osis,

201

6 (u

nder

revi

ew, 2

8 M

ay 2

016)

.

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NSCY

CLOS

ERIN

E/

TERI

ZIDO

NE

NO

CYCL

OSER

INE/

TE

RIZI

DONE

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

succ

ess

vers

us fa

ilure

/rel

apse

/dea

th fo

r cyc

lose

rine

and

teriz

idon

e fro

m In

divi

dual

pat

ient

dat

a m

eta-

anal

ysis

(Ahu

ja s

D, e

t al.

PlOs

Med

201

2)a

32

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

no

t ser

ious

no

ne

3115

/424

0 (7

3.5%

) 18

64/2

914

(64.

0%)

OR 1

.5

(0.9

to

2.2)

a

95 m

ore

per 1

,000

(fr

om 7

3 m

ore

to

117

mor

e)

VE

RY l

OW

CRIt

ICAl

succ

ess

vers

us fa

ilure

/rel

apse

for c

yclo

serin

e an

d te

rizid

one

(ass

esse

d wi

th: a

ggre

gate

d da

ta m

eta-

anal

ysis

201

5)

53ob

serv

atio

nal

stud

ies

serio

us

serio

us

not s

erio

us

serio

us

none

44

74/5

285

(84.

7%)2

1969

/247

9 (7

9.4%

)3no

t es

timab

le49

mor

e pe

r 1,0

00

(from

56

fewe

r to

155

mor

e)

VE

RY l

OW

CRIt

ICAl

succ

ess

vers

us fa

ilure

/rel

apse

/dea

th fo

r cyc

lose

rine

and

teriz

idon

e (a

sses

sed

with

: agg

rega

ted

data

met

a-an

alys

is 2

015)

53ob

serv

atio

nal

stud

ies

serio

us

serio

us

not s

erio

us

serio

us

none

44

74/5

916

(75.

6%)4

1969

/282

3 (6

9.7%

)5no

t es

timab

le5

few

er

per 1

,000

(fr

om 1

39

fewe

r to

129

mor

e)

VE

RY l

OW

CRIt

ICAl

2121

ANNE

X 4:

GRA

DE tA

blEs

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NSCY

CLOS

ERIN

E/

TERI

ZIDO

NE

NO

CYCL

OSER

INE/

TE

RIZI

DONE

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

Drug

dis

cont

inue

d du

e to

maj

or p

sych

iatri

c to

xicity

from

cyc

lose

rine

used

to tr

eat M

DR-t

b (a

sses

sed

with

: Hwa

ng, e

t al.

Int J

tube

rc l

ung

Dis.

201

2 (s

yste

mat

ic re

view

))b

26

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

se

rious

no

nec

144/

1923

(7

.5%

) -

not

estim

able

c

VERY

lOW

CRIt

ICAl

Drug

dis

cont

inue

d du

e to

toxic

ity (a

ll ty

pes)

from

cyc

lose

rine

used

to tr

eat M

DR-t

b (a

sses

sed

with

: Hwa

ng tJ

, et a

l. In

t J tu

berc

lun

g Di

s. 2

012

(sys

tem

atic

revi

ew))

b

27

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

se

rious

no

nec

201/

2164

(9

.3%

) -

not

estim

able

c

VERY

lOW

CRIt

ICAl

serio

us a

dver

se e

vent

s (G

rade

3 o

r 4, o

r dru

gs s

topp

ed d

ue to

adv

erse

eve

nts)

in p

atie

nts

on c

yclo

serin

e as

par

t of a

MDR

-tb

regi

men

(ass

esse

d wi

th: a

ggre

gate

d da

ta m

eta-

anal

ysis

201

5)

16

obse

rvat

iona

l st

udie

s se

rious

no

t ser

ious

no

t ser

ious

no

t ser

ious

no

nec

96/2

140

(4.5

%)d

-no

t es

timab

lec

VE

RY l

OW

CRIt

ICAl

Drug

dis

cont

inue

d du

e to

toxic

ity (a

ll ty

pes)

from

teriz

idon

e us

ed to

trea

t MDR

-tb

(ass

esse

d wi

th: H

wang

tJ, e

t al.

Int J

tube

rc l

ung

Dis.

201

2 (s

yste

mat

ic re

view

))b

10

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

se

rious

no

nec

111/

707

(15.

7%)

-no

t es

timab

lec,

e

VERY

lOW

CRIt

ICAl

Cl: c

onfid

ence

lim

its; F

E: fi

xed

effe

cts;

OR:

odd

s ra

tioa A

djus

ted

for a

ge, e

xten

t of d

isea

se, H

IV, a

nd p

rior t

reat

men

t with

firs

t-lin

e or

sec

ond-

line

tb d

rugs

. Pat

ient

s on

cyc

lose

rine

and

teriz

idon

e we

re c

ombi

ned

toge

ther

for t

his

anal

ysis

.b N

o re

gion

al d

iffer

ence

s ob

serv

ed.

c ser

ious

adv

erse

eve

nts

(sAE

s) re

porte

d in

pat

ient

s we

re a

ttrib

uted

to a

med

icin

e by

the

auth

ors

who

were

unb

linde

d an

d us

ed n

on-s

tand

ardi

zed

met

hods

to d

efine

, asc

erta

in a

nd re

port

sAEs

. No

valid

com

paris

ons

are

poss

ible

with

pat

ient

s no

t on

the

targ

et m

edic

ine,

bec

ause

sAE

s in

thes

e pa

tient

s co

uld

be d

ue to

oth

er d

rugs

rece

ived.

d Poo

led

prop

ortio

n: F

E 95

% C

l: 3

.6%

–5.5

%.

e ter

izido

ne a

nd c

yclo

serin

e we

re c

ompa

red

in th

ree

of th

e st

udie

s. A

utho

rs re

porte

d no

diff

eren

ces

and

conc

lude

d th

at th

e ef

fect

of t

erizi

done

var

ied

from

not

bei

ng d

iffer

ent t

o be

ing

mod

erat

ely

bette

r tha

n cy

clos

erin

e.

22

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): M

enzi

es R

, Bas

tos M

, Lan

Z (1

1 N

ovem

ber 2

015)

Que

stio

n: L

inez

olid

com

pare

d to

no

linez

olid

for a

dult

patie

nts o

n tr

eatm

ent f

or M

DR

-TB/

XD

R-T

B

Sett

ing:

Tre

atm

ent o

f adu

lts w

ith ri

fam

pici

n-re

sista

nt T

B/M

DR

-/X

DR

-TB

usin

g co

nven

tiona

l reg

imen

s las

ting

abou

t 24

mon

ths,

in lo

w a

nd h

igh

reso

urce

setti

ngs,

with

in h

ospi

tal o

r am

bula

tory

mod

els o

f car

e

Bib

liogr

aphy

: (1)

Alte

t MN

, Vid

al R

, Milá

C, R

odrig

o T,

Cas

als M

, Mir

I, et

al. M

onito

ring c

hang

es in

anti-

tube

rcul

osis

trea

tmen

t: as

soci

ated

fact

ors

dete

rmin

ed at

the t

ime o

f dia

gnos

is. In

t J T

uber

c Lun

g Dis.

201

3;17

(11)

:143

5–41

. (2)

Car

roll

MW

, Lee

M, C

ai Y

, Hal

laha

n C

W, S

haw

PA

, Min

JH, e

t al

. Fre

quen

cy o

f adv

erse

reac

tions

to fi

rst-

and

seco

nd-li

ne an

ti-tu

berc

ulos

is ch

emot

hera

py in

a K

orea

n co

hort

. Int

J Tu

berc

Lun

g Dis.

201

2;16

(7):9

61–

966.

(3)

De

Lore

nzo

S, A

lffen

aar

JW, S

otgi

u G

, Cen

tis R

, D’A

mbr

osio

L, T

iber

i S, e

t al

. Effi

cacy

and

safe

ty o

f mer

open

em-c

lavul

anat

e ad

ded

to

linez

olid

-con

tain

ing

regi

men

s in

the

trea

tmen

t of M

DR

-/X

DR

-TB.

Eur

Res

pir J

. 201

3;41

(6):1

386–

92. (

4) Ji

ang

R-H

, Xu

H-B

, Li L

. Com

para

tive

role

s of m

oxifl

oxac

in an

d le

voflo

xaci

n in

the t

reat

men

t of p

ulm

onar

y mul

tidru

g-re

sista

nt tu

berc

ulos

is: a

retr

ospe

ctiv

e stu

dy. I

nt J

Ant

imic

rob

Age

nts.

2013

;42(

1):3

6–41

. (5)

Koh

W-J,

Kw

on O

J, G

wak

H, C

hung

JW

, Cho

S-N

, Kim

WS,

et

al. D

aily

300

mg

dose

of l

inez

olid

for

the

trea

tmen

t of

in

trac

tabl

e m

ultid

rug-

resis

tant

and

ext

ensiv

ely

drug

-resis

tant

tube

rcul

osis.

J A

ntim

icro

b C

hem

othe

r. 20

09;6

4(2)

:388

–91.

(6) L

ee M

, Lee

J, C

arro

ll M

W, C

hoi H

, Min

S, S

ong T

, et a

l. Li

nezo

lid fo

r Tre

atm

ent o

f Chr

onic

Ext

ensiv

ely D

rug-

Res

istan

t Tub

ercu

losis

. N E

ngl J

Med

. 201

2;36

7(16

):150

8–18

. (7)

Mig

none

F, C

odec

asa L

R, S

colfa

ro C

, Raff

aldi

I, L

ance

lla L

, Fer

rare

se M

, et a

l. Th

e spr

ead

of d

rug-

resis

tant

tube

rcul

osis

in ch

ildre

n: an

Ital

ian

case

serie

s. Ep

idem

iol I

nfec

t. 20

14;1

42(1

0):2

049–

56. (

8) P

aday

atch

i N, M

ac K

enzi

e WR

, Hirs

ch-M

over

man

Y, F

eng P

-J, V

illar

ino

E, S

aukk

onen

J, et

al.

Less

ons f

rom

a ra

ndom

ised

clin

ical

tria

l for

mul

tidru

g-re

sista

nt tu

berc

ulos

is. In

t J T

uber

c Lun

g Dis.

201

2;16

(12)

:158

2–7.

(9) S

ingl

a R, C

amin

ero

JA,

Jaisw

al A

, Sin

gla N

, Gup

ta S

, Bal

i RK

, et a

l. Li

nezo

lid: a

n eff

ectiv

e, sa

fe an

d ch

eap

drug

for p

atie

nts f

ailin

g mul

tidru

g-re

sista

nt tu

berc

ulos

is tr

eatm

ent

in In

dia.

Eur

Res

pir J

. 201

2;39

(4):9

56–9

62. (

10) S

chec

ter G

F, S

cott

C, T

rue L

, Raft

ery

A, F

lood

J, M

ase S

. Lin

ezol

id in

the t

reat

men

t of m

ultid

rug-

resis

tant

tube

rcul

osis.

Clin

Infe

ct D

is. 2

010;

50(1

):49–

55. (

11) T

ang

S, Y

ao L

, Hao

X, Z

hang

X, L

iu G

, Liu

X, e

t al.

Effica

cy, s

afet

y an

d to

lerab

ility

of

line

zolid

for t

he tr

eatm

ent o

f XD

R-T

B: a

stud

y in

Chi

na. E

ur R

espi

r J. 2

015;

45(1

):161

–70.

(12)

Udw

adia

ZF,

Sen

T, M

ohar

il G

. Ass

essm

ent o

f lin

ezol

id effi

cacy

and

safe

ty in

MD

R- a

nd X

DR

-TB

: an

Indi

an p

ersp

ectiv

e. Eu

r Res

pir J

. 201

0;35

(4):9

36–9

38–9

40.

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

TC

ERTA

INTY

O

F EV

IDEN

CE

IMP

OR

TAN

CE

NO. O

F ST

UDIE

SST

UDY

DESI

GNRI

SK O

F BI

ASIN

CONS

ISTE

NCY

INDI

RECT

NESS

IMPR

ECIS

ION

OTHE

R CO

NSID

ERAT

IONS

LINE

ZOLI

DNO

LIN

EZOL

IDRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in X

DR-t

b pa

tient

s gi

ven

linez

olid

(ass

esse

d wi

th: R

Ct in

Chi

na, 2

009–

2011

(tan

g, e

t al,

2015

))a

1 ra

ndom

ized

trial

s se

rious

no

t ser

ious

no

t ser

ious

se

rious

st

rong

ass

ocia

tion

23/2

9 (7

9.3%

)b11

/29

(37.

9%)c

not

estim

able

414

mor

e pe

r 1,0

00

(from

184

m

ore

to

644

mor

e)

M

ODER

AtE

CRIt

ICAl

2323

ANNE

X 4:

GRA

DE tA

blEs

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

TC

ERTA

INTY

O

F EV

IDEN

CE

IMP

OR

TAN

CE

NO. O

F ST

UDIE

SST

UDY

DESI

GNRI

SK O

F BI

ASIN

CONS

ISTE

NCY

INDI

RECT

NESS

IMPR

ECIS

ION

OTHE

R CO

NSID

ERAT

IONS

LINE

ZOLI

DNO

LIN

EZOL

IDRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus.

failu

re/r

elap

se/d

eath

/def

ault

in M

DR-t

b or

XDR

-tb

patie

nts

give

n lin

ezol

id (a

sses

sed

with

: 1RC

t +

6 ob

serv

atio

nal s

tudi

es c

ombi

ned)

7 ob

serv

atio

nal

stud

iesd

very

se

rious

se

rious

no

t ser

ious

se

rious

no

ne

153/

198

(77.

3%)e

387/

606

(63.

9%)f

not

estim

able

134

mor

e pe

r 1,0

00

(from

64

mor

e to

20

4 m

ore)

VE

RY l

OW

CRIt

ICAl

Deat

h (v

ersu

s al

l oth

er o

utco

mes

) in

MDR

-tb

and

XDR-

tb p

atie

nts

give

n lin

ezol

id (a

sses

sed

with

: 1RC

t +

6 ob

serv

atio

nal s

tudi

es c

ombi

ned)

7 ob

serv

atio

nal

stud

iesd

very

se

rious

se

rious

no

t ser

ious

se

rious

no

ne

21/2

12

(9.9

%)

65/4

68

(13.

9%)

not

estim

able

40 fe

wer

pe

r 1,0

00

(91

fewe

r to

11 m

ore)

VE

RY l

OW

CRIt

ICAl

Grad

e 3–

4 se

rious

adv

erse

eve

nts

and/

or d

rugs

sto

pped

due

to li

nezo

lid (a

sses

sed

with

: int

erna

l com

para

tor g

roup

s)g,

h

4 ob

serv

atio

nal

stud

iesh,

ive

ry

serio

us

serio

us

not s

erio

us

serio

us

none

11

/49

(22.

4%)

112/

1305

(8

.6%

) no

t es

timab

le13

9 m

ore

per 1

,000

(2

1 m

ore

to

257

mor

e)

VE

RY l

OW

CRIt

ICAl

Grad

e 3–

4 se

rious

adv

erse

eve

nts

and/

or d

rugs

sto

pped

due

to li

nezo

lid 6

00 m

g/da

y (a

sses

sed

with

: lar

gely

unc

ontro

lled

obse

rvat

iona

l stu

dies

)j

8 ob

serv

atio

nal

stud

iesi,j

very

se

rious

se

rious

no

t ser

ious

se

rious

no

ne28

/190

(1

4.7%

)kno

t es

timab

le

VE

RY l

OW

CRIt

ICAl

Cl: c

onfid

ence

lim

it; R

Ct: r

ando

mize

d co

ntro

lled

trial

a Met

hod

of ra

ndom

izatio

n no

t des

crib

ed, h

ence

risk

of a

lloca

tion

bias

unk

nown

. stu

dy w

as n

ot b

linde

d, h

ence

risk

of a

scer

tain

men

t bia

s, a

nd s

mal

l num

ber o

f sub

ject

s.b 9

5% C

l: 6

5%–9

4%.

c 95%

Cl:

20%

–56%

.d A

ll we

re s

mal

l stu

dies

. the

1 R

Ct w

as v

ery

smal

l and

unb

linde

d wi

th u

ncle

ar ra

ndom

izatio

n. th

e 6

obse

rvat

iona

l had

indi

vidu

alize

d re

gim

ens.

e 95%

Cl:

73%

–84%

.f 9

5% C

l: 4

6%–9

0%.

g Not

sho

wing

the

effe

cts

in tw

o st

udie

s fo

r pat

ient

s re

ceiv

ing

1200

mg

per d

ay (9

/51;

18%

).h A

ltet 2

013;

Car

roll

2012

; Mig

none

201

4; P

aday

atch

i 201

2 (o

nly

Pada

yatc

hi re

porte

d th

e do

se).

i the

inte

rven

tion

grou

p wa

s gi

ven

linez

olid

at a

sta

rt do

se o

f 120

0 m

g pe

r day

for 4

–6 w

eeks

and

follo

wed

by a

dos

e of

300

–600

mg

per d

ay.

j Koh

200

9; s

chec

ter 2

010;

Udw

adia

201

0; s

ingl

a 20

12; l

ee 2

012;

De

lore

nzo

2013

; Jia

ng 2

013;

Pad

ayat

chi 2

012

(onl

y Pa

daya

tchi

repo

rted

sAE

in g

roup

not

rece

ivin

g lin

ezol

id; s

ingl

a (6

00 m

g vs

120

0 m

g) a

nd

De l

oren

zo (6

00 m

g vs

>60

0 m

g) c

ompa

red

sAE

at d

iffer

ent d

oses

).k 9

5% C

l: 1

0%–2

1%.

24

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): R

onal

d L,

Cer

igo

H, F

ox G

, Men

zies

R (1

1 N

ovem

ber 2

015)

Que

stio

n: C

lofa

zim

ine c

ompa

red

to n

o cl

ofaz

imin

e for

the t

reat

men

t of a

dults

with

rifa

mpi

cin-

resis

tant

TB

or M

DR

-TB

Sett

ing:

Tre

atm

ent o

f adu

lts w

ith r

ifam

pici

n-re

sista

nt T

B/M

DR

-TB/

XD

R-T

B us

ing

conv

entio

nal r

egim

ens l

astin

g ab

out 2

4 m

onth

s and

shor

ter

MD

R-T

B re

gim

ens,

in lo

w an

d hi

gh re

sour

ce se

ttin

gs, w

ithin

hos

pita

l or a

mbu

lato

ry m

odel

s of c

are (

as w

ell a

s non

-tube

rcul

ous m

ycob

acte

ria (N

TM

) in

som

e out

com

es fo

r SA

E)

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

TC

ERTA

INTY

O

F EV

IDEN

CE

IMP

OR

TAN

CE

NO. O

F ST

UDIE

SST

UDY

DESI

GNRI

SK O

F BI

ASIN

CONS

ISTE

NCY

INDI

RECT

NESS

IMPR

ECIS

ION

OTHE

R CO

NSID

ERAT

IONS

CLOF

AZIM

INE

NO

CLOF

AZIM

INE

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in M

DR-t

b pa

tient

s on

clo

fazim

ine

(ass

esse

d wi

th: i

ndiv

idua

l pat

ient

dat

a m

eta-

anal

ysis

(201

0))a

31

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

not s

erio

us

none

45

9/80

6 (5

6.9%

)b32

92/4

970

(66.

2%)c

adju

sted

OR

1.4

(0

.4 to

4.

0)

10 m

ore

per 1

,000

(fr

om 2

20

fewe

r to

340

mor

e)

VE

RY l

OW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/d

eath

in n

on-X

DR M

DR-t

b pa

tient

s wi

th c

lofa

zimin

e in

thei

r reg

imen

(ass

esse

d wi

th: 1

RCt

201

0–20

11 (t

ang

s, e

t al.

2015

))

1 ra

ndom

ized

trial

s se

rious

dno

t ser

ious

eno

t ser

ious

se

rious

est

rong

ass

ocia

tion

39/4

9 (7

9.6%

)f28

/47

(59.

6%)g

not

estim

able

200

mor

e pe

r 1,0

00

(from

60

fewe

r to

450

mor

em

M

ODER

AtE

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

(ass

esse

d wi

th: 1

RCt

+ 5

coh

orts

of M

DR/X

DR p

atie

nts)

h

6 ob

serv

atio

nal

stud

iesi

very

se

rious

se

rious

no

t ser

ious

se

rious

no

ne

75/1

02

(73.

5%)j

68/9

2 (7

3.9%

)kno

t es

timab

le10

few

er

per 1

,000

(fr

om 2

10

fewe

r to

170

mor

e)

VE

RY l

OW

CRIt

ICAl

serio

us a

dver

se e

vent

s re

sulti

ng in

dru

g di

scon

tinua

tion

in M

DR-/

XDR-

tb p

atie

nts

on c

lofa

zimin

e (a

sses

sed

with

: com

para

tive

stud

ies)

l

5 ob

serv

atio

nal

stud

ies

very

se

rious

se

rious

no

t ser

ious

se

rious

no

ne

2/81

(2.5

%)

281/

658

(42.

7%)

not

estim

able

VE

RY l

OW

CRIt

ICAl

2525

ANNE

X 4:

GRA

DE tA

blEs

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

TC

ERTA

INTY

O

F EV

IDEN

CE

IMP

OR

TAN

CE

NO. O

F ST

UDIE

SST

UDY

DESI

GNRI

SK O

F BI

ASIN

CONS

ISTE

NCY

INDI

RECT

NESS

IMPR

ECIS

ION

OTHE

R CO

NSID

ERAT

IONS

CLOF

AZIM

INE

NO

CLOF

AZIM

INE

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

serio

us a

dver

se e

vent

s re

sulti

ng in

dru

g di

scon

tinua

tion

in N

tM p

atie

nts

on c

lofa

zimin

e (a

sses

sed

with

: unc

ontro

lled

stud

ies)

l

6 ob

serv

atio

nal

stud

ies

very

se

rious

se

rious

se

rious

se

rious

no

ne

25/1

95

(12.

8%)

not

estim

able

VERY

lOW

CR

ItIC

Al

serio

us a

dver

se e

vent

s re

sulti

ng in

dru

g di

scon

tinua

tion

in N

tM p

atie

nts

on c

lofa

zimin

e (a

sses

sed

with

: com

para

tive

stud

ies

only

)l

4 ob

serv

atio

nal

stud

ies

very

se

rious

se

rious

se

rious

se

rious

no

ne

6/18

1 (3

.3%

) 15

/167

(9.0

%)

not

estim

able

VE

RY l

OW

CRIt

ICAl

Cl: c

onfid

ence

lim

its; R

E: ra

ndom

effe

cts

a Out

com

es w

ere

com

pare

d in

per

sons

who

rece

ived

clof

azim

ine

vers

us th

ose

who

rece

ived

no G

roup

5 d

rugs

. Adj

uste

d es

timat

e fro

m p

rope

nsity

sco

re m

atch

ing

was

done

, pat

ient

s wi

th c

lofa

zimin

e m

atch

ed to

pa

tient

s fro

m c

entre

s wh

ere

clof

azim

ine

was

not u

sed.

b RE

valu

e on

poo

led

met

a-an

alys

is: 6

3% (9

5% C

l: 4

9%–7

8%).

c RE

valu

e on

poo

led

met

a-an

alys

is: 6

2% (9

5% C

l: 4

5%–7

9%).

d Met

hod

of ra

ndom

izatio

n no

t des

crib

ed, a

nd n

o bl

indi

ng, i

ncre

asin

g ris

k of

allo

catio

n bi

as a

nd a

scer

tain

men

t bia

s.e O

ne s

tudy

in fi

ve c

entre

s in

one

cou

ntry

(Chi

na) o

nly.

f 95%

Cl:

68%

–91%

.g 9

5% C

l: 4

6%–7

4%.

h ben

efit w

as s

een

in o

ne R

Ct, b

ut in

5 s

mal

l obs

erva

tiona

l stu

dies

pat

ient

s re

ceiv

ing

clof

azim

ine

had

wors

e ou

tcom

es. t

hese

regi

men

s we

re in

divi

dual

ized

so th

ere

is ri

sk o

f bia

s (c

onfo

undi

ng b

y in

dica

tion)

.i o

ne ra

ndom

ized

cont

rol t

rial +

5 c

ohor

ts.

j Adj

uste

d pr

opor

tion

73%

; 95%

Cl:

64%

–82%

.k A

djus

ted

prop

ortio

n 89

%; 9

5% C

l: 7

3%–1

00%

.l A

dver

se e

vent

s re

porte

d in

pat

ient

s ta

king

clo

fazim

ine

were

attr

ibut

ed to

the

drug

by

auth

ors

who

were

unb

linde

d an

d us

ed n

on-s

tand

ardi

zed

met

hods

to d

efine

, asc

erta

in a

nd re

port

adve

rse

even

ts. N

o va

lid

com

paris

ons

are

poss

ible

with

pat

ient

s no

t tak

ing

clof

azim

ine,

bec

ause

adv

erse

eve

nts

in p

atie

nts

not r

ecei

ving

clo

fazim

ine

coul

d be

due

to o

ther

dru

gs re

ceive

d co

ncom

itant

ly.m

P=0

.04;

trea

tmen

t fai

lure

als

o si

gnifi

cant

ly lo

wer t

han

in c

ontro

l (11

% v

ersu

s 29

%; P

=0.0

3).

26

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): W

inte

rs N

, But

ler-L

apor

te G

, Men

zies

D (1

1 N

ovem

ber 2

015)

Que

stio

n: M

acro

lides

(cla

rithr

omyc

in, a

zith

rom

ycin

) com

pare

d to

no

mac

rolid

es fo

r tre

atm

ent o

f adu

lts w

ith ri

fam

pici

n-re

sista

nt T

B or

MD

R-T

B.

Sett

ing:

Tre

atm

ent o

f adu

lts w

ith ri

fam

pici

n-re

sista

nt T

B/M

DR

-TB/

XD

R-T

B us

ing c

onve

ntio

nal r

egim

ens l

astin

g abo

ut 2

4 m

onth

s, in

low

and

high

re

sour

ce se

tting

s, w

ithin

hos

pita

l or a

mbu

lato

ry m

odel

s of c

are (

as w

ell a

s non

-tube

rcul

ous m

ycob

acte

ria (N

TM

) in

som

e out

com

es fo

r SA

E)

Bib

liogr

aphy

: Win

ters

N, B

utler

-Lap

orte

G, M

enzi

es D

. Effi

cacy

and

safe

ty o

f Wor

ld H

ealth

Org

aniz

atio

n gr

oup

5 dr

ugs f

or m

ultid

rug-

resis

tant

tu

berc

ulos

is tr

eatm

ent.

Eur R

espi

r J. 2

015;

46(5

):146

1–70

.

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

MAC

ROLI

DES

(CLA

RITH

RO-

MYC

IN,

AZIT

HROM

YCIN

)NO

M

ACRO

LIDE

SRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

in M

DR-t

b pa

tient

s on

cla

rithr

omyc

in (H

IV u

ninf

ecte

d)

2 ob

serv

atio

nal

stud

iesa

serio

us

not s

erio

us

not s

erio

us

serio

us

none

20

/61

(32.

8%)

59/1

91

(30.

9%)

not

estim

able

19

mor

e pe

r 1,0

00

(from

10

fewe

r to

11 m

ore)

VE

RY l

OW

CRIt

ICAl

serio

us a

dver

se e

vent

s in

NtM

pat

ient

s on

cla

rithr

omyc

in (H

IV u

ninf

ecte

d) (a

sses

sed

with

: ran

dom

ized

cont

rolle

d tri

als)

3 ra

ndom

ized

trial

s no

t se

rious

se

rious

se

rious

bse

rious

no

nec

31/1

74

(17.

8%)

26/1

75

(14.

9%)

not

estim

able

10

mor

e pe

r 1,0

00

(from

60

fewe

r to

70 m

ore)

VE

RY l

OW

CRIt

ICAl

serio

us a

dver

se e

vent

s in

NtM

pat

ient

s on

cla

rithr

omyc

in (H

IV u

ninf

ecte

d) (a

sses

sed

with

: unc

ontro

lled

coho

rts)

15

obse

rvat

iona

l st

udie

sdse

rious

ese

rious

se

rious

bno

t ser

ious

no

ne

41/6

15

(6.7

%)

-no

t es

timab

le

VE

RY l

OW

CRIt

ICAl

serio

us a

dver

se e

vent

s in

NtM

pat

ient

s on

cla

rithr

omyc

in (H

IV in

fect

ed) (

asse

ssed

with

: ran

dom

ized

cont

rolle

d tri

als)

8 ra

ndom

ized

trial

s no

t se

rious

no

t ser

ious

se

rious

bse

rious

no

nec,

f10

8/10

88

(9.9

%)

118/

1111

(1

0.6%

) no

t es

timab

le7

few

er

per 1

,000

(fr

om 2

0 fe

wer t

o 20

mor

e)

lO

W

CRIt

ICAl

2727

ANNE

X 4:

GRA

DE tA

blEs

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

MAC

ROLI

DES

(CLA

RITH

RO-

MYC

IN,

AZIT

HROM

YCIN

)NO

M

ACRO

LIDE

SRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

serio

us a

dver

se e

vent

s in

NtM

pat

ient

s on

cla

rithr

omyc

in (H

IV in

fect

ed) (

asse

ssed

with

: unc

ontro

lled

coho

rts)

6 ob

serv

atio

nal

stud

iesd

serio

use

not s

erio

us

serio

usb

not s

erio

us

none

12

2/58

4 (2

0.9%

)g-

not

estim

able

e

VERY

lOW

CR

ItIC

Al

serio

us a

dver

se e

vent

s in

NtM

pat

ient

s on

azit

hrom

ycin

(HIV

uni

nfec

ted)

(ass

esse

d wi

th: u

ncon

trolle

d co

horts

)

5 ob

serv

atio

nal

stud

iesd

serio

use

serio

us

serio

usb

not s

erio

us

none

7/

197

(3

.6%

)hno

t es

timab

lee

VE

RY l

OW

CRIt

ICAl

serio

us a

dver

se e

vent

s in

NtM

pat

ient

s on

azit

hrom

ycin

(HIV

infe

cted

) (as

sess

ed w

ith: r

ando

mize

d co

ntro

lled

trial

s)

7 ra

ndom

ized

trial

s no

t se

rious

se

rious

se

rious

bse

rious

no

nec,

f11

3/12

15

(9.3

%)

57/1

196

(4.8

%)

not

estim

able

40 m

ore

per 1

,000

(fr

om 3

0 fe

wer t

o 10

0 m

ore)

VE

RY l

OW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in M

DR-t

b pa

tient

s on

mac

rolid

es (a

sses

sed

with

: ind

ivid

ual p

atie

nt d

ata

met

a-an

alys

is (A

huja

sD,

et a

l. 20

12; F

ox G

, et a

l. 20

15))

31

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

us

not s

erio

us

not s

erio

us

none

i25

4/39

6 (6

4.1%

)j32

92/4

970

(66.

2%)k

adju

sted

OR

0.7

(0

.3 to

1.

9)l

20 m

ore

per 1

,000

(fr

om 1

20

fewe

r to

150

mor

e)

VE

RY l

OW

CRIt

ICAl

Cl: c

onfid

ence

lim

its; O

R: o

dds

ratio

a Con

trolle

d co

horts

.b b

ased

on

stud

ies

of p

atie

nts

on p

reve

ntive

or c

urat

ive tr

eatm

ent f

or n

on-tu

berc

ulou

s m

ycob

acte

rial d

isea

se.

c Pat

ient

s wi

th a

dvan

ced

HIV,

and

stu

dies

from

pre

-ant

iretro

vira

ls e

ra.

d Un-

cont

rolle

d co

horts

.e U

nblin

ded

stud

ies;

adv

erse

eve

nts

attri

bute

d to

stu

dy d

rugs

by

auth

ors

with

non

-sta

ndar

dize

d m

etho

ds.

f ser

ious

adv

erse

eve

nts

expe

cted

to b

e m

ore

frequ

ent i

n th

ese

patie

nts

(adv

ance

d HI

V di

seas

e an

d no

ant

iretro

vira

l tre

atm

ent).

g 95%

Cl:

12%

–27%

.h 9

5% C

l: 0

%–8

%.

i Adj

uste

d es

timat

es u

sing

pro

pens

ity s

core

mat

chin

g.j A

djus

ted

estim

ate:

75%

(95%

Cl:

69%

–81%

).k A

djus

ted

estim

ates

73%

(95%

Cl:

66%

–81%

).l A

djus

ted

odds

ratio

est

imat

ed u

sing

pro

pens

ity s

core

mat

chin

g. R

efer

ence

pop

ulat

ion

for t

his

estim

ate

is p

atie

nts

in c

entre

s wh

ere

this

dru

g wa

s no

t use

d at

all.

28

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): F

ox G

, Men

zies

R, e

t al.

(11

Nov

embe

r 201

5)

Que

stio

n: Th

ioac

etaz

one c

ompa

red

to n

o th

ioac

etaz

one f

or tr

eatm

ent o

f adu

lts w

ith ri

fam

pici

n-re

sista

nt T

B an

d M

DR

-TB.

Sett

ing:

Tre

atm

ent o

f adu

lts w

ith ri

fam

pici

n-re

sista

nt T

B/M

DR

-TB/

XD

R-T

B us

ing c

onve

ntio

nal r

egim

ens l

astin

g abo

ut 2

4 m

onth

s, in

low

and

high

re

sour

ce se

tting

s, w

ithin

hos

pita

l or a

mbu

lato

ry m

odel

s of c

are.

Bib

liogr

aphy

: (1)

Fox

G, e

t al.

Gro

up 5

dru

gs fo

r mul

tidru

g-re

sista

nt tu

berc

ulos

is: in

divi

dual

pat

ient

dat

a met

a-an

alys

is (u

nder

revi

ew).

(2) A

huja

SD

, A

shki

n D

, Ave

ndan

o M

, Ban

erje

e R, B

auer

M, B

ayon

a JN

, et a

l. Mul

tidru

g res

istan

t pul

mon

ary t

uber

culo

sis tr

eatm

ent r

egim

ens a

nd p

atie

nt o

utco

mes

: an

indi

vidu

al p

atie

nt d

ata m

eta-

anal

ysis

of 9

,153

pat

ient

s. PL

oS M

ed. 2

012;

9(8)

:e10

0130

0.

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

TC

ERTA

INTY

O

F EV

IDEN

CE

IMP

OR

TAN

CE

NO. O

F ST

UDIE

SST

UDY

DESI

GNRI

SK O

F BI

ASIN

CONS

ISTE

NCY

INDI

RECT

NESS

IMPR

ECIS

ION

OTHE

R CO

NSID

ERAT

IONS

THIO

ACET

AZON

ENO

TH

IOAC

ETAZ

ONE

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in p

atie

nts

on th

ioac

etaz

one

as p

art o

f MDR

-tb

treat

men

t (as

sess

ed w

ith: i

ndiv

idua

l pat

ient

dat

a m

eta-

anal

ysis

)

31a

obse

rvat

iona

l st

udie

s ve

ry

serio

us

serio

usb

not s

erio

us

not s

erio

us

all p

laus

ible

resi

d-ua

l con

foun

ding

wo

uld

redu

ce th

e de

mon

stra

ted

effe

ct

491/

612

(80.

2%)c

3670

/564

7 (6

5.0%

)dad

just

ed

OR 2

.1

(0.8

to

5.5)

e

22 m

ore

per 1

,000

(fr

om 3

1 le

ss to

74

mor

e)f

VE

RY l

OW

CRIt

ICAl

Cl: c

onfid

ence

lim

its; R

E: ra

ndom

effe

cts

a In

7 of

thes

e st

udie

s at

leas

t one

per

son

rece

ived

thio

acet

azon

e (ra

nge:

1–6

71 p

er s

tudy

).b I

- squa

red

= 0%

(95%

Cl:

0%

–71%

).c R

E ad

just

ed %

= 8

0% (9

5% C

l: 7

7%–8

3%).

d RE

adju

sted

% =

72%

(95%

Cl:

63%

–80%

), am

ong

cont

rols

who

did

not

rece

ive th

ioac

etaz

one

in s

tudi

es w

here

thio

acet

azon

e wa

s no

t give

ne A

djus

ted

usin

g RE

mul

tivar

iabl

e an

alys

is w

ith p

rope

nsity

sco

re m

atch

ing

to a

djus

t for

pot

entia

l con

foun

ding

bet

ween

pat

ient

s ta

king

thio

acet

azon

e an

d m

atch

ed c

ontro

ls in

stu

dies

whe

re th

ioac

etaz

one

was

not u

sed

f RE

anal

ysis

, onl

y in

clud

ing

7 st

udie

s wh

ere

thio

acet

azon

e wa

s us

ed.

2929

ANNE

X 4:

GRA

DE tA

blEs

Aut

hor(

s): B

asto

s M, L

an Z

, Men

zies

R (1

1 N

ovem

ber 2

015)

Que

stio

n: p-

amin

osal

icyl

ic ac

id co

mpa

red

to n

o p-

amin

osal

icyl

ic ac

id fo

r tre

atm

ent o

f adu

lts w

ith ri

fam

pici

n-re

sista

nt T

B or

MD

R-T

B.

Sett

ing:

Tre

atm

ent o

f adu

lts w

ith ri

fam

pici

n-re

sista

nt T

B/M

DR

-TB/

XD

R-T

B us

ing c

onve

ntio

nal r

egim

ens l

astin

g abo

ut 2

4 m

onth

s, in

low

and

high

re

sour

ce se

tting

s, w

ithin

hos

pita

l or a

mbu

lato

ry m

odel

s of c

are

Bib

liogr

aphy

: (1)

Ahu

ja S

D, A

shki

n D

, Ave

ndan

o M

, Ban

erje

e R, B

auer

M, B

ayon

a JN

, et a

l. M

ultid

rug

resis

tant

pul

mon

ary

tube

rcul

osis

trea

tmen

t re

gim

ens a

nd p

atie

nt o

utco

mes

: an

indi

vidu

al p

atie

nt d

ata

met

a-an

alys

is of

9,1

53 p

atie

nts.

PLoS

Med

. 201

2;9(

8):e

1001

300.

(2) B

asto

s M, L

an Z

, M

enzi

es R

. An

upda

ted

syst

emat

ic re

view

and

met

a-an

alys

is fo

r tre

atm

ent o

f mul

tidru

g-re

sista

nt tu

berc

ulos

is, 2

016

(und

er re

view

, 28

May

201

6).

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

TC

ERTA

INTY

O

F EV

IDEN

CE

IMP

OR

TAN

CE

NO. O

F ST

UDIE

SST

UDY

DESI

GNRI

SK O

F BI

ASIN

CONS

ISTE

NCY

INDI

RECT

NESS

IMPR

ECIS

ION

OTHE

R CO

NSID

ERAT

IONS

P-AM

INOS

ALI-

CYLI

C AC

IDNO

P-A

MIN

O-SA

LICY

LIC

ACID

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in p

atie

nts

on p

-am

inos

alic

ylic

aci

d (P

As),

as p

art o

f a M

DR-t

b re

gim

en (a

sses

sed

with

: ind

ivid

ual p

atie

nt d

ata

met

a-an

alys

is (2

012)

)

32

obse

rvat

iona

l st

udie

s se

rious

ano

t ser

ious

no

t ser

ious

no

t ser

ious

al

l pla

usib

le re

sid-

ual c

onfo

undi

ng

woul

d re

duce

the

dem

onst

rate

d ef

fect

2162

/287

1 (7

5.3%

) 28

17/4

283

(65.

8%)

aOR

1.0

(0.8

to

1.4)

b

105

mor

e pe

r 1,0

00

(from

110

fe

wer t

o 12

0 m

ore)

lO

W

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se in

pat

ient

s on

PAs

as

part

of a

MDR

-tb

regi

men

(ass

esse

d wi

th: a

ggre

gate

dat

a m

eta-

anal

ysis

(201

5)

55

obse

rvat

iona

l st

udie

s se

rious

cno

t ser

ious

no

t ser

ious

no

t ser

ious

no

ned

4981

/574

4 (8

6.7%

)e29

68/3

595

(82.

6%)f

49 m

ore

per 1

,000

(fr

om

7 fe

wer

to 1

07

mor

e)l l

VE

RY l

OW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in p

atie

nts

on P

As a

s pa

rt of

a M

DR-t

b re

gim

en (a

sses

sed

with

: agg

rega

te d

ata

met

a-an

alys

is (2

015)

g

55

obse

rvat

iona

l st

udie

s se

rious

cno

t ser

ious

no

t ser

ious

no

t ser

ious

no

ned

4981

/627

6 (7

9.4%

)h29

68/4

521

(65.

6%)i

54 m

ore

per 1

,000

(fr

om 3

4 fe

wer t

o 14

4 m

ore)

l

VE

RY l

OW

CRIt

ICAl

serio

us a

dver

se e

vent

s (G

rade

3 o

r 4, o

r dru

gs s

topp

ed d

ue to

adv

erse

eve

nts)

in p

atie

nts

on P

As, a

s pa

rt of

a M

DR-t

b re

gim

en (a

sses

sed

with

: agg

rega

ted

data

met

a-an

alys

is 2

015)

16

obse

rvat

iona

l st

udie

s se

rious

no

t ser

ious

no

t ser

ious

no

t ser

ious

no

nej

208/

1706

(1

2.2%

)kno

t es

timab

le

VE

RY l

OW

CRIt

ICAl

30

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Cl: c

onfid

ence

lim

its; F

E: fi

xed

effe

cts

a Ind

ivid

ual p

atie

nt d

ata

take

n fro

m 3

2 ob

serv

atio

nal s

tudi

es in

whi

ch m

ost p

atie

nts

rece

ived

indi

vidu

alize

d tre

atm

ent.

Risk

of s

elec

tion

bias

, and

con

foun

ding

by

indi

catio

n.b a

OR: O

dds

ratio

adj

uste

d fo

r age

, HIV

, aci

d-fa

st b

acill

us s

mea

r, ch

est r

adio

grap

h ca

vita

tion,

and

prio

r tre

atm

ent w

ith fi

rst l

ine,

and

sec

ond

line

tb d

rugs

.c V

ery

serio

us li

mita

tions

– a

ll st

udie

s we

re o

bser

vatio

nal –

lead

ing

to ri

sk o

f sel

ectio

n an

d in

form

atio

n bi

as. I

n 20

stu

dies

the

patie

nts

were

give

n st

anda

rdize

d re

gim

ens,

but

in th

e re

mai

ning

40

stud

ies

ther

apy

was

indi

vidu

alize

d, le

adin

g to

risk

of c

onfo

undi

ng b

y in

dica

tion.

d Una

djus

ted

anal

ysis

.e P

oole

d pr

opor

tion:

93%

(95%

Cl:

83%

–96%

).f P

oole

d pr

opor

tion:

90%

(95%

Cl:

85%

–95%

).g F

rom

agg

rega

te d

ata

met

a-an

alys

is: P

atie

nts

with

XDR

-tb

excl

uded

from

ana

lyse

s, w

here

pos

sibl

e.h P

oole

d pr

opor

tion:

81%

(95%

Cl:

75%

–87%

).i P

oole

d pr

opor

tion:

78%

(95%

Cl:

71%

–85%

).j s

erio

us a

dver

se e

vent

s (s

AEs)

repo

rted

in p

atie

nts

were

attr

ibut

ed to

a m

edic

ine

by th

e au

thor

s wh

o we

re u

nblin

ded

and

used

non

-sta

ndar

dize

d m

etho

ds to

defi

ne, a

scer

tain

and

repo

rt sA

Es. N

o va

lid c

ompa

rison

s ar

e po

ssib

le w

ith p

atie

nts

not o

n th

e ta

rget

med

icin

e, b

ecau

se s

AEs

in th

ese

patie

nts

coul

d be

due

to o

ther

dru

gs re

ceive

d.k P

oole

d pr

opor

tion:

FE

95%

Cl:

10.

6%–1

3.9%

.l R

isk

diffe

renc

e fro

m a

djus

ted

anal

ysis

.

3131

ANNE

X 4:

GRA

DE tA

blEs

Aut

hor(

s): B

asto

s M, L

an Z

, Men

zies

R (1

1 N

ovem

ber 2

015)

Que

stio

n: P

yraz

inam

ide c

ompa

red

to n

o py

razi

nam

ide f

or ad

ults

with

rifa

mpi

cin-

resis

tant

TB

or M

DR

-TB.

Sett

ing:

Tre

atm

ent o

f adu

lts w

ith r

ifam

pici

n-re

sista

nt T

B/M

DR

-TB/

XD

R-T

B us

ing

conv

entio

nal r

egim

ens l

astin

g ab

out 2

4 m

onth

s and

shor

ter

MD

R-T

B re

gim

ens,

in lo

w an

d hi

gh re

sour

ce se

tting

s, w

ithin

hos

pita

l or a

mbu

lato

ry m

odel

s of c

are.

Bib

liogr

aphy

: (1)

Ahu

ja S

D, A

shki

n D

, Ave

ndan

o M

, Ban

erje

e R, B

auer

M, B

ayon

a JN

, et a

l. M

ultid

rug

resis

tant

pul

mon

ary

tube

rcul

osis

trea

tmen

t re

gim

ens a

nd p

atie

nt o

utco

mes

: an

indi

vidu

al p

atie

nt d

ata

met

a-an

alys

is of

9,1

53 p

atie

nts.

PLoS

Med

. 201

2;9(

8):e

1001

300.

(2) B

asto

s M, L

an Z

, M

enzi

es R

. An

upda

ted

syst

emat

ic re

view

and

met

a-an

alys

is fo

r tre

atm

ent o

f mul

tidru

g-re

sista

nt tu

berc

ulos

is, 2

016

(und

er re

view

, 28

May

201

6).

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

TC

ERTA

INTY

O

F EV

IDEN

CE

IMP

OR

TAN

CE

NO. O

F ST

UDIE

SST

UDY

DESI

GNRI

SK O

F BI

ASIN

CONS

ISTE

NCY

INDI

RECT

NESS

IMPR

ECIS

ION

OTHE

R CO

NSID

ERAT

IONS

PYRA

ZINA

MID

ENO

PY

RAZI

NAM

IDE

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se/d

eath

in p

atie

nts

on p

yraz

inam

ide

as p

art o

f a M

DR-t

b re

gim

en (a

sses

sed

with

: ind

ivid

ual p

atie

nt d

ata

met

a-an

alys

is (A

huja

sD,

et a

l. Pl

Os M

ed. 2

012)

20

obse

rvat

iona

l st

udie

s se

rious

no

t ser

ious

no

t ser

ious

no

t ser

ious

no

ne

2454

/377

5 (6

5.0%

) 55

/89

(61.

8%)

aOR

1.3

(1.1

to

1.6)

a

32 m

ore

per 1

000

(from

10

mor

e to

60

mor

e)

VE

RY l

OW

CRIt

ICAl

serio

us a

dver

se e

vent

s (G

rade

3–4

eve

nts,

or d

rugs

sto

pped

due

to a

dver

se e

vent

s) in

pat

ient

s on

pyr

azin

amid

e as

par

t of a

MDR

-tb

regi

men

(ass

esse

d wi

th: a

ggre

gate

d da

ta m

eta-

anal

ysis

201

5)

19

obse

rvat

iona

l st

udie

s se

rious

no

t ser

ious

no

t ser

ious

no

t ser

ious

no

neb

56/2

023

(2.8

%)c

not

estim

able

VERY

lOW

CR

ItIC

Al

Cl: c

onfid

ence

lim

its; F

E: fi

xed

effe

cts

a aOR

: odd

s ra

tio a

djus

ted

for a

ge, H

IV, a

cid-

fast

bac

illus

sm

ear,

ches

t rad

iogr

aph

cavi

tatio

n, a

nd p

rior t

reat

men

t with

firs

t-lin

e an

d se

cond

-line

tb d

rugs

.b s

erio

us a

dver

se e

vent

s (s

AEs)

repo

rted

in p

atie

nts

were

attr

ibut

ed to

a m

edic

ine

by th

e au

thor

s wh

o we

re u

nblin

ded

and

used

non

-sta

ndar

dize

d m

etho

ds to

defi

ne, a

scer

tain

and

repo

rt sA

Es. N

o va

lid c

ompa

rison

s ar

e po

ssib

le w

ith p

atie

nts

not o

n th

e ta

rget

med

icin

e, b

ecau

se s

AEs

in th

ese

patie

nts

coul

d be

due

to o

ther

dru

gs re

ceive

d.c P

oole

d pr

opor

tion:

FE

95%

Cl:

2.1

%–3

.7%

.

32

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

3. M

DR

-TB

reg

imen

com

posi

tion

– p

aedi

atric

indi

vidu

al p

atie

nt d

ata

met

a-an

alys

is (

PIC

O 1

)A

utho

r(s)

: Eliz

abet

h H

arau

sz, A

ntho

ny G

arci

a-Pr

ats,

Sim

on S

chaa

f, St

epha

nie

Law,

Dic

k M

enzi

es, J

enni

fer

Furin

, Tam

ara

Kre

do a

nd A

nnek

e C

. H

esse

ling o

n be

half

of th

e Pae

diat

ric M

DR

-TB

IPD

Gro

up (1

1 N

ovem

ber 2

015)

Que

stio

n: L

ater

-gen

erat

ion

fluor

oqui

nolo

nes c

ompa

red

to n

o la

ter-

gene

ratio

n flu

oroq

uino

lone

s for

chi

ldre

n w

ith M

DR

-TB

(exc

ludi

ng c

onfir

med

X

DR

-TB)

.

Sett

ing:

Inte

rnat

iona

l

Bib

liogr

aphy

: Ref

er to

Ann

ex 6

, Sec

tion

3 fo

r a su

mm

ary o

f thi

s unp

ublis

hed

stud

y (H

arau

sz E

, Gar

cia-

Prat

s AJ,

Scha

af S

, Law

S, F

urin

J, K

redo

T, e

t al

., for

The C

olla

bora

tive G

roup

for M

eta-

Ana

lysis

of P

aedi

atric

Indi

vidu

al P

atie

nt D

ata i

n M

DR

-TB.

 A sy

stem

atic

revi

ew an

d in

divi

dual

pat

ient

dat

a m

eta-

anal

ysis

of tr

eatm

ent a

nd o

utco

mes

amon

g chi

ldre

n w

ith m

ulti-

drug

resis

tant

tube

rcul

osis.

 A p

relim

inar

y rep

ort f

or th

e Gui

delin

e Dev

elop

men

t G

roup

Mee

ting o

f the

Wor

ld H

ealth

Org

aniz

atio

n, N

ovem

ber 9

–11

2015

).

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

LATE

R-

GENE

RATI

ON

FLUO

ROQU

I-NO

LONE

S

NO L

ATER

- GE

NERA

TION

FL

UORO

QUI-

NOLO

NES

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– co

nfirm

ed c

ases

(IPD

ana

lysi

s): n

= 6

23

12

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

no

t ser

ious

no

ne

480/

551

(87.

1%)

36/4

5 (8

0.0%

) OR

0.7

10

(0.0

94 to

5.

370)

a

37 fe

wer

pe

r 100

0 (fr

om 1

80

fewe

r to

110

mor

e)

VE

RY l

OW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die/

lost

to fo

llow

up –

unc

onfir

med

cas

es (I

PD a

naly

sis)

: n =

219

b

3 ob

serv

atio

nal

stud

ies

serio

us

serio

us

not s

erio

us

not s

erio

us

none

19

/21

(90.

5%)

169/

184

(91.

8%)

OR 0

.667

(0

.064

to

6.96

6)a,

b

47 fe

wer

pe

r 100

0 (fr

om 1

3 fe

wer t

o 10

8 m

ore)

VE

RY l

OW

CRIt

ICAl

Cl: c

onfid

ence

lim

its; O

R: o

dds

ratio

a All

effe

ct e

stim

ates

sho

wn a

re a

djus

ted

for a

ge, H

IV s

tatu

s, g

ende

r, tb

dis

ease

sev

erity

and

site

(ran

dom

effe

cts

mod

el w

ith c

lust

erin

g by

site

).b U

ncon

firm

ed c

ases

incl

ude

lost

to fo

llow

up in

this

ana

lysi

s on

ly.

3333

ANNE

X 4:

GRA

DE tA

blEs

Aut

hor(

s): E

lizab

eth

Har

ausz

, Ant

hony

Gar

cia-

Prat

s, Si

mon

Sch

aaf,

Step

hani

e La

w, D

ick

Men

zies

, Jen

nife

r Fu

rin, T

amar

a K

redo

and

Ann

eke

C.

Hes

selin

g on

beha

lf of

the P

aedi

atric

MD

R-T

B IP

D G

roup

(11

Nov

embe

r 201

5)

Que

stio

n: S

econ

d-lin

e inj

ecta

ble a

gent

com

pare

d to

no

seco

nd-li

ne in

ject

able

agen

t for

child

ren

with

MD

R-T

B (e

xclu

ding

confi

rmed

XD

R-T

B)

Sett

ing:

Inte

rnat

iona

l

Bib

liogr

aphy

: Ref

er to

Ann

ex 6

, Sec

tion

3 fo

r a su

mm

ary o

f thi

s unp

ublis

hed

stud

y (H

arau

sz E

, Gar

cia-

Prat

s AJ,

Scha

af S

, Law

S, F

urin

J, K

redo

T, e

t al

., for

The C

olla

bora

tive G

roup

for M

eta-

Ana

lysis

of P

aedi

atric

Indi

vidu

al P

atie

nt D

ata i

n M

DR

-TB.

 A sy

stem

atic

revi

ew an

d in

divi

dual

pat

ient

dat

a m

eta-

anal

ysis

of tr

eatm

ent a

nd o

utco

mes

amon

g chi

ldre

n w

ith m

ulti-

drug

resis

tant

tube

rcul

osis.

 A p

relim

inar

y rep

ort f

or th

e Gui

delin

e Dev

elop

men

t G

roup

Mee

ting o

f the

Wor

ld H

ealth

Org

aniz

atio

n, N

ovem

ber 9

–11

2015

).

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

SECO

ND-L

INE

IN

JECT

ABLE

AG

ENT

NO S

ECON

D LI

NE

INJE

CTAB

LE

AGEN

TRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– co

nfirm

ed c

ases

(IPD

ana

lysi

s): n

= 6

23

25

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

no

t ser

ious

no

ne

493/

566

(87.

1%)

41/5

7 (7

1.9%

) OR

3.3

2 (1

.53

to

7.21

)a

43 m

ore

per 1

000

(from

107

fe

wer t

o 19

4 m

ore)

VE

RY l

OW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– un

confi

rmed

cas

es (I

PD a

naly

sis)

: n =

219

12

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

no

t ser

ious

no

ne

154/

157

(98.

1%)

58/6

2 (9

3.5%

) OR

1.3

8 (0

.14

to

13.5

0)a

11 m

ore

per 1

000

(from

108

fe

wer t

o 12

9 m

ore)

VE

RY l

OW

CRIt

ICAl

Cl: c

onfid

ence

lim

it; O

R: o

dds

ratio

a All

effe

ct e

stim

ates

sho

wn a

re a

djus

ted

for a

ge, H

IV s

tatu

s, g

ende

r, tb

dis

ease

sev

erity

and

site

(ran

dom

effe

cts

mod

el w

ith c

lust

erin

g by

site

).

34

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): E

lizab

eth

Har

ausz

, Ant

hony

Gar

cia-

Prat

s, Si

mon

Sch

aaf,

Step

hani

e La

w, D

ick

Men

zies

, Jen

nife

r Fu

rin, T

amar

a K

redo

and

Ann

eke

C.

Hes

selin

g on

beha

lf of

the P

aedi

atric

MD

R-T

B IP

D G

roup

(11

Nov

embe

r 201

5)

Que

stio

n: E

thio

nam

ide/

prot

hion

amid

e com

pare

d to

no

ethi

onam

ide/

prot

hion

amid

e for

child

ren

with

MD

R-T

B (e

xclu

ding

confi

rmed

XD

R-T

B)

Sett

ing:

Inte

rnat

iona

l

Bib

liogr

aphy

: Ref

er to

Ann

ex 6

, Sec

tion

3 fo

r a su

mm

ary o

f thi

s unp

ublis

hed

stud

y (H

arau

sz E

, Gar

cia-

Prat

s AJ,

Scha

af S

, Law

S, F

urin

J, K

redo

T, e

t al

., for

The C

olla

bora

tive G

roup

for M

eta-

Ana

lysis

of P

aedi

atric

Indi

vidu

al P

atie

nt D

ata i

n M

DR

-TB.

 A sy

stem

atic

revi

ew an

d in

divi

dual

pat

ient

dat

a m

eta-

anal

ysis

of tr

eatm

ent a

nd o

utco

mes

amon

g chi

ldre

n w

ith m

ulti-

drug

resis

tant

tube

rcul

osis.

 A p

relim

inar

y rep

ort f

or th

e Gui

delin

e Dev

elop

men

t G

roup

Mee

ting o

f the

Wor

ld H

ealth

Org

aniz

atio

n, N

ovem

ber 9

–11

2015

).

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

ETHI

ONAM

IDE/

PROT

HION

A-M

IDE

NO

ETHI

ONAM

IDE/

PROT

HION

A-M

IDE

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– co

nfirm

ed c

ases

(IPD

ana

lysi

s): n

= 6

23

24

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

no

t ser

ious

no

ne

493/

574

(85.

9%)

41/4

9 (8

3.7%

) OR

2.0

4 (0

.29

to

14.6

0)a

59 fe

wer

pe

r 100

0 (fr

om 1

80

fewe

r to

60 m

ore)

VE

RY l

OW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– un

confi

rmed

cas

es (I

PD a

naly

sis)

: n =

219

11

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

no

t ser

ious

no

ne

181/

187

(96.

8%)

31/3

2 (9

6.9%

) OR

1.0

8 (0

.05

to

21.9

0)a

19 fe

wer

pe

r 100

0 (fr

om 1

39

fewe

r to

102

mor

e)

VE

RY l

OW

CRIt

ICAl

Cl: c

onfid

ence

lim

its; O

R: o

dds

ratio

a All

effe

ct e

stim

ates

sho

wn a

re a

djus

ted

for a

ge, H

IV s

tatu

s, g

ende

r, tb

dis

ease

sev

erity

and

site

(ran

dom

effe

cts

mod

el w

ith c

lust

erin

g by

site

).

3535

ANNE

X 4:

GRA

DE tA

blEs

Aut

hor(

s): E

lizab

eth

Har

ausz

, Ant

hony

Gar

cia-

Prat

s, Si

mon

Sch

aaf,

Step

hani

e La

w, D

ick

Men

zies

, Jen

nife

r Fu

rin, T

amar

a K

redo

and

Ann

eke

C.

Hes

selin

g on

beha

lf of

the P

aedi

atric

MD

R-T

B IP

D G

roup

(11

Nov

embe

r 201

5)

Que

stio

n: C

yclo

serin

e/te

rizid

one c

ompa

red

to n

o cy

clos

erin

e/te

rizid

one f

or in

child

ren

with

MD

R-T

B (e

xclu

ding

confi

rmed

XD

R-T

B)

Sett

ing:

Inte

rnat

iona

l

Bib

liogr

aphy

: Ref

er to

Ann

ex 6

, Sec

tion

3 fo

r a su

mm

ary o

f thi

s unp

ublis

hed

stud

y (H

arau

sz E

, Gar

cia-

Prat

s AJ,

Scha

af S

, Law

S, F

urin

J, K

redo

T, e

t al

., for

The C

olla

bora

tive G

roup

for M

eta-

Ana

lysis

of P

aedi

atric

Indi

vidu

al P

atie

nt D

ata i

n M

DR

-TB.

 A sy

stem

atic

revi

ew an

d in

divi

dual

pat

ient

dat

a m

eta-

anal

ysis

of tr

eatm

ent a

nd o

utco

mes

amon

g chi

ldre

n w

ith m

ulti-

drug

resis

tant

tube

rcul

osis.

 A p

relim

inar

y rep

ort f

or th

e Gui

delin

e Dev

elop

men

t G

roup

Mee

ting o

f the

Wor

ld H

ealth

Org

aniz

atio

n, N

ovem

ber 9

–11

2015

).

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NSCY

CLOS

ERIN

E/

TERI

ZIDO

NE

NO

CYCL

OSER

INE/

TE

RIZI

DONE

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die/

lost

– c

onfir

med

cas

es o

nly

(IPD

anal

ysis

): n

= 70

1

24

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

no

t ser

ious

no

ne

307/

339

(90.

6%)

227/

284

(79.

9%)

OR 1

.70

(0.9

1 to

3.

19)a

3 fe

wer

pe

r 100

0 (fr

om 9

0 fe

wer t

o 97

mor

e)

VE

RY l

OW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– un

confi

rmed

cas

es (I

PD a

naly

sis)

: n =

219

10

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

no

t ser

ious

no

ne

132/

134

(98.

5%)

80/8

5 (9

4.1%

) OR

0.3

8 (0

.01

to

28.9

0)a

13 fe

wer

pe

r 100

0 (fr

om 1

06

fewe

r to

81 m

ore)

VE

RY l

OW

CRIt

ICAl

Cl: c

onfid

ence

lim

its; O

R: o

dds

ratio

a All

effe

ct e

stim

ates

sho

wn a

re a

djus

ted

for a

ge, H

IV s

tatu

s, g

ende

r, tb

dis

ease

sev

erity

and

site

(ran

dom

effe

cts

mod

el w

ith c

lust

erin

g by

site

).

36

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): E

lizab

eth

Har

ausz

, Ant

hony

Gar

cia-

Prat

s, Si

mon

Sch

aaf,

Step

hani

e La

w, D

ick

Men

zies

, Jen

nife

r Fu

rin, T

amar

a K

redo

and

Ann

eke

C.

Hes

selin

g on

beha

lf of

the P

aedi

atric

MD

R-T

B IP

D G

roup

(11

Nov

embe

r 201

5)

Que

stio

n: C

lofa

zim

ine c

ompa

red

to n

o cl

ofaz

imin

e for

child

ren

with

MD

R tu

berc

ulos

is (e

xclu

ding

confi

rmed

XD

R-T

B)

Sett

ing:

Inte

rnat

iona

l

Bib

liogr

aphy

: Ref

er to

Ann

ex 6

, Sec

tion

3 fo

r a su

mm

ary o

f thi

s unp

ublis

hed

stud

y (H

arau

sz E

, Gar

cia-

Prat

s AJ,

Scha

af S

, Law

S, F

urin

J, K

redo

T, e

t al

., for

The C

olla

bora

tive G

roup

for M

eta-

Ana

lysis

of P

aedi

atric

Indi

vidu

al P

atie

nt D

ata i

n M

DR

-TB.

 A sy

stem

atic

revi

ew an

d in

divi

dual

pat

ient

dat

a m

eta-

anal

ysis

of tr

eatm

ent a

nd o

utco

mes

amon

g chi

ldre

n w

ith m

ulti-

drug

resis

tant

tube

rcul

osis.

 A p

relim

inar

y rep

ort f

or th

e Gui

delin

e Dev

elop

men

t G

roup

Mee

ting o

f the

Wor

ld H

ealth

Org

aniz

atio

n, N

ovem

ber 9

–11

2015

).

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

TC

ERTA

INTY

O

F EV

IDEN

CE

IMP

OR

TAN

CE

NO. O

F ST

UDIE

SST

UDY

DESI

GNRI

SK O

F BI

ASIN

CONS

ISTE

NCY

INDI

RECT

NESS

IMPR

ECIS

ION

OTHE

R CO

NSID

ERAT

IONS

CLOF

AZIM

INE

NO

CLOF

AZIM

INE

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– co

nfirm

ed c

ases

(IPD

ana

lysi

s): n

= 6

23

9 ob

serv

atio

nal

stud

ies

serio

us

serio

us

not s

erio

us

serio

us

none

18

/23

(78.

3%)

516/

600

(86.

0%)

OR 0

.46

(0.0

2 to

10

.00)

a

47 m

ore

per 1

000

(from

81

fewe

r to

170

mor

e)

VE

RY l

OW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– un

confi

rmed

cas

es (I

PD a

naly

sis)

: n =

219

2 ob

serv

atio

nal

stud

ies

serio

us

serio

us

not s

erio

us

serio

us

none

4/

4 (1

00.0

%)

208/

215

(96.

7%)

OR 0

.25

(0.1

2 to

5.

30)b

47 m

ore

per 1

000

(from

14

fewe

r to

107

mor

e)

VE

RY l

OW

CRIt

ICAl

Cl: c

onfid

ence

lim

its; O

R: o

dds

ratio

a Effe

ct e

stim

ates

for t

he c

onfir

med

are

adj

uste

d fo

r age

, HIV

sta

tus,

gen

der,

tb d

isea

se s

ever

ity a

nd s

ite (r

ando

m e

ffect

s m

odel

with

clu

ster

ing

by s

ite).

b Effe

ct e

stim

ate

is n

ot a

djus

ted.

3737

ANNE

X 4:

GRA

DE tA

blEs

Aut

hor(

s): E

lizab

eth

Har

ausz

, Ant

hony

Gar

cia-

Prat

s, Si

mon

Sch

aaf,

Step

hani

e La

w, D

ick

Men

zies

, Jen

nife

r Fu

rin, T

amar

a K

redo

and

Ann

eke

C.

Hes

selin

g on

beha

lf of

the P

aedi

atric

MD

R-T

B IP

D G

roup

(11

Nov

embe

r 201

5)

Que

stio

n: P

yraz

inam

ide c

ompa

red

to n

o py

razi

nam

ide f

or ch

ildre

n w

ith M

DR

tube

rcul

osis

(exc

ludi

ng co

nfirm

ed X

DR

-TB)

Sett

ing:

Inte

rnat

iona

l

Bib

liogr

aphy

: Ref

er to

Ann

ex 6

, Sec

tion

3 fo

r a su

mm

ary o

f thi

s unp

ublis

hed

stud

y (H

arau

sz E

, Gar

cia-

Prat

s AJ,

Scha

af S

, Law

S, F

urin

J, K

redo

T, e

t al

., for

The C

olla

bora

tive G

roup

for M

eta-

Ana

lysis

of P

aedi

atric

Indi

vidu

al P

atie

nt D

ata i

n M

DR

-TB.

 A sy

stem

atic

revi

ew an

d in

divi

dual

pat

ient

dat

a m

eta-

anal

ysis

of tr

eatm

ent a

nd o

utco

mes

amon

g chi

ldre

n w

ith m

ulti-

drug

resis

tant

tube

rcul

osis.

 A p

relim

inar

y rep

ort f

or th

e Gui

delin

e Dev

elop

men

t G

roup

Mee

ting o

f the

Wor

ld H

ealth

Org

aniz

atio

n, N

ovem

ber 9

–11

2015

).

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

TC

ERTA

INTY

O

F EV

IDEN

CE

IMP

OR

TAN

CE

NO. O

F ST

UDIE

SST

UDY

DESI

GNRI

SK O

F BI

ASIN

CONS

ISTE

NCY

INDI

RECT

NESS

IMPR

ECIS

ION

OTHE

R CO

NSID

ERAT

IONS

PYRA

ZINA

MID

ENO

PY

RAZI

NAM

IDE

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– co

nfirm

ed c

ases

(IPD

ana

lysi

s): n

= 6

23

26

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

no

t ser

ious

no

ne

499/

582

(85.

7%)

35/4

1 (8

5.4%

) OR

0.4

5 (0

.01

to

33.4

0)a

66 fe

wer

pe

r 100

0 (fr

om 1

60

fewe

r to

26 m

ore)

VE

RY l

OW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– un

confi

rmed

cas

es (I

PD a

naly

sis)

: n =

219

12

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

no

t ser

ious

no

ne

187/

194

(96.

4%)

25/2

5 (1

00.0

%)

OR 0

.490

(0

.027

to

8.84

0)b

50 fe

wer

pe

r 100

0 (fr

om 1

14

fewe

r to

14 m

ore)

VE

RY l

OW

CRIt

ICAl

Cl: c

onfid

ence

lim

its; O

R: o

dds

ratio

a Effe

ct e

stim

ates

for c

onfir

med

are

adj

uste

d fo

r age

, HIV

sta

tus,

gen

der,

tb d

isea

se s

ever

ity a

nd s

ite (r

ando

m e

ffect

s m

odel

with

clu

ster

ing

by s

ite)

b OR

for u

ncon

firm

ed c

ases

is n

ot a

djus

ted.

38

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): E

lizab

eth

Har

ausz

, Ant

hony

Gar

cia-

Prat

s, Si

mon

Sch

aaf,

Step

hani

e La

w, D

ick

Men

zies

, Jen

nife

r Fu

rin, T

amar

a K

redo

and

Ann

eke

C.

Hes

selin

g on

beha

lf of

the P

aedi

atric

MD

R-T

B IP

D G

roup

(11

Nov

embe

r 201

5)

Que

stio

n: H

igh

dose

ison

iazi

d co

mpa

red

to n

o hi

gh d

ose i

soni

azid

for c

hild

ren

with

MD

R-T

B (e

xclu

ding

confi

rmed

XD

R-T

B)a

Sett

ing:

Inte

rnat

iona

l

Bib

liogr

aphy

: Ref

er to

Ann

ex 6

, Sec

tion

3 fo

r a su

mm

ary o

f thi

s unp

ublis

hed

stud

y (H

arau

sz E

, Gar

cia-

Prat

s AJ,

Scha

af S

, Law

S, F

urin

J, K

redo

T, e

t al

., for

The C

olla

bora

tive G

roup

for M

eta-

Ana

lysis

of P

aedi

atric

Indi

vidu

al P

atie

nt D

ata i

n M

DR

-TB.

 A sy

stem

atic

revi

ew an

d in

divi

dual

pat

ient

dat

a m

eta-

anal

ysis

of tr

eatm

ent a

nd o

utco

mes

amon

g chi

ldre

n w

ith m

ulti-

drug

resis

tant

tube

rcul

osis.

 A p

relim

inar

y rep

ort f

or th

e Gui

delin

e Dev

elop

men

t G

roup

Mee

ting o

f the

Wor

ld H

ealth

Org

aniz

atio

n, N

ovem

ber 9

–11

2015

).

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

TC

ERTA

INTY

O

F EV

IDEN

CE

IMP

OR

TAN

CE

NO. O

F ST

UDIE

SST

UDY

DESI

GNRI

SK O

F BI

ASIN

CONS

ISTE

NCY

INDI

RECT

NESS

IMPR

ECIS

ION

OTHE

R CO

NSID

ERAT

IONS

HIGH

DOS

E

ISON

IAZI

DNO

HIG

H DO

SE

ISON

IAZI

DRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– co

nfirm

ed c

ases

(IPD

ana

lysi

s): n

= 6

23

6 ob

serv

atio

nal

stud

ies

serio

usa

serio

us

not s

erio

us

not s

erio

us

none

13

0/13

3 (9

7.7%

) 40

4/49

0 (8

2.4%

) OR

6.9

7 (2

.11

to

23.0

0)b

120

mor

e pe

r 100

0 (fr

om 5

9 m

ore

to

187

mor

e)

VE

RY l

OW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– un

confi

rmed

cas

es (I

PD a

naly

sis)

: n =

219

c

1 ob

serv

atio

nal

stud

ies

serio

usa

serio

us

not s

erio

us

not s

erio

us

none

85

/85

(100

.0%

) 12

7/13

4 (9

4.8%

) OR

10.

06

(0.5

6 to

17

8.40

)c

VERY

lOW

CR

ItIC

Al

Cl: c

onfid

ence

lim

its; O

R: o

dds

ratio

a Mos

t of t

he c

ases

rece

ivin

g hi

gh-d

ose

ison

iazid

wer

e fro

m c

ohor

ts in

sou

th A

frica

, so

desp

ite a

djus

ting

for s

tudy

site

, the

re m

ay s

till b

e so

me

resi

dual

con

foun

ding

.b E

ffect

est

imat

es s

hown

are

adj

uste

d fo

r age

, HIV

sta

tus,

gen

der,

tb d

isea

se s

ever

ity a

nd s

ite (r

ando

m e

ffect

s m

odel

with

clu

ster

ing

by s

ite).

c OR

for t

he u

ncon

firm

ed c

ases

is n

ot a

djus

ted.

3939

ANNE

X 4:

GRA

DE tA

blEs

Aut

hor(

s): E

lizab

eth

Har

ausz

, Ant

hony

Gar

cia-

Prat

s, Si

mon

Sch

aaf,

Step

hani

e La

w, D

ick

Men

zies

, Jen

nife

r Fu

rin, T

amar

a K

redo

and

Ann

eke

C.

Hes

selin

g on

beha

lf of

the P

aedi

atric

MD

R-T

B IP

D G

roup

(11

Nov

embe

r 201

5)

Que

stio

n: p-

amin

osal

icyl

ic ac

id co

mpa

red

to n

o p-

amin

osal

icyl

ic ac

id fo

r chi

ldre

n w

ith M

DR

-TB

(exc

ludi

ng co

nfirm

ed X

DR

-TB)

Sett

ing:

Inte

rnat

iona

l

Bib

liogr

aphy

: Ref

er to

Ann

ex 6

, Sec

tion

3 fo

r a su

mm

ary o

f thi

s unp

ublis

hed

stud

y (H

arau

sz E

, Gar

cia-

Prat

s AJ,

Scha

af S

, Law

S, F

urin

J, K

redo

T, e

t al

., for

The C

olla

bora

tive G

roup

for M

eta-

Ana

lysis

of P

aedi

atric

Indi

vidu

al P

atie

nt D

ata i

n M

DR

-TB.

 A sy

stem

atic

revi

ew an

d in

divi

dual

pat

ient

dat

a m

eta-

anal

ysis

of tr

eatm

ent a

nd o

utco

mes

amon

g chi

ldre

n w

ith m

ulti-

drug

resis

tant

tube

rcul

osis.

 A p

relim

inar

y rep

ort f

or th

e Gui

delin

e Dev

elop

men

t G

roup

Mee

ting o

f the

Wor

ld H

ealth

Org

aniz

atio

n, N

ovem

ber 9

–11

2015

).

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NSP-

AMIN

OSAL

I-CY

LIC

ACID

NO

P-AM

INOS

ALI-

CYLI

C AC

ID

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– co

nfirm

ed c

ases

(IPD

ana

lysi

s): n

= 6

23

20

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

no

t ser

ious

no

ne

115/

135

(85.

2%)

419/

488

(85.

9%)

OR 0

.52

(0.2

6 to

1.

07)a

5 fe

wer

pe

r 100

0 (fr

om 1

10

fewe

r to

95 m

ore)

VE

RY l

OW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die/

lost

to fo

llow

up –

unc

onfir

med

cas

es (I

PD a

naly

sis)

: n =

237

b

8 ob

serv

atio

nal

stud

ies

serio

us

serio

us

not s

erio

us

serio

us

none

69

/75

(92.

0%)

143/

162

(88.

3%)

OR 0

.18

(0.0

2 to

1.

76)a,

b

27 fe

wer

pe

r 100

0 (fr

om 6

0 fe

wer t

o 11

5 m

ore)

VE

RY l

OW

CRIt

ICAl

Cl: c

onfid

ence

lim

its; O

R: o

dds

ratio

a All

effe

ct e

stim

ates

for c

onfir

med

cas

es a

re a

djus

ted

for a

ge, H

IV s

tatu

s, g

ende

r, tb

dis

ease

sev

erity

and

site

(ran

dom

effe

cts

mod

el w

ith c

lust

erin

g by

site

).b O

R fo

r the

unc

onfir

med

cas

es in

clud

es lo

st to

follo

w up

in th

is c

alcu

latio

n on

ly.

40

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Aut

hor(

s): E

lizab

eth

Har

ausz

, Ant

hony

Gar

cia-

Prat

s, Si

mon

Sch

aaf,

Step

hani

e La

w, D

ick

Men

zies

, Jen

nife

r Fu

rin, T

amar

a K

redo

and

Ann

eke

C.

Hes

selin

g on

beha

lf of

the P

aedi

atric

MD

R-T

B IP

D G

roup

(11

Nov

embe

r 201

5)

Que

stio

n: C

larit

hrom

ycin

com

pare

d to

no

clar

ithro

myc

in fo

r chi

ldre

n w

ith M

DR

-TB

(exc

ludi

ng co

nfirm

ed X

DR

-TB)

Sett

ing:

Inte

rnat

iona

l

Bib

liogr

aphy

: Ref

er to

Ann

ex 6

, Sec

tion

3 fo

r a su

mm

ary o

f thi

s unp

ublis

hed

stud

y (H

arau

sz E

, Gar

cia-

Prat

s AJ,

Scha

af S

, Law

S, F

urin

J, K

redo

T, e

t al

., for

The C

olla

bora

tive G

roup

for M

eta-

Ana

lysis

of P

aedi

atric

Indi

vidu

al P

atie

nt D

ata i

n M

DR

-TB.

 A sy

stem

atic

revi

ew an

d in

divi

dual

pat

ient

dat

a m

eta-

anal

ysis

of tr

eatm

ent a

nd o

utco

mes

amon

g chi

ldre

n w

ith m

ulti-

drug

resis

tant

tube

rcul

osis.

 A p

relim

inar

y rep

ort f

or th

e Gui

delin

e Dev

elop

men

t G

roup

Mee

ting o

f the

Wor

ld H

ealth

Org

aniz

atio

n, N

ovem

ber 9

–11

2015

).

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

TC

ERTA

INTY

O

F EV

IDEN

CE

IMP

OR

TAN

CE

NO. O

F ST

UDIE

SST

UDY

DESI

GNRI

SK O

F BI

ASIN

CONS

ISTE

NCY

INDI

RECT

NESS

IMPR

ECIS

ION

OTHE

R CO

NSID

ERAT

IONS

CLAR

ITHR

OMYC

INNO

CL

ARIT

HROM

YCIN

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– co

nfirm

ed c

ases

(IPD

ana

lysi

s): n

= 6

23

11

obse

rvat

iona

l st

udie

s se

rious

se

rious

no

t ser

ious

se

rious

no

ne

22/3

2 (6

8.8%

) 51

2/59

1 (8

6.6%

) OR

0.2

4 (0

.04

to

1.51

)a

24 fe

wer

pe

r 100

0 (fr

om 2

20

fewe

r to

170

mor

e)

VE

RY l

OW

CRIt

ICAl

treat

men

t suc

cess

ver

sus

fail/

rela

pse/

die

– un

confi

rmed

cas

es (I

PD a

naly

sis)

: n =

219

2 ob

serv

atio

nal

stud

ies

serio

us

serio

us

not s

erio

us

serio

us

none

3/

3 (1

00.0

%)

209/

216

(96.

8%)

not

estim

able

VE

RY l

OW

CRIt

ICAl

Cl: c

onfid

ence

lim

its; O

R: o

dds

ratio

a All

effe

ct e

stim

ates

sho

wn a

re a

djus

ted

for a

ge, H

IV s

tatu

s, g

ende

r, tb

dis

ease

sev

erity

and

site

(ran

dom

effe

cts

mod

el w

ith c

lust

erin

g by

site

).

4141

ANNE

X 4:

GRA

DE tA

blEs

4.

The

role

of s

urge

ry (

PIC

O 4

)

Aut

hor(

s): H

arris

RC

, Kha

n M

S, A

llen

V, M

oore

DA

J, Fi

eldi

ng K

, Gra

ndje

an L

, and

the

LSH

TM

MD

R-T

B su

rger

y sy

stem

atic

revi

ew g

roup

(11

Nov

embe

r 201

5)

Que

stio

n: S

urge

ry co

mpa

red

to n

o su

rger

y for

trea

tmen

t of M

DR

or X

DR

TB

Sett

ing:

Geo

rgia

, Lat

via,

Rus

sia, S

outh

Afri

ca, S

outh

Kor

ea an

d Tu

rkey

Bib

liogr

aphy

: (1)

Har

ris R

C, K

han

MS,

Mar

tin L

J, A

llen

V, M

oore

DA

J, Fi

eldi

ng K

, et a

l. an

d th

e LS

HT

M M

DR

-TB

surg

ery

syst

emat

ic re

view

gr

oup.

The e

ffect

of s

urge

ry o

n th

e out

com

e of t

reat

men

t for

mul

tidru

g-re

sista

nt tu

berc

ulos

is: a

syst

emat

ic re

view

and

met

a-an

alys

is. B

MC

Infe

ct D

is.

2016

;16(

1). (

2) D

ravn

iece

G, C

ain

KP,

Hol

tz T

H, R

ieks

tina V

, Lei

man

e V, Z

ales

kis R

. Adj

unct

ive r

esec

tiona

l lun

g sur

gery

for e

xten

sivel

y dru

g-re

sista

nt

tube

rcul

osis.

Eur

Res

pir J

. 200

9;34

(1):1

80–1

83. (

3) G

egia

M, K

alan

dadz

e I,

Kem

pker

RR

, Mag

ee M

J, Bl

umbe

rg H

M. A

djun

ctiv

e su

rger

y im

prov

es

trea

tmen

t out

com

es am

ong p

atie

nts w

ith m

ultid

rug-

resis

tant

and

exte

nsiv

ely d

rug-

resis

tant

tube

rcul

osis.

Int J

Infe

ct D

is. 20

12;1

6:e3

91–3

96. (

4) K

arag

öz

T, Y

azic

ioğl

u M

oçin

O, P

azar

li P,

Sen

ol T

, Yet

iş D

uman

D, D

uman

G, e

t al.

The t

reat

men

t res

ults

of p

atie

nts w

ith m

ultid

rug r

esist

ant t

uber

culo

sis an

d fa

ctor

s affe

ctin

g tre

atm

ent o

utco

me.

Tube

rk T

orak

s. 20

09;5

7:38

3–39

2. (5

) Kes

havj

ee S

, Gel

man

ova I

Y, F

arm

er P

E, M

ishus

tin S

P, S

trel

is A

K, A

ndre

ev

YG, e

t al.

Trea

tmen

t of e

xten

sivel

y dr

ug-re

sista

nt tu

berc

ulos

is in

Tom

sk, R

ussia

: a re

tros

pect

ive c

ohor

t stu

dy. L

ance

t 200

8;37

2:14

03–1

409.

(6) K

im

H-R

, Hw

ang S

S, K

im H

J, Le

e SM

, Yoo

C-G

, Kim

YW

, et a

l. Im

pact

of e

xten

sive d

rug r

esist

ance

on

trea

tmen

t out

com

es in

non

-HIV

-infe

cted

pat

ient

s w

ith m

ultid

rug-

resis

tant

tube

rcul

osis.

Clin

Infe

ct D

is. 2

007;

45(1

0):1

290–

1295

. (7)

Kim

DH

, Kim

HJ,

Park

S-K

, Kon

g S-J,

Kim

YS,

Kim

T-H

, et a

l. Tr

eatm

ent o

utco

mes

and

long

-term

surv

ival

in p

atie

nts w

ith ex

tens

ivel

y dru

g-re

sista

nt tu

berc

ulos

is. A

m J

Res

pir C

rit C

are M

ed. 2

008;

178:

1075

–108

2.

(8) K

wak

N, K

im H

R, Y

oo C

G, K

im Y

W, H

an S

K, Y

im JJ

. Cha

nges

in tr

eatm

ent o

utco

mes

of m

ultid

rug-

resis

tant

tube

rcul

osis.

Int J

Tub

erc

Lung

D

is. 2

015;

19:5

25–5

30. (

9) K

won

YS,

Kim

YH

, Suh

GY,

Chu

ng M

P, K

im H

, Kw

on O

J, et

al.

Trea

tmen

t out

com

es fo

r HIV

-uni

nfec

ted

patie

nts w

ith

mul

tidru

g-re

sista

nt an

d ex

tens

ivel

y dru

g-re

sista

nt tu

berc

ulos

is. C

lin In

fect

Dis.

200

8;47

:496

–502

. (10

) Lei

man

e V, R

ieks

tina V

, Hol

tz T

H, Z

arov

ska

E, S

krip

cono

ka V

, Thor

pe L

E, et

al. C

linic

al o

utco

me o

f ind

ivid

ualis

ed tr

eatm

ent o

f mul

tidru

g-re

sista

nt tu

berc

ulos

is in

Lat

via:

a re

tros

pect

ive c

ohor

t st

udy.

Lanc

et 2

005;

365:

318–

326.

(11)

Mitn

ick

CD

1, S

hin

SS, S

eung

KJ,

Ric

h M

L, A

twoo

d SS

, Fur

in JJ

, et a

l. Com

preh

ensiv

e tre

atm

ent o

f ext

ensiv

ely

drug

-resis

tant

tube

rcul

osis.

New

Eng

l J M

ed 2

008;

359:

563–

574.

(12)

She

an K

P, W

illco

x PA

, Siw

endu

SN

, Las

erso

n K

F, G

ross

L, K

amm

erer

S, e

t al

. Tre

atm

ent o

utco

me

and

follo

w-u

p of

mul

tidru

g-re

sista

nt tu

berc

ulos

is pa

tient

s, W

est C

oast

/Win

elan

ds, S

outh

Afri

ca, 1

992–

2002

. Int

J Tu

berc

Lu

ng D

is. 2

008;

12(1

0):1

182–

1189

. (13

) Skl

yuev

S, L

evin

A, T

chei

mac

h E,

Kra

snov

D. P

C-6

58–0

2 C

ompl

ex tr

eatm

ent a

ppro

ach

for p

atie

nts w

ith

destr

uctiv

e pul

mon

ary

tube

rcul

osis

by ap

plic

atio

n of

endo

bron

chia

l val

ve. I

nt J

Tube

rc L

ung

Dis.

201

3;17

(12,

Sup

p.2)

:S32

9–33

0. (1

4) T

ahao

ğlu

K,

Tör

ün T

, Sev

im T

, Ata

ç G, K

ir A

, Kar

asul

u L,

et a

l. Th

e tre

atm

ent o

f mul

tidru

g-re

sista

nt tu

berc

ulos

is in

Tur

key.

N E

ngl J

Med

. 200

1;34

5:17

0–17

4.

(15)

Tör

ün T

, Tah

aoğl

u K

, Ozm

en I,

Sev

im T

, Ata

ç G, K

ir A

, et a

l. Th

e rol

e of s

urge

ry an

d flu

oroq

uino

lone

s in

the t

reat

men

t of m

ultid

rug-

resis

tant

tu

berc

ulos

is. In

t J T

uber

c Lun

g Dis.

200

7;11

(9):9

79–9

85.

42

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

QU

ALI

TYIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NSSU

RGER

YNO

SUR

GERY

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

Cure

d (fo

llow

up: r

ange

0.5

to 1

0 ye

ars;

ass

esse

d wi

th: W

HO d

efini

tion)

5 ob

serv

atio

nal

stud

ies

serio

usa–

gno

t ser

ious

hno

t ser

ious

ino

t ser

ious

no

nej

118/

157

(75.

2%)

308/

561

(54.

9%)

OR 3

.03

(1.5

9 to

5.

78)

238

mor

e pe

r 1,0

00

(from

110

m

ore

to

327

mor

e)

VE

RY l

OW

CRIt

ICAl

succ

essf

ul o

utco

me

(follo

w up

: ran

ge 0

.25

to 7

yea

rs; a

sses

sed

with

: cur

e or

trea

tmen

t suc

cess

, WHO

defi

nitio

n)

14

obse

rvat

iona

l st

udie

s se

rious

a–

g,k,

lno

t ser

ious

mno

t ser

ious

nno

t ser

ious

no

nej,o

371/

453

(81.

9%)p

1197

/200

6 (5

9.7%

) OR

2.6

2 (1

.94

to

3.54

)p

198

mor

e pe

r 1,0

00

(from

145

m

ore

to

243

mor

e)

VE

RY l

OW

CRIt

ICAl

Deat

h (fo

llow

up: r

ange

0.5

to 1

0 ye

ars;

ass

esse

d wi

th: a

ll-ca

use

mor

talit

y or

tb m

orta

lity)

5 ob

serv

atio

nal

stud

ies

serio

usa–

f,k,q

–sno

t ser

ious

mse

rious

tse

rious

sno

nej

11/1

91

(5.8

%)

52/7

20 (7

.2%

) OR

0.8

2 (0

.41

to

1.64

)

12 fe

wer

pe

r 1,0

00

(from

41

fewe

r to

41 m

ore)

VE

RY l

OW

CRIt

ICAl

loss

to fo

llow

up (p

revi

ousl

y de

faul

t) (fo

llow

up: r

ange

0.5

to 1

0 ye

ars;

ass

esse

d wi

th: W

HO d

efini

tion)

4 ob

serv

atio

nal

stud

ies

seri-

ousa–

f,uno

t ser

ious

mno

t ser

ious

vno

t ser

ious

no

nej,w

6/15

6

(3.8

%)

77/6

13

(12.

6%)

OR 0

.35

(0.1

5 to

0.

81)x

78 fe

wer

pe

r 1,0

00

(from

21

fewe

r to

105

fewe

r)

VE

RY l

OW

CRIt

ICAl

treat

men

t fai

lure

(fol

low

up: r

ange

0.5

to 1

0 ye

ars;

ass

esse

d wi

th: W

HO d

efini

tion

)

5 ob

serv

atio

nal

stud

ies

serio

us

a–g,

kno

t ser

ious

mno

t ser

ious

vno

t ser

ious

no

nej,w

8/19

1

(4.2

%)

82/7

20

(11.

4%)

OR 0

.38

(0.1

8 to

0.

81)

67 fe

wer

pe

r 1,0

00

(from

20

fewe

r to

91 fe

wer)

VE

RY l

OW

CRIt

ICAl

trans

fer o

ut (f

ollo

w up

: not

repo

rted)

2 ob

serv

atio

nal

stud

ies

serio

us

a–c,

f,y,z

not s

erio

usaa

not s

erio

us

not s

erio

usaa

none

z,bb

0/13

9

(0.0

%)

6/30

5

(2.0

%)

not

estim

able

VERY

lOW

CR

ItIC

Al

4343

ANNE

X 4:

GRA

DE tA

blEs

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

QU

ALI

TYIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NSSU

RGER

YNO

SUR

GERY

RELA

TIVE

(9

5% C

L)AB

SOLU

TE

(95%

CL)

Rela

pse

or re

laps

e/fa

ilure

– n

ot re

porte

d

- -

- -

- -

- -

- -

see

com

men

t -

Adve

rse

even

ts fr

om s

urge

ry (f

ollo

w up

: ran

ge 1

.5 to

10

year

s)

1 ob

serv

atio

nal

stud

ies

serio

usa,

b,f

not s

erio

uscc

not s

erio

us

not s

erio

uscc

publ

icat

ion

bias

stro

ngly

su

spec

teddd

2/66

(3%

) sur

gica

l pat

ient

s di

ed d

ue

to s

urgi

cal c

ompl

icat

ions

.

VERY

lOW

CR

ItIC

Al

Cl: C

onfid

ence

lim

its; O

R: O

dds

ratio

a Do

not a

ddre

ss o

r adj

ust f

or c

onfo

unde

rs a

nd s

ome

stud

ies

do n

ot fu

lly d

escr

ibe

the

popu

latio

n –

Drav

niec

e, e

t al.

2009

; Kar

agoz

, et a

l. 20

09; K

im e

t al.

2007

; Kwa

k et

al.

2015

; Kwo

n et

al.

2008

; Mitn

ick,

et a

l. 20

08; s

hean

, et a

l. 20

08; s

klyu

ev, e

t al.

2013

; tah

aogl

u, e

t al.

2001

; and

toru

n, e

t al.

2007

.b R

etro

spec

tive

obse

rvat

iona

l stu

dies

do

not h

ave

rand

omiza

tion

and

have

inhe

rent

bia

s in

who

is o

ffere

d su

rger

y –

Drav

niec

e, e

t al.

2009

; Kar

agoz

, et a

l. 20

09; K

esha

vjee

, et a

l. 20

08; K

im e

t al.

2007

; Kim

, et a

l. 20

08; K

wak,

et a

l. 20

15; K

won,

et a

l. 20

08; l

eim

ane,

et a

l. 20

05; M

itnic

k, e

t al.

2008

; she

an, e

t al.

2008

; tah

aogl

u, e

t al.

2001

; and

toru

n, e

t al.

2007

.c U

ncer

tain

ty in

repr

esen

tativ

enes

s of

stu

dy p

opul

atio

n –

Drav

niec

e, e

t al.

2009

; Kar

agoz

, et a

l. 20

09; K

im e

t al.

2007

; Kwa

k, e

t al.

2015

; Kwo

n et

al.

2008

; she

an, e

t al.

2008

; and

taha

oglu

, et a

l. 20

01d N

o es

timat

e of

var

iabi

lity

give

n –

Drav

niec

e, e

t al.

(200

9) a

nd ta

haog

lu, e

t al.

(200

1).

e Num

ber o

f “lo

st to

follo

w-up

” rep

orte

d, b

ut c

hara

cter

istic

s no

t des

crib

ed –

taha

oglu

, et a

l. (2

001)

.f l

engt

h of

follo

w up

not

des

crib

ed o

r adj

uste

d fo

r in

anal

ysis

– D

ravn

iece

, et a

l. 20

09; K

im, e

t al.

2007

; Kwa

k, e

t al.

2015

; Kwo

n, e

t al.

2008

; lei

man

e, e

t al.

2005

; Mitn

ick,

et a

l. 20

08; s

hean

, et a

l. 20

08; t

ahao

glu,

et

al.

2001

; and

toru

n, e

t al.

2007

.g I

n su

rgic

al s

tudi

es, i

t is

not p

ossi

ble

to b

lind

patie

nts

or th

e st

udy

team

. Out

com

e as

sess

ors

coul

d be

blin

ded,

and

is s

omew

hat i

mpo

rtant

for a

sses

sing

cur

e us

ing

smea

r as

an o

utco

me

indi

cato

r. Ho

weve

r, pe

rson

nel

othe

r tha

n th

e di

agno

sing

phy

sici

an, g

ener

ally

con

duct

labo

rato

ry a

sses

smen

t. Fo

r tre

atm

ent s

ucce

ss/f

ailu

re th

ere

is a

risk

of r

epor

ting

bias

due

to la

ck o

f blin

ding

whe

re d

ata

are

prog

ram

mat

ic, a

s th

ere

may

be

over

-repo

rting

due

to p

rogr

amm

atic

targ

ets

and

coul

d be

bia

sed

by k

nowl

edge

of s

urgi

cal s

tatu

s.h M

oder

ate

I-squ

ared

(54.

2%) a

nd o

verla

ppin

g Cl

s be

twee

n st

udie

s, a

nd a

re th

us n

ot d

owng

rade

d.i s

ome

varia

tion

in d

urat

ion

of fo

llow-

up in

out

com

e de

finiti

on, h

owev

er it

is n

ot d

owng

rade

d as

alo

ne it

is n

ot c

lass

ified

as

serio

us fo

r thi

s ou

tcom

e.j A

ll st

udie

s ar

e co

hort

base

d, a

nd th

eref

ore

ther

e m

ay b

e so

me

conf

ound

ing

due

to p

atie

nt a

lloca

tion

to s

urge

ry o

r no

surg

ery.

Patie

nts

who

are

mor

e un

well

may

be

mor

e lik

ely

to b

e re

com

men

ded

for s

urge

ry

(ther

efor

e ca

usin

g un

dere

stim

ate

of e

ffect

size

). Ho

weve

r, th

e m

ost s

ick

are

ofte

n no

t offe

red

surg

ery

as th

ey m

ay b

e to

o un

well

or th

e di

seas

e m

ay b

e to

o di

ssem

inat

ed to

allo

w su

rger

y (th

eref

ore

over

estim

atin

g ef

fect

si

ze).

In a

dditi

on, t

here

may

be

varia

tion

in th

e po

pula

tion

offe

red

surg

ery

by s

ettin

g or

sur

geon

. As

ther

e is

a s

peci

fic w

indo

w fo

r sur

gery

, the

se b

iase

s m

ay h

ave

an im

pact

on

estim

atio

n of

effe

ct s

ize, t

houg

h it

is

uncl

ear w

heth

er th

ey w

ould

bia

s th

e es

timat

ion

in a

par

ticul

ar d

irect

ion,

and

are

a re

flect

ion

of th

e re

ality

of t

he p

atie

nt g

roup

offe

red

surg

ery.

ther

efor

e, th

e re

view

ers

deci

ded

not t

o up

grad

e or

dow

ngra

de th

e ra

ting.

k Rep

orts

num

ber,

but n

ot s

umm

ary

stat

istic

s or

pre

cisi

on fo

r thi

s sp

ecifi

c ou

tcom

e –

leim

ane,

et a

l. (2

005)

and

Mitn

ick,

et a

l. (2

008)

l Abs

tract

onl

y, ou

tcom

e an

d pa

tient

cha

ract

eris

tics

not c

lear

ly d

escr

ibed

– D

ravn

iece

, et a

l. (2

009)

m l

ow I-

squa

red

and

over

lapp

ing

Cls

betw

een

stud

ies,

so

not d

owng

rade

d.n M

ost s

tudi

es fo

llowe

d W

HO o

utco

me

defin

ition

s. s

ome

varia

tion

in d

urat

ion

of fo

llow

up to

ass

ess

outc

ome

but n

ot d

owng

rade

d as

alo

ne is

not

cla

ssifi

ed a

s se

rious

issu

e fo

r thi

s ou

tcom

e.o E

mpt

y lo

wer r

ight

qua

dran

t of f

unne

l plo

t. Ho

weve

r, it

seem

s th

at s

mal

ler (

less

pre

cise

) stu

dies

are

repo

rting

lowe

r effe

ct e

stim

ate

so if

pub

licat

ion

bias

wer

e to

exis

t thi

s wo

uld

sugg

est t

he c

urre

nt e

stim

ate

effe

ct

mea

sure

is c

onse

rvat

ive. P

er p

roto

col,

stud

ies

with

<10

sur

gica

l par

ticip

ants

wer

e ex

clud

ed, t

here

fore

the

very

sm

alle

st o

f stu

dies

wer

e no

t inc

lude

d. P

lot i

s no

t suf

ficie

ntly

asy

mm

etric

al to

rais

e se

rious

con

cern

s, a

nd

any

bias

wou

ld a

ppea

r to

caus

e an

und

eres

timat

e of

effe

ct, t

here

fore

qua

lity

is n

ot d

owng

rade

d.

44

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

p n=1

3 fo

r OR

estim

ates

, but

n=1

1 fo

r num

bers

of p

atie

nts

sum

mar

ized

in th

e ta

ble,

as

only

two

stud

ies

repo

rt ef

fect

est

imat

e ra

ther

than

the

num

ber o

f pat

ient

s wi

th th

e ou

tcom

e an

d th

e de

nom

inat

or.

q In

surg

ical

stu

dies

, it i

s no

t pos

sibl

e to

blin

d pa

tient

s or

stu

dy te

am. O

utco

me

asse

ssor

s co

uld

be b

linde

d, b

ut u

nim

porta

nt in

mor

talit

y ou

tcom

e as

no

subj

ectiv

ity in

ass

essm

ent.

r tim

e pe

riod

of fo

llow

up v

ery

varia

ble,

and

for p

atie

nts

with

follo

w up

for <

2 ye

ars

the

follo

w up

per

iod

is p

oten

tially

insu

ffici

ent f

or m

orta

lity

outc

ome

– sh

ean,

et a

l. (2

008)

and

toru

n, e

t al.

(200

7).

s Po

oled

Cls

cro

ss th

e nu

ll. E

vent

rate

is lo

w an

d po

st h

oc o

ptim

al in

form

atio

n si

ze c

alcu

latio

n in

dica

ted

num

ber i

nclu

ded

in a

sses

smen

t of t

his

outc

ome

is to

o lo

w to

give

suf

ficie

nt p

ower

.t V

aria

tion

betw

een

stud

ies

in o

utco

me

defin

ition

use

d (a

ll-ca

use

vers

us tb

-onl

y). U

ncle

ar/v

aria

ble

perio

d ov

er w

hich

dea

th w

as a

sses

sed

(e.g

. die

d du

ring

treat

men

t, wi

thin

six

mon

ths

of c

ompl

etio

n, o

r afte

r two

ye

ars)

.u I

n su

rgic

al s

tudi

es, i

t is

not p

ossi

ble

to b

lind

patie

nts

or s

tudy

team

. Out

com

e as

sess

ors

coul

d be

blin

ded,

but

whe

re d

ata

are

prog

ram

mat

ic th

ey a

re u

nlik

ely

to b

e. th

is c

ould

intro

duce

und

eres

timat

e in

repo

rting

of

defa

ult,

but t

his

bias

is u

nlik

ely

to v

ary

betw

een

stud

y gr

oups

.v M

ostly

use

WHO

defi

nitio

n, m

inor

var

iatio

n in

defi

nitio

n in

som

e st

udie

s, b

ut s

uffic

ient

ly d

irect

not

to d

owng

rade

.w

OR (s

imila

r to

rela

tive

risk

give

n th

e in

frequ

ency

of t

he e

vent

) is

<0.5

and

the

uppe

r con

fiden

ce li

mit

woul

d st

ill p

rovi

de a

clin

ical

ly s

igni

fican

t ben

efit,

ther

efor

e th

is w

ould

be

cons

ider

ed a

larg

e ef

fect

size

. How

ever

, th

e qu

ality

is n

ot u

pgra

ded

as a

ccor

ding

to G

RADE

met

hodo

logy

this

sho

uld

not b

e do

ne if

the

risk

of b

ias

is s

erio

us.

x n=2

stu

dies

had

no

patie

nts

lost

to fo

llow-

up in

the

surg

ery

grou

p, s

o 0.

5 ha

s be

en a

dded

to a

ll ce

lls in

ord

er th

at a

Cl

can

be c

alcu

late

d. th

e su

mm

ary

OR re

stric

ted

to th

e 2

stud

ies

that

had

at l

east

one

pat

ient

lo

st to

follo

w-up

in e

ach

grou

p is

0.4

7 (9

5% C

l: 0

.18,

1.2

4).

y Alth

ough

repo

rted

sepa

rate

ly, u

nlik

ely

that

cle

ar d

iffer

entia

tion

has

been

mad

e be

twee

n “lo

ss to

follo

w-up

” and

“tra

nsfe

r out

”.z s

uspe

cted

und

erre

porti

ng o

f out

com

e, b

ut u

ncer

tain

as

to h

ow th

is w

ould

impa

ct th

e co

nclu

sion

s.aa

No

pool

ed e

stim

ate,

so

insu

ffici

ent e

vide

nce

to a

sses

s.bb

Onl

y tw

o pu

blic

atio

ns, s

o no

t pos

sibl

e to

ass

ess

publ

icat

ion

bias

, but

give

n ho

w fe

w re

port

this

out

com

e pu

blic

atio

n bi

as m

ay b

e pl

ausi

ble.

cc O

ne s

tudy

and

no

com

para

tor g

roup

so

not p

ossi

ble

to e

stim

ate.

dd l

ikel

y th

at c

ompl

icat

ions

occ

urre

d in

oth

er s

tudi

es, b

ut h

ave

eith

er n

ot b

een

repo

rted

or h

ave

been

incl

uded

in a

ll-ca

use

deat

hs.

4545

ANNE

X 4:

GRA

DE tA

blEs

Aut

hor(

s): F

ox G

J, M

itnic

k C

D, B

ened

etti

A, C

han

ED, B

ecer

ra M

, Chi

ang

C-Y

, Kes

havj

ee S

, Koh

W-J,

Shi

raish

i Y, V

iiklep

p P,

Yim

J-J,

Pasv

ol G

, R

ober

t J, S

him

TS,

Shi

n SS

, Men

zies

R (1

1 N

ovem

ber 2

015)

Que

stio

n: E

lect

ive p

artia

l lun

g res

ectio

n co

mpa

red

to n

o su

rger

y for

pat

ient

s on

trea

tmen

t for

MD

R-T

B

Sett

ing:

Whi

ch t

ypes

of s

urge

ry e

ncom

pass

ed (

lobe

ctom

y, se

gmen

tect

omy,

wed

ge re

sect

ion)

? D

efini

tion

of n

on-re

spon

se a

nd a

dver

se o

utco

me

of

surg

ery;

defi

nitio

n of

ext

ensiv

e di

seas

e; h

ow s

peci

aliz

ed w

ere

the

cent

res/

prac

titio

ners

whi

ch p

rovi

ded

surg

ery

(ext

erna

l val

idity

)? U

nder

whi

ch

cond

ition

s to

indi

cate

rese

ctio

n su

rger

y and

whe

n to

cont

rain

dica

te; b

efor

e or a

fter c

ultu

re co

nver

sion.

Bib

liogr

aphy

: Fox

GJ,

Mitn

ick

CD

, Ben

edet

ti A

, Cha

n ED

, Bec

erra

M, C

hian

g C-Y

, et a

l. Su

rger

y as a

n ad

junc

tive t

reat

men

t for

mul

tidru

g-re

sista

nt

tube

rcul

osis:

an in

divi

dual

pat

ient

dat

a met

a-an

alys

is. C

lin In

fect

Dis.

201

6;62

(7):8

87–9

5.

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

ELEC

TIVE

PA

RTIA

L

LUNG

RE

SECT

ION

NO S

URGE

RYRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

succ

ess

vers

us tr

eatm

ent f

ailu

re o

r rel

apse

(ass

esse

d wi

th: I

ndiv

idua

l pat

ient

dat

a m

eta-

anal

ysis

)

26a

obse

rvat

iona

l st

udie

sbno

t se

rious

cno

t ser

ious

dno

t ser

ious

eno

t ser

ious

fno

ne

185/

204

(90.

7%)g

1134

/139

8 (8

1.1%

)hOR

2.4

(0

.4 to

15

.6)i

100

mor

e pe

r 100

0 (fr

om 1

74

mor

e to

17

9 fe

wer)

lO

W

CRIt

ICAl

succ

ess

vers

us tr

eatm

ent f

ailu

re o

r rel

apse

or d

eath

(ass

esse

d wi

th: I

ndiv

idua

l pat

ient

dat

a m

eta-

anal

ysis

)

26a

obse

rvat

iona

l st

udie

sbno

t se

rious

cno

t ser

ious

dno

t ser

ious

eno

t ser

ious

fno

ne

185/

214

(86.

4%)j

1134

/170

2 (6

6.6%

)kOR

2.0

(0

.4 to

9.

5)i

133

mor

e pe

r 100

0 (fr

om 2

22

fewe

r to

284

mor

e)

lO

W

CRIt

ICAl

succ

ess

vers

us tr

eatm

ent f

ailu

re o

r rel

apse

or d

eath

or l

oss

to fo

llow-

up (a

sses

sed

with

: Ind

ivid

ual p

atie

nt d

ata

met

a-an

alys

is)

26a

obse

rvat

iona

l st

udie

sbno

t se

rious

cno

t ser

ious

dno

t ser

ious

eno

t ser

ious

fno

ne

185/

229

(80.

8%)l

1134

/219

3 (5

1.7%

)mOR

3.5

(1

.5 to

8.

1)i

272

mor

e pe

r 100

0 (fr

om 9

9 m

ore

to

380

mor

e)

lO

W

CRIt

ICAl

46

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

ELEC

TIVE

PA

RTIA

L

LUNG

RE

SECT

ION

NO S

URGE

RYRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

Deat

h ve

rsus

trea

tmen

t fai

lure

or r

elap

se o

r suc

cess

(ass

esse

d wi

th: I

ndiv

idua

l pat

ient

dat

a m

eta-

anal

ysis

)

26a

obse

rvat

iona

l st

udie

sbno

t se

rious

cno

t ser

ious

dno

t ser

ious

eno

t ser

ious

fno

ne

10/2

14

(4.7

%)

304/

1702

(1

7.9%

) OR

0.6

(0

.2 to

2.

2)i

63 fe

wer

pe

r 100

0 (fr

om 1

37

fewe

r to

145

mor

e)

lO

W

CRIt

ICAl

Cl: c

onfid

ence

lim

its; O

R: o

dds

ratio

a 26

stud

ies

incl

ude

18 s

tudi

es w

here

sur

gery

was

per

form

ed, a

nd e

ight

stu

dies

whe

re s

urge

ry w

as n

ot p

erfo

rmed

.b L

imita

tions

. All

data

are

from

obs

erva

tiona

l stu

dies

. the

bac

kgro

und

med

icat

ion

regi

men

and

the

qual

ity o

f sur

gery

and

oth

er c

are

are

expe

cted

to d

iffer

bet

ween

the

stud

ies.

bia

s ex

pect

ed b

ecau

se th

e de

cisi

on to

op

erat

e an

d th

e ty

pe o

f sur

gery

are

usu

ally

clo

sely

link

ed to

pro

gnos

tic fa

ctor

s su

ch a

s se

verit

y/se

rious

ness

of t

he c

ondi

tion,

the

exte

nt o

f res

ista

nce

patte

rn, e

ffect

ivene

ss o

f the

med

ical

opt

ions

ava

ilabl

e an

d th

e pa

tient

resp

onse

to tr

eatm

ent.

c Ris

k of

bia

s. A

ll in

clud

ed s

tudi

es a

re o

bser

vatio

nal,

and

sele

ctio

n bi

as is

a s

ubst

antia

l ris

k. P

atie

nt s

elec

tion

for s

urge

ry m

ay b

e bi

ased

towa

rds

patie

nts

with

mor

e fa

vour

able

pro

gnos

tic fa

ctor

s or

the

oppo

site

. le

ngth

of t

reat

men

t diff

ered

sub

stan

tially

bet

ween

sur

gica

l and

non

-sur

gica

l pat

ient

s, s

ugge

stin

g th

at d

iffer

ence

s in

the

back

grou

nd m

edic

al re

gim

ens

may

als

o af

fect

out

com

es; a

lthou

gh th

is a

nd o

ther

mea

sure

d po

tent

ial c

onfo

unde

rs w

ere

incl

uded

in th

e ad

just

ed a

naly

sis

of e

ffect

.d I

ncon

sist

ency

. bas

ed o

n es

timat

ed I

2 R .

Estim

ates

for t

he fi

rst t

wo o

utco

mes

(suc

cess

ver

sus

treat

men

t fai

lure

or r

elap

se +

/- d

eath

) wer

e ve

ry s

imila

r but

OR

for s

ucce

ss in

crea

ses

when

indi

vidu

als

who

were

lost

to

follo

w-up

wer

e in

clud

ed in

the

anal

ysis

.e I

ndire

ctne

ss. N

o in

dire

ctne

ss e

xpec

ted

give

n th

at a

ll pa

tient

s we

re o

n tre

atm

ent f

or M

DR-/

XDR-

tb. t

he o

utco

mes

(suc

cess

, tre

atm

ent f

ailu

re, r

elap

se a

nd d

eath

) wer

e am

ong

thos

e sc

ored

as

criti

cal b

y th

e Gu

idel

ine

Deve

lopm

ent G

roup

; los

s to

follo

w up

was

not

one

of t

he s

peci

fied

outc

omes

but

is re

leva

nt to

the

ques

tion.

f Im

prec

isio

n. 9

5% c

onfid

ence

lim

its fo

r effe

ct e

stim

ate

appl

ied

with

adj

ustm

ent.

g Poo

led

prop

ortio

n 93

% (8

9%–9

7%).

h Poo

led

prop

ortio

n 77

% (6

9%–8

5%).

i Adj

uste

d ef

fect

est

imat

es. t

he m

etho

d of

adj

ustm

ent w

as o

ne to

one

pro

pens

ity s

core

mat

chin

g be

twee

n su

rgic

al p

atie

nts

and

non-

surg

ical

pat

ient

s, fr

om n

on-s

urgi

cal s

tudi

es.

j Poo

led

prop

ortio

n 90

% (8

6%–9

4%).

k Poo

led

prop

ortio

n 64

% (5

4%–7

3%).

l Poo

led

prop

ortio

n 66

% (6

2%–7

0%).

m P

oole

d pr

opor

tion

51%

(40%

–62%

).

4747

ANNE

X 4:

GRA

DE tA

blEs

Aut

hor(

s): F

ox G

J, M

itnic

k C

D, B

ened

etti

A, C

han

ED, B

ecer

ra M

, Chi

ang

C-Y

., K

esha

vjee

S, K

oh W

-J, S

hira

ishi Y

, Viik

lepp

P, Y

im J-

J, Pa

svol

G,

Rob

ert J

, Shi

m T

S, S

hin

SS, M

enzi

es R

Que

stio

n: E

lect

ive p

neum

onec

tom

y com

pare

d to

no

surg

ery f

or p

atie

nts o

n tr

eatm

ent o

f MD

R-T

B.

Sett

ing:

Bef

ore o

r afte

r cul

ture

conv

ersio

n; w

hich

com

paris

on gr

oup

wou

ld h

ave (

a) fa

ilure

/ re

lapse

, (b)

failu

re /

relap

se /

deat

h, an

d (c

) fai

lure

/ re

lapse

/ d

eath

/ lo

ss to

follo

w u

p.

Bib

liogr

aphy

: Fox

GJ,

Mitn

ick

CD

, Ben

edet

ti A

, Cha

n ED

, Bec

erra

M, C

hian

g C-Y

, et a

l. Su

rger

y as a

n ad

junc

tive t

reat

men

t for

mul

tidru

g-re

sista

nt

tube

rcul

osis:

an in

divi

dual

pat

ient

dat

a met

aana

lysis

. Clin

Infe

ct D

is. 2

016;

62(7

):887

–95.

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

ELEC

TIVE

PN

EUM

ONEC

-TO

MY

NO S

URGE

RYRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

succ

ess

vers

us tr

eatm

ent f

ailu

re o

r rel

apse

(ass

esse

d wi

th: i

ndiv

idua

l pat

ient

dat

a m

eta-

anal

ysis

)

26a

obse

rvat

iona

l st

udie

s no

t se

rious

bno

t ser

ious

cno

t ser

ious

dno

t ser

ious

eno

ne

72/9

1 (7

9.1%

)f11

34/1

398

(81.

1%)g

OR 0

.8

(0.1

to

6.0)

h

4 fe

wer

pe

r 100

(fr

om 1

5 m

ore

to 5

1 fe

wer)

lO

W

CRIt

ICAl

succ

ess

vers

us tr

eatm

ent f

ailu

re o

r rel

apse

or d

eath

(ass

esse

d wi

th: i

ndiv

idua

l pat

ient

dat

a m

eta-

anal

ysis

)

26a

obse

rvat

iona

l st

udie

s no

t se

rious

bno

t ser

ious

cno

t ser

ious

dno

t ser

ious

eno

ne

72/1

05

(68.

6%)i

1134

/170

2 (6

6.6%

)jOR

0.7

(0

.1 to

3.

0)h

8 fe

wer

pe

r 100

(fr

om 1

9 m

ore

to 5

0 fe

wer)

lO

W

CRIt

ICAl

succ

ess

vers

us tr

eatm

ent f

ailu

re o

r rel

apse

or d

eath

or l

oss

to fo

llow-

up (a

sses

sed

with

: ind

ivid

ual p

atie

nt d

ata

met

a-an

alys

is)

26a

obse

rvat

iona

l st

udie

s no

t se

rious

cno

t ser

ious

cno

t ser

ious

dno

t ser

ious

eno

ne

72/1

17

(61.

5%)k

1134

/219

3 (5

1.7%

)lOR

1.4

(0

.7 to

3.

2)h

83 m

ore

per 1

000

(from

89

fewe

r to

257

mor

e)

lO

W

CRIt

ICAl

48

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

QU

ALI

TY A

SSES

SM

ENT

NO

. O

F PA

TIEN

TSEF

FEC

T

CER

TAIN

TY

OF

EVID

ENC

EIM

PO

RTA

NC

ENO

. OF

STUD

IES

STUD

Y DE

SIGN

RISK

OF

BIAS

INCO

NSIS

TENC

YIN

DIRE

CTNE

SSIM

PREC

ISIO

NOT

HER

CONS

IDER

ATIO

NS

ELEC

TIVE

PN

EUM

ONEC

-TO

MY

NO S

URGE

RYRE

LATI

VE

(95%

CL)

ABSO

LUTE

(9

5% C

L)

Deat

h ve

rsus

suc

cess

or t

reat

men

t fai

lure

or r

elap

se (a

sses

sed

with

: ind

ivid

ual p

atie

nt d

ata

met

a-an

alys

is)

26a

obse

rvat

iona

l st

udie

s no

t se

rious

bno

t ser

ious

cno

t ser

ious

dno

t ser

ious

eno

ne

14/1

05

(13.

3%)

304/

1702

(1

7.9%

) OR

1.8

(0

.6 to

5.

1)h

103

mor

e pe

r 100

0 (fr

om 6

3 fe

wer t

o 34

7 m

ore)

lO

W

CRIt

ICAl

Cl: c

onfid

ence

lim

its; O

R: o

dds

ratio

a 26

stud

ies

incl

ude

18 s

tudi

es w

here

sur

gery

was

per

form

ed, a

nd e

ight

stu

dies

whe

re s

urge

ry w

as n

ot p

erfo

rmed

.b R

isk

of b

ias.

All

incl

uded

stu

dies

are

obs

erva

tiona

l, an

d se

lect

ion

bias

is a

sub

stan

tial r

isk.

Pat

ient

sel

ectio

n fo

r sur

gery

may

be

bias

ed to

ward

s pa

tient

s wi

th m

ore

favo

urab

le p

rogn

ostic

fact

ors

or th

e op

posi

te.

leng

th o

f tre

atm

ent d

iffer

ed s

ubst

antia

lly b

etwe

en s

urgi

cal a

nd n

on-s

urgi

cal p

atie

nts,

sug

gest

ing

that

diff

eren

ces

in th

e ba

ckgr

ound

med

ical

regi

men

s m

ay a

lso

affe

ct o

utco

mes

; alth

ough

this

and

oth

er m

easu

red

pote

ntia

l con

foun

ders

wer

e in

clud

ed in

the

adju

sted

ana

lysi

s of

effe

ct.

c Inc

onsi

sten

cy. b

ased

on

estim

ated

I-sq

uare

d R.

Est

imat

es fo

r the

firs

t two

out

com

es (s

ucce

ss v

ersu

s tre

atm

ent f

ailu

re o

r rel

apse

+/-

dea

th) w

ere

very

sim

ilar b

ut O

R fo

r suc

cess

incr

ease

s wh

en in

divi

dual

s wh

o we

re

lost

to fo

llow-

up w

ere

incl

uded

in th

e an

alys

is.

d Ind

irect

ness

. No

indi

rect

ness

exp

ecte

d gi

ven

that

all

patie

nts

were

on

treat

men

t for

MDR

-/XD

R-tb

. the

out

com

es (s

ucce

ss, t

reat

men

t fai

lure

, rel

apse

and

dea

th) w

ere

amon

g th

ose

scor

ed a

s cr

itica

l by

the

Guid

elin

e De

velo

pmen

t Gro

up; l

oss

to fo

llow

up w

as n

ot o

ne o

f the

spe

cifie

d ou

tcom

es b

ut is

rele

vant

to th

e qu

estio

n.e I

mpr

ecis

ion.

95%

con

fiden

ce li

mits

for e

ffect

est

imat

e ap

plie

d wi

th a

djus

tmen

t.f P

oole

d pr

opor

tion

79%

(71%

–88%

).g P

oole

d pr

opor

tion

77%

(6%

–85%

).h E

ffect

est

imat

es. A

djus

ted

effe

ct e

stim

ates

app

lyin

g on

e to

one

pro

pens

ity s

core

mat

chin

g be

twee

n su

rgic

al p

atie

nts

and

non-

surg

ical

pat

ient

s fro

m n

on-s

urgi

cal s

tudi

es.

i Poo

led

prop

ortio

n 69

% (6

0%–7

8%).

j Poo

led

prop

ortio

n 64

% (5

4%–7

3%).

k Poo

led

prop

ortio

n 62

% (5

4%–7

1%).

l Poo

led

prop

ortio

n 51

% (4

0%–6

2%).

49

AN

NE

X 5

Evid

ence

to

deci

sion

tab

les

1. S

tand

ardi

zed

shor

ter r

egim

ens

vers

us lo

nger

regi

men

s fo

r the

tre

atm

ent

of M

DR

-TB

Popu

latio

n:Ad

ults

or c

hild

ren

with

mul

tidru

g or

rifa

mpi

cin-

resi

stan

t tb

(MDR

/RR-

tb)

Back

grou

nd:

the

inte

rest

in re

duci

ng th

e du

ratio

n of

trea

tmen

t for

MDR

-tb

has

mot

ivate

d a

num

ber o

f ini

tiativ

es to

trea

t pat

ient

s wi

th s

horte

r reg

imen

s un

der p

rogr

amm

atic

as

well

as tr

ial c

ondi

tions

. In

the

past

few

year

s, re

sults

from

thre

e st

udie

s of

pat

ient

s on

sh

orte

r reg

imen

s ha

ve b

een

repo

rted

and

othe

r stu

dies

hav

e be

gun,

incl

udin

g bo

th

obse

rvat

iona

l coh

orts

and

RCt

s in

diff

eren

t set

tings

. Ear

ly re

sults

from

obs

erva

tiona

l st

udie

s in

ban

glad

esh,

Cam

eroo

n an

d Ni

ger u

sing

regi

men

s la

stin

g 12

mon

ths

or

less

hav

e sh

own

muc

h hi

gher

trea

tmen

t suc

cess

com

pare

d wi

th lo

nger

con

vent

iona

l re

gim

ens

when

trea

ting

patie

nts

with

spe

cific

incl

usio

n cr

iteria

. Give

n th

e lim

ited

expe

rienc

e in

the

use

of th

ese

shor

ter M

DR-t

b re

gim

ens,

WHO

’s po

sitio

n ha

s un

til

now

reco

mm

ende

d su

ch re

gim

ens

to o

nly

be u

sed

with

in a

con

text

of o

pera

tiona

l re

sear

ch a

nd u

nder

clo

se m

onito

ring

for e

ffect

ivene

ss a

nd s

afet

y du

ring

and

afte

r th

e en

d of

trea

tmen

t. th

e fir

st fi

ndin

gs fr

om o

ngoi

ng R

Cts

eval

uatin

g th

is re

gim

en in

di

ffere

nt c

ount

ries

are

not e

xpec

ted

befo

re th

e en

d of

201

7.

Inte

rven

tion:

stan

dard

ized

shor

ter r

egim

ens

Com

paris

on:

long

er re

gim

ens

Mai

n ou

tcom

es:

treat

men

t suc

cess

ver

sus

failu

re/r

elap

se; t

reat

men

t suc

cess

ver

sus

failu

re/

rela

pse/

deat

h; tr

eatm

ent s

ucce

ss v

ersu

s fa

ilure

/rel

apse

/dea

th/l

oss

to

follo

w-up

Sett

ing:

Amon

g pa

tient

s wh

o ha

d no

his

tory

of p

revi

ous

treat

men

t with

sec

ond-

line

drug

s; s

horte

r reg

imen

s re

fer t

o th

ose

last

ing

up to

12

mon

ths;

long

er

regi

men

s la

st 1

8 m

onth

s or

mor

e. N

ote

that

the

“long

er re

gim

ens”

gro

up

pool

s da

ta fr

om s

tudi

es th

at d

iffer

ed in

the

com

bina

tion

and

num

ber o

f dr

ugs,

in th

e du

ratio

n of

trea

tmen

t, an

d in

the

use

of a

sta

ndar

dize

d ve

rsus

an

indi

vidu

alize

d ap

proa

ch. H

ence

the

pool

ed e

stim

ates

do

not n

eces

saril

y re

flect

the

outc

omes

ass

ocia

ted

with

the

regi

men

reco

mm

ende

d in

the

2011

W

HO d

rug-

resi

stan

t tb

guid

elin

es.

Pers

pect

ive:

Mor

e ex

tens

ive u

se o

f sho

rter M

DR-t

b re

gim

ens

for p

atie

nts

who

are

elig

ible

, wi

th c

onse

quen

t im

prov

ed p

atie

nt q

ualit

y of

life

thro

ugh

redu

ctio

n of

tre

atm

ent d

urat

ion,

bet

ter a

dher

ence

and

out

com

es, a

nd lo

wer r

esou

rce

use.

50

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Ass

essm

ent

JUD

GEM

ENT

RES

EAR

CH

EVID

ENC

EA

DD

ITIO

NA

L C

ON

SID

ERAT

ION

S

PROBLEMIs

the

prob

lem

a p

riorit

y?

No

P

roba

bly

no

P

roba

bly

yes

Ye

s

Var

ies

D

on’t

know

An e

stim

ated

hal

f a m

illio

n ne

w ca

ses

of

MDR

-tb

emer

ge e

ach

year

nec

essi

tatin

g tre

atm

ent.

Only

abo

ut o

ne fo

urth

of t

hese

we

re re

porte

d to

be

plac

ed o

n tre

atm

ent

in re

cent

yea

rs.

Outc

omes

of M

DR-t

b tre

atm

ent o

n a

glob

al le

vel a

re p

oor w

ith m

uch

loss

to

follo

w up

and

dea

th; o

nly

abou

t one

hal

f of

cas

es h

ave

a su

cces

sful

out

com

e at

th

e en

d of

trea

tmen

t.

MDR

-tb

is a

glo

bal c

halle

nge

and

acce

ss to

trea

tmen

t ofte

n pr

oble

mat

ic, w

ith re

gi-

men

s be

ing

typi

cally

of l

ong

dura

tion,

toxic

and

exp

ensi

ve.

ther

e is

cle

arly

an

inte

rest

in re

duci

ng th

e du

ratio

n of

trea

tmen

t, si

mpl

ifyin

g th

e ad

min

istra

tion

of th

e re

gim

en, a

nd p

rovi

ding

pat

ient

s wi

th a

saf

er c

ombi

natio

n of

m

edic

ines

that

can

cur

e th

em in

the

larg

e m

ajor

ity o

f ins

tanc

es.

DESIRABLE EFFECTS

How

sub

stan

tial a

re th

e de

sira

ble

antic

ipat

ed e

ffec

ts?

tr

ivia

l

sm

all

M

oder

ate

l

arge

Var

ies

D

on’t

know

In c

ontra

st to

long

er re

gim

ens,

sho

rter

MDR

-tb

regi

men

s ha

ve b

een

repo

rted

to

give

rela

pse-

free

cure

rate

s of

ove

r 85%

am

ong

sele

cted

pat

ient

s. th

e ev

iden

ce

sum

mar

ized

for t

he u

pdat

e of

thes

e gu

idel

ines

has

sho

wn s

ucce

ss ra

tios

to

be s

tatis

tical

ly s

igni

fican

tly h

ighe

r am

ong

patie

nts

treat

ed w

ith th

e sh

orte

r reg

imen

co

mpa

red

with

thos

e tre

ated

with

long

er

regi

men

s (e

ven

when

adj

uste

d fo

r cer

-ta

in fa

ctor

s).

Very

few

obse

rvat

ions

are

ava

ilabl

e up

to n

ow o

n th

e pe

rform

ance

of s

horte

r M

DR-t

b re

gim

ens

in th

e pr

esen

ce o

f add

ition

al re

sist

ance

.Ex

clus

ion

crite

rion:

Pre

viou

sly

treat

ed M

DR-t

b pa

tient

s wi

th s

econ

d-lin

e dr

ugs

(this

m

ay n

ot o

nly

be a

fact

or o

f dru

g re

sist

ance

but

bec

ause

thes

e pa

tient

s m

ay d

iffer

in

beha

viou

r, ad

here

nce)

. In

east

ern

Euro

pean

/cen

tral A

sian

set

tings

whe

re re

sist

ance

pa

ttern

s ar

e m

ore

wide

-rang

ing

and

wher

e Ds

t to

som

e of

the

drug

s is

cha

lleng

ing,

th

e re

gim

en m

ay b

e ex

pect

ed to

be

less

effe

ctive

. so

prev

ious

trea

tmen

t with

a re

g-im

en c

onta

inin

g se

cond

-line

dru

gs is

an

excl

usio

n cr

iterio

n (a

ccur

ate

info

rmat

ion

on p

revi

ous

drug

his

tory

may

be

diffi

cult

to g

et fr

om p

atie

nt o

r med

ical

file

s).

UNDESIRABLE EFFECTS

How

sub

stan

tial a

re th

e un

desi

rabl

e an

ticip

ated

ef

fect

s?

lar

ge

M

oder

ate

s

mal

l

triv

ial

V

arie

s

Don

’t kn

ow

Use

of th

e sh

orte

r reg

imen

s ha

s be

en a

ssoc

iate

d wi

th lo

wer l

evel

s of

adv

erse

ev

ents

, eve

n wh

en th

ese

were

col

lect

ed m

ore

syst

emat

ical

ly w

ithin

a fr

amew

ork

of

oper

atio

nal r

esea

rch.

 Ga

tiflox

acin

, the

fluo

roqu

inol

one

of c

hoic

e fo

r the

sho

rter M

DR-t

b re

gim

en, u

ntil

rece

ntly

was

repo

rted

to b

e as

soci

ated

with

dys

glyc

aem

ia in

eld

erly

pat

ient

s tre

ated

for c

ondi

tions

oth

er th

an tb

. sin

ce th

en g

atifl

oxac

in w

as s

hown

to n

ot

incr

ease

dys

glyc

aem

ia w

hen

used

as

part

of fo

ur-m

onth

regi

men

s fo

r tb

treat

men

t. th

e be

nefit

s fo

r its

use

are

exp

ecte

d to

out

weig

h th

e ris

ks w

hen

the

drug

has

a

mai

nsta

y ro

le in

the

treat

men

t of a

con

ditio

n as

ser

ious

as

MDR

-tb.

the

shor

ter r

egim

ens

do n

ot in

clud

e a

num

ber o

f dru

gs th

at a

re m

ost o

ften

asso

ci-

ated

with

ser

ious

or d

istre

ssin

g ad

vers

e ev

ents

(suc

h as

cyc

lose

rine,

PAs

, lin

ezol

id).

thes

e ca

n th

us b

e re

serv

ed to

be

used

as

part

of a

sal

vage

regi

men

sho

uld

the

patie

nt n

ot re

spon

d to

a s

horte

r reg

imen

.

CERTAINTY OF EVIDENCE

Wha

t is

the

over

all c

erta

inty

of t

he e

vide

nce

of e

ffec

ts?

V

ery

low

l

ow

M

oder

ate

H

igh

N

o in

clud

ed s

tudi

es

All d

ata

anal

ysed

for t

his

upda

te w

ere

deriv

ed fr

om o

bser

vatio

nal s

tudi

es. t

he

resu

lts o

f ran

dom

ized

cont

rolle

d tri

al

data

are

not

exp

ecte

d be

fore

the

end

of

2017

.

5151

ANNE

X 5:

EVI

DENC

E tO

DEC

IsIO

N tA

blEs

JUD

GEM

ENT

RES

EAR

CH

EVID

ENC

EA

DD

ITIO

NA

L C

ON

SID

ERAT

ION

S

VALUES

Is th

ere

impo

rtan

t unc

erta

inty

abo

ut o

r var

iabi

lity

in

how

muc

h pe

ople

val

ue th

e m

ain

outc

omes

?

Impo

rtant

unc

erta

inty

or v

aria

bilit

y

Pos

sibl

y im

porta

nt u

ncer

tain

ty o

r var

iabi

lity

P

roba

bly

no im

porta

nt u

ncer

tain

ty o

r var

iabi

lity

N

o im

porta

nt u

ncer

tain

ty o

r var

iabi

lity

N

o kn

own

unde

sira

ble

outc

omes

BALANCE OF EFFECTS

Does

the

bala

nce

betw

een

desi

rabl

e an

d un

desi

rabl

e ef

fect

s fa

vour

the

inte

rven

tion

or th

e co

mpa

rison

?

Fav

ours

the

com

paris

on

P

roba

bly

favo

urs

the

com

paris

on

D

oes

not f

avou

r eith

er th

e in

terv

entio

n or

the

c

ompa

rison

Pro

babl

y fa

vour

s th

e in

terv

entio

n

Fav

ours

the

inte

rven

tion

V

arie

s

Don

’t kn

ow

RESOURCES REQUIRED

How

larg

e ar

e th

e re

sour

ce re

quire

men

ts (

cost

s)?

l

arge

cos

ts

M

oder

ate

cost

s

Neg

ligib

le c

osts

and

sav

ings

Mod

erat

e sa

ving

s

lar

ge s

avin

gs

V

arie

s

Don

’t kn

ow

No re

sear

ch e

vide

nce

was

iden

tified

.

CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES

Wha

t is

the

cert

aint

y of

the

evid

ence

of r

esou

rce

requ

irem

ents

(co

sts)

?

Ver

y lo

w

low

Mod

erat

e

Hig

h

No

incl

uded

stu

dies

No re

sear

ch e

vide

nce

was

iden

tified

.

52

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

JUD

GEM

ENT

RES

EAR

CH

EVID

ENC

EA

DD

ITIO

NA

L C

ON

SID

ERAT

ION

S

COST EFFECTIVENESS

Does

the

cost

-eff

ectiv

enes

s of

the

inte

rven

tion

favo

ur

the

inte

rven

tion

or th

e co

mpa

rison

?

Fav

ours

the

com

paris

on

P

roba

bly

favo

urs

the

com

paris

on

D

oes

not f

avou

r eith

er th

e in

terv

entio

n or

the

com

paris

on

P

roba

bly

favo

urs

the

inte

rven

tion

F

avou

rs th

e in

terv

entio

n

Var

ies

N

o in

clud

ed s

tudi

es

No re

sear

ch e

vide

nce

was

iden

tified

.

EQUITY

Wha

t wou

ld b

e th

e im

pact

on

heal

th e

quity

?

Red

uced

Pro

babl

y re

duce

d

Pro

babl

y no

impa

ct

P

roba

bly

incr

ease

d

Incr

ease

d

Var

ies

D

on’t

know

No re

sear

ch e

vide

nce

was

iden

tified

.Al

thou

gh n

o re

liabl

e da

ta a

re a

vaila

ble

on th

e co

sts

of s

horte

r tb

regi

men

s, it

is

expe

cted

that

bot

h dr

ug c

osts

and

pro

gram

me

cost

s wo

uld

not b

e hi

gher

than

lo

nger

regi

men

s. th

is w

ould

mea

n th

at m

ore

reso

urce

s wo

uld

be a

vaila

ble

for t

he

treat

men

t of m

ore

patie

nts.

ACCEPTABILITY

Is th

e in

terv

entio

n ac

cept

able

to k

ey s

take

hold

ers?

N

o

Pro

babl

y no

Pro

babl

y ye

s

Yes

V

arie

s

Don

’t kn

ow

the

shor

ter M

DR-t

b re

gim

ens

have

bee

n su

cces

sful

ly im

plem

ente

d in

a n

umbe

r of

setti

ngs

in A

frica

and

Asi

a in

rece

nt y

ears

thro

ugh

the

effo

rts o

f a n

umbe

r of t

echn

i-ca

l age

ncie

s an

d na

tiona

l pro

gram

mes

. the

inte

rven

tion

is a

ccep

tabl

e to

clin

icia

ns

and

patie

nts.

5353

ANNE

X 5:

EVI

DENC

E tO

DEC

IsIO

N tA

blEs

JUD

GEM

ENT

RES

EAR

CH

EVID

ENC

EA

DD

ITIO

NA

L C

ON

SID

ERAT

ION

S

FEASIBILITY

Is th

e in

terv

entio

n fe

asib

le to

impl

emen

t?

No

P

roba

bly

no

P

roba

bly

yes

Ye

s

Var

ies

D

on’t

know

the

inte

rven

tion

has

been

suc

cess

fully

impl

emen

ted

unde

r a n

umbe

r of s

ettin

gs,

and

even

sup

porte

d by

maj

or d

onor

s su

ch a

s th

e Gl

obal

Fun

d to

Fig

ht A

IDs,

tb a

nd

Mal

aria

.su

pply

of c

lofa

zimin

e, w

hich

is in

dica

ted

as a

lepr

osy

drug

, is

a pr

oble

m in

lat

in

Amer

ica

and

else

wher

e. 

No q

ualit

y-as

sure

d so

urce

of g

atifl

oxac

in –

a c

heap

fluo

roqu

inol

one

(whi

ch w

as th

e co

rner

ston

e of

the

shor

ter M

DR-t

b re

gim

en u

ntil

rela

tivel

y re

cent

ly),

is a

vaila

ble

toda

y. th

ere

has

been

a g

loba

l sho

rtage

in m

anuf

actu

ring

follo

wing

the

repo

rted

risk

of a

ssoc

iate

d dy

sgly

caem

ia. t

his

has

sinc

e be

en s

hown

to b

e m

uch

less

ser

ious

an

d th

e be

nefit

s wo

uld

likel

y ou

twei

gh ri

sks

when

the

drug

is u

sed

to tr

eat a

con

di-

tion

as s

erio

us a

s M

DR-t

b.Ho

weve

r, th

e W

HO re

com

men

datio

n fo

r the

use

of s

horte

r MDR

-tb

regi

men

and

an

upd

ate

of th

e W

HO M

odel

Ess

entia

l Med

icin

es l

ist (

whic

h as

yet

doe

s no

t fea

-tu

re c

lofa

zimin

e an

d ga

tiflox

acin

as

tb d

rugs

) will

be

expe

cted

to h

ave

a fa

vour

able

im

pact

on

drug

man

ufac

ture

rs a

nd fu

el th

eir i

nter

est t

o in

vest

in th

e pr

oduc

tion

of

thes

e tw

o dr

ugs.

Con

clus

ions

SH

OU

LD S

TAN

DA

RD

IZED

SH

OR

TER

REG

IMEN

S B

E U

SED

FO

R T

HE

TREA

TMEN

T O

F M

DR

-TB

IN

STE

AD

OF

LON

GER

REG

IMEN

S (

ALL

CA

SES

; R

EGA

RD

LES

S O

F P

YR

AZ

I-N

AM

IDE

OR

FLU

OR

OQ

UIN

OLO

NE

SU

SC

EPTI

BIL

ITY)?

Type

of re

com

men

dati

onst

rong

reco

mm

enda

tion

agai

nst t

he in

terv

entio

n

Cond

ition

al re

com

men

datio

n ag

ains

t the

inte

rven

tion

Cond

ition

al re

com

men

datio

n fo

r eith

er th

e in

terv

entio

n or

th

e co

mpa

rison

Cond

ition

al re

com

men

datio

n fo

r the

inte

rven

tion

stro

ng re

com

men

datio

n fo

r the

in

terv

entio

n

Rec

omm

enda

tion

In p

atie

nts

with

rifa

mpi

cin-

resi

stan

t tb

or M

DR-t

b wh

o ha

ve n

ot b

een

prev

ious

ly tr

eate

d wi

th s

econ

d-lin

e dr

ugs

and

in w

hom

resi

stan

ce to

fluo

roqu

inol

ones

and

se

cond

-line

inje

ctab

le a

gent

s ha

s be

en e

xclu

ded

or is

con

side

red

high

ly u

nlik

ely,

the

WHO

Gui

delin

e De

velo

pmen

t Gro

up re

com

men

ds th

at a

sho

rter M

DR-t

b re

gi-

men

may

be

used

inst

ead

of a

con

vent

iona

l reg

imen

(con

ditio

nal r

ecom

men

datio

n, v

ery

low

certa

inty

in th

e ev

iden

ce)

Just

ifica

tion

All d

ata

used

to a

sses

s th

e sh

orte

r MDR

-tb

treat

men

t reg

imen

s we

re d

erive

d fro

m o

bser

vatio

nal s

tudi

es. I

ndiv

idua

l pat

ient

dat

a fro

m b

angl

ades

h (s

uppo

rted

by

the

Dam

ien

Foun

datio

n), U

zbek

ista

n (s

uppo

rted

by M

édec

ins

sans

Fro

ntiè

res

(MsF

)) a

nd s

wazil

and

(MsF

) as

well

as a

ggre

gate

d da

ta fr

om s

ub-s

ahar

an A

frica

n co

untri

es (s

uppo

rted

by th

e UN

ION

and

Actio

n Da

mie

n; b

enin

, bur

kina

Fas

o, b

urun

di, C

amer

oon,

Cen

tral A

frica

n Re

publ

ic, D

R Co

ngo,

Nig

er) w

ere

incl

uded

in

the

anal

ysis

. the

se w

ere

com

pare

d wi

th th

e ou

tcom

es o

f pat

ient

s wi

thou

t pre

viou

s ex

posu

re to

sec

ond-

line

tb d

rugs

who

wer

e in

clud

ed in

the

adul

t ind

ivid

ual

patie

nt d

ata

(aIP

D) a

naly

sis.

the

stan

dard

out

com

es u

sed

in th

e in

terv

entio

n an

d co

mpa

rato

r arm

s la

rgel

y co

mpl

ied

with

the

stan

dard

ized

outc

omes

use

d by

tb

prog

ram

mes

.th

e an

alys

es p

erfo

rmed

for t

he u

pdat

e of

the

guid

elin

es s

howe

d th

at p

atie

nts

who

rece

ived

shor

ter M

DR-t

b tre

atm

ent r

egim

ens

had

a st

atis

tical

ly s

igni

fican

t hig

her

likel

ihoo

d of

trea

tmen

t suc

cess

than

thos

e wh

o re

ceive

d lo

nger

con

vent

iona

l reg

imen

s. th

e nu

mbe

r of r

elap

ses

was

very

low,

alth

ough

this

may

hav

e be

en th

e re

sult

of th

e re

lativ

ely

smal

l num

ber o

f pat

ient

s fo

llowe

d up

. As

expe

cted

, tre

atm

ent s

ucce

ss w

as lo

wer i

n pa

tient

s wi

th a

dditi

onal

resi

stan

ce to

pyr

azin

amid

e an

d/or

fluo

-ro

quin

olon

es, e

ven

if in

gen

eral

it re

mai

ned

high

and

exc

eede

d th

at in

the

patie

nts

on in

divi

dual

ized,

long

er re

gim

ens

(alth

ough

the

diffe

renc

es w

ere

not s

tatis

tical

ly

sign

ifica

nt).

54

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Sub

grou

p co

nsid

erat

ions

Until

mor

e ev

iden

ce is

ava

ilabl

e, W

HO re

com

men

ds th

at th

e sh

orte

r MDR

-tb

regi

men

not

be

used

in p

atie

nts

who

have

bee

n pr

evio

usly

trea

ted

with

sec

ond-

line

drug

s fo

r mor

e th

an o

ne m

onth

or w

ho h

ave

know

n re

sist

ance

to m

edic

ines

in th

e re

gim

en. t

his

reco

mm

enda

tion

is s

ubje

ct to

pat

ient

s ha

ving

bee

n te

sted

for i

n vi

tro re

sist

ance

to a

t lea

st fl

uoro

quin

olon

es a

nd th

e in

ject

able

age

nt u

sed

in th

e re

gim

en b

efor

e st

artin

g tre

atm

ent.

In th

e ab

senc

e of

relia

ble

test

ing,

pat

ient

s wh

o ar

e hi

ghly

unl

ikel

y to

be

infe

cted

with

resi

stan

t stra

ins

base

d on

clin

ical

or r

ecen

t rep

rese

ntat

ive s

urve

illan

ce d

ata

may

als

o be

elig

ible

for t

he s

horte

r MDR

-tb

regi

men

.Pe

ople

livin

g wi

th H

IV n

eed

to b

e gi

ven

the

sam

e co

nsid

erat

ion

for t

reat

men

t with

the

shor

ter M

DR-t

b tre

atm

ent r

egim

en a

s pe

ople

who

are

HIV

ser

oneg

ative

.Ch

ildre

n we

re g

ener

ally

exc

lude

d fro

m s

tudi

es o

f sho

rter M

DR-t

b tre

atm

ent r

egim

ens.

How

ever

, the

re is

no

plau

sibl

e bi

olog

ical

reas

on to

bel

ieve

that

thes

e re

gi-

men

s ar

e le

ss e

ffect

ive in

chi

ldre

n th

an in

adu

lts. A

s a

resu

lt, it

is re

com

men

ded

that

chi

ldre

n wi

th p

ulm

onar

y rif

ampi

cin-

resi

stan

t tb/

MDR

-tb

be g

iven

the

sam

e co

nsid

erat

ion

for t

reat

men

t with

a s

horte

r MDR

-tb

treat

men

t reg

imen

as

adul

ts.

Preg

nanc

y wa

s an

exc

lusi

on c

riter

ion

for s

horte

r MDR

-tb

treat

men

t reg

imen

stu

dies

. two

of t

he c

ore

com

pone

nts

of th

e sh

orte

r MDR

-tb

regi

men

s –

the

inje

ctab

le

agen

t and

eth

iona

mid

e (o

r pro

thio

nam

ide)

– a

re u

sual

ly c

ontra

indi

cate

d in

pre

gnan

cy. W

ithho

ldin

g th

ese

med

icin

es fr

om th

e sh

orte

r MDR

-tb

treat

men

t reg

imen

co

uld

howe

ver s

erio

usly

com

prom

ise

its e

ffect

ivene

ss. t

hus

for p

regn

ant w

omen

it is

reco

mm

ende

d th

at a

n in

divi

dual

ized,

long

er re

gim

en b

e us

ed w

hich

can

allo

w th

e in

clus

ion

of fo

ur o

r mor

e ef

fect

ive m

edic

ines

with

no

know

n te

rato

geni

c pr

oper

ties.

Extra

pulm

onar

y di

seas

e. t

he fi

ndin

gs fr

om s

tudi

es o

f sho

rter M

DR-t

b re

gim

en w

ere

limite

d to

pat

ient

s wi

th p

ulm

onar

y di

seas

e, a

nd th

ey c

anno

t be

extra

pola

ted

dire

ctly

to a

ll di

ffere

nt fo

rms

of e

xtra

pulm

onar

y tb

. No

reco

mm

enda

tion

is th

us p

ossi

ble

at th

is s

tage

to u

se th

e sh

orte

r reg

imen

in p

atie

nts

with

ext

rapu

lmon

ary

MDR

-tb.

Resi

stan

ce a

dditi

onal

to is

onia

zid

and

rifam

pici

n. In

pat

ient

s in

fect

ed w

ith s

train

s kn

own

or s

trong

ly s

uspe

cted

of b

eing

resi

stan

t to

one

or m

ore

drug

s in

the

shor

ter M

DR-t

b tre

atm

ent r

egim

en (e

.g. p

yraz

inam

ide)

, it i

s re

com

men

ded

that

the

shor

ter r

egim

en n

ot b

e us

ed u

ntil

mor

e ev

iden

ce b

ecom

es a

vaila

ble

abou

t its

pe

rform

ance

in s

uch

a si

tuat

ion.

Impl

emen

tati

on

cons

ider

atio

nsIn

ord

er to

repr

oduc

e th

e hi

gh c

ure

rate

s ac

hiev

ed b

y th

e st

udie

s in

clud

ed in

the

revi

ews

for t

his

guid

ance

, all

effo

rts n

eed

to b

e m

ade

to a

void

the

acqu

isiti

on o

f ad

ditio

nal r

esis

tanc

e, th

roug

h ca

refu

l sel

ectio

n of

pat

ient

s to

be

enro

lled,

and

effe

ctive

pat

ient

sup

port

to e

nabl

e fu

ll ad

here

nce

to tr

eatm

ent.

It is

reco

mm

ende

d th

at p

atie

nts

be te

sted

for s

usce

ptib

ility

or r

esis

tanc

e to

fluo

roqu

inol

ones

and

to th

e se

cond

-line

inje

ctab

le a

gent

use

d in

the

regi

men

bef

ore

bein

g st

arte

d on

a

shor

ter M

DR-t

b re

gim

en. P

atie

nts

with

stra

ins

resi

stan

t to

any

of th

e tw

o gr

oups

of m

edic

ines

sho

uld

be tr

ansf

erre

d to

trea

tmen

t with

a lo

nger

, ind

ivid

ualis

ed re

gi-

men

. the

ava

ilabi

lity

of re

liabl

e an

d ra

pid

test

s wo

uld

be v

alua

ble

to d

ecid

e (w

ithin

a fe

w da

ys) w

hich

pat

ient

s wo

uld

be e

ligib

le fo

r sho

rter M

DR-t

b re

gim

ens,

and

wh

at m

odifi

catio

ns to

long

er M

DR-t

b re

gim

ens

are

nece

ssar

y ba

sed

on th

e re

sist

ance

det

ecte

d. In

pat

ient

s wi

th c

onfir

med

rifa

mpi

cin-

resi

stan

t tb

or M

DR-t

b, th

e M

tbDR

sl a

ssay

may

be

used

as

the

initi

al te

st, o

ver c

ultu

re a

nd p

heno

typi

c Ds

t, to

det

ect r

esis

tanc

e to

fluo

roqu

inol

ones

and

to th

e se

cond

-line

inje

ctab

le d

rugs

(c

ondi

tiona

l rec

omm

enda

tions

; cer

tain

ty o

f evi

denc

e fo

r dire

ct te

stin

g of

spu

tum

from

low

to m

oder

ate)

. thi

s ap

plie

s to

test

ing

in b

oth

child

ren

and

adul

ts. I

ndire

ct

test

ing

may

incl

ude

biol

ogic

al s

ampl

es fr

om e

xtra

pulm

onar

y si

tes.

Whi

le re

sist

ance

-con

ferri

ng m

utat

ions

to fl

uoro

quin

olon

es d

etec

ted

by th

e M

tbDR

sl a

ssay

are

hi

ghly

cor

rela

ted

with

phe

noty

pic

resi

stan

ce to

oflo

xaci

n an

d le

voflo

xaci

n, th

e co

rrela

tion

with

mox

iflox

acin

and

gat

iflox

acin

is le

ss c

lear

and

the

incl

usio

n of

mox

i-flo

xaci

n or

gat

iflox

acin

in a

MDR

-tb

regi

men

is b

est g

uide

d by

phe

noty

pic

Dst

resu

lts.

In s

ettin

gs in

whi

ch la

bora

tory

cap

acity

for D

st to

fluo

roqu

inol

ones

and

inje

ctab

le a

gent

s is

not

yet

ava

ilabl

e, th

e cl

inic

ian

and

the

tb p

rogr

amm

e m

anag

er w

ould

ne

ed to

dec

ide

on th

e ba

sis

of th

e lik

elih

ood

of re

sist

ance

to th

ese

med

icin

es, i

nfor

med

by

the

patie

nt’s

clin

ical

his

tory

and

rece

nt re

pres

enta

tive

surv

eilla

nce

data

.th

e ev

iden

ce fo

r the

effe

ctive

ness

and

saf

ety

of th

e sh

orte

r MDR

-tb

regi

men

der

ives

from

stu

dies

whe

re th

is tr

eatm

ent w

as a

dmin

iste

red

unde

r fai

rly s

tand

ardi

zed

cond

ition

s wi

th re

lativ

ely

little

var

iatio

n in

the

cont

ent a

nd d

urat

ion.

thus

, the

reco

mm

enda

tion

on th

e us

e of

the

shor

ter M

DR-t

b re

gim

en is

mad

e un

der t

he p

rem

-is

e th

at it

is im

plem

ente

d as

per

the

com

posi

tion

and

dura

tion

used

in th

e ob

serv

atio

nal s

tudi

es. R

epla

cem

ent o

f med

icin

es a

nd p

rolo

ngat

ion/

shor

teni

ng o

f the

du

ratio

n wo

uld

only

be

perm

issi

ble

with

in th

e pa

ram

eter

s ap

plie

d in

thes

e st

udie

s (e

.g. g

atifl

oxac

in re

plac

ed b

y m

oxifl

oxac

in; p

roth

iona

mid

e re

plac

ed b

y et

hion

a-m

ide;

inte

nsive

pha

se p

rolo

nged

up

to s

ix m

onth

s in

cas

e of

no

sput

um c

onve

rsio

n).

two

stap

les

of th

e re

gim

en, c

lofa

zimin

e an

d hi

gh-d

ose

ison

iazid

, may

be

diffi

cult

to p

rocu

re in

som

e co

untri

es. M

oreo

ver,

ther

e ar

e no

goo

d pa

edia

tric

form

ula-

tions

of c

lofa

zimin

e an

d di

vidi

ng th

e ca

psul

e in

to s

mal

ler d

oses

is a

lmos

t im

poss

ible

, mak

ing

dosi

ng in

chi

ldre

n un

certa

in. G

iven

the

glob

al s

horta

ge in

the

supp

ly

of q

ualit

y-as

sure

d ga

tiflox

acin

in re

cent

yea

rs, t

he s

ites

wher

e ob

serv

atio

nal s

tudi

es h

ave

been

con

duct

ed h

ave

had

to s

ubst

itute

this

age

nt w

ith m

oxifl

oxac

in. t

his

has

led

to a

n im

porta

nt in

crea

se in

the

over

all p

rice

of th

e re

gim

en, w

ith m

oxifl

oxac

in ty

pica

lly a

ccou

ntin

g fo

r abo

ut o

ne h

alf o

f ove

rall

drug

cos

ts. t

he im

plem

enta

-tio

n of

thes

e gu

idel

ines

at t

he n

atio

nal l

evel

nee

ds to

ens

ure

that

suf

ficie

nt q

uant

ities

of t

hese

med

icin

es a

re a

vaila

ble

to m

eet t

he d

eman

d an

d th

at n

o st

ock-

outs

oc

cur.

5555

ANNE

X 5:

EVI

DENC

E tO

DEC

IsIO

N tA

blEs

Mon

itor

ing

and

eval

uati

onPa

tient

s wh

o re

ceive

a s

horte

r MDR

-tb

treat

men

t reg

imen

nee

d to

be

mon

itore

d du

ring

treat

men

t and

afte

r com

plet

ion

usin

g sc

hedu

les

of re

leva

nt c

linic

al a

nd

labo

rato

ry te

stin

g wh

ich

have

bee

n su

cces

sful

ly a

pplie

d in

the

stud

ies

unde

r fiel

d co

nditi

ons.

the

WHO

fram

ewor

k fo

r act

ive tb

dru

g-sa

fety

mon

itorin

g an

d m

anag

e-m

ent (

aDsM

) nee

ds to

be

appl

ied

to e

nsur

e ap

prop

riate

act

ion

to re

spon

d pr

ompt

ly to

adv

erse

eve

nts

and

an a

ccep

tabl

e le

vel o

f mon

itorin

g fo

r the

m, a

long

side

th

e m

onito

ring

for t

reat

men

t out

com

es.

Res

earc

h pr

ioriti

es• s

tREA

M s

tudy

resu

lts w

ill b

e av

aila

ble

in a

few

year

s bu

t the

pan

el fe

lt co

mfo

rtabl

e to

mak

e th

e co

nditi

onal

reco

mm

enda

tions

.

• the

WHO

Gui

delin

e De

velo

pmen

t Gro

up d

iscu

ssed

the

rese

arch

prio

ritie

s fo

r red

ucin

g th

e du

ratio

n of

MDR

-tb

regi

men

s an

d hi

ghlig

hted

the

follo

wing

prio

ritie

s: –Fu

ture

rese

arch

nee

ds to

incl

ude

the

effe

ctive

ness

/saf

ety

of th

e sh

orte

r MDR

-tb

treat

men

t reg

imen

in s

ubgr

oups

whi

ch h

ave

been

sys

tem

atic

ally

exc

lude

d fro

m

stud

y pr

otoc

ols

(e.g

. chi

ldre

n, p

atie

nts

with

diff

eren

t for

ms

of e

xtra

pulm

onar

y di

seas

e) a

nd in

set

tings

whe

re b

ackg

roun

d re

sist

ance

to d

rugs

oth

er th

an fl

uoro

-qu

inol

ones

and

sec

ond-

line

inje

ctab

le a

gent

s is

hig

h (e

.g. p

yraz

inam

ide

or h

igh-

leve

l iso

niaz

id re

sist

ance

). –Im

plem

enta

tion

rese

arch

on

the

intro

duct

ion

of th

e sh

orte

r MDR

-tb

regi

men

. –st

udie

s on

cos

t effe

ctive

ness

.

2. R

egim

ens

wit

h in

divi

dual

ized

com

posi

tion

and

dur

atio

n fo

r ad

ults

and

chi

ldre

n w

ith

MD

R-T

B

in w

hom

a s

hort

er M

DR

-TB

reg

imen

can

not

be u

sed

Popu

latio

n:Ad

ults

and

chi

ldre

n wi

th ri

fam

pici

n-re

sist

ant t

b/M

DR-t

b in

wh

om a

sho

rter M

DR-t

b re

gim

en c

anno

t be

used

back

grou

nd:

A nu

mbe

r of r

ifam

pici

n-re

sist

ant t

b/M

DR-t

b pa

tient

s (c

hild

ren

and

adul

ts) a

re e

xpec

ted

not t

o be

elig

ible

for t

he s

horte

r MDR

-tb

regi

men

reco

mm

ende

d el

sewh

ere

in th

ese

guid

elin

es. t

hese

in

clud

e pa

tient

s wh

o we

re p

revi

ousl

y tre

ated

with

sec

ond-

line

tb m

edic

ines

for m

ore

than

one

m

onth

, ind

ivid

uals

infe

cted

with

stra

ins

resi

stan

t to

one

or m

ore

drug

s in

the

shor

ter M

DR-t

b re

gim

en, a

nd p

atie

nts

with

ext

rapu

lmon

ary

dise

ase.

In th

ese

patie

nts,

a lo

nger

regi

men

is u

su-

ally

indi

cate

d, w

ith a

 com

posi

tion

and

dura

tion

indi

vidu

alize

d to

incr

ease

the

likel

ihoo

d of

the

regi

men

’s ef

fect

ivene

ss a

nd a

chie

ve a

goo

d ba

lanc

e of

exp

ecte

d be

nefit

s to

har

ms.

thes

e re

g-im

ens

have

bee

n in

use

for s

ever

al y

ears

in m

any

diffe

rent

geo

grap

hica

l set

tings

but

thei

r use

ha

s be

en li

mite

d to

pub

lishe

d ob

serv

atio

nal s

tudi

es o

f pat

ient

s fo

llowe

d up

und

er p

rogr

am-

mat

ic c

ondi

tions

, with

onl

y so

litar

y RC

ts d

esig

ned

and

cond

ucte

d to

ass

ess

the

bene

fit /

saf

ety

of th

e lo

nger

regi

men

s.Fo

r the

201

6 up

date

of t

hese

gui

delin

es, W

HO h

as u

sed

thre

e di

ffere

nt s

ourc

es o

f evi

denc

e to

su

mm

arize

the

effe

cts,

nam

ely:

 i)

A sy

stem

atic

revi

ew a

nd s

tudy

-leve

l met

a-an

alys

is fo

r the

effe

ct o

f ind

ivid

ual s

econ

d-lin

e dr

ugs

in M

DR-t

b tre

atm

ent (

see

Anne

x 6

for s

umm

ary

of u

npub

lishe

d st

udy)

.ii)

An

indi

vidu

al-p

atie

nt d

ata

anal

ysis

for 9

153

MDR

-tb

patie

nts

near

ly a

ll of

who

m a

re a

dults

(u

p to

201

0) (A

huja

sD,

et a

l. Pl

os M

ed. 2

012;

9(8)

:e10

0130

0).

iii) A

n in

divi

dual

-pat

ient

dat

a an

alys

is fo

r 974

pae

diat

ric M

DR-t

b pa

tient

s (s

ee A

nnex

6 fo

r su

mm

ary

of u

npub

lishe

d st

udy)

.

Inte

rven

tion:

A lo

nger

regi

men

of i

ndiv

idua

lized

com

posi

tion

and

dura

tion

Com

paris

on:

Othe

r

Mai

n ou

tcom

es:

Cure

d/co

mpl

eted

by

the

end

of tr

eatm

ent;

cultu

re c

onve

rsio

n by

six

mon

ths;

trea

tmen

t fai

lure

; rel

apse

; sur

viva

l (or

dea

th);

adve

rse

reac

tions

(sev

erity

, typ

e, o

rgan

cla

ss)

setti

ng:

treat

men

t adm

inis

tere

d to

pat

ient

s in

bot

h ho

spita

l and

am

bula

tory

set

tings

; the

dis

tribu

tion

of th

e st

udie

s an

d da

ta

was

glob

al

Pers

pect

ive:

the

long

er re

gim

en is

rese

rved

for a

dult

and

paed

iatri

c pa

tient

s wh

o ar

e in

elig

ible

for t

he s

horte

r MDR

-tb

regi

men

du

e to

add

ition

al re

sist

ance

, ext

rapu

lmon

ary

dise

ase,

or o

ther

co

ntra

indi

catio

ns. t

he d

esig

n of

the

regi

men

’s co

mpo

sitio

n is

revi

sed

to o

ptim

ize th

e us

e of

ava

ilabl

e m

edic

ines

bas

ed

on a

vaila

ble

evid

ence

and

thus

it m

axim

izes

the

likel

ihoo

d of

pa

tient

s ha

ving

a s

ucce

ssfu

l out

com

e at

its

end.

56

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Ass

essm

ent

JUD

GEM

ENT

RES

EAR

CH

EVID

ENC

EA

DD

ITIO

NA

L C

ON

SID

ERAT

ION

SDESIRABLE EFFECTS

How

sub

stan

tial a

re th

e de

sira

ble

antic

ipat

ed e

ffec

ts?

tr

ivia

l

sm

all

M

oder

ate

l

arge

Var

ies

D

on’t

know

treat

men

t of M

DR-t

b in

adu

lts a

nd c

hild

ren

with

lo

nger

sec

ond-

line

regi

men

s is

kno

wn to

incr

ease

th

e lik

elih

ood

of c

ure

and

lowe

r the

risk

of c

hro-

nici

ty a

nd d

eath

(Ahu

ja s

D, e

t al.

Plos

Med

. 20

12;9

(8):e

1001

300;

 sed

don

JA, e

t al.

thor

ax.

2014

;69(

5):4

58–6

4.).

Rece

nt re

view

s ha

ve s

hown

th

at s

ucce

ss ra

tios

aver

agin

g to

abo

ut 6

0% in

ad

ults

with

 MDR

-tb

and

90%

in c

hild

ren

are

pos-

sibl

e am

ong

patie

nts

treat

ed u

nder

pro

gram

mat

ic

cond

ition

s.A

num

ber o

f the

sec

ond-

line

med

icat

ions

are

ass

oci-

ated

with

und

esira

ble

adve

rse

effe

cts

in b

oth

adul

ts

and

child

ren

with

MDR

-tb,

whi

ch a

t tim

es le

ad to

se

rious

out

com

es a

nd d

isco

ntin

uatio

n or

sub

stan

-tia

l cha

nge

in re

gim

ens

(blo

ss E

, et a

l. In

t J tu

berc

lu

ng D

is. 2

010;

14(3

):275

–81;

 sed

don

JA, e

t al.

Jour

nal o

f Inf

ectio

n. 2

013;

66(4

):320

–9; s

ee a

lso

body

of g

uide

lines

(inc

ludi

ng ta

ble

7), G

RADE

tabl

es

in A

nnex

4 a

nd s

umm

arie

s of

unp

ublis

hed

stud

ies

in

Anne

x 6

for m

ore

deta

ils o

n ef

fect

ivene

ss a

nd s

afet

y of

long

er M

DR-t

b re

gim

ens

in a

dults

and

chi

ldre

n).

the

likel

ihoo

d of

suc

cess

is e

xpec

ted

to v

ary

depe

ndin

g on

a n

umbe

r of

patie

nt fa

ctor

s (s

ever

ity o

f dis

ease

, res

ista

nce

patte

rns)

and

hea

lth c

are

serv

ices

(acc

ess

to d

iffer

ent m

edic

atio

ns o

f goo

d-qu

ality

, pat

ient

mon

itor-

ing

and

supp

ort).

UNDESIRABLE EFFECTS

How

sub

stan

tial a

re th

e un

desi

rabl

e an

ticip

ated

eff

ects

?

lar

ge

M

oder

ate

s

mal

l

triv

ial

V

arie

s

Don

’t kn

ow

the

likel

ihoo

d of

har

ms

is e

xpec

ted

to v

ary

depe

ndin

g on

a n

umbe

r of

patie

nt fa

ctor

s (c

omor

bidi

ty, d

isea

se s

ever

ity) a

nd th

e he

alth

inte

rven

-tio

n (c

hoic

e of

dru

gs, p

ill-b

urde

n an

d dr

ug–d

rug

inte

ract

ions

, ade

quac

y of

sa

fety

mon

itorin

g an

d su

ppor

t, op

tions

to s

witc

h dr

ugs

in c

ase

of a

dver

se

reac

tions

). th

e fa

ct th

at lo

nger

regi

men

s ar

e co

mpo

sed

of a

t lea

st fi

ve

med

icat

ions

in th

e in

tens

ive p

hase

incr

ease

s th

e lik

elih

ood

of a

dditi

ve

adve

rse

effe

cts

and

inte

ract

ions

.th

e re

clas

sific

atio

n of

PAs

to G

roup

D3

impl

ies

that

this

med

icat

ion

that

is

ofte

n re

spon

sibl

e fo

r man

y un

desi

rabl

e ef

fect

s wo

uld

be u

sed

less

ofte

n.M

oreo

ver,

it is

exp

ecte

d th

at a

larg

er p

ropo

rtion

of p

atie

nts

will

be p

lace

d on

the

shor

ter M

DR-t

b re

gim

en la

stin

g 9–

12 m

onth

s, w

hich

con

tain

s le

ss

med

icat

ions

ass

ocia

ted

with

maj

or a

dver

se e

ffect

s (c

yclo

serin

e, li

nezo

lid,

PAs;

eth

iona

mid

e /

prot

hion

amid

e lim

ited

to th

e in

tens

ive p

hase

whi

ch is

sh

orte

r tha

n in

mos

t lon

ger r

egim

ens)

.

CERTAINTY OF EVIDENCE

Wha

t is

the

over

all c

erta

inty

of t

he e

vide

nce

of e

ffec

ts?

V

ery

low

l

ow

M

oder

ate

H

igh

N

o in

clud

ed s

tudi

es

Mos

t of t

he d

ata

revi

ewed

for b

oth

effe

ctive

ness

and

sa

fety

der

ive fr

om o

bser

vatio

nal s

tudi

es w

ith li

mite

d po

ssib

ilitie

s of

adj

ustm

ent.

the

qual

ity o

f the

evi

-de

nce

from

the

few

rand

omize

d tri

als

was

mar

ked

down

ward

s be

caus

e of

impr

ecis

ion

(sin

gle

stud

ies

with

rela

tivel

y sm

all n

umbe

rs o

f obs

erva

tions

).

Effo

rts w

ere

mad

e to

use

indi

vidu

al-le

vel p

atie

nt d

ata

wher

e po

ssib

le

in b

oth

adul

ts a

nd c

hild

ren

to a

djus

t for

cov

aria

tes

that

cou

ld in

fluen

ce

outc

omes

. How

ever

, res

idua

l con

foun

ding

is v

ery

likel

y to

hav

e be

en s

ub-

stan

tial i

n m

any

of th

e an

alys

es.

5757

ANNE

X 5:

EVI

DENC

E tO

DEC

IsIO

N tA

blEs

JUD

GEM

ENT

RES

EAR

CH

EVID

ENC

EA

DD

ITIO

NA

L C

ON

SID

ERAT

ION

S

BALANCE OF EFFECTSDo

es th

e ba

lanc

e be

twee

n de

sira

ble

and

unde

sira

ble

effe

cts

favo

ur th

e in

terv

entio

n or

the

com

paris

on?

F

avou

rs th

e co

mpa

rison

Pro

babl

y fa

vour

s th

e co

mpa

rison

Doe

s no

t fav

our e

ither

the

inte

rven

tion

or th

e co

mpa

rison

Pro

babl

y fa

vour

s th

e in

terv

entio

n

Fav

ours

the

inte

rven

tion

V

arie

s

Don

’t kn

ow

No re

sear

ch e

vide

nce

was

iden

tified

.FEASIBILITY

Is th

e in

terv

entio

n fe

asib

le to

impl

emen

t?

No

P

roba

bly

no

P

roba

bly

yes

Ye

s

Var

ies

D

on’t

know

ther

e ha

s be

en a

ste

ady

incr

ease

in th

e nu

mbe

r of

rifam

pici

n-re

sist

ant t

b/M

DR-t

b pa

tient

s pl

aced

on

seco

nd-li

ne tr

eatm

ent g

loba

lly a

nd re

ports

to W

HO

show

that

in 2

014,

111

000

pat

ient

s we

re s

tarte

d on

trea

tmen

t (Gl

obal

tube

rcul

osis

repo

rt 20

15

(WHO

/HtM

/tb/

2015

.22)

; app

s.wh

o.in

t/iri

s/bi

tstr

eam

/106

65/1

9110

2/1/

9789

2415

6505

9_en

g.pd

f)

long

er, i

ndiv

idua

lized

regi

men

s ha

ve b

een

succ

essf

ully

use

d to

trea

t M

DR-t

b pa

tient

s fo

r the

pas

t few

dec

ades

, und

er a

var

iety

of s

ettin

gs in

bo

th h

igh-

and

low-

reso

urce

situ

atio

ns. E

fforts

in lo

w- a

nd m

iddl

e-in

com

e se

tting

s ha

ve b

een

supp

orte

d th

roug

h do

mes

tic fu

ndin

g an

d al

so e

xter

-na

lly b

y m

ajor

don

ors

like

UsAI

D an

d th

e Gl

obal

Fun

d to

Fig

ht A

IDs,

tb

and

Mal

aria

.th

e av

aila

bilit

y of

cor

e se

cond

-line

dru

gs re

quire

d to

com

pose

the

long

er

regi

men

s ha

s im

prov

ed in

rece

nt y

ears

. the

Glo

bal D

rug

Faci

lity

now

incl

udes

mos

t of t

he d

rugs

on

its c

atal

ogue

. the

pric

e of

the

drug

s ha

s al

so d

ecre

ased

ove

r tim

e, in

clud

ing

that

of l

inez

olid

and

mox

iflox

acin

, as

the

gene

ric m

anuf

actu

re o

f the

se a

gent

s ha

s in

crea

sed

(mos

t dru

gs in

Gr

oups

A to

D w

ith th

e ex

cept

ion

of th

e ne

w dr

ugs

beda

quili

ne a

nd d

ela-

man

id a

re n

ow o

ff pa

tent

).th

ere

are

still

cha

lleng

es in

the

proc

urem

ent o

f cer

tain

dru

gs. b

edaq

uilin

e an

d de

lam

anid

rem

ain

expe

nsive

alth

ough

initi

ative

s ha

ve s

ucce

ssfu

lly

dona

ted

beda

quili

ne in

the

past

few

year

s an

d m

ade

dela

man

id a

vaila

ble

at a

lowe

r cos

t to

low-

inco

me

coun

tries

. the

re is

no 

qual

ity-a

ssur

ed s

ourc

e of

gat

iflox

acin

(a c

heap

late

r-gen

erat

ion

fluor

oqui

nolo

ne),

whic

h is

ava

ila-

ble

toda

y gi

ven

a gl

obal

sho

rtage

in m

anuf

actu

re fo

llowi

ng a

repo

rted

risk

of a

ssoc

iate

d dy

sgly

cem

ia (t

his

risk

has

sinc

e be

en s

hown

to b

e m

uch

lowe

r in

tb p

atie

nts

and

bene

fits

woul

d lik

ely

outw

eigh

risk

s wh

en th

e dr

ug

is u

sed

to tr

eat a

con

ditio

n as

ser

ious

as

MDR

-tb)

. Clo

fazim

ine

supp

lies

are

also

lim

ited

and

this

dru

g is

indi

cate

d pr

imar

ily fo

r lep

rosy

and

use

d “o

ff-la

bel”

for t

he tr

eatm

ent o

f MDR

-tb.

bot

h cl

ofaz

imin

e an

d ga

tiflox

acin

do

not

as

yet f

eatu

re o

n th

e W

HO M

odel

lis

ts o

f Ess

entia

l Med

icin

es a

s tb

dru

gs.

the

prog

ram

mat

ic m

anag

emen

t of d

rug-

resi

stan

t tb

has

beco

me

a m

ain-

stay

com

pone

nt o

f man

y na

tiona

l tb

prog

ram

mes

and

sev

eral

cou

ntrie

s ha

ve s

ucce

ssfu

lly in

trodu

ced

a so

und

mon

itorin

g fra

mew

ork

to fo

llow

up

patie

nts

for r

espo

nse

to tr

eatm

ent a

nd to

saf

egua

rd p

atie

nt s

afet

y.

58

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Con

clus

ions

SH

OU

LD A

REG

IMEN

OF

IND

IVID

UA

LIZ

ED C

OM

PO

SIT

ION

AN

D D

UR

ATIO

N B

E U

SED

IN

AD

ULT

S A

ND

CH

ILD

REN

WIT

H R

IFA

MP

ICIN

-RES

ISTA

NT

TB/

MD

R-T

B I

N W

HO

M

A S

HO

RTE

R M

DR

-TB

REG

IMEN

CA

NN

OT

BE

USED

?

Type

of

reco

mm

enda

tion

stro

ng re

com

men

datio

n ag

ains

t th

e in

terv

entio

n

Cond

ition

al re

com

men

datio

n ag

ains

t the

inte

rven

tion

Cond

ition

al re

com

men

datio

n fo

r eith

er th

e in

terv

entio

n or

the

com

paris

on

Cond

ition

al re

com

men

datio

n fo

r th

e in

terv

entio

n

stro

ng re

com

men

datio

n fo

r the

in

terv

entio

n

the

reco

mm

enda

tions

app

ly to

chi

ldre

n an

d ad

ults

 with

rifa

mpi

cin-

resi

stan

t tb/

MDR

-tb

(see

als

o un

der s

ubgr

oup

cons

ider

atio

ns).

In c

hild

ren

with

out s

ever

e di

seas

e (s

ever

ity d

efine

d in

the

paed

iatri

c in

divi

dual

pat

ient

dat

a (p

IPD)

on

the

basi

s of

poo

r nut

ritio

nal s

tatu

s, e

xten

sive

dis

ease

on

ches

t rad

iogr

a-ph

y, pr

esen

ce o

f sev

ere

form

s of

ext

rapu

lmon

ary

dise

ase

and

HIV

sero

-pos

itivi

ty),

the

inje

ctab

le a

gent

s m

ay b

e ex

clud

ed fr

om th

e re

gim

en.

Rec

omm

enda

tion

a) In

pat

ient

s wi

th ri

fam

pici

n-re

sist

ant t

b or

MDR

-tb,

the

Guid

elin

e De

velo

pmen

t Gro

up re

com

men

ds a

regi

men

with

at l

east

five

effe

ctive

tb m

edic

ines

dur

ing

the

inte

nsive

ph

ase,

incl

udin

g py

razin

amid

e pl

us fo

ur c

ore

seco

nd-li

ne tb

med

icin

es, o

ne c

hose

n fro

m G

roup

A, o

ne fr

om G

roup

b, a

nd a

t lea

st tw

o fro

m G

roup

C [1

] (co

nditi

onal

reco

mm

en-

datio

n, v

ery

low

certa

inty

in th

e ev

iden

ce).

If th

e m

inim

um o

f effe

ctive

tb m

edic

ines

can

not b

e co

mpo

sed

as a

bove

, an

agen

t fro

m G

roup

D2

and

othe

r age

nts

from

Gro

up D

3 m

ay b

e ad

ded

to b

ring

the

tota

l to

five

[2].

b) In

pat

ient

s wi

th ri

fam

pici

n-re

sist

ant t

b or

MDR

-tb,

 the

Guid

elin

e De

velo

pmen

t Gro

up re

com

men

ds th

at th

e re

gim

en b

e fu

rther

stre

ngth

ened

with

hig

h-do

se is

onia

zid a

nd/o

r et

ham

buto

l (co

nditi

onal

reco

mm

enda

tion,

ver

y lo

w ce

rtain

ty in

the

evid

ence

).[1

] Gro

up A

=lev

oflox

acin

, mox

iflox

aci,

gatifl

oxac

in; G

roup

b=a

mik

acin

, cap

reom

ycin

, kan

amyc

in, (

stre

ptom

ycin

); Gr

oup

C= e

thio

nam

ide

(or p

roth

iona

mid

e), c

yclo

serin

e (o

r ter

-izi

done

), lin

ezol

id, c

lofa

zimin

e; in

chi

ldre

n wi

th n

on-s

ever

e di

seas

e Gr

oup

b m

edic

ines

may

be

excl

uded

[2] G

roup

D2=

beda

quili

ne, d

elam

anid

; Gro

up D

3=p-

amin

osal

icyl

ic a

cid,

Imip

enem

-cila

stat

in, m

erop

enem

, am

oxic

illin

-cla

vula

nate

, (th

ioac

etaz

one)

5959

ANNE

X 5:

EVI

DENC

E tO

DEC

IsIO

N tA

blEs

Just

ifica

tion

Desi

rabl

e an

d un

desi

rabl

e ef

fect

s

A. F

luor

oqui

nolo

nes

base

d on

the

evid

ence

revi

ews,

the

GDG

conc

lude

d th

at tr

eatm

ent w

ith la

ter-g

ener

atio

n flu

oroq

uino

lone

s (d

efine

d fo

r the

se g

uide

lines

as

high

-dos

e le

voflo

xaci

n, m

oxifl

oxac

in,

and

gatifl

oxac

in) s

igni

fican

tly im

prov

es tr

eatm

ent o

utco

mes

in a

dults

with

rifa

mpi

cin-

resi

stan

t tb

or M

DR-t

b. th

is g

roup

of d

rugs

is c

onsi

dere

d to

be

the

mos

t im

porta

nt c

ompo

-ne

nt o

f the

cor

e M

DR-t

b re

gim

en a

nd th

e be

nefit

s fro

m th

eir u

se o

utwe

ighs

pot

entia

l ris

ks. t

hey

shou

ld th

eref

ore

alwa

ys b

e in

clud

ed u

nles

s th

ere

is a

n ab

solu

te c

ontra

indi

catio

n fo

r the

ir us

e. th

e or

der o

f pre

fere

nce

for t

he in

clus

ion

of th

e la

ter-g

ener

atio

n flu

oroq

uino

lone

s in

MDR

-tb

regi

men

s is

as

follo

ws: h

igh-

dose

levo

floxa

cin,

mox

iflox

acin

and

gat

i-flo

xaci

n. It

is re

com

men

ded

that

oflo

xaci

n be

pha

sed

out f

rom

MDR

-tb

regi

men

s an

d th

at c

ipro

floxa

cin

is n

ever

use

d du

e to

the

limite

d ev

iden

ce fo

r the

ir ef

fect

ivene

ss. A

lthou

gh

the

pIPD

had

hig

h le

vels

of c

onfo

undi

ng a

nd in

suffi

cien

t num

bers

to a

dequ

atel

y an

alys

e th

e tre

atm

ent e

ffect

of h

igh-

dose

levo

floxa

cin,

mox

iflox

acin

and

gat

iflox

acin

, dat

a fro

m

adul

ts w

ith M

DR-t

b sh

ows

a tre

atm

ent b

enefi

t. th

eref

ore

thes

e re

com

men

datio

ns h

ave

been

ext

rapo

late

d to

chi

ldre

n.

Fluo

roqu

inol

ones

in g

ener

al h

ave

a go

od s

afet

y pr

ofile

and

con

side

ring

the

serio

usne

ss o

f rifa

mpi

cin-

resi

stan

t tb/

MDR

-tb,

the

pote

ntia

l for

dru

g-re

late

d ha

rms

is o

ffset

by

the

bene

fits

from

thei

r use

. Alth

ough

adv

erse

eve

nts

were

poo

rly re

cord

ed, i

n th

e st

udy-

leve

l met

a-an

alys

is, t

he fr

eque

ncy

of s

AEs

(defi

ned

as G

rade

3–4

adv

erse

eve

nts

or m

edi-

cine

s st

oppe

d pe

rman

ently

due

to a

dver

se e

vent

) attr

ibut

ed to

fluo

roqu

inol

ones

was

low

(1.2

%–2

.8%

). M

oxifl

oxac

in c

arrie

s a

risk

of Q

t pr

olon

gatio

n, a

cau

se fo

r con

cern

whe

n us

ed in

com

bina

tion

with

med

icat

ions

that

hav

e a

sim

ilar e

ffect

(inc

ludi

ng b

edaq

uilin

e an

d de

lam

anid

). th

ere

are

fewe

r con

cern

s ab

out t

he c

ardi

otox

icity

of l

evofl

oxac

in a

nd g

at-

iflox

acin

, an

impo

rtant

con

side

ratio

n gi

ven

that

sev

eral

oth

er s

econ

d-lin

e dr

ugs

have

Qt-

prol

ongi

ng p

oten

tial.

Conc

erns

abo

ut d

ysgl

ycae

mia

repo

rted

in 2

006

in p

atie

nts

treat

ed w

ith g

atifl

oxac

in fo

r con

ditio

ns o

ther

than

tb le

d th

e pa

rent

com

pany

to s

top

man

ufac

ture

of t

he d

rug,

and

a

glob

al s

horta

ge in

qua

lity-

assu

red

form

ulat

ions

of t

his

drug

ens

ued.

A tr

ial o

f a fo

ur-m

onth

sta

ndar

dize

d re

gim

en fo

r dru

g-su

scep

tible

tb th

at in

clud

ed g

atifl

oxac

in (4

00 m

g on

ce

daily

) pub

lishe

d in

201

4 re

porte

d no

sig

nific

ant r

isk

of h

yper

glyc

aem

ia a

ssoc

iate

d wi

th e

xpos

ure

to g

atifl

oxac

in. A

lthou

gh a

dver

se e

vent

s we

re p

oorly

reco

rded

the

data

for t

his

revi

ew s

howe

d th

at th

ere

was

a lo

wer r

isk

of s

erio

us a

dver

se e

vent

s (s

AEs;

defi

ned

as G

rade

3–4

adv

erse

eve

nts

or d

rugs

sto

pped

due

to a

dver

se e

vent

) in

patie

nts

taki

ng g

ati-

floxa

cin

(3.6

%) t

han

in th

ose

who

did

not,

incl

udin

g th

ose

rece

ivin

g no

fluo

roqu

inol

ones

(8%

; not

sta

tistic

ally

sig

nific

ant).

the

frequ

ency

of s

AEs

asso

ciat

ed w

ith g

atifl

oxac

in w

as

thus

com

para

ble

to th

e on

e as

soci

ated

with

fluo

roqu

inol

ones

in th

e st

udy-

leve

l met

a-an

alys

is.

B. S

econ

d-lin

e in

ject

able

age

nts

base

d on

the

avai

labl

e ev

iden

ce, s

econ

d-lin

e in

ject

able

age

nts

were

ass

ocia

ted

with

an

incr

ease

d lik

elih

ood

of tr

eatm

ent s

ucce

ss w

hen

incl

uded

in a

long

er M

DR-t

b tre

atm

ent

regi

men

(the

sm

all s

ize o

f the

pop

ulat

ion

not r

ecei

ving

an

inje

ctab

le a

gent

in th

e aI

PD li

mite

d th

e po

wer t

o de

tect

an

impa

ct o

f thi

s cl

ass

of a

gent

s). I

t is

ther

efor

e re

com

men

ded

that

adu

lts w

ith ri

fam

pici

n-re

sist

ant t

b or

MDR

-tb

alwa

ys re

ceive

a s

econ

d-lin

e in

ject

able

age

nt a

s pa

rt of

thei

r reg

imen

unl

ess

ther

e is

an

impo

rtant

con

train

dica

tion.

In c

hil-

dren

with

mild

form

s of

dis

ease

, how

ever

, the

har

ms

asso

ciat

ed w

ith th

is g

roup

of m

edic

atio

ns m

ay o

utwe

igh

pote

ntia

l ben

efits

and

ther

efor

e in

ject

able

age

nts

may

be

excl

uded

in

this

gro

up. t

he G

DG b

ased

this

dec

isio

n up

on th

e ob

serv

atio

n th

at tr

eatm

ent s

ucce

ss in

chi

ldre

n wi

th c

linic

ally

-dia

gnos

ed d

isea

se (w

hich

was

ass

ocia

ted

with

less

sev

ere

clin

ical

man

ifest

atio

ns) w

as in

gen

eral

hig

h an

d di

d no

t diff

er s

igni

fican

tly b

etwe

en p

atie

nts

who

rece

ived

a Gr

oup

b m

edic

atio

n (9

8.1%

) and

thos

e wh

o di

d no

t (93

.5%

). Fo

r ch

ildre

n wi

th a

dditi

onal

resi

stan

ce to

fluo

roqu

inol

ones

, Gro

up b

med

icat

ion

is b

est r

etai

ned.

the

choi

ce o

f whi

ch o

f the

thre

e st

anda

rd a

gent

s to

use

– a

mik

acin

, cap

reom

ycin

or k

anam

ycin

– w

ould

be

dete

rmin

ed b

y th

e lik

elih

ood

of e

ffect

ivene

ss a

nd im

plem

enta

tion

cons

ider

atio

ns. W

hile

stre

ptom

ycin

is n

ot u

sual

ly in

clud

ed w

ith th

e se

cond

-line

dru

gs it

can

be

used

as

the

inje

ctab

le a

gent

of t

he c

ore

MDR

-tb

regi

men

if n

one

of th

e th

ree

othe

r age

nts

can

be u

sed

and

if th

e st

rain

is u

nlik

ely

to b

e re

sist

ant t

o it.

60

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Adve

rse

effe

cts

need

to b

e ca

refu

lly m

onito

red

for w

hile

usi

ng s

econ

d-lin

e in

ject

able

age

nts.

Hea

ring

loss

and

nep

hrot

oxic

ity a

re a

mon

g th

e m

ost f

requ

ent a

nd m

ost s

ever

e si

de e

ffect

s. H

owev

er, s

kin

rash

, hyp

erse

nsiti

vity

and

per

iphe

ral n

ephr

opat

hy m

ay a

lso

occu

r. th

e ris

k of

adv

erse

effe

cts

incr

ease

s wi

th th

e to

tal c

umul

ative

dos

e of

sec

ond-

line

inje

ctab

le a

gent

s, s

o ca

utio

n ha

s to

be

exer

cise

d wh

en g

iven

to p

eopl

e wh

o ha

ve p

revi

ousl

y re

ceive

d th

ese

med

icat

ions

, inc

ludi

ng s

trept

omyc

in a

s pa

rt of

a re

gim

en fo

r dru

g-su

scep

tible

tb. I

n ch

ildre

n es

peci

ally,

hea

ring

loss

can

hav

e a

prof

ound

impa

ct o

n qu

ality

of l

ife, a

ffect

ing

acqu

isiti

on o

f lan

guag

e an

d th

e ab

ility

to le

arn

at s

choo

l.

Alth

ough

adv

erse

eve

nts

are

poor

ly re

porte

d, th

e da

ta fo

r thi

s re

view

foun

d th

at 7

.3%

of a

dult

patie

nts

(10.

1% in

chi

ldre

n) h

ad s

AEs

attri

bute

d to

sec

ond-

line

inje

ctab

le a

gent

s.

In a

stu

dy fo

cuse

d on

hea

ring

loss

in c

hild

ren

with

tb, 2

4% o

f chi

ldre

n tre

ated

for M

DR-t

b wi

th a

n in

ject

able

age

nt h

ad h

earin

g lo

ss a

nd 6

4% o

f chi

ldre

n ha

d pr

ogre

ssio

n of

he

arin

g lo

ss a

fter c

ompl

etin

g it

(in th

is s

tudy

, 30%

of t

he c

hild

ren

were

HIV

-infe

cted

).

C. O

ther

cor

e se

cond

-line

age

nts

Whe

n de

sign

ing

the

core

MDR

-tb

treat

men

t reg

imen

, two

or m

ore

of th

e fo

llowi

ng fo

ur m

edic

ines

are

to b

e in

clud

ed: e

thio

nam

ide

(or p

roth

iona

mid

e), c

yclo

serin

e (o

r ter

-izi

done

), lin

ezol

id a

nd c

lofa

zimin

e, u

sual

ly in

this

ord

er o

f pre

fere

nce,

unl

ess

the

bala

nce

of b

enefi

ts-to

-har

ms

for t

he in

divi

dual

pat

ient

dem

ands

oth

erwi

se. G

roup

C a

gent

s ar

e in

clud

ed to

brin

g th

e to

tal e

ffect

ive s

econ

d-lin

e tb

med

icin

es in

the

core

regi

men

to a

t lea

st fo

ur d

urin

g th

e in

tens

ive p

hase

of t

he re

gim

en. I

n ad

ditio

n, if

pyr

azin

amid

e ca

nnot

be

incl

uded

or c

ount

ed u

pon,

ano

ther

age

nt is

add

ed. E

thio

nam

ide

can

be u

sed

inte

rcha

ngea

bly

with

pro

thio

nam

ide,

and

teriz

idon

e in

stea

d of

cyc

lose

rine.

Give

n th

e la

ck o

f rel

iabl

e Ds

t fo

r dru

gs b

elon

ging

to G

roup

C, t

he c

hoic

e of

whi

ch o

nes

to in

clud

e is

det

erm

ined

by

the

bala

nce

of d

esira

ble

to u

ndes

irabl

e ef

fect

s an

d by

impl

e-m

enta

tion

cons

ider

atio

ns. t

he a

dult

and

paed

iatri

c IP

D m

eta-

anal

yses

sho

wed

an in

crea

se in

the

likel

ihoo

d of

trea

tmen

t suc

cess

whe

n M

DR-t

b tre

atm

ent r

egim

ens

incl

uded

cy

clos

erin

e (m

argi

nally

sta

tistic

ally

sig

nific

ant)

and

ethi

onam

ide/

prot

hion

amid

e (s

tatis

tical

ly s

igni

fican

t onl

y in

adu

lts; i

n th

e pI

PD th

e va

st m

ajor

ity o

f chi

ldre

n di

d no

t rec

eive

et

hion

amid

e or

pro

thio

nam

ide

and

sign

ifica

nce

test

ing

was

ther

efor

e no

t alw

ays

poss

ible

for w

ant o

f a s

uffic

ient

num

ber o

f con

trols

). In

con

trast

to c

yclo

serin

e/te

rizid

one

and

ethi

onam

ide/

prot

hion

amid

e, R

Ct d

ata

from

a fe

w re

cent

stu

dies

are

now

ava

ilabl

e fo

r clo

fazim

ine

and

linez

olid

. lin

ezol

id h

as s

hown

a s

tatis

tical

ly s

igni

fican

t tre

atm

ent b

ene-

fit in

bot

h RC

t an

d co

hort

stud

ies

in a

dult

patie

nts,

with

this

ben

efit b

eing

mos

t pro

noun

ced

in p

atie

nts

with

add

ition

al re

sist

ance

to fl

uoro

quin

olon

es a

nd w

ith X

DR-t

b. b

oth

the

adul

t and

pae

diat

ric IP

D sh

owed

no

sign

ifica

nt in

crea

se in

trea

tmen

t suc

cess

ass

ocia

ted

with

the

use

of c

lofa

zimin

e, w

hile

line

zolid

was

use

d to

o sp

arin

gly

in th

e co

horts

in

clud

ed to

allo

w a

conc

lusi

ve a

naly

sis.

Ethi

onam

ide

and

prot

hion

amid

e ca

use

gast

roin

test

inal

dis

turb

ance

, in

parti

cula

r vom

iting

, whi

ch c

an li

mit

tole

rabi

lity.

Hypo

thyr

oidi

sm m

ay o

ccur

, esp

ecia

lly in

com

bina

tion

with

PA

s. H

ypot

hyro

idis

m is

reve

rsib

le u

pon

cess

atio

n of

dru

gs. A

lthou

gh a

dver

se e

vent

s ar

e po

orly

repo

rted,

the

data

for t

his

revi

ew fo

und

that

8.2

% o

f pat

ient

s ha

d sA

Es d

ue to

et

hion

amid

e or

pro

thio

nam

ide.

Cycl

oser

ine

has

a we

ll-es

tabl

ishe

d as

soci

atio

n wi

th n

euro

psyc

hiat

ric a

dver

se e

ffect

s. H

owev

er, t

he a

IPD

met

a-an

alys

is re

veal

ed lo

w le

vels

of s

AEs,

alth

ough

dat

a on

adv

erse

ev

ents

wer

e po

orly

repo

rted

(4.5

% in

the

stud

y-le

vel m

eta-

anal

ysis

con

duct

ed fo

r thi

s up

date

). A

met

a-an

alys

is p

ublis

hed

in 2

013

com

parin

g th

e ad

vers

e ef

fect

s of

cyc

lose

rine

with

teriz

idon

e fo

und

that

teriz

idon

e ha

d lit

tle to

no

bene

fit o

ver c

yclo

serin

e wi

th re

gard

to a

dver

se e

ffect

s.

Adve

rse

effe

cts

of li

nezo

lid in

clud

e th

rom

bocy

tope

nia

and

anae

mia

. the

se c

an b

e se

vere

and

life

thre

aten

ing,

alth

ough

thes

e ad

vers

e ef

fect

s ar

e re

vers

ible

with

ces

satio

n of

dru

g or

on

som

e oc

casi

ons

with

lowe

ring

the

drug

dos

e (u

sual

ly fr

om 6

00 m

g da

ily to

300

mg

daily

). Ha

emat

olog

ic to

xiciti

es a

re le

ss c

omm

on w

ith c

urre

nt s

trate

gies

of o

nce-

daily

do

sing

. Per

iphe

ral n

euro

path

y m

ay o

r may

not

impr

ove

with

ces

satio

n of

dru

g. th

e ou

tcom

e of

opt

ic n

euro

path

y up

on c

essa

tion

of li

nezo

lid is

less

cle

ar, a

nd s

houl

d be

trea

ted

as a

med

ical

em

erge

ncy.

Give

n th

e po

tent

ially

ser

ious

adv

erse

effe

cts

of li

nezo

lid –

par

ticul

arly

ana

emia

, thr

ombo

cyto

peni

a, la

ctic

aci

dosi

s, p

erip

hera

l neu

ropa

thy

and

optic

neu

-ro

path

y –

the

deci

sion

to u

se li

nezo

lid m

ust b

alan

ce it

s ris

ks a

nd b

enefi

ts a

nd th

e av

aila

bilit

y of

oth

er tb

med

icin

es. D

ue to

the

pote

ntia

l for

sev

ere

adve

rse

even

ts, l

inez

olid

use

ne

eds

to b

e ac

com

pani

ed b

y cl

ose

mon

itorin

g fo

r adv

erse

eve

nts.

Whe

re th

is is

not

pos

sibl

e, li

nezo

lid w

ould

bes

t be

rese

rved

for M

DR-t

b pa

tient

s wh

o ha

ve a

dditi

onal

dru

g re

sist

ance

, or X

DR-t

b pa

tient

s, o

r for

thos

e wh

o ar

e in

tole

rant

to o

ther

com

pone

nts

of th

e co

re re

gim

en.

6161

ANNE

X 5:

EVI

DENC

E tO

DEC

IsIO

N tA

blEs

Clof

azim

ine

prob

ably

con

tribu

tes

to th

e st

erili

zing

func

tion

of M

DR-t

b re

gim

ens

wher

e py

razin

amid

e is

not

effe

ctive

. the

sin

gle

rand

omize

d co

ntro

l tria

l, al

thou

gh it

had

ser

i-ou

s m

etho

dolo

gica

l con

cern

s, s

howe

d a

stat

istic

ally

sig

nific

ant t

reat

men

t ben

efit a

ssoc

iate

d wi

th th

e us

e of

clo

fazim

ine.

How

ever

, muc

h of

the

evid

ence

for i

ts e

ffect

in M

DR-t

b is

bas

ed o

n ob

serv

atio

nal s

tudi

es, w

hich

sho

wed

confl

ictin

g or

inco

nclu

sive

find

ings

. One

of t

he m

ain

adve

rse

effe

cts

of c

lofa

zimin

e is

ski

n di

scol

orat

ion/

dark

enin

g, w

hich

may

be

dis

tress

ing

to p

atie

nts.

In th

e RC

t, th

e ad

vers

e ev

ents

repo

rted

were

mos

tly li

mite

d to

ski

n co

nditi

ons

and

disc

olor

atio

n, a

nd d

id n

ot le

ad to

dis

cont

inua

tion

in th

e us

e of

the

drug

. Ove

rall,

sm

all r

ates

of a

dver

se e

vent

s we

re n

oted

in o

bser

vatio

nal s

tudi

es. s

AEs

appe

ar to

be

rela

tivel

y un

com

mon

. the

re h

as b

een

som

e ev

iden

ce th

at c

lofa

zimin

e m

ay

prol

ong

the

Qt in

terv

al, s

o ca

utio

n is

adv

ised

whe

n us

ing

this

med

icat

ion

in c

ombi

natio

n wi

th o

ther

dru

gs a

lso

know

n to

hav

e th

e sa

me

effe

ct.

D. A

dd-o

n ag

ents

this

gro

up o

f med

icin

es in

clud

es d

rugs

that

do

not f

orm

par

t of t

he c

ore

seco

nd-li

ne a

gent

s. It

is s

plit

into

thre

e su

bgro

ups:

Grou

p D1

con

sist

s of

pyr

azin

amid

e, e

tham

buto

l and

hig

h-do

se is

onia

zid. t

hese

age

nts

are

usua

lly a

dded

to c

ore

seco

nd-li

ne m

edic

atio

ns, u

nles

s th

e ris

ks fr

om c

onfir

med

resi

st-

ance

, pill

bur

den,

into

lera

nce

or d

rug–

drug

inte

ract

ions

out

weig

h po

tent

ial b

enefi

ts.

the

aIPD

sho

wed

impr

oved

like

lihoo

d of

suc

cess

(ver

sus

treat

men

t fai

lure

, rel

apse

or d

eath

com

bine

d) in

pat

ient

s wh

o ha

d py

razin

amid

e in

clud

ed in

thei

r reg

imen

s. th

is e

ffect

wa

s si

gnifi

cant

bot

h st

atis

tical

ly a

nd in

abs

olut

e te

rms.

the

pIPD

did

not

sho

w a

sign

ifica

nt tr

eatm

ent e

ffect

with

use

of p

yraz

inam

ide.

In m

any

setti

ngs,

rifa

mpi

cin-

resi

stan

t tb

stra

ins

frequ

ently

hav

e ad

ditio

nal r

esis

tanc

e to

pyr

azin

amid

e (in

the

orde

r of 5

0%–6

0%).

Whi

le it

wou

ld b

e de

sira

ble

to a

void

giv

ing

pyra

zinam

ide

to p

atie

nts

whos

e st

rain

s ar

e re

sist

ant t

o th

e dr

ug, i

t is

ackn

owle

dged

that

relia

ble

Dst

for p

yraz

inam

ide

is v

ery

ofte

n un

avai

labl

e in

reso

urce

-con

stra

ined

set

tings

. Alth

ough

adv

erse

eve

nts

are

poor

ly

repo

rted,

the

data

from

the

stud

y-le

vel m

eta-

anal

ysis

sho

wed

that

2.8

% o

f pat

ient

s wh

o re

ceive

d py

razin

amid

e ha

d sA

Es a

ttrib

uted

to it

. the

bal

ance

of d

esira

ble

to u

ndes

ira-

ble

effe

cts

favo

urs

the

addi

tion

of p

yraz

inam

ide

to th

e co

re s

econ

d-lin

e M

DR-t

b re

gim

en b

y de

faul

t, un

less

resi

stan

ce is

con

firm

ed fr

om re

liabl

e Ds

t, or

ther

e ar

e we

ll-fo

unde

d re

ason

s to

bel

ieve

that

the

stra

in is

resi

stan

t, or

ther

e ar

e ot

her c

ontra

-indi

catio

ns fo

r its

use

, par

ticul

arly

risk

of s

igni

fican

t tox

icity

. As

for t

he d

rugs

from

the

core

regi

men

, if

pyra

zinam

ide

is c

ompr

omis

ed o

r can

not b

e us

ed, m

ore

agen

ts fr

om G

roup

C a

nd s

ubse

quen

tly G

roup

D a

re a

dded

unt

il fiv

e ef

fect

ive d

rugs

are

pre

sent

in th

e in

tens

ive p

hase

of

the

regi

men

the

reco

mm

enda

tion

for t

he in

clus

ion

of h

igh-

dose

ison

iazid

in a

dult

MDR

-tb

regi

men

s is

larg

ely

base

d on

evi

denc

e fro

m th

e an

alys

is o

f pIP

D. th

is a

naly

sis

show

ed a

sta

tisti-

cally

sig

nific

ant i

ncre

ased

like

lihoo

d of

trea

tmen

t suc

cess

(ver

sus

treat

men

t fai

lure

, rel

apse

or d

eath

com

bine

d) in

chi

ldre

n wi

th b

acte

riolo

gica

lly c

onfir

med

MDR

-tb,

eve

n af

ter

adju

stm

ent f

or a

ge, H

IV s

tatu

s, s

ex, t

b di

seas

e se

verit

y an

d tre

atm

ent c

entre

(tre

atm

ent w

ith h

igh-

dose

ison

iazid

was

alm

ost e

xclu

sive

ly d

one

in s

outh

Afri

can

site

s). A

n RC

t of

hi

gh-d

ose

ison

iazid

ther

apy

for M

DR-t

b in

adu

lts fo

und

no in

crea

sed

risk

of h

epat

otox

icity

. Add

ition

ally,

hig

h-do

se is

onia

zid w

as v

ery

well

tole

rate

d in

chi

ldre

n wi

th d

rug

susc

epti-

ble

tube

rcul

ous

men

ingi

tis in

a la

rge

coho

rt st

udy

from

the

Wes

tern

Cap

e (v

an to

orn

R, e

t al.

Pedi

atr I

nfec

t Dis

J. 2

014;

33(3

):248

–52)

.

Ison

iazid

is re

com

men

ded

alon

gsid

e a

full

MDR

-tb

regi

men

in p

atie

nts

with

rifa

mpi

cin-

resi

stan

t tb

stra

ins

confi

rmed

or s

uspe

cted

to b

e su

scep

tible

to is

onia

zid. H

igh-

dose

is

onia

zid is

one

of t

he c

ore

com

pone

nts

of th

e sh

orte

r MDR

-tb

treat

men

t reg

imen

. stra

ins

bear

ing

mut

atio

ns in

the

prom

oter

regi

on o

f the

inhA

gen

e m

ay h

ave

a m

inim

um in

hib-

itory

con

cent

ratio

n (M

IC) t

o is

onia

zid, w

hich

is lo

w en

ough

to b

e ov

erco

me

by h

igh-

dose

ison

iazid

; and

in s

uch

setti

ngs

the

drug

may

stil

l add

ben

efit.

Howe

ver,

this

mut

atio

n ha

s be

en a

ssoc

iate

d wi

th h

igh-

leve

l eth

iona

mid

e re

sist

ance

and

ther

efor

e, if

pre

sent

, eth

iona

mid

e (o

r pro

thio

nam

ide)

may

hav

e to

be

repl

aced

in th

e re

gim

en. I

n se

tting

s wi

th e

le-

vate

d pr

eval

ence

of h

igh-

leve

l iso

niaz

id re

sist

ance

ass

ocia

ted

with

kat

G m

utat

ions

, hig

h-do

se is

onia

zid m

ay b

e le

ss e

ffect

ive a

nd th

eref

ore

its ro

utin

e us

e m

ay n

ot b

e wa

rrant

ed.

susc

eptib

ility

to e

thio

nam

ide

(or p

roth

iona

mid

e) is

not

affe

cted

by

thes

e m

utat

ions

and

can

be

used

in c

ombi

natio

n wi

th h

igh-

dose

ison

iazid

if th

e is

onia

zid re

sist

ance

mut

atio

n is

not

kno

wn.

62

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

the

aIPD

did

not

sho

w an

y st

atis

tical

ly s

igni

fican

t ass

ocia

tion

betw

een

use

of e

tham

buto

l and

like

lihoo

d of

suc

cess

. Eth

ambu

tol m

ay c

ause

ocu

lar t

oxic

ity, w

hich

can

be

diffi

cult

to d

iagn

ose

in y

oung

chi

ldre

n, a

lthou

gh th

is ri

sk is

redu

ced

if th

e do

se d

oes

not e

xcee

d re

com

men

ded

limits

(0.5

% o

f sAE

s re

porte

d as

soci

ated

with

the

met

a-an

alys

is c

on-

duct

ed fo

r thi

s re

view

alth

ough

the

repo

rting

of a

dver

se e

vent

s da

ta is

ofte

n in

com

plet

e). s

peci

al c

are

is n

eede

d wh

en re

nal f

unct

ion

is c

ompr

omis

ed. R

ifam

pici

n-re

sist

ant t

b/M

DR-t

b st

rain

s m

ay a

lso

be re

sist

ant t

o et

ham

buto

l, pa

rticu

larly

in th

ose

patie

nts

who

have

bee

n tre

ated

with

this

dru

g pr

evio

usly.

How

ever

Dst

for t

his

drug

is n

ot c

onsi

dere

d re

liabl

e an

d re

prod

ucib

le. t

he p

oten

tial b

enefi

t tha

t eth

ambu

tol m

ay a

dd to

a c

ore

MDR

-tb

regi

men

nee

ds to

be

bala

nced

car

eful

ly w

ith th

e in

conv

enie

nce

of a

ddin

g an

othe

r m

edic

ine

to th

e re

gim

en a

nd th

e ris

ks fo

r ass

ocia

ted

harm

s.

Grou

p D2

is m

ade

up o

f bed

aqui

line

and

dela

man

id, t

wo n

ew d

rugs

that

hav

e be

en re

leas

ed in

rece

nt y

ears

. WHO

has

issu

ed in

terim

pol

icy

on th

e us

e of

thes

e m

edic

ines

in

2013

and

201

4. th

e cu

rrent

gui

delin

es m

ake

no c

hang

e to

the

prev

ious

reco

mm

enda

tions

on

how

beda

quili

ne a

nd d

elam

anid

may

be

adde

d to

a c

ore

MDR

-tb

regi

men

in

adul

ts (n

o re

com

men

datio

n fo

r chi

ldre

n). t

he W

HO p

olic

y on

the

role

of D

2 ag

ents

, inc

ludi

ng th

eir p

oten

tial u

se in

chi

ldre

n, w

as u

nder

revi

ew a

t the

tim

e of

the

prod

uctio

n of

th

ese

guid

elin

es.

Grou

p D3

con

sist

s of

p-a

min

osal

icyl

ic a

cid

(PAs

), im

ipen

em–c

ilast

atin

, mer

open

em, c

lavu

lana

te a

nd th

ioac

etaz

one.

thes

e dr

ugs

are

only

to b

e us

ed w

hen

a M

DR-t

b re

gim

en

with

at l

east

five

effe

ctive

dru

gs (i

.e. p

rimar

ily fo

ur c

ore

seco

nd-li

ne m

edic

ines

plu

s py

razin

amid

e) c

anno

t be

othe

rwis

e co

mpo

sed.

the

aIPD

, as

well

as th

e st

udy-

leve

l met

a-an

alys

is c

ondu

cted

for t

he c

urre

nt g

uide

lines

revi

sion

, fou

nd n

o si

gnifi

cant

effe

ct o

f PAs

on

treat

men

t suc

cess

. In

addi

tion,

PAs

use

is

asso

ciat

ed w

ith a

hig

h fre

quen

cy o

f adv

erse

effe

cts

(12.

2% s

AEs

in th

e m

eta-

anal

ysis

und

erta

ken

for t

his

stud

y). P

As is

thus

rese

rved

for s

ituat

ions

whe

n th

ere

is n

o op

tion

to

use

othe

r dru

gs.

Carb

apen

ems

(imip

enem

–cila

stin

or m

erop

enem

) app

ear t

o be

hyd

roly

zed

mor

e sl

owly

by

M. t

uber

culo

sis

when

com

bine

d wi

th c

lavu

lani

c ac

id. C

lavu

lana

te h

as s

hown

poo

r re

sults

in in

vitr

o st

udie

s an

d in

ear

ly b

acte

ricid

al a

ctiv

ity (E

bA) s

tudi

es. t

he a

IPD

show

ed th

at p

atie

nts

treat

ed w

ith c

lavu

lana

te w

ere

mor

e lik

ely

to h

ave

poor

trea

tmen

t out

-co

mes

, alth

ough

this

may

be

due

to c

onfo

undi

ng b

y th

e hi

gher

like

lihoo

d th

at p

atie

nts

rece

ivin

g th

is d

rug

tend

ed to

hav

e m

ore

seve

re d

isea

se (n

ot a

ll co

nfou

ndin

g co

uld

be

adju

sted

for i

n th

e an

alys

is).

WHO

reco

mm

ends

that

whe

neve

r cla

vula

nate

and

car

bape

nem

s ar

e in

clud

ed in

regi

men

s th

ey a

re to

be

alwa

ys u

sed

toge

ther

. Cla

vula

nate

is o

nly

avai

labl

e as

com

bina

tion

prep

arat

ions

con

tain

ing

amox

icill

in. t

he s

pect

rum

of a

dver

se e

ffect

s as

soci

ated

with

am

oxac

illin

–cla

vula

nate

and

car

bape

nem

s is

to a

larg

e ex

tent

id

entic

al to

that

ass

ocia

ted

with

the

peni

cilli

ns.

thio

acet

azon

e ha

s be

en u

sed

exte

nsive

ly in

the

past

as

part

of fi

rst-l

ine

com

bina

tion

ther

apy

for t

b, b

ased

on

RCt

evid

ence

of e

ffect

ivene

ss. U

se o

f the

dru

g in

tb tr

eatm

ent h

as

howe

ver b

een

rest

ricte

d si

nce

the

early

199

0s d

ue to

the

seve

re s

kin

reac

tions

it c

ause

s, in

clud

ing

stev

ens-

John

son

synd

rom

e an

d to

xic e

pide

rmal

nec

roly

sis

(whi

ch c

an le

ad

to d

eath

, esp

ecia

lly in

peo

ple

livin

g wi

th H

IV),

and

the

wide

spre

ad a

vaila

bilit

y of

saf

er, a

fford

able

alte

rnat

ives

for t

he c

ombi

natio

n tb

regi

men

s. If

thio

acet

azon

e is

bei

ng c

onsi

d-er

ed a

s pa

rt of

a M

DR-t

b tre

atm

ent r

egim

en, c

lose

mon

itorin

g fo

r sev

ere

skin

reac

tions

is re

quire

d an

d it

is im

pera

tive

that

the

patie

nt b

e te

sted

for H

IV, a

nd th

at th

e dr

ug n

ot b

e us

ed if

the

patie

nt is

HIV

ser

opos

itive

M. t

uber

culo

sis

is in

trins

ical

ly re

sist

ant t

o th

e m

acro

lide

clas

s of

ant

ibio

tics.

the

evid

ence

revi

ews

for t

he c

urre

nt g

uide

lines

sho

wed

no in

dica

tion

of th

e ef

fect

ivene

ss o

f dru

gs

of th

is c

lass

(cla

rithr

omyc

in, a

zithr

omyc

in),

whic

h ha

ve a

t tim

es b

een

incl

uded

in M

DR-t

b re

gim

ens

in b

oth

adul

ts a

nd c

hild

ren.

In a

dditi

on, t

he a

IPD

show

ed a

n in

crea

sed

risk,

al

thou

gh n

ot s

tatis

tical

ly s

igni

fican

t, fo

r poo

r out

com

es in

pat

ient

s re

ceiv

ing

mac

rolid

es a

lthou

gh m

acro

lides

app

eare

d to

be

safe

in p

rolo

nged

use

. Mac

rolid

es a

re a

ssoc

iate

d wi

th Q

t pr

olon

gatio

n, w

hich

wou

ld b

e of

par

ticul

ar c

once

rn if

pat

ient

s ar

e re

ceiv

ing

othe

r tb

drug

s th

at m

ay h

ave

a si

mila

r ris

k, s

uch

as m

oxifl

oxac

in, c

lofa

zimin

e, b

edaq

uilin

e or

de

lam

anid

. WHO

ther

efor

e re

com

men

ds th

at c

larit

hrom

ycin

and

azit

hrom

ycin

not

be

incl

uded

in M

DR-t

b re

gim

ens.

Adve

rse

effe

cts

of P

As in

clud

e ga

stro

inte

stin

al d

istu

rban

ce a

nd h

ypot

hyro

idis

m (i

n pa

rticu

lar w

hen

give

n in

com

bina

tion

with

eth

iona

mid

e/pr

othi

onam

ide)

. Hyp

othy

roid

ism

is

reve

rsib

le u

pon

cess

atio

n of

the

drug

s. A

lthou

gh a

dver

se e

vent

s ar

e po

orly

repo

rted,

the

data

for t

his

revi

ew fo

und

that

12.

2% o

f pat

ient

s ha

d sA

Es (d

efine

d as

Gra

de 3

–4

adve

rse

even

ts o

r dru

gs s

topp

ed d

ue to

adv

erse

eve

nt) a

ttrib

uted

to P

As. t

he p

IPD

show

ed p

ossi

bilit

y of

trea

tmen

t har

m a

ssoc

iate

d wi

th th

e us

e of

PAs

(not

sta

tistic

ally

sig

nif-

ican

t). H

owev

er, P

As is

freq

uent

ly g

iven

to c

hild

ren

with

few

othe

r tre

atm

ent o

ptio

ns, a

nd th

eref

ore

this

effe

ct m

ay b

e du

e to

con

foun

ding

by

indi

catio

n (s

ites

that

had

poo

rer

outc

omes

with

PAs

als

o ha

d si

gnifi

cant

ly h

ighe

r rat

es o

f chi

ldre

n wh

o we

re H

IV s

erop

ositi

ve, m

alno

uris

hed,

had

sev

ere

pulm

onar

y di

seas

e an

d wh

o ha

d ad

ditio

nal r

esis

tanc

e to

flu

oroq

uino

lone

s an

d th

e se

cond

-line

inje

ctab

le m

edic

ines

).

6363

ANNE

X 5:

EVI

DENC

E tO

DEC

IsIO

N tA

blEs

Sub

grou

p co

nsid

erat

ions

Rifa

mpi

cin-

resi

stan

t TB/

MDR

-TB

with

add

ition

al re

sist

ance

to fl

uoro

quin

olon

es, s

econ

d-lin

e in

ject

able

age

nts

and

XDR-

TBIn

rifa

mpi

cin-

resi

stan

t tb/

MDR

-tb

patie

nts

with

con

firm

ed o

r wel

l-fou

nded

bel

ief o

f res

ista

nce

to m

edic

atio

ns fr

om G

roup

A (fl

uoro

quin

olon

es) o

r Gro

up b

(sec

ond-

line

inje

cta-

ble)

, sub

stitu

tion

of d

rugs

from

thes

e cl

asse

s pr

ocee

ds a

s de

taile

d be

low.

If a

ny o

f the

com

pone

nts

of th

e re

gim

en –

the

four

cor

e se

cond

-line

med

icin

es a

nd p

yraz

inam

ide

– is

co

nsid

ered

not

to b

e ef

fect

ive, a

dditi

onal

age

nts

from

Gro

ups

D2 o

r D3

are

adde

d. th

is is

alm

ost a

lway

s ne

cess

ary

when

resi

stan

ce to

bot

h Gr

oups

A a

nd b

dru

gs (i

.e. X

DR-t

b)

is p

rese

nt. A

n an

alys

is o

f ind

ivid

ual d

ata

colle

cted

for t

he u

pdat

e of

the

WHO

dru

g-re

sist

ant t

b tre

atm

ent g

uide

lines

of 2

011

conc

lude

d th

at re

gim

ens

cont

aini

ng m

ore

drug

s we

re a

ssoc

iate

d wi

th th

e hi

ghes

t odd

s of

suc

cess

for M

DR-t

b pa

tient

s wh

o ha

d ad

ditio

nal r

esis

tanc

e to

fluo

roqu

inol

ones

and

/or s

econ

d-lin

e in

ject

able

age

nts.

the

curre

nt W

HO

advi

ce w

hen

desi

gnin

g re

gim

ens

for p

atie

nts

with

resi

stan

ce to

fluo

roqu

inol

ones

, sec

ond-

line

inje

ctab

le m

edic

atio

ns a

nd X

DR-t

b co

ntin

ues

to a

pply.

Acce

ss to

rapi

d di

agno

stic

test

ing

whic

h co

uld

relia

bly

iden

tify

resi

stan

ce to

fluo

roqu

inol

ones

or i

njec

tabl

e m

edic

atio

ns w

ould

hel

p cl

inic

ians

to d

ecid

e ho

w to

mod

ify lo

nger

M

DR-t

b re

gim

ens.

the

Geno

type

Mtb

DRsl

line

pro

be a

ssay

 may

now

be

used

as

an in

itial

test

, ove

r phe

noty

pic

cultu

re-b

ased

Dst

, to

dete

ct re

sist

ance

to fl

uoro

quin

olon

es

and

seco

nd-li

ne in

ject

able

dru

gs (c

ondi

tiona

l rec

omm

enda

tion;

cer

tain

ty o

f evi

denc

e lo

w to

mod

erat

e fo

r dire

ct te

stin

g). G

enot

ype

Mtb

DRsl

can

be

used

in b

oth

child

ren

and

adul

ts a

nd a

s a

dire

ct a

nd in

dire

ct te

st (f

or e

xtra

pulm

onar

y sa

mpl

es).

Whi

le re

sist

ance

-con

ferri

ng m

utat

ions

to fl

uoro

quin

olon

es d

etec

ted

by th

e M

tbDR

sl a

ssay

are

hig

hly

corre

-la

ted

with

phe

noty

pic

resi

stan

ce to

oflo

xaci

n an

d le

voflo

xaci

n, th

e co

rrela

tion

with

mox

iflox

acin

and

gat

iflox

acin

is le

ss c

lear

and

the

incl

usio

n of

mox

iflox

acin

or g

atifl

oxac

in in

a

MDR

-tb

regi

men

is b

est g

uide

d by

phe

noty

pic

Dst

resu

lts.

TB o

f the

cen

tral

ner

vous

sys

tem

the

treat

men

t of t

uber

culo

us m

enin

gitis

rela

ted

to ri

fam

pici

n-re

sist

ant o

r MDR

stra

ins

is b

est g

uide

d by

dru

g su

scep

tibili

ty re

sults

and

the

know

n pr

oper

ties

of tb

dru

gs to

pen

e-tra

te th

e ce

ntra

l ner

vous

sys

tem

(CNs

). In

pat

ient

s wi

th ri

fam

pici

n-re

sist

ant t

b/M

DR-t

b m

enin

gitis

, it i

s re

com

men

ded

that

the

med

icat

ions

sel

ecte

d fo

r the

regi

men

hav

e go

od

CNs

pene

tratio

n pr

oper

ties.

the

fluor

oqui

nolo

nes

reco

mm

ende

d by

thes

e gu

idel

ines

hav

e go

od C

Ns p

enet

ratio

n, a

s do

eth

iona

mid

e (o

r pro

thio

nam

ide)

, cyc

lose

rine

(or t

erizi

done

) and

line

zolid

. Py

razin

amid

e ha

s go

od C

Ns p

enet

ratio

n, a

lthou

gh c

autio

n sh

ould

be

exer

cise

d, a

s a

larg

e pe

rcen

tage

of M

DR-t

b st

rain

s m

ay b

e re

sist

ant.

Ison

iazid

pen

etra

tes

the

CNs

very

we

ll, w

ith h

ighe

r dos

es re

achi

ng a

dequ

ate

MIC

s in

the

cere

bros

pina

l flui

d. D

ue to

its

good

CNs

pen

etra

tion,

hig

h-do

se is

onia

zid is

reco

mm

ende

d as

par

t of t

he tr

eatm

ent r

egi-

men

unl

ess

high

-leve

l res

ista

nce

is k

nown

to e

xist.

PAs

and

etha

mbu

tol d

o no

t pen

etra

te th

e CN

s we

ll an

d sh

ould

not

be

coun

ted

upon

am

ong

the

num

ber o

f effe

ctive

dru

gs to

trea

t MDR

-tb

men

ingi

tis. K

anam

ycin

, am

ikac

in

and

stre

ptom

ycin

onl

y pe

netra

te th

e ce

rebr

ospi

nal fl

uid

in th

e pr

esen

ce o

f men

inge

al in

flam

mat

ion.

ther

e ar

e lit

tle d

ata

on th

e CN

s pe

netra

tion

of c

apre

omyc

in, c

lofa

zimin

e,

beda

quili

ne o

r del

aman

id.

Peop

le li

ving

with

HIV

the

com

posi

tion

of th

e tre

atm

ent r

egim

en fo

r MDR

-tb

does

not

diff

er fo

r peo

ple

livin

g wi

th H

IV. H

owev

er, t

hioa

ceta

zone

sho

uld

not b

e gi

ven

to p

atie

nts

who

are

HIV

posi

tive.

If

thio

acet

azon

e is

bei

ng c

onsi

dere

d as

par

t of a

trea

tmen

t reg

imen

HIV

infe

ctio

n ne

eds

to b

e re

liabl

y ex

clud

ed in

the

patie

nt.

64

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

Impl

emen

tati

on

cons

ider

atio

nsth

e im

plem

enta

tion

of M

DR-t

b ch

emot

hera

py is

feas

ible

und

er p

rogr

amm

atic

con

ditio

ns, a

s ha

s be

en a

mpl

y sh

own

by th

e gl

obal

exp

ansi

on in

the

use

of lo

nger

MDR

-tb

regi

-m

ens

world

wide

, par

ticul

arly

in th

e pa

st d

ecad

e. C

hang

es m

ade

by th

e cu

rrent

revi

sion

to th

e gr

oupi

ng o

f the

med

icin

es a

nd to

the

com

posi

tion

of th

e lo

nger

regi

men

are

not

ex

pect

ed to

hav

e m

ajor

impa

ct o

n th

eir c

ontin

ued

use.

Mos

t of t

he fl

uoro

quin

olon

es a

nd th

e in

ject

able

age

nts

are

read

ily a

vaila

ble,

as

are

the

maj

ority

of t

he G

roup

C a

nd G

roup

D

agen

ts. t

he la

test

WHO

Mod

el l

ists

of E

ssen

tial M

edic

ines

(Aug

ust 2

015)

incl

udes

mos

t of t

he a

gent

s in

Gro

ups

A to

D e

xcep

t for

gat

iflox

acin

and

thio

acet

azon

e. H

owev

er, c

lo-

fazim

ine,

mer

open

em, i

mip

enem

–cila

stat

in a

nd a

mox

icill

in–c

lavu

lana

te a

re li

sted

for i

ndic

atio

ns o

ther

than

tb, w

hile

bed

aqui

line

and

dela

man

id a

re o

nly

incl

uded

in th

e ad

ult

list.

Othe

r spe

cific

fact

ors

impo

rtant

for i

mpl

emen

tatio

n ar

e di

scus

sed

in th

e re

spec

tive

sect

ions

bel

ow.

Whe

re p

ossi

ble

a pa

tient

with

rifa

mpi

cin-

resi

stan

t tb/

MDR

-tb

stra

in n

eeds

to b

e te

sted

for s

usce

ptib

ility

to m

edic

ines

pla

nned

for i

nclu

sion

in th

e re

gim

en. t

he a

vaila

bilit

y of

re

liabl

e te

sts

for s

usce

ptib

ility

to fl

uoro

quin

olon

es a

nd to

the

seco

nd-li

ne in

ject

able

dru

gs (w

hich

wou

ld g

ive re

sults

with

in a

few

days

) is

valu

able

to e

nsur

e th

at lo

nger

MDR

-tb

regi

men

s ar

e st

reng

then

ed a

s ne

cess

ary

(refe

renc

e is

mad

e to

the

reco

mm

enda

tions

on

the

use

of li

ne p

robe

ass

ay fo

r sec

ond-

line

drug

s –

the

Mtb

DRsl

ass

ay).

Whe

re re

liabl

e Ds

t is

not

an

optio

n, p

roof

of t

he e

ffect

ivene

ss o

f a m

edic

ine

need

s to

be

base

d on

a c

aref

ul c

linic

al h

isto

ry o

f the

pat

ient

’s pr

evio

us e

xpos

ure

to th

e m

edic

ine,

of

sign

ifica

nt c

onta

ct w

ith a

noth

er ri

fam

pici

n-re

sist

ant t

b/M

DR-t

b pa

tient

who

se a

ntib

iogr

amm

e is

doc

umen

ted,

and

from

kno

wled

ge o

f the

pre

vale

nt re

sist

ance

pat

tern

s ce

ntre

d on

repr

esen

tativ

e dr

ug-re

sist

ance

sur

veill

ance

. bot

h th

e Ds

t an

d th

e in

divi

dual

clin

ical

his

tory

sho

uld

be c

onsi

dere

d wh

en c

onst

ruct

ing

a tre

atm

ent r

egim

en. t

he o

nly

relia

ble

labo

rato

ry te

sts

for t

b dr

ug s

usce

ptib

ility

(or r

esis

tanc

e) th

at a

re w

idel

y us

ed to

day

are

thos

e fo

r iso

niaz

id, r

ifam

pici

n, fl

uoro

quin

olon

es a

nd s

econ

d-lin

e in

ject

able

age

nts.

A. F

luor

oqui

nolo

nes

both

levo

floxa

cin

and

mox

iflox

acin

are

com

mon

ly u

sed

to tr

eat M

DR-t

b. l

evofl

oxac

in is

mor

e wi

dely

ava

ilabl

e th

an m

oxifl

oxac

in, w

hich

is m

ore

expe

nsive

alth

ough

a re

duct

ion

in

its p

rice

is e

xpec

ted

in th

e co

min

g ye

ars.

Gatifl

oxac

in w

as a

n af

ford

able

dru

g an

d ha

d be

en c

omm

only

use

d by

tb tr

eatm

ent p

rogr

amm

es u

ntil

the

conc

erns

abo

ut it

s dy

sgly

caem

ic e

ffect

s le

d to

a g

loba

l sho

rtage

in

this

med

icin

e. If

man

ufac

ture

of q

ualit

y-as

sure

d fo

rmul

atio

ns o

f the

dru

g re

star

ts, i

t cou

ld s

ubst

antia

lly lo

wer t

he c

osts

of r

egim

ens

by s

ubst

itutin

g m

ore

expe

nsive

opt

ions

in

fluor

oqui

nolo

nes.

Mox

iflox

acin

is re

lativ

ely

easy

to a

dmin

iste

r to

olde

r chi

ldre

n. H

owev

er, t

he ta

blet

mus

t be

split

to a

ccom

mod

ate

dosi

ng in

you

nger

chi

ldre

n an

d it

is h

ighl

y un

pala

tabl

e on

ce s

plit

or c

rush

ed. l

evofl

oxac

in is

ava

ilabl

e as

a s

uspe

nsio

n.B.

Sec

ond-

line

inje

ctab

le a

gent

sth

ese

agen

ts p

rese

nt p

robl

ems

to a

dmin

iste

r par

ente

rally

on

a da

ily b

asis

for s

ever

al m

onth

s, o

ften

nece

ssita

ting

hosp

italiz

atio

n. G

ivin

g in

ject

ions

to c

hild

ren

and

unde

rwei

ght

adul

ts is

par

ticul

arly

pai

nful

and

unw

elco

me.

C. O

ther

age

nts

Ethi

onam

ide

and

prot

hion

amid

e ar

e in

expe

nsive

, rea

dily

ava

ilabl

e wo

rldwi

de a

nd e

asily

adm

inis

tere

d.Cy

clos

erin

e ha

s be

en o

ne o

f the

sta

ndar

d dr

ugs

for t

he tr

eatm

ent o

f MDR

-tb

for s

ever

al y

ears

and

ther

efor

e ex

perie

nce

in it

s us

e is

wid

espr

ead.

It is

inex

pens

ive.

teriz

idon

e is

less

wid

ely

used

but

is a

vaila

ble

on th

e GD

F Pr

oduc

ts l

ist.

Clof

azim

ine

is in

expe

nsive

but

it c

an b

e di

fficu

lt to

pro

cure

.th

e im

plem

enta

tion

of th

ese

guid

elin

es a

t nat

iona

l lev

el n

eeds

to e

nsur

e th

at s

uffic

ient

qua

ntiti

es o

f the

se m

edic

ines

are

ava

ilabl

e to

mee

t the

dem

and

and

that

no

stoc

k-ou

ts

occu

r. M

oreo

ver,

give

n th

at th

ere

are

no g

ood

paed

iatri

c fo

rmul

atio

ns th

e ca

psul

e co

nten

ts n

eed

to b

e ex

pres

sed

man

ually

and

div

ided

into

sm

alle

r dos

es, w

ith ri

sks

of in

corre

ct

dosi

ng in

chi

ldre

n.W

hen

linez

olid

is u

sed,

ther

e ne

eds

to b

e cl

ose

mon

itorin

g fo

r sid

e ef

fect

s, p

artic

ular

ly a

naem

ia, t

hrom

bocy

tope

nia,

lact

ic a

cido

sis,

per

iphe

ral n

euro

path

y an

d op

tic n

euro

path

y, as

thes

e ca

n be

sev

ere

and

life

thre

aten

ing.

His

toric

ally

line

zolid

has

bee

n ve

ry e

xpen

sive

, how

ever

, it h

as re

cent

ly c

ome

off p

aten

t and

the

avai

labi

lity

of g

ener

ic p

rodu

cts

has

redu

ced

its m

arke

t pric

e su

bsta

ntia

lly a

nd it

may

dec

reas

e ev

en fu

rther

.

6565

ANNE

X 5:

EVI

DENC

E tO

DEC

IsIO

N tA

blEs

D. A

dd-o

n ag

ents

Pyra

zinam

ide

is in

expe

nsive

, rea

dily

ava

ilabl

e an

d ea

sy to

adm

inis

ter.

Ison

iazid

is in

expe

nsive

. It i

s im

porta

nt to

con

side

r the

epi

dem

iolo

gy o

f hig

h-le

vel v

ersu

s lo

w-le

vel i

soni

azid

mut

atio

ns in

a p

opul

atio

n be

fore

sta

ndar

d tre

atm

ent r

egim

ens

incl

udin

g hi

gh-d

ose

ison

iazid

are

reco

mm

ende

d.Et

ham

buto

l is

inex

pens

ive a

nd re

adily

ava

ilabl

e.PA

s m

ay b

e di

fficu

lt to

obt

ain

alth

ough

it is

ava

ilabl

e th

roug

h th

e GD

F. Ot

herw

ise

it is

rela

tivel

y in

expe

nsive

and

eas

y to

adm

inis

ter.

Amox

acill

in-c

lavu

lana

te is

inex

pens

ive a

nd e

asily

obt

aina

ble.

How

ever

, the

car

bape

nem

s ar

e ex

pens

ive a

nd a

re d

ifficu

lt to

adm

inis

ter a

s th

ey m

ust b

e gi

ven

two

or th

ree

times

pe

r day

via

an

intra

veno

us li

ne.

thio

acet

ezon

e is

inex

pens

ive b

ut it

has

lim

ited

avai

labi

lity

and

it is

not

cur

rent

ly a

vaila

ble

thro

ugh

the

GDF.

the

curre

nt re

visi

on o

f the

gui

delin

es d

id n

ot re

-ana

lyse

the

optim

al d

urat

ion

of tr

eatm

ent (

inte

nsive

and

con

tinua

tion

phas

es).

the

reco

mm

enda

tions

from

the

2011

gui

de-

lines

that

wer

e ba

sed

on th

e aI

PD m

eta-

anal

ysis

, thu

s co

ntin

ue to

app

ly. th

e 20

11 g

uide

lines

con

ditio

nally

reco

mm

ende

d an

inte

nsive

pha

se o

f eig

ht m

onth

s fo

r mos

t MDR

-tb

patie

nts

and

tota

l tre

atm

ent d

urat

ion

of 2

0 m

onth

s in

pat

ient

s wh

o ha

d no

t bee

n pr

evio

usly

trea

ted.

the

dura

tion

may

nee

d to

be

mod

ified

acc

ordi

ng to

the

patie

nt’s

resp

onse

to

ther

apy.

the

asso

ciat

ion

betw

een

treat

men

t suc

cess

and

the

tota

l len

gth

of tr

eatm

ent w

as le

ss c

lear

in p

atie

nts

who

had

been

pre

viou

sly-

treat

ed c

ompa

red

with

thos

e wh

o ha

d no

t, al

thou

gh th

e lik

elih

ood

of tr

eatm

ent s

ucce

ss a

ppea

red

to p

eak

betw

een

27.6

and

30.

5 m

onth

s. th

e nu

mbe

r of o

bser

vatio

ns w

as a

lso

far f

ewer

than

for t

hose

who

had

no

pre

viou

s M

DR-t

b tre

atm

ent.

As a

resu

lt no

reco

mm

enda

tion

on to

tal d

urat

ion

was

mad

e in

the

2011

revi

sion

for p

revi

ousl

y tre

ated

pat

ient

s. M

any

of th

e rif

ampi

cin-

resi

stan

t tb

/MDR

-tb

patie

nts

who

will

be in

elig

ible

for t

he s

horte

r MDR

-tb

regi

men

and

refe

rred

for t

reat

men

t with

long

er re

gim

ens

woul

d ha

ve b

een

treat

ed w

ith s

econ

d-lin

e m

edic

a-tio

n in

the

past

; in

thes

e pa

tient

s un

certa

intie

s wi

ll re

mai

n on

the

optim

al d

urat

ion

of tr

eatm

ent a

nd th

eref

ore

the

leng

th o

f the

rapy

wou

ld n

eed

to b

e gu

ided

prim

arily

by

the

resp

onse

to th

erap

y.

Mon

itor

ing

and

eval

uati

onPa

tient

s on

long

er M

DR-t

b tre

atm

ent r

egim

ens

need

to b

e m

onito

red

for r

espo

nse

to tr

eatm

ent a

nd fo

r saf

ety

usin

g re

ason

able

sch

edul

es o

f rel

evan

t clin

ical

and

labo

rato

ry

test

ing.

Fra

mew

orks

for t

he s

urve

illan

ce o

f bac

terio

logi

cal s

tatu

s, d

rug

resi

stan

ce a

nd o

utco

mes

hav

e be

en fa

irly

stan

dard

ized

over

the

past

dec

ade.

the

syst

emat

ic m

onito

ring

of a

dver

se e

vent

s du

ring

and

afte

r the

end

of t

reat

men

t is

a m

ore

rece

nt in

trodu

ctio

n in

tb p

rogr

amm

es a

nd e

xper

ienc

e in

thei

r im

plem

enta

tion

is s

till d

evel

opin

g in

man

y co

un-

tries

. Its

ratio

nale

is la

rgel

y de

fined

by

mor

e fre

quen

t use

of n

ew a

nd re

-pur

pose

d m

edic

atio

ns in

MDR

-tb

treat

men

t reg

imen

s in

the

world

, at t

imes

in c

ombi

natio

ns fo

r whi

ch

ther

e ha

s be

en v

ery

limite

d ex

perie

nce

of u

se.

Res

earc

h pr

ioriti

es• A

nee

d fo

r mor

e ra

ndom

ized

cont

rol s

tudi

es, e

spec

ially

invo

lvin

g th

e ne

w dr

ugs

and

regi

men

s.

• Incl

usio

n an

d se

para

te re

porti

ng o

f out

com

es fo

r key

sub

grou

ps in

suc

h st

udie

s, e

spec

ially

chi

ldre

n an

d HI

V-po

sitiv

e in

divi

dual

s on

trea

tmen

t.

• Mor

e co

mpl

ete

reco

rdin

g of

adv

erse

eve

nts

and

stan

dard

ized

data

reco

rdin

g on

org

an c

lass

, ser

ious

ness

, sev

erity

, and

cer

tain

ty o

f ass

ocia

tion,

to a

llow

relia

ble

com

paris

on o

f th

e as

soci

atio

n be

twee

n ad

vers

e ev

ents

and

exp

osur

e to

diff

eren

t med

icin

es.

• Iden

tifica

tion

of fa

ctor

s th

at d

eter

min

e th

e op

timal

dur

atio

n of

trea

tmen

t (e.

g. p

revi

ous

treat

men

t his

tory

, bas

elin

e re

sist

ance

pat

tern

s, s

ite o

f dis

ease

, chi

ld/a

dult)

.

• Det

erm

inat

ion

of th

e m

inim

um n

umbe

r of d

rugs

and

trea

tmen

t dur

atio

n (e

spec

ially

in p

atie

nts

prev

ious

ly tr

eate

d fo

r MDR

-tb)

.

• Con

ditio

ns u

nder

whi

ch in

ject

able

-spa

ring

regi

men

s ca

n be

use

d in

bot

h ch

ildre

n an

d ad

ults

(e.g

. sur

roga

tes

for s

ever

ity /

ext

ent o

f dis

ease

, alte

rnat

ive m

edic

atio

n).

• Pha

rmac

okin

etic

stu

dies

to d

eter

min

e op

timal

dru

g do

sing

and

saf

ety

(esp

ecia

lly in

pre

gnan

cy).

• Impr

oved

dia

gnos

tics

and

drug

-sus

cept

ibili

ty te

stin

g m

etho

ds (e

.g. w

hich

test

for p

yraz

inam

ide)

.

• Palli

ative

and

end

-of-l

ife c

are

in p

atie

nts

with

ver

y ad

vanc

ed re

sist

ance

pat

tern

s.

66

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

3. E

lect

ive

part

ial l

ung

rese

ctio

n ve

rsus

no

surg

ery

for

pati

ents

on

trea

tmen

t fo

r M

DR

-TB

Popu

latio

n:Pa

tient

s on

trea

tmen

t for

MDR

-tb

back

grou

nd:

surg

ery

has

been

use

d to

trea

t tb

patie

nts

sinc

e be

fore

the

adve

nt o

f che

mot

her-

apy.

With

the

chal

leng

ing

pros

pect

of i

nade

quat

e re

gim

ens

to tr

eat M

DR/X

DR-t

b an

d th

e ris

k fo

r ser

ious

seq

uela

e, th

e ro

le o

f pul

mon

ary

surg

ery

is b

eing

re-e

valu

ated

as

a m

eans

to “d

ebul

k” in

tract

able

pat

holo

gy in

the

lung

and

to re

duce

bac

teria

l loa

d an

d th

us im

prov

e pr

ogno

sis.

the

revi

ew fo

r thi

s qu

estio

n is

bas

ed u

pon

an in

divi

dual

, pat

ient

-leve

l met

a-an

aly-

sis

to e

valu

ate

the

effe

ctive

ness

of d

iffer

ent f

orm

s of

ele

ctive

sur

gery

as

an a

djun

ct

to c

ombi

natio

n m

edic

al th

erap

y fo

r MDR

-tb

(sup

plem

ente

d by

a li

tera

ture

revi

ew).

Dem

ogra

phic

, clin

ical

, bac

terio

logi

cal,

surg

ical

and

out

com

e da

ta o

n M

DR-t

b pa

tient

s on

trea

tmen

t wer

e ob

tain

ed fr

om th

e au

thor

s of

26

coho

rt st

udie

s, id

entifi

ed fr

om

thre

e sy

stem

atic

revi

ews

of M

DR-t

b tre

atm

ent.

the 

anal

yses

sum

mar

ized

in th

e GR

ADE

tabl

es c

onsi

st o

f thr

ee s

trata

com

parin

g tre

at-

men

t suc

cess

(cur

e an

d co

mpl

etio

n) w

ith d

iffer

ent c

ombi

natio

ns o

f tre

atm

ent f

ailu

re,

rela

pse,

dea

th a

nd lo

ss to

follo

w-up

. two

set

s of

suc

h ta

bles

wer

e pr

epar

ed fo

r: (i)

pa

rtial

pul

mon

ary

rese

ctio

n an

d (ii

) pne

umon

ecto

my.

Parti

al p

ulm

onar

y re

sect

ion

was

sign

ifica

ntly

ass

ocia

ted

with

trea

tmen

t suc

cess

whe

n co

mpa

red

with

all

othe

r ou

tcom

es p

ut to

geth

er (t

reat

men

t fai

lure

or r

elap

se o

r dea

th o

r los

s to

follo

w-up

) (P

<0.0

5). P

rogn

osis

app

eare

d to

be

bette

r whe

n su

rger

y wa

s pe

rform

ed a

fter c

ultu

re

conv

ersi

on. N

o ef

fect

was

obs

erve

d in

 pne

umon

ecto

my.

Desp

ite a

num

ber o

f pot

entia

l bia

ses

and

limita

tions

whi

ch c

ould

not

be

adju

sted

for,

parti

al lu

ng re

sect

ion

surg

ery

afte

r cul

ture

con

vers

ion

may

hel

p im

prov

e ou

tcom

es in

se

lect

ed p

atie

nts

who

do n

ot re

spon

d to

app

ropr

iate

med

icat

ion.

Refe

renc

e: F

ox G

J, M

itnic

k CD

, ben

edet

ti A,

Cha

n ED

, bec

erra

M, C

hian

g C-

Y, et

al.

surg

ery

as a

n ad

junc

tive

treat

men

t for

mul

tidru

g-re

sist

ant t

uber

culo

sis:

An

indi

vidu

al

patie

nt d

ata

met

aana

lysi

s. C

lin In

fect

Dis

. 201

6;62

(7):8

87–9

5.

Inte

rven

tion:

Elec

tive

parti

al lu

ng re

sect

ion

Com

paris

on:

No s

urge

ry

Mai

n ou

tcom

es:

succ

ess

vers

us tr

eatm

ent f

ailu

re o

r rel

apse

; suc

cess

ver

sus

treat

men

t fai

lure

or

rela

pse

or d

eath

; suc

cess

ver

sus

treat

men

t fai

lure

or r

elap

se o

r dea

th o

r lo

ss to

follo

w-up

; dea

th v

ersu

s tre

atm

ent f

ailu

re o

r rel

apse

or s

ucce

ss.

setti

ng:

Whi

ch ty

pes

of s

urge

ry e

ncom

pass

ed (l

obec

tom

y, se

gmen

tect

omy,

wedg

e re

sect

ion)

; defi

nitio

n of

non

-resp

onse

and

adv

erse

out

com

e of

sur

gery

; def

-in

ition

of e

xten

sive

dis

ease

; how

spe

cial

ized

were

the

cent

res/

prac

titio

ners

wh

ich

prov

ided

sur

gery

(ext

erna

l val

idity

); un

der w

hich

con

ditio

ns to

indi

-ca

te re

sect

ion

surg

ery

and

when

to c

ontra

indi

cate

; bef

ore

or a

fter c

ultu

re

conv

ersi

on.

Pers

pect

ive:

Defin

ing

bette

r the

role

of s

urge

ry; d

ecis

ion

when

to o

pera

te a

nd ty

pe o

f in

terv

entio

n; a

nd it

s im

pact

in p

atie

nts

on tr

eatm

ent f

or M

DR-t

b or

XDR

-tb.

6767

ANNE

X 5:

EVI

DENC

E tO

DEC

IsIO

N tA

blEs

Ass

essm

ent

JUD

GEM

ENT

RES

EAR

CH

EVID

ENC

EA

DD

ITIO

NA

L C

ON

SID

ERAT

ION

SDESIRABLE EFFECTS

How

sub

stan

tial a

re th

e de

sira

ble

antic

ipat

ed e

ffec

ts?

tr

ivia

l

sm

all

M

oder

ate

l

arge

Var

ies

D

on’t

know

In th

e su

rgic

al m

eta-

anal

ysis

that

exa

min

ed a

ll fo

rms

of s

urge

ry to

geth

er,

ther

e wa

s a

stat

istic

ally

sig

nific

ant i

mpr

ovem

ent i

n cu

re a

nd s

ucce

ssfu

l tre

atm

ent o

utco

mes

am

ong

patie

nts

who

rece

ived

surg

ery.

Howe

ver,

when

th

e in

divi

dual

pat

ient

dat

a m

eta-

anal

ysis

exa

min

ed p

atie

nts

that

und

er-

went

par

tial l

ung

rese

ctio

n an

d th

ose

that

und

erwe

nt p

neum

onec

tom

y, ve

rsus

pat

ient

s th

at d

id n

ot u

nder

go s

urge

ry, t

hose

that

und

erwe

nt p

artia

l lu

ng re

sect

ion

had

stat

istic

ally

sig

nific

ant h

ighe

r rat

es o

f tre

atm

ent s

ucce

ss.

thos

e th

at u

nder

went

pne

umon

ecto

my

did

not h

ave

bette

r out

com

es th

an

thos

e wh

o di

d no

t und

ergo

sur

gery

.th

ere

are

seve

ral c

avea

ts to

this

dat

a. s

elec

tion

bias

may

be

an is

sue,

as

patie

nts

who

were

det

erm

ined

to b

e he

alth

y en

ough

to u

nder

go s

urge

ry w

ere

the

only

peo

ple

who

unde

rwen

t sur

gery

. Peo

ple

livin

g wi

th H

IV w

ere

excl

uded

fro

m th

e IP

D. A

dditi

onal

ly, a

lthou

gh th

ere

is li

kely

qui

te a

bit

of c

onfo

undi

ng,

patie

nts

with

XDR

-tb

were

foun

d to

hav

e si

gnifi

cant

ly w

orse

out

com

es w

hen

they

und

erwe

nt s

urge

ry.

Rate

s of

dea

th d

id n

ot d

iffer

sig

nific

antly

bet

ween

thos

e wh

o un

derw

ent s

ur-

gery

ver

sus

thos

e wh

o re

ceive

d m

edic

al tr

eatm

ent o

nly.

ther

e wa

s no

t eno

ugh

data

on

adve

rse

even

ts o

r sur

gica

l com

plic

atio

ns to

do

an

anal

ysis

.Re

fere

nce:

 Fox

GJ,

Mitn

ick

CD, b

ened

etti

A, C

han

ED, b

ecer

ra M

, Chi

ang

C-Y,

et a

l. su

rger

y as

an

adju

nctiv

e tre

atm

ent f

or m

ultid

rug-

resi

stan

t tub

er-

culo

sis:

An

indi

vidu

al p

atie

nt d

ata

met

aana

lysi

s. C

lin In

fect

Dis

. 201

6;

62(7

):887

–95.

Effe

ct e

xpec

ted

to b

e m

oder

ate

in th

e av

erag

e pa

tient

con

side

red

appr

opria

te fo

r sur

gery

.

UNDESIRABLE EFFECTS

How

sub

stan

tial a

re th

e un

desi

rabl

e an

ticip

ated

eff

ects

?

lar

ge

M

oder

ate

s

mal

l

triv

ial

V

arie

s

Don

’t kn

ow

Unce

rtain

ty a

bout

per

iope

rativ

e or

pos

t-ope

rativ

e co

mpl

icat

ions

.

CERTAINTY OF EVIDENCE

Wha

t is

the

over

all c

erta

inty

of t

he e

vide

nce

of e

ffec

ts?

V

ery

low

l

ow

M

oder

ate

H

igh

N

o in

clud

ed s

tudi

es

No re

sear

ch e

vide

nce

was

iden

tified

.su

bsta

ntia

l het

erog

enei

ty e

xpec

ted

in a

num

-be

r of p

aram

eter

s in

clud

ing

the

crite

ria u

sed

to

sele

ct c

andi

date

s fo

r sur

gery

, the

type

/qua

lity

of in

terv

entio

n, th

e ef

fect

ivene

ss o

f con

com

itant

ch

emot

hera

py a

nd o

ther

sup

porti

ve m

easu

res,

and

th

e rig

our a

nd le

ngth

of t

ime

durin

g wh

ich

effe

cts

(ben

efici

al o

r adv

erse

) wer

e m

onito

red.

68

WHO

TREA

TMEN

T GU

IDEL

INES

FOR

DRU

G-RE

SIST

ANT T

UBER

CULO

SIS,

201

6 UP

DATE

JUD

GEM

ENT

RES

EAR

CH

EVID

ENC

EA

DD

ITIO

NA

L C

ON

SID

ERAT

ION

S

BALANCE OF EFFECTSDo

es th

e ba

lanc

e be

twee

n de

sira

ble

and

unde

sira

ble

effe

cts

favo

ur th

e in

terv

entio

n or

the

com

paris

on?

F

avou

rs th

e co

mpa

rison

Pro

babl

y fa

vour

s th

e co

mpa

rison

Doe

s no

t fav

our e

ither

the

inte

rven

tion

or th

e co

mpa

rison

Pro

babl

y fa

vour

s th

e in

terv

entio

n

Fav

ours

the

inte

rven

tion

V

arie

s

Don

’t kn

ow

No re

sear

ch e

vide

nce

was

iden

tified

.lo

ng te

rm s

eque

lae,

som

e of

whi

ch m

ay b

e ul

ti-m

atel

y fa

tal,

may

be

unkn

own.

the

bene

fits

vary

dep

endi

ng o

n th

e po

pula

tion

sele

ctio

n; h

owev

er, o

vera

ll th

e ef

fect

s of

sur

gery

ap

pear

to b

e be

nefic

ial a

s lo

ng a

s pa

tient

s ar

e se

lect

ed c

aref

ully

for s

urge

ry.

Desp

ite th

e un

know

n m

agni

tude

of p

erio

pera

tive

com

plic

atio

ns th

e pa

nel a

ssum

ed th

at o

vera

ll th

ere

is a

net

ben

efit f

rom

sur

gery

.

FEASIBILITY

Is th

e in

terv

entio

n fe

asib

le to

impl

emen

t?

No

P

roba

bly

no

P

roba

bly

yes

Ye

s

Var

ies

D

on’t

know

No re

sear

ch e

vide

nce

was

iden

tified

.su

rger

y is

use

d ex

tens

ively

in m

any

coun

tries

but

th

e qu

ality

var

ies.

If pr

ogra

mm

es in

vest

in s

urge

ry in

pre

fere

nce

to

othe

r com

pone

nts

ther

e ar

e op

portu

nity

cos

ts.

Equi

ty is

sues

: the

re is

an

issu

e of

acc

ess

to h

igh

qual

ity s

urge

ry s

o eq

uity

is “p

roba

bly

redu

ced”

and

in

equi

ty is

a p

ossi

bilit

y.Ac

cept

abili

ty to

sta

keho

lder

s an

d pa

tient

s: “v

arie

s”

depe

ndin

g on

the

stak

ehol

der.

Con

clus

ions

ELEC

TIV

E PA

RTI

AL

LUN

G R

ESEC

TIO

N V

ERSU

S N

O S

UR

GER

Y F

OR

PAT

IEN

TS O

N T

REA

TMEN

T FO

R M

DR

-TB

Type

of

reco

mm

enda

tion

stro

ng re

com

men

datio

n ag

ains

t th

e in

terv

entio

n

Cond

ition

al re

com

men

datio

n ag

ains

t the

inte

rven

tion

Cond

ition

al re

com

men

datio

n fo

r eith

er th

e in

terv

entio

n or

the

com

paris

on

Cond

ition

al re

com

men

datio

n fo

r th

e in

terv

entio

n

stro

ng re

com

men

datio

n fo

r the

in

terv

entio

n

Votin

g re

sults

of t

he G

DG fo

r con

ditio

nal r

ecom

men

datio

n on

ele

ctive

par

tial s

urge

ry: 1

5 in

favo

ur; 1

aga

inst

; 1 a

bste

ntio

n; 2

no

reco

mm

enda

tion;

2 n

ot a

vaila

ble

Rec

omm

enda

tion

In p

atie

nts

with

rifa

mpi

cin-

resi

stan

t tb

or M

DR- t

b, th

e W

HO G

uide

line

Deve

lopm

ent G

roup

sug

gest

s th

at e

lect

ive p

artia

l lun

g re

sect

ion

(lobe

ctom

y or

wed

ge re

sect

ion)

may

be

used

alo

ngsi

de a

n ap

prov

ed M

DR-t

b re

gim

en (c

ondi

tiona

l rec

omm

enda

tion,

ver

y lo

w ce

rtain

ty in

the

evid

ence

).

6969

ANNE

X 5:

EVI

DENC

E tO

DEC

IsIO

N tA

blEs

Just

ifica

tion

In th

e su

rgic

al m

eta-

anal

ysis

that

exa

min

ed a

ll fo

rms

of s

urge

ry to

geth

er, t

here

was

a s

tatis

tical

ly s

igni

fican

t im

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pe o

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)

70

ANNEX 6

Summaries of unpublished data used for the recommendations

1. Short MDR-TB regimens: meta-analyses of data from published and unpublished studies

F Ahmad Khan1, E C Casas2, P DuCros3, MA Hamid Salim4, V Schwoebel5, A Trébucq5, Atadjan Khamraev6, Welile Sikhondze7, D Falzon8, D Menzies1

1 Respiratory Epidemiology and Clinical Research Unit & McGill International TB Centre, McGill University, Montreal, Canada; 2 Médecins Sans Frontières-Operational Center Amsterdam, The Netherlands & Médecins Sans Frontières-OCA Swaziland; 3 Manson Unit, Médecins Sans Frontières, London, UK; 4 National TB Programme of Bangladesh, USAID-MDR-TB Project, Dhaka, Bangladesh; 5 International Union Against Tuberculosis and Lung Disease, Paris, France; 6 Ministry of Health, Nukus, Karakalpakstan, Uzbekistan; 7 National TB Control Program, Ministry of Health, Swaziland Ministry of Health, Swaziland; 8 World Health Organization, Global TB Programme, Geneva, Switzerland

BackgroundFor the treatment of multidrug-resistant tuberculosis (MDR-TB), the World Health Organization (WHO) recommends an intensive phase of at eight months, and total treatment duration of at least 20 months. Shortening the treatment duration without compromising efficacy would substantially reduce the burden that prolonged therapy places on patients and programmes. To inform updated policy recommendations, we synthesized data from published and unpublished studies of MDR-TB patients treated with standardized regimens based on the 9-month “Bangladesh regimen” initially described by Van Deun and co-workers in 2010 (1).

MethodsAn expert committee identified published and ongoing studies of MDR-TB patients treated with standardized regimens of up to 12 months in duration (“short MDR-TB regimens”) that were based on the Bangladesh regimen. We sought to: (i) estimate the probability of treatment success (cure or treatment completion) versus an unfavourable outcome (failure/relapse, death, or default); (ii) identify baseline characteristics associated with these outcomes; and (iii) compare outcomes to those reported in patients treated with regimens of conventional duration (at least 18 months). Patients were included if they had MDR-TB confirmed by culture or molecular drug-susceptibility testing (DST). We also included patients with rifampicin-resistant TB in whom isoniazid DST had not been performed. Aggregate (study-level) meta-analyses were performed to estimate pooled proportions using data from all studies. To identify patient characteristics associated with outcomes, we conducted individual patient data meta-analyses stratified by characteristics of interest. Lastly, we compared outcomes with short MDR-TB regimens to those with longer duration regimens. To do so, we used data from MDR-TB patients treated with regimens of at least 18 months (“longer regimens”) taken from a previous individual patient meta-analysis. Hence, the comparison group included many different regimens, some of which were individualized, and not all

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ANNEX 6: sUMMARIEs OF UNPUblIsHED DAtA UsED FOR tHE RECOMMENDAtIONs

of which met existing WHO recommendations for MDR-TB treatment. Meta-analyses used random effects models with the exact binomial likelihood method.

ResultsSix studies were identified. Three are ongoing and shared interim data for this analysis. One published and two ongoing studies provided individual patient data. The description of the studies and patients is reported in Table A6.1.1.

Exclusion criteria

Five studies excluded patients that had previously been treated with second-line anti-TB medications. The following exclusion criteria were used in some of the studies: pregnancy, age <14 years, severe liver or renal co-morbidity, baseline XDR-TB, baseline resistance to moxifloxacin, baseline resistance to ofloxacin, resistance to at least two second-line injectables, severe clinical condition, baseline QT prolongation and extrapulmonary TB.

Regimens

In all six studies, the minimum duration of the intensive phase was four months. The intensive phase could be extended by two months – exceptionally up to four months in the Swaziland series – in the absence of conversion. The duration of the continuation phase was five months in four studies, and eight months in two studies. The intensive phase regimens typically consisted of kanamycin, moxifloxacin (usual dose) or gatifloxacin (high or usual dose), high-dose isoniazid, prothionamide, clofazimine, pyrazinamide and ethambutol. In all studies, the continuation phase regimen included the same fluoroquinolone (moxifloxacin or gatifloxacin), clofazimine, pyrazinamide and ethambutol; prothionamide was also continued in three studies. All treatment was under direct observation, and in most studies either some or all patients were hospitalized for a portion of the treatment.

Outcome definitions

Outcomes of cure, treatment completion, failure, death and default were reported in all studies. Relapse was defined as a positive culture, post treatment completion. Because this outcome was rare and only reported in the three published studies, the few relapse cases were counted as failures.

Aggregate meta-analyses

Rates of successful and unsuccessful treatment are reported in Table A6.1.2. The proportion of those successfully treated was higher with standardized short regimens. When death and “loss to follow-up” were included as unsuccessful outcomes along with failure/relapse, the percentage success was significantly higher in patients on the shorter regimens compared with those on the longer regimen (confidence limits not overlapping).

Individual patient data meta-analyses

When stratified by baseline susceptibility to fluoroquinolone and pyrazinamide, the proportion of patients successfully treated remained consistently greater with standardized short MDR-TB regimens; however, the confidence limits overlapped. There was a trend towards worsening treatment outcomes in

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WHO TREATMENT GUIDELINES FOR DRUG-RESISTANT TUBERCULOSIS, 2016 UPDATE

both the short regimens group, and the longer regimen group, in patients with fluoroquinolone- and/or pyrazinamide-resistant MDR-TB.

ConclusionShort MDR-TB regimens based on the “Bangladesh regimen” have shown promising results in patients that have never been treated with second-line drugs and with baseline susceptibility to fluoroquinolones and pyrazinamide. There is a paucity of data on relapse; however, the available evidence suggests relapse is rare.

Table A6.1.1. Description of studies and patients

BANGLADESH 2005–2011

NIGER 2008–2010

CAMEROON 2008–2011

UZBEKISTAN 2013–2015

MULTIPLE 2013–2015

SWAZILAND 2014–2015

Status Published Published Published Ongoing Ongoing Ongoing

Data available for meta-analysis

Individual patient Aggregate Aggregate Individual patient Aggregate Individual patient

Data available on relapse at 2 years post-end of treatment

Yes Yes No No No No

Patients eligible for initiation of MDR treatment

640 124 323 NR 1169 114

Patients with MDR-TB or rifampicin-resist-ant TB confirmed

527† 97† 237† 117* 1169** 76*

Excluded from analysis, n (%)

34 (6.4%) 32 (33.0%) 87 (36.7%) 52 (44.4%)Ω 761 (65.1%)*** 52 (68.4%) Ω

Included, n (%) 493 (93.5%) 65 (67.0%) 150 (63.3%)  65 (55.6%)  408 (34.9%)  24 (31.5%)

Age (± standard deviation, or IQR)

 33.6 (±12.9) 31 (27–38)  35.1 34.1 (±14.3)  35.1  35.2 (±14.4)

Female, n (%)  150/493 (30.4%) 12/65 (18.5%) 73/150 (48.7%) 35/65 (53.8%) 152/408 (37.3%)  13/24 (54.2%)

Primary MDR, n (%) 4/493 (0.8%) 1/65 (1.5%) 1/150 (0.1%) 47/61 (77.0%) 59/407 (14.5%) 20/24 (83.3%)

HIV, n (%)  0  1/58 (1.7%) 30/150 (20%) 0/44  91/407 (22.4%) 16/24 (66.7%)

Smear positive, n (%) 475/493 (96.3%) 54/65 (83.1%) 150/150 (100%) 28/62 (45.2%) 354/406 (87.2%) 12/23 (52.2%)

Chest radiograph cavities, n (%)

 99/493 (20.1%) 23/65 (35.4%)  NR 26/61 (42.6%)  NR  NR

Pyrazinamide resist-ance, n (%)

99/240 (41.3%) NR  NR 33/39 (84.6%)  80/150 (51.3%) 10/14 (71.4%)

Ethambutol resistance, n (%)

321/493 (65.1%) 45/65 (69.2%)  NR 31/44 (70.5%) NR 12/17 (70.6%)

MDR: multidrug-resistant; tb: tuberculosis; NR: not reportedMultiple: benin, burkina Faso, burundi, Cameroon, Central Africa Republic, Democratic Republic of Congo, Niger.† Isoniazid and rifampicin resistance confirmed in all participants.* Includes participants with rifampicin-resistant tb in whom Dst to isoniazid was not performed (Uzbekistan, n=7; swaziland, n=6).** Includes participants with rifampicin-resistant tb in whom Dst to isoniazid was not performed (n=137) or with Dst-confirmed susceptibility to

isoniazid (n=22).*** 409/761 never initiated the short MDR-tb regimen: 65 with prior exposure to second-line drugs; 1 with XDR-tb; 112 lost prior to initiation; 34

died prior to initiation; 197 other (pregnancy, children, medical/social contra-indications, refusals, non-residents).Ω Majority of exclusions were accounted for by participants in whom short MDR-tb treatment was ongoing, or had ended recently: Uzbekistan,

39/52; swaziland, 47/52.

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ANNEX 6: sUMMARIEs OF UNPUblIsHED DAtA UsED FOR tHE RECOMMENDAtIONs

Table A6.1.2. Pooled treatment outcomes from aggregate data meta-analyses

OUTCOMESTANDARDIZED SHORT MDR-TB REGIMENS,

6 STUDIES LONGER REGIMENS, 31 STUDIES

SUCCESS/NWEIGHTED PROPORTION

(95% CL) SUCCESS/NWEIGHTED PROPORTION

(95% CL)

success versus failure or relapse

1008/1033 97.5% (92.4%–99.2%) 4033/4639 91.2% (86.1%–94.6%)

success versus failure, relapse or death

1008/1116 90.3% (87.8%–92.4%) 4033/5850 78.3% (71.2%–84.0%)

success versus failure, relapse, death, or loss to follow up

1008/1205 83.7% (79.2%–87.4%) 4033/7665 61.7% (53.1%–69.6%)

Cl: Confidence limitsMeta-analyses used random-effects models.In the shorter regimens, data on relapse were only available in the three published studies.Bold indicates that 95% Cl does not overlap with the longer regimens group.

Reference1. Van Deun A, Maug AKJ, Salim MAH, Das PK, Sarker MR, Daru P, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2010;182(5):684–692.

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WHO TREATMENT GUIDELINES FOR DRUG-RESISTANT TUBERCULOSIS, 2016 UPDATE

2. An updated systematic review and meta-analysis for treatment of multidrug-resistant tuberculosis

Mayara Lisboa Bastos1, Zhiyi Lan2, Dick Menzies2

1 Internal Medicine Graduate Program, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil2 Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill University, Montreal, Canada

IntroductionTreatment for MDR-TB or XDR-TB requires lengthy use of second-line TB drugs, although the regimens used vary widely. The WHO 2011 guidelines recommended that MDR-TB treatment include as a minimum pyrazinamide, one second-line injectable (kanamycin, amikacin or capreomycin), one later generation fluoroquinolone (levofloxacin or moxifloxacin), and at least two Group 4 drugs (ethionamide/prothionamide, cycloserine/terizidone or p-aminosalicylic acid). We performed a systematic review to update the evidence for MDR-TB treatment to inform the WHO Guideline Development Group.

Methods

Literature search and study selectionThe PICO (Patients, Intervention, Comparator and Outcomes) questions were developed by the WHO Guideline Development Group in 2014–2015 to assist evidence reviews to inform its 2016 update of the guidance on MDR-TB treatment. The main focus of this review was the efficacy and safety of available drugs for the treatment of MDR-TB patients. The following groups of drugs were analyzed: first-line drugs (pyrazinamide, ethambutol, and high dose isoniazid), injectable drugs (streptomycin, kanamycin, amikacin, and capreomycin), fluoroquinolones (ofloxacin, levofloxacin and moxifloxacin), drugs from Group 4 (ethionamide/prothionamide, cycloserine /terizidone and p-aminosalicylic acid (PAS)), and the new drug bedaquiline. Drugs from Group 5 were not included in our review since at least four independent systematic reviews were recently conducted for these drugs.

Three major databases were used for our search: MEDLINE (through OVID), EMBASE (through OVID) and The Cochrane Library. The search strategy used a combination of Medical Subject Heading (MeSH) terms and free-text words in titles, abstracts and key words. Terms related to MDR-TB and XDR-TB, drugs of interest and treatment outcomes were included. Since this is an update from previous reviews which included studies published up to December 2008 our search was limited to the period from January 2009 to August 2015. The detailed search strategy is available in the supplemental material.

Two independent reviewers screened titles, abstracts and full texts, with consensus in each stage. A third reviewer was consulted to resolve possible disagreements. We included studies published in English, French, Chinese, Portuguese and Spanish. All studies that met the following inclusion criteria were selected: (i) MDR-TB confirmed by phenotypic tests (GeneXpert® was not adequate unless confirmed); (ii) pulmonary TB (studies that had more than 10% extrapulmonary patients and did not report the outcomes separately were excluded); (iii) cohorts or RCTs with a minimum of 25 MDR-TB (or XDR-TB) patients treated; (iv) a clear regimen specifying the drugs received; and (v) at least reported one of the following outcomes: end-of-treatment outcomes, six-month culture conversion, adverse events due to MDR-TB treatment. Studies that evaluated short regimens (<18 months) were excluded.

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Data abstractionData from eligible studies were abstracted using a standardized data abstraction form (see supplemental material). We recorded information of age, sex, HIV (and use of antiretroviral treatment), acid-fast bacillus smear results, chest radiograph cavitation, prior TB treatment (with first-line drugs or second-line drugs), drug susceptibility test results, number of patients that received each drug, duration of treatment, and whether the regimen was standardized or individualized. Outcomes abstracted included: end of treatment outcomes defined according to published criteria, six-month sputum culture conversion and serious adverse events (SAEs; defined as Grade 3–4 events, or defined operationally as drugs discontinued permanently). For SAEs, we recorded the study definition of severity and the drug responsible for the event, if identified.

Data synthesis and statistical analysisFor end of treatment outcomes, we compared success (defined as cured or treatment completed) to: (i) failure or relapse; or (ii) failure or relapse or death. We examined the relationship between end of treatment outcomes and six-month culture conversion; the number of patients receiving each specific drug, average number of drugs used, and duration of treatment; as well as the average value for each cohort of major clinical and demographic characteristics of the patients. If HIV information or age were missing, values were estimated using information from other studies in this review from the same country, and if no such study was available, from data published by the World Bank or WHO. Variables were categorized according to the distribution observed (i.e. in median, terciles or quartiles).

Occurrence of adverse events was pooled if the study identified the drug responsible for the event and if the event was classified as Grade 3 to 4 severity, or the drug of interest was permanently stopped.

All statistical analyses were performed using SAS (version 9.2 Institute, Cary, NC, USA). Linear mixed models were used to pool the proportion with events (NLIMIXED procedure in SAS). For pooling the proportions of adverse events, we used generalized linear mixed model (GLIMMIX procedure in SAS).

ResultsA total of 2336 titles were identified, and after eliminating duplicates and non-relevant publications based on review of titles and abstracts, 250 were selected for full text review, of which 74 met the review inclusion criteria. 19 studies reported adverse events that were classified as Grade 3 or 4, or required permanent discontinuation of the drug, and identified the drug responsible.

Pooled treatment success rate was 26% (CI 95%, 23%–30%) in XDR-TB patients, compared to 60% in all cohorts of MDR-TB patients (with or without additional second-line resistance). The occurrence of SAE ranged from 0.5% to 12.2% (Table A6.2.1). Less than 3% of patients receiving fluoroquinolones or pyrazinamide experienced an SAE, compared to more than 5% of patients receiving second-line injectables or a thiamide (ethionamide or prothionamide).

ConclusionThis review identified 74 studies, with 84 distinct cohorts, published since January 2009 that reported treatment regimens and outcomes in 17 494 MDR-TB and XDR-TB patients. These studies reported

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WHO TREATMENT GUIDELINES FOR DRUG-RESISTANT TUBERCULOSIS, 2016 UPDATE

adverse events, six-month culture conversion and end of treatment outcomes. Treatment outcomes were substantially worse in patients with XDR-TB, and somewhat worse in patients who received standardized regimens for MDR-TB. However, despite the large number of studies and patients, no other treatment parameter, including number or duration of drugs, and individual drugs were associated with improved six-month culture conversion, or end of treatment outcomes.  This may reflect the limitations and difficulties of pooling this data rather than true lack of differences in efficacy of regimens or individual drugs. This review highlights the need for more standardized reporting as well as evidence from well-designed randomized trials, or from meta-analysis of pooled individual patient data set from multiple observational studies. 

Table A6.2.1. Occurrence of serious adverse events (SAEs), attributed to specific drugs in treatment of MDR-TB or XDR-TB

(Results from 19 studies (20 cohorts) that reported Grade 3–4 adverse events, or drugs permanently stopped due to adverse events, and identified the drug responsible for the adverse events.)

DRUG

ARMS/COHORTS REPORTING SAE AND

USED THE DRUG

N PATIENTS RECEIVED THE

DRUG

SERIOUS ADVERSE EVENTS DUE TO DRUG

N PATIENTS WITH SAE RELATED TO

THE DRUG POOLED ESTIMATE1

(CI 95%)

Pyrazinamide 19 2023 56 2.8% (2.1%-3.7%)

Ethambutol 16 1325 6 0.5% (0.2%-1.1%)

Injectable 19 2538 184 7.3% (6.2%-8.4%)

later gen. FQN 13 827 10 1.2% (0.6%-2.4%)

Ofx/Cfx 9 1408 40 2.8% (1.9%-4.1%)

thiamide 17 2106 173 8.2% (7.0%-9.6%)

Cycloserine 16 2140 96 4.5% (3.6%-5.5%)

PAs 16 1706 208 12.2% (10.6%-13.9%)

later gen. FQN: later generation fluoroquinolone (includes gatifloxacin /levofloxacin /moxifloxacin), Ofx/Cfx: ofloxacin/ciprofloxacin, PAs: p-aminosalicylic acid1 Pooled using Proc Glimmix in sAs – fixed effects meta-analysis.

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ANNEX 6: sUMMARIEs OF UNPUblIsHED DAtA UsED FOR tHE RECOMMENDAtIONs

3. A systematic review and individual patient data meta-analysis of treatment and outcomes among children with multidrug- resistant tuberculosis

Elizabeth Harausz1, Anthony J. Garcia-Prats2, H. Simon Schaaf2, Stephanie Law3, Jennifer Furin4, Tamara Kredo5, Anna Turkova6, Dick Menzies3 and Anneke C. Hesseling2 for The Collaborative Group for Meta-Analysis of Paediatric Individual Patient Data in MDR-TB

1 Military HIV Research Program, Bethesda, USA2 Desmond Tutu TB Centre, Department of Paediatrics and Health Sciences, Faculty of Medicine and Health Sciences, Stellenbosch

University, Tygerberg, South Africa3 Montreal Chest Institute, McGill University, Montreal, Canada4 Department of Global Health and Social Medicine, Harvard Medical School, USA5 South African Medical Research Council, Cape Town, South Africa6 Imperial College Healthcare NHS Trust, Institute of Clinical Trials and Methodology, London, United Kingdom,

IntroductionMultidrug-resistant tuberculosis (MDR-TB) in children is under-recognized, under-diagnosed and under-reported. Despite approximately 32 000 children developing MDR-TB each year (1) and historical studies showing mortality rates from TB of 40%, 16% and 5% for infants, toddlers and young children, respectively (2), very little is known about optimal treatment for children with MDR-TB. Treatment of MDR-TB is difficult, requiring use of toxic medications for at least 18 months with formulations and regimens not suited to children. However, individual studies have reported successful treatment outcomes in at least 80% of children treated for MDR-TB (3). A more rigorous evidence base is needed to help inform the management of MDR-TB treatment in children. A systemic review in 2012 sought to better quantify treatment outcomes in children, however, many questions remain on how to optimize successful treatment outcomes and minimize adverse events (3).

In order to address key questions regarding the treatment of MDR-TB and to inform paediatric-specific guidelines, we undertook a systematic review and individual patient data meta-analysis (IPD) of children with MDR-TB. The objective was to provide information on the management of children with MDR-TB by analysing determinants of key treatment outcomes among children treated for MDR-TB, and addressing questions specifically relevant to the paediatric population with MDR-TB (Table A6.3.1).

Methods

Eligibility criteriaData sets were eligible if they included a minimum of three children (aged <15 years) within a defined treatment cohort who were treated for clinically diagnosed or bacteriologically confirmed pulmonary or extrapulmonary MDR-TB, and for whom treatment outcomes were reported, using standard World Health Organization (WHO) TB case definitions (4,5). Eligibility criteria were applied at the individual level, so that studies reporting on both adults and children could be considered eligible if they otherwise met the specified criteria. Both published and unpublished data were included, without date restriction. Eligible study designs included controlled and non-controlled retrospective and prospective studies and

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WHO TREATMENT GUIDELINES FOR DRUG-RESISTANT TUBERCULOSIS, 2016 UPDATE

case series. All cohorts containing children included in a previous systematic review and individual patient data meta-analysis of MDR-TB were considered eligible (6). Only reports written in Dutch, English, French, Russian and Spanish were included. We excluded studies that utilized only combinations of rifampicin, isoniazid (INH), pyrazinamide (PZA), ethambutol (EMB) or streptomycin to treat MDR-TB, as this is now considered inadequate therapy.

Identifying primary reportsTo identify eligible reports, including conference abstracts, we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases up to 30 September 2014, with a search strategy, using a combination of the search terms, viz. “tuberculosis”, “multidrug resistance”, “MDR-TB”, “multidrug-resistant”, and “children”, both as exploded MESH headings and free-text terms, and without language restriction. The specific search strategies for Pubmed and Embase are presented in Appendix 6A. We also reviewed conference abstracts from the annual meeting of the International Union Against Tuberculosis and Lung Diseases.

To identify additional published and unpublished data we contacted experts in the field of paediatric MDR-TB. We also requested additional data through multiple routes, such as at national and international conferences and training events, and through international and in-country organizations working in paediatric MDR-TB, including the Sentinel Project on Pediatric Drug-Resistant Tuberculosis, the WHO Childhood TB sub-Group, Médecins Sans Frontières (MSF), the United States and European CDC, International Union Against Tuberculosis and Lung Disease (UNION), National Institutes of Health (NIH) and others.

Report selection and reviewAll abstracts were screened by EH and a researcher with the South African Cochrane Centre to select full text reports to review. All full text reports were reviewed independently by two reviewers (EH, AGP, HSS, JF, ACH) to assess for eligibility, except reports in Dutch, French, Russian and Spanish, which were reviewed by a single reviewer (from among AT, EH, ACH and JF). A third reviewer resolved any disagreements about study selection. If report eligibility was unclear, two attempts were made to contact the authors of the primary report; and if we could not make contact after two unsuccessful attempts, these reports were excluded.

Individual patient data abstractionThe authors of all eligible studies were contacted to access individual patient data. Individual patient data were used following a written agreement with the study team by the original authors, which included confirmation of ethical approval according to local guidelines.

Data were collected on multiple factors which could influence treatment decision and outcome, including: demographic characteristics, nutritional status, HIV status and antiretroviral usage, adult MDR-TB source case information, culture confirmed versus clinical diagnosis, information on disease location (pulmonary or extrapulmonary) and severity (using a standard approach), drug susceptibility test results, the use of individual drugs, and the duration of drug use within the treatment regimen. Data were collected on acid-fast bacillus (smear) microscopy and culture conversion, adverse effects, as well as WHO-defined treatment

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outcomes including cure, treatment completion, culture conversion by six months, treatment failure, relapse, loss to follow-up and mortality. Severity of disease on chest radiograph, based on a standardized disease severity classification developed for an international paediatric TB randomized control trial (Palmer M, personal communication), was graded independently by two reviewers (EH, ACH) as either severe or non-severe; disagreements were arbitrated by a third reviewer (HSS). The primary authors of all included reports were contacted as needed to resolve any queries.

In order to contextualize the clinical data, information was also requested from each primary author on site-level characteristics, including but not limited to methods for TB diagnosis, availability and type of drug-susceptibility testing performed, how treatment outcomes were defined, and how adverse effects were assessed.

A database was created, and primary data from each study were entered into the database.

AnalysisThe analysis was planned to address PICO question 1, as per Table A6.3.1. Primary analyses focused on success versus failure/relapse/death in children with confirmed MDR-TB only. There were no paediatric data available to address the section in PICO question 1 regarding rifampicin mono-resistant TB.

Table A6.3.1. WHO-defined PICO question 1, in HIV-infected and uninfected children aged 0–14 years with MDR-TB; and which individual drugs in the regimens are likely to lead to the outcomes listed below?

POPULATION INTERVENTION COMPARATOR OUTCOMES

MDR-tb without resist-ance to the second-line drugs

A second-line regimena which includes: • Cured/completed by end of treatment

• Failure

• Relapse

• survival (or death)

• Adverse reactions from tb drugs (severity, type, organ class)

– pyrazinamide – no pyrazinamide

– injectable agents (Km/Am/Cm)

– no injectable agents (Km/Am/Cm)

– prothionamide/ethionamide – no prothionamide/ethionamide

– cycloserine or terizidone – no cycloserine or terizidone

– PAs – no PAs

– later-generation fluoroquinolone2 – no later-generation fluoroquinoloneb

– high-dose isoniazid – no high-dose isoniazid

– clofazimine – no clofazimine

– linezolid – no linezolid

– other individual Group 5 drugs – no other individual Group 5 drugs

a Data from regimens lasting up to 12 months were not included in this question.b Moxifloxacin or gatifloxacin; any use of standard or high-dose levofloxacin was included as levofloxacin use.

For all analyses, treatment outcomes were dichotomized as either successful or unsuccessful. Successful outcome was defined as when cure was achieved or treatment was completed, and unsuccessful outcome was defined as failure, relapse or death. There were inadequate numbers of events to support analysis of

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failure/relapse. The primary analyses estimated the odds of treatment success (versus fail/relapse/death) associated with the use of each drug among patients with bacteriologically confirmed MDR-TB but without confirmed XDR-TB. To assess the effect of fluoroquinolones, the use of any later generation fluoroquinolone was compared to a regimen excluding the use of a later generation fluoroquinolone.

All analyses were repeated on patients with clinically diagnosed MDR-TB (i.e. not bacteriologically confirmed MDR-TB), where the data supported analyses.  Children with confirmed XDR-TB were excluded from the primary analysis.

For all adjusted analyses, we fitted random-effects logistic regressions (random intercept and random slopes, when possible, and only random intercept when not) by maximum likelihood with quadrature approximation, using PROC GLIMMIX in SAS software (version 9.4, SAS Institute, Cary, North Carolina). Patients were considered to be clustered within studies, and intercepts and slopes of the main exposure variables were allowed to vary across studies. This was to account for unmeasured differences between patient populations across studies, as well as site-specific differences in data ascertainment, measurement and other factors. Estimates were adjusted for four covariates: age (dichotomized as under five years old and 5–15 years old), sex, HIV infection and severe TB disease (defined as being underweight or malnourished, having oedema, having low weight for age, having severe extrapulmonary disease, or having severe disease on chest radiograph). In order to improve data modelling, given some missing data on HIV status, children from countries with very low HIV prevalence who did not have an HIV test done were assumed to be HIV negative, following consultation with the study investigators. For the main analyses, single imputation (as opposed to multiple imputation) was performed where missing values for the four covariates used in multivariable analyses were substituted with the mean value from the other participants of the same study to which the individual belonged. In sensitivity analyses, multiple imputation using chained equations was used for missing values. All statistical analyses were performed using SAS 9.4.

Data on adverse events were sparse, and therefore we chose to provide descriptive analysis only for key toxicities in studies consistently reporting adverse events; in particular the incidence of ototoxicity (descriptive analysis only) because it is a frequent and serious side effect of aminoglycosides, which are a cornerstone of treatment, and of particular interest to health care providers and patients with MDR-TB.

Assessment of overall quality of evidenceThe quality of studies was described using a modified Newcastle-Ottawa tool (Appendix 6B) adapted for use in paediatric MDR-TB. We assessed the quality of evidence across the studies with Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (7) defining the quality of evidence for each outcome as “the extent to which one can be confident that an estimate of effect or association is close to the quantity of specific interest” (8). The quality rating across studies has four levels: high, moderate, low or very low. Randomized controlled trials are initially categorized as providing high quality evidence, but the quality can be downgraded. Similarly, other types of controlled trials and observational studies are categorized as providing low quality evidence but the quality can be upgraded if justified. Factors that decrease the quality of evidence include limitations in design, indirectness of evidence, unexplained heterogeneity or inconsistency of results, imprecision of results or high probability of publication bias. Factors that can increase the quality level of a body of evidence include studies with a large magnitude of effect, and studies in which all plausible confounding would lead to an underestimation of effect.

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EthicsThe Health Research Ethics Committee of the Faculty of Medicine and Health Sciences and Stellenbosch University provided ethical approval for this study.

Results

Search results and report selectionFigure A6.3.1 presents a summary of the search results and report selection. Results from searching the database and other sources yielded 2771 search results, which were narrowed down to 242 results, after screening of abstracts (Figure A6.3.1). Of these 242 papers reviewed and 210 were excluded. Included in these excluded studies were 89 studies in which the authors were contacted when eligibility criteria were unclear; of those authors, 48 never replied, 18 confirmed that their study did not meet inclusion criteria and 1 study was rejected as it did not include primary data (a systematic review). It’s important to note that the vast majority of these queries were for studies that were primarily adult studies but may have possibly contained a small number of children, however the precise number was often not specified. It is therefore unlikely that a large number of children were missed from these excluded studies.

Twenty-seven studies (from 32 studies requested) provided individual patient data (9–26) that included data from 974 patients. Two authors declined to share data, two authors could not get Internal Review Board permission in time to share their data and one author no longer had access to the primary data (Figure A6.3.1).

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Figure A6.3.1. Flow diagram of study selection for systematic review and individual patient meta-analysis of children with multidrug-resistant tuberculosis

Report characteristicsGeographic distribution of the data received from sites from 18 countries is shown in Figure A6.3.2. Patients from six continents were included; the majority were from Africa. Four countries (India, Pakistan, Russia and South Africa) are among the 30 high-burden TB countries. Details of the included studies are presented in Appendix 6B.

No. of studies for which IPD was not provided

n=5n=2: authors declinedn=2: ethical approval not obtainedn=1: data no longer available

No. of studies identified through other sources

n=10

No. of studies identified through database searching

n=2,761

No. of studies screenedn=2,771

No. of studies excludedn=2,529 

No. of studies excludedn=210

n=125: <3 children includedn=18: Duplicate study populationn=48: unclear; no reply from authorn=18: did not meet eligibilityn=1: not primary data

No. of studies for which IPD was requested

n=32

No. of studies for which IPD was provided, n=27

No. of participants for which IPD was provided, n=974

No. of full text studies screened for eligibility

n=242

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Figure A6.3.2. Details of geographic locations of patients included in the individual patient data meta-analysis (the number indicates the number of participants included at each location)

Summary patient data and outcomesData from 974 children that were included in the analysis showed median age of 7.1 years and 44% males. The HIV status was known in 822 children, of whom 44% had HIV infection. Two-hundred thirty seven children had clinically diagnosed MDR-TB, and 737 children had bacteriologically confirmed MDR-TB. Of those with a confirmed diagnosis, 35 had MDR-TB with additional resistance to a fluoroquinolone, 28 had MDR-TB with additional second-line injectable resistance and 36 had XDR-TB (i.e. resistance to both a fluoroquinolone and a second-line injectable). Children with XDR-TB were not included in the primary analysis and data from children with additional resistance to a fluoroquinolone or a second-line injectable agent were combined with MDR-TB (see methods). Key clinical and demographic characteristics, stratified by clinically diagnosed versus bacteriologically confirmed MDR-TB are shown in Table A6.3.2. Treatment outcomes summarized for the entire data set are shown in Table A6.3.3. Some children were listed as “cured”, because they were bacteriologically diagnosed with TB disease, but their MDR-TB was not confirmed by drug-susceptibility testing.

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Table A6.3.2. Key demographic and clinical characteristics among children with clinically diagnosed or bacteriologically confirmed multidrug-resistant tuberculosis

CLINICALLY DIAGNOSED MDR-TB

N = 237 (%)

BACTERIOLOGICALLY CONFIRMED MDR OR PRE-XDR

N = 701 (%)

Age

• Under 5 years

• 5 to 15 years156 (66)81 (34)

231 (33)470 (67)

Malnourished*

• Yes

• No

• Unknown

47 (19.8)67 (28.3)

123 (51.9)

274 (39.1)366 (52.2)

61 (8.7)

severe Disease on chest radiograph**

• Yes

• No

• Unknown

68 (28.7)126 (53.2)43 (18.1)

519 (74.0)163 (23.3)

19 (2.7)

severe Extrapulmonary Disease*** 24 (10.1) 103 (14.7)

HIV status

• HIV-infected

• HIV-uninfected

• HIV status unknown

36 (15.2)141 (59.5)60 (25.3)

318 (45.4)300 (42.8)83 (11.8)

A combined variable of “severe disease: included the presence of malnutrition* or severe disease on chest radiograph** or severe extrapulmonary disease***, given missing data on these three variables, individually.

Table A6.3.3. Summary of treatment outcomes for children with multidrug-resistant tuberculosis

CLINICALLY DIAGNOSED MDR-TB

N = 237

CONFIRMED MDR-TB WITH-OUT CONFIRMED XDR-TB

N = 701

CONFIRMED XDR-TB

N = 36

Cured 46 (19.3%) 327 (46.6%) 23 (64%)

Completed treatment 166 (69.7%) 209 (29.8%) 7 (19%)

Fail or relapse 0 14 (1.9%) 1 (3%)

Death 7 (2.9%) 73 (10.4%) 3 (8%)

lost to follow-up 18 (8%) 77 (11%) 2 (6%)

The results for primary outcome analysis of treatment benefit for individual drugs are presented in GRADE tables (see Annex 4). Note that although numbers are small, children who did not receive a second-line injectable, but who had clinically diagnosed/unconfirmed disease (and in general had less severe disease, Table A6.3.2) did well (93.5% successful outcomes, see GRADE table for second-line injectables). Children who did not receive a second-line injectable tended to have less severe TB disease overall, and have lower rates of malnutrition, severe disease (on chest radiograph) and severe extrapulmonary TB disease (see Table A6.3.4).

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Adverse events were in general poorly reported. Only nine datasets consistently reported toxicities, and these data are presented in Table A6.3.5.

Table A6.3.4. Characteristics of children who received a second-line injectable (SLI) versus those who did not

TREATED WITH SLI NOT TREATED WITH SLI

N % N %

severe disease 296 91% 30 9%

Malnourished 239 93% 18 7%

severe pulmonary disease on chest radiograph 479 92% 40 8%

severe extrapulmonary disease 85 83% 18 17%

Table A6.3.5. Frequency of specific toxicities in studies that reported adverse events (N=306 subjects in 9 datasets where adverse events were consistently reported)

SIDE EFFECT NUMBER OF CHILDREN DENOMINATOR % EVENTS

Hearing loss 39 383 10.1%

Peripheral neuropathy 2 383 0.5%

Optic neuropathy 11 383 2.9%

thyroid dysfunction 50 383 13.1%

liver toxicity 16 383 4.2%

Arthropathy 20 383 5.2%

Nephrotoxicity 2 383 0.5%

Note: secondary analyses are planned in the future, including analyses of outcomes in children with shorter durations of injectable treatment, stratified by severe and non-severe tb disease, and by bacteriological status.

DiscussionThis first ever systematic review and IPD of paediatric MDR-TB, which included a large number of children, shows overall good treatment outcome with 76.4% of children with bacteriologically confirmed MDR-TB, and 89% of children with unconfirmed MDR-TB, having successful treatment outcomes. More than two-thirds of children had bacteriologically confirmed MDR-TB, which strengthens the quality of data from this review, given the fact that TB in children is typically paucibacillary in nature. The overall mortality was low (10.4% in children with confirmed disease, and 2.9% in the unconfirmed group). Children with confirmed XDR-TB although a small number (n=36) had favourable treatment outcomes in 83% of cases.

Most children (77%) received injectable drugs. There was a high prevalence of HIV infection, with 45% of children in the confirmed and 15% in the unconfirmed MDR-TB group, being HIV-infected; HIV testing was relatively complete. A high proportion of children had chest radiographic or features of

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extrapulmonary disease compatible with severe TB, as well as malnutrition. The overall good treatment outcomes should therefore be seen in the context of HIV co-infection and more severe disease, indicating that good outcomes are achievable in children with MDR-TB.

There are a number of notable findings from the analysis of the impact of individual second-line drugs. The use of second-line injectable drugs significantly predicted the treatment success versus failure/relapse/death (OR: 3.32; 95% CI: 1.53–7.21) in children with confirmed MDR-TB. This has to be seen in the context of high toxicity with hearing loss reported in 10.1% of the studies that reported on safety outcomes. However, children with clinically (unconfirmed) diagnosed MD-TB (who tended to have less severe disease) had good outcomes when not treated with a second-line injectable. These data are supportive of the practice of using injectable sparing regimens in children with less severe disease in order to spare children from SAEs associated with second-line injectables, without an adverse impact on treatment outcomes.

High-dose isoniazid (used in approximately 25% of subjects, at a dose of 15–20 mg/kg), predicted treatment success (versus failure/relapse/death; OR: 6.97; 95% CI: 2.11–23.03), even after adjusting for site in the analysis (high-dose isoniazid was most frequently used in South African sites). Another consideration to this finding is that high-dose isoniazid is also typically used in combination with ethionamide/prothionamide.

Later-generation fluoroquinolones (primarily moxifloxacin; since there was virtually no reported use of gatifloxacin) did not appear to offer a treatment benefit. However, only 10% of cases in the dataset received later-generation fluoroquinolones, which may have masked any benefit associated with their use.

In general, these findings of individual drug effects should be taken in the context of the use of multiple drugs as part of MDR-TB treatment regimens.

LimitationsThis individual patient data (IPD) is limited by the overall low quality of studies; most studies included were retrospective or prospective observational cohort studies and there were no trials that could be included. The overall sample size was modest compared to adult IPD datasets, and estimates were frequently imprecise while some associations were not estimated due to limited data (e.g. relapse/failure). There were no data available yet on the novel drugs, delamanid and bedaquiline, for inclusion in this IPD. We also had a very small sample of children with confirmed XDR-TB. Toxicity was frequently poorly assessed while missing data regarding HIV status was handled by imputation. Missing data on individual variables of nutritional status and disease severity were handled using a composite disease severity variable.

In summary, this first paediatric specific IPD has provided data for guideline development of high clinical and programmatic relevance. Overall, the proportion of children with favourable treatment outcome, even with severe TB and with HIV co-infection, was good. Data regarding the use of novel drugs, bedaquiline and delamanid in children, are urgently needed. Future questions should focus on the use of shorter (<18 months) regimens and injectable-sparing regimens in children. Paediatric-specific treatment evidence is important to allow for inclusion of children in evidence-based MDR-TB treatment guidelines.

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References1. Jenkins HE, Tolman AW, Yuen CM, Parr JB, Keshavjee S, Pérez-Vélez CM, et al. Incidence of multidrug-resistant

tuberculosis disease in children: systematic review and global estimates. Lancet. 2014; 383(9928):1572–9.

2. Wallgren A. Primary tuberculous infections in young adult life and in childhood. Am J Dis Child. 1941; 61: 577–589

3. Ettehad D, Schaaf HS, Seddon JA, Cooke GS, Ford N. Treatment outcomes for children with multidrug resistant tuberculosis: a systemic review and meta-analysis. Lancet Infec Dis. 2012; 12: 449–56.

4. Guidance for national tuberculosis programmes on the management of tuberculosis in children: second edition. Geneva: World Health Organization; 2014 (http://www.who.int/tb/publications/childtb_guidelines/en/, accessed 14 May 2016).

5. Definitions and reporting framework for tuberculosis: 2013 revision (updated December 2014). Geneva: World Health Organization; 2013 (http://apps.who.int/iris/bitstream/10665/79199/1/9789241505345_eng.pdf, accessed 14 May 2016).

6. Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, et al; Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Med. 2012;9(8):e1001300. Epub 2012 Aug 28. PMID: 22952439

7. Guyatt GH, Oxman AD, Schunemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol. 2011;64(4):380–2.

8. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011 (http://www.cochrane-handbook.org, accessed 14 May 2016).

9. Chan ED, Laurel V, Strand MJ, Chan JF, Huynh ML, Goble M, et al. Treatment and outcome analysis of 205 patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2004;169(10):1103–9.

10. Drobac PC, Mukherjee JS, Joseph JK, Mitnick C, Furin JJ, del Castillo H, et al. Community-based therapy for children with multidrug-resistant tuberculosis. Pediatrics. 2006;117(6):2022–9.

11. Fairlie L, Beylis NC, Reubenson G, Moore DP, Madhi SA. High prevalence of childhood multi-drug resistant tuberculosis in Johannesburg, South Africa: a cross sectional study. BMC Infect Dis. 2011;11:28.

12. Gegia M, Jenkins HE, Kalandadze I, Furin J. Outcomes of children treated for tuberculosis with second-line medications in Georgia, 2009–2011. Int J Tuberc Lung Dis. 2013;17(5):624–9.

13. Banerjee R, Allen J, Westenhouse J, Oh P, Elms W, Desmond E, et al. Extensively drug-resistant tuberculosis in California, 1993–2006. Clin Infect Dis. 2008;47(4):450–7.

14. Hicks RM, Padayatchi N, Shah NS, Wolf A, Werner L, Sunkari VB, et al. Malnutrition associated with unfavorable outcome and death among South African MDR-TB and HIV co-infected children. Int J Tuberc Lung Dis. 2014;18(9):1074–83.

15. Isaakidis P, Paryani R, Khan S, Mansoor H, Manglani M, Valiyakath A, et al. Poor outcomes in a cohort of HIV-infected adolescents undergoing treatment for multidrug-resistant tuberculosis in Mumbai, India. PLoS One. 2013; 8(7):e68869.

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18. Moore BK, Anyalechi E, van der Walt M, Smith S, Erasmus L, Lancaster J, et al. Epidemiology of drug-resistant tuberculosis among children and adolescents in South Africa, 2005–2010. Int J Tuberc Lung Dis. 2015;19(6):663–9.

19. Kuksa L, Riekstina V, Leimane V, Ozere I, Skenders G, Van den Bergh R, et al. Multi- and extensively drug-resistant tuberculosis in Latvia: trends, characteristics and treatment outcomes. Public Health Action. 2014; 4(Suppl 2):S47–53.

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22. Seddon JA, Hesseling AC, Godfrey-Faussett P, Schaaf HS. High treatment success in children treated for multidrug-resistant tuberculosis: an observational cohort study. Thorax. 2014;69(5):458–64.

23. Kim DH, Kim HJ, Park SK, Kong SJ, Kim YS, Kim TH, et al. Treatment outcomes and long-term survival in patients with extensively drug-resistant tuberculosis. Am J Respir Crit Care Med. 2008;178(10):1075–82.

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APPENDIX 6A

Search strategies

DATABASE: PUBMED; SEARCH DATE: 01 OCTOBER 2014

SEARCH QUERYITEMS FOUND

#25 search ((#22 AND #23) NOt (animals[mh] NOt humans[mh])) 1653

#24 search (#22 AND #23) 1653

#23 search (infant[mh] OR infant[tiab] OR infants[tiab] OR infancy[tiab] OR toddler*[tiab] OR preterm*[tiab] OR prematur*[tiab] OR postmatur*[tiab] OR baby[tiab] OR babies[tiab] OR neonat*[tiab] OR newborn[tiab] OR preschool*[tiab] OR pre-school*[tiab] OR child[mh] OR child*[tiab] OR kindergar*[tiab] OR pupil*[tiab] OR schoolchild*[tiab] OR teen*[tiab] OR youth[tiab] OR youths[tiab] OR youngster*[tiab] OR young person*[tiab] OR young people[tiab] OR minors[mh] OR minors[tiab] OR puberty[mh] OR puberty[tiab] OR pubescen*[tiab] OR prepubescen*[tiab] OR paediatric*[tiab] OR pediatric*[tiab] OR peadiatric*[tiab] OR schools[mh:noexp] OR school*[tiab] OR kid[tiab] OR kids[tiab] OR boy*[tiab] OR girl*[tiab] OR creche*[tiab] OR highschool*[tiab] OR juvenil*[tiab] OR adolescent[mh] OR adolescen*[tiab] OR under ag*[tiab] OR underag*[tiab])

3521601

#22 search (tuberculosis, multidrug-resistant[mh] OR multidrug resistant tuberculosis[tiab] OR drug resistant tuberculosis[tiab] OR multiple drug resistant tuberculosis[tiab] OR MDR tuberculosis[tiab] OR MDR tb[tiab] OR MDRtb[tiab] OR ((drug resistance[tiab] OR multidrug resistance[tiab] OR multiple drug resistance[tiab] OR multiresistant[tiab] OR multi resistant[tiab]) AND (tuberculosis[tiab] OR tb[tiab]))

8600

DATABASE: EMBASE; SEARCH DATE: 01 OCTOBER 2014

NO. QUERY RESULTS

#8  #3 NOt #7 1837

#7  #4 NOt #6 5002895

#6  #4 AND #5 1303481

#5  ‘human’/de OR ‘normal human’/de OR ‘human cell’/de 15207023

#4  ‘animal’/de OR ‘animal experiment’/de OR ‘invertebrate’/de OR ‘animal tissue’/de OR ‘animal cell’/de OR ‘nonhuman’/de

6306376

#3  #1 AND #2 1889

#2  ‘infant’/exp OR infant:ab,ti OR infants:ab,ti OR infancy:ab,ti OR toddler*:ab,ti OR preterm*:ab,ti OR prematur*:ab,ti OR postmatur*:ab,ti OR baby:ab,ti OR babies:ab,ti OR neonat*:ab,ti OR newborn:ab,ti OR preschool*:ab,ti OR pre+school*:ab,ti OR ‘child’/exp OR child*:ab,ti OR kindergar*:ab,ti OR pupil*:ab,ti OR schoolchild*:ab,ti OR teen*:ab,ti OR youth:ab,ti OR youths:ab,ti OR youngster*:ab,ti OR ‘young person’:ab,ti OR ‘young persons’:ab,ti OR ‘young people’:ab,ti OR ‘minors’/exp OR minors:ab,ti OR ‘puberty’/exp OR puberty:ab,ti OR pubescen*:ab,ti OR prepubescen*:ab,ti OR paediatric*:ab,ti OR pediatric*:ab,ti OR peadiatric*:ab,ti OR ‘schools’/exp OR school*:ab,ti OR kid:ab,ti OR kids:ab,ti OR boy*:ab,ti OR girl*:ab,ti OR creche*:ab,ti OR highschool*:ab,ti OR ‘juvenile’/exp OR juvenil*:ab,ti OR ‘adolescent’/exp OR adolescen*:ab,ti OR (under NEXt/1 ag*):ab,ti OR underag*:ab,ti

4649411

#1  ‘multidrug resistant tuberculosis’/exp OR ‘multidrug resistant tuberculosis’:ab,ti OR ‘drug resist-ant tuberculosis’:ab,ti OR ‘multiple drug resistant tuberculosis’:ab,ti OR ‘mdr tuberculosis’:ab,ti OR ‘mdr tb’:ab,ti OR (‘drug resistance’:ab,ti OR ‘multidrug resistance’:ab,ti OR ‘multiple drug resistance’:ab,ti OR multiresistant:ab,ti AND (tuberculosis:ab,ti OR tb:ab,ti))

9249

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APP

END

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