who consolidated who recommendations on dr-tb
TRANSCRIPT
WHO consolidated WHO recommendations on DR-TB
management
Global TB Programme, Geneva, SwitzerlandMay 2019
Consolidation of WHO guidelines and advice on MDR-TB management
ConsolidatedDR-TB treatment
Guidelines
GROUP MEDICINES
Group A Levofloxacin OR Moxifloxacin Lfx / MfxBedaquiline BdqLinezolid Lzd
Group B Clofazimine CfzCycloserine OR Terizidone Cs/ Trd
Group C Ethambutol EDelamanid DlmPyrazinamide ZImipenem-cilastatin OR Meropenem Ipm-Cln / MpmAmikacin (OR Streptomycin) Am (S)Ethionamide OR Prothionamide Eto / Ptop-aminosalicylic acid PAS
Longer MDR-TB regimensRevised classification of component medicines
Longer MDR-TB regimensComposition
• All three most effective medicines from Group A ( Lfx or Mfx; Bdq, Lzd) are strongly recommended for all patients
Relative risk for (i) treatment failure or relapse and (ii) death (versus treatment success), 2018 IPD-MA for longer MDR-TB regimens
Group A Treatment failure or relapse vs. treatment
success
Death vs. treatment success
Number treated
Adjusted OR
(95% CI)
Number treated
Adjusted OR
(95% CI)
Levofloxacin ORmoxifloxacin
3,143 0.3 (0.1-0.5) 3,551 0.2 (0.1-0.3)
Bedaquiline* 1,391 0.3 (0.2-0.4) 1,480 0.2 (0.2-0.3)
Linezolid 1,216 0.3 (0.2-0.5) 1,286 0.3 (0.2-0.3)
- Bdq for patients > 18 yrs (Strong recommendation) - Bdq may also be included in for patients aged 6-17 yrs
Longer MDR-TB regimensComposition
• Add one or both medicines from Group B
Relative risk for (i) treatment failure or relapse and (ii) death (versus treatment success), 2018 IPD-MA for longer MDR-TB regimens
Group B Treatment failure or relapse vs. treatment success
Death vs. treatment success
Number treated
Adjusted OR
(95% CI)
Number treated
Adjusted OR
(95% CI)
Clofazimine 991 0.3 (0.2-0.5) 1,096 0.4 (0.3-0.6)Cycloserine ORterizidone
5,483 0.6 (0.4-0.9) 6,160 0.6 (0.5-0.8)
Longer MDR-TB regimens
Relative risk for (i) treatment failure or relapse and (ii) death (versus treatment success), 2018 IPD-MA for longer MDR-TB regimens and delamanid Trial 213 (intent-to-treat population)Group C Treatment failure or
relapse vs. treatment success
Death vs. treatment success
Number treated
Adjusted OR
(95% CI)
Number treated
Adjusted OR
(95% CI)
Ethambutol 1,163 0.4 (0.1-1.0) 1,245 0.5 (0.1-1.7)Delamanid 289 1.1 (0.4-2.8)* 290 1.2 (0.5-3.0)*
Pyrazinamide 1,248 2.7 (0.7-10.9) 1,272 1.2 (0.1-15.7)Imp-cln OR meropenem 206 0.4 (0.2-0.7) 204 0.2 (0.1-0.5)Amikacin 635 0.3 (0.1-0.8) 727 0.7 (0.4-1.2)Streptomycin 226 0.5 (0.1-2.1) 238 0.1 (0.0-0.4)Ethionamide ORprothionamide
2,582 1.6 (0.5-5.5) 2,750 2.0 (0.8-5.3)
p-aminosalicylic acid 1,564 3.1 (1.1-8.9) 1,609 1.0 (0.6-1.6)
* unadjusted risk ratios as defined by the study investigators of Trial 213 by month 24
Composition• Add to complete the regimens and when medicines
from group A or B cannot be used
Longer MDR-TB regimens
Relative risk for (i) treatment failure or relapse and (ii) death (versus treatment success), 2018 IPD-MA for longer MDR-TB regimens
Other medicines Treatment failure or relapse vs. treatment
success
Death vs. treatment success
Number treated
Adjusted OR
(95% CI)
Number treated
Adjusted OR
(95% CI)
Kanamycin 2,946 1.9 (1.0-3.4) 3,269 1.1 (0.5-2.1)Capreomycin 777 2.0 (1.1-3.5) 826 1.4 (0.7-2.8)Amoxicillin-clavulanic acid 492 1.7 (1.0-3.0) 534 2.2 (1.3-3.6)
• Kanamycin and Capreomycin linked to pooreroutcomes in IPD meta-analysis and no longerrecommended
Composition
Longer MDR-TB regimensRegimen composition
Choice of medicines depends upon the • expected balance of effectiveness and harms• preference for oral over injectable agents• the results of drug-susceptibility testing (DST)• reliability of DST methods• population drug resistance levels• history of previous use of medicine in a patient• drug tolerability• potential drug-drug interactions
Longer MDR-TB regimensSerious adverse events (SAEs) in patients on longer MDR-TB regimens
Medicine Absolute risk of AEMedian % 95% credible
intervalBedaquiline 2.4% [0.7, 7.6]Moxifloxacin 2.9% [1.4, 5.6]Amoxycillin-Clavulanic acid 3.0% [1.5, 5.8]Clofazimine 3.6% [1.3, 8.6]Ethambutol 4.0% [2.4, 6.8]Levofloxacin 4.1% [1.9, 8.8]Streptomycin 4.5% [2.3, 8.8]Cycloserine / terizidone 7.8% [5.8, 10.9]Capreomycin 8.4% [5.7, 12.2]Pyrazinamide 8.8% [5.6, 13.2]Ethionamide / prothionamide 9.5% [6.5, 14.5]Amikacin 10.3% [6.6, 17.0]Kanamycin 10.8% [7.2, 16.1]p-aminosalicylic acid 14.3% [10.1, 20.7]Thioacetazone 14.6% [4.9, 37.6]Linezolid 17.2% [10.1, 27.0]
Longer MDR-TB regimensNumber of agents
• All three Group A agents and at least one Group B agent should be included to
ensure that treatment starts with:
➢ at least four TB agents likely to be effective and
➢ at least three agents are included for the rest of treatment
Number of likely effective agents*
Treatment failure or relapse vs. treatment
success
Death vs. treatment success
Adjusted OR (95% CI) Adjusted OR (95% CI)
IP
4 vs 5 1.0 (0.7-1.3) 1.1 (0.9-1.5)6 vs 5 1.0 (0.6-1.7) 0.9 (0.6-1.3)2 vs 1 highly effective agent* 0.9 (0.5-1.6) 0.6 (0.3-0.96)>2 vs 1 highly effective agent* 0.6 (0.2-1.8) 0.4 (0.2-1.01)
CP
2 vs 3 1.3 (0.8-2.1) 1.3 (0.8-2.0)4 vs 3 1.2 (0.9-1.5) 1.0 (0.8-1.3)>1 vs 1 highly effective agent* 0.5 (0.1-1.7) 0.8 (0.2-2.5)
* Highly effective agent = Lfx, Mfx, Gfx (if DST=susceptible) and Lzd, Bdq, Imp-Cln, Mpm (unless resistance documented)
• The optimal duration of Bdq, Dlm and Lzd is not known. Use of Bdq & Dlm beyond 6 months still considered “off label”
• Amx-Clv to be used only with Imp-Cln or Mpm and do not count as a separate effective agent
• Eto/Pto and PAS only proposed for regimens which do not contain Bdq, Lzd, Cfz or Dlm (or very last resort)
• Delamanid may be included in the treatment of MDR/RR-TB patients aged 3 years or more
Longer MDR-TB regimens
Longer MDR-TB regimensDuration & bacteriological monitoring
Regimen duration (conditional upon response)
• Total length = 18-20 months
• Time after conversion = 15-17 months
• Injectable phase (if applicable) = 6-7 months
Monitoring patient response
In MDR/RR-TB patients on longer regimens:
✓ Sputum culture in addition to sputum smearmicroscopy is recommended to monitor treatmentresponse (Strong recommendation)
✓ It is desirable for sputum culture to be repeated atmonthly intervals
▪ Other important markers of treatment response:- patients general condition- weight gain over time- results of other texts and etc
Duration & bacteriological monitoring
Shorter MDR-TB regimen
Stud
y resu
lts
STREAM Stage 1 trial: In patients eligible for STR, the likelihood of tr. success was close to 80% in both arms
Observational studies: A comparable likelihood of tr. success with longer regimens overall
Higher risk of failure or relapse in the STR, especially when resistance was present or when Group A agents were included in longer regimens.
The shorter regimen had a lower risk of treatment interruption
• Preference by the clinician and patient for a longer MDR-TB regimen• Confirmed resistance or suspected ineffectiveness to a medicine in the shorter MDR-TB regimen (except isoniazid resistance)• Exposure to one or more 2nd line medicines in the shorter MDR-TB regimen for >1 month (unless susceptibility to these 2nd line medicines is confirmed)• Intolerance to medicines in the shorter MDR-TB regimen or risk of toxicity (e.g. drug-drug interactions)• Pregnancy• Disseminated, meningeal or central nervous system TB• Any extrapulmonary disease in PLHIV• One or more medicines in the shorter MDR-TB regimen not available
YESFAILING SHORTER REGIMEN or NON-RESPONSE,
DRUG INTOLERANCE, EMERGENCE OF ANY OTHER EXCLUSION CRITERION
Standardized, shorter MDR-TB regimen
may be offered(conditional recommendation)
NO
New, individualized longer MDR-TB
regimens
Shorter MDR-TB regimenTighter criteria, different landscape
• Programmes already implementing the shorter MDR-TB regimen with good results and capacity to monitor for ototoxicity • switch from Km to Am• while Km is used close follow-up for non-response to
treatment or early relapse• lower the threshold to switch non responders to a new
longer regimen
• Programmes planning to offer the shorter regimen to newly-diagnosed patients to continue only if they have DST capacity to exclude at least FQ and SLI resistance
• Programmes considering modified shorter regimens (e.g. replacing injectable with BDQ) can do so as operational research
Shorter MDR-TB regimen (2)Implications for future use
Longer MDR-TB regimensImplementation considerations
❑ Fully oral regimen is possible and should become preferred option for most patients
❑ Access to rapid diagnostic tests, and DST remains crucial for the better choice of treatment regimen
❑ All recommended agents are available via the GDF❑ Kanamycin and capreomycin are no longer recommended
to use❑ Amikacin and streptomycin lower down in priority
ranking (if audiometry possible)
Modified Shorter MDR-TB regimenImplementing under operational research
• The following steps recommended:– Develop appropriate protocol:
• Specifying the eligibility criteria, regimen composition, monitoring schedules etc.
– Approval by a national ethics review committee:
• Protocol should be approved ahead of any patient enrolment.
– Treatment delivery under WHO-recommended standards:
• informed consent; adherence to principles of good clinical practice; aDSM; and regular patient monitoring to assess regimen effectiveness.
– May solicit WHO advice prior to initiating operational research for modified shorter regimens.
,,Systematically
assessing and
addressing the
needs and
expectations of
patients who should
be provided with
emotional,
educational and
economic support
based on their
needs’’
END TB Strategy Pillar 1 : integrated, patient-centered care and prevention
80% treatment success is reachable
when a properly designed MDR-TB
regimen is delivered with a patient-
centred care approach
Health education and counselling on thedisease and treatment adherence should beprovided to patients on TB treatment
(Strong recommendation, moderatecertainty of evidence)
Recommendation 1
Information and education
A package of treatment adherence interventions may be offered for patients on TB treatment in conjunction with the selection of a suitable treatment administration optionRemarks:
• Treatment adherence interventions include social support, communication with patient, medication monitor, and staff education.
• Treatment administration options include DOT, VOT, non-daily DOT (e.g. not every dose supervised treatment, weekly or a few times per week supervision), or unsupervised treatment).
• The interventions should be selected on the basis of the assessment of individual patient's needs, provider's resources and conditions for implementation.
Recommendation 2
Treatment adherence package
One or more of the following treatment adherence interventions may be offered to patients on TB treatment or to health-care providers:• material support to patient (e.g. meals, food baskets, food supplements, food vouchers,
transport subsidies, living allowance, housing incentives, or financial bonus)
• psychological support to patient (e.g. counselling sessions or peer-group support)
• tracers (e.g. telephone calls, SMS or home visit) or digital medication monitor
• staff education (adherence education, chart or visual reminder, educational tools and desktop
aids for decision-making and reminder)
Recommendation 3
Treatment adherence interventions
The following treatment administration optionsmay be offered to patients on TB treatment:
Recommendation 4Treatment administration options
TREATMENT ADMINISTRATION OPTIONS
Community- or home-based directly observed treatment (DOT) is
recommended over health facility-based DOT or unsupervised
treatment
DOT administered by trained lay providers or health-care workers is
recommended over DOT administered by family members or
unsupervised treatment .
Video supported treatment (VOT) may replace DOT when the
technology and internet provision are available and can be operated
by health-care providers and patients
Treatment principles (1)
• Ahead of enrolment on MDR-TB treatment, all patients should receive appropriate counselling to enable informed and participatory decision-making.
• Patient information material needs to reflect the new changes so that patients are appropriately informed about their treatment options.
See Companion handbook for more details on patient-centred carehttps://apps.who.int/iris/bitstream/handle/10665/130918/9789241548809_eng.pdf
Treatment principles (2)• Social support to enable
adherence to treatment is very important to ensure a patient-centred approach to the delivery of care.
• Active TB drug safety monitoring and management (aDSM) is essential for all patients enrolled on MDR-TB treatment.
Overall, the following principles can be
followed for patient-centred care and support:
1. Develop a treatment partnership with your patient and ensure that he or she is aware of rights and responsibilities
regarding TB treatment and care.
2. Focus on your patient’s concerns and priorities.
3. Use the 5 A’s: Assess, Advise, Agree, Assist and Arrange
4. Link the patient with a DOT provider for MDR-TB regimens (also called a drug-resistant TB treatment supporter).
5. Support patient self-management, as it relates to personal care and needs.
6. Organize proactive follow-up care.
7. Involve expert patients, peer educators and support staff in your health facility.
8. Link the patient to community-based resources and support and to the government social protection scheme for
which the patient is eligible according to local law.
9. Use written information – registers, treatment plans, treatment cards and written information for patients – for
documenting, monitoring and reminding.
10. Work as a team with the patient.
11. Assure continuity of care.
▪ Patient-centered care
is the heart of the
management of TB
▪ Patient support guidelines
are an essential
component of MDR TB
management
WHO recommends countries to rapidly adjust theirnational treatment policies, drug procurement plansand monitoring systems to quickly switch MDR-TBpatients to the new priority medicines and expresses astrong desirability to have a fully oral treatment.
Regimens that deviate significantly from thoserecommended may be investigated under operationalresearch conditions, making sure that the patient’s bestinterest are served, collecting data of use for futurepolicy updates.
Key messages for country implementation
Acknowledgements (non exhaustive)Guideline Development Group (GDG 2018): Holger Schünemann (Chair), Geraint (Rhys) Davies (Co-chair), Eden Abadiano Mariano, Susan Abdel Rahman, Sarabjit S Chadha, Daniela Cirillo, Fernanda Dockhorn Costa Johansen, Bernard Fourie, Edwin Herrera-Flores, Ayuko Hirai, Alexander Kay, Rafael Laniado-laborin, Lawrence Mbuagbaw, Payam Nahid, Austin Arinze Obiefuna, Cristina Popa, Wipa Reechaipichitkul, Maria Rodriguez, Adman Skirry Shabangu, Sabira Tahseen, Carrie Tudor, Zarir Udwadia, Andrew Vernon.
Evidence reviewers: McGill University (Canada) - Richard (Dick) Menzies, Zhiyi Lan, Jonathon Campbell, Faiz Ahmad Khan, Syed Abidi
External Review Group (ERG): Essam Elmoghazi, Mildred Fernando-Pancho, Anna Marie Celina Garfin, Barend (Ben) Marais, Andrei Maryandyshev, Alberto Matteelli, Giovanni Battista Migliori, Thato Mosidi, Nguyen Viet Nhung, Rohit Sarin, Welile Sikhondze, Ivan SOLOVIC, Pedro Suarez, Carlos Torres
WHO Guideline Steering Group: Nicola Cocco, Dennis Falzon, Giuliano Gargioni, Chris Gilpin, LicéGonzalez-Angulo, Malgorzata Grzemska, Ernesto Jaramillo, Alexei Korobitsyn, Corinne Merle, Lorenzo Moja, Fuad Mirzayev, Piero Luigi Olliaro, Andreas Alois Reis, Satvinder Singh, Karin Weyer, Matteo Zignol
WHO rapporteur: Kerri Viney
WHO Guideline Review Committee (GRC): Nathan Ford, Susan Norris
Acknowledgements (non exhaustive)Observers: Charles Daley, Kelly Dooley, Gregory Kearns, Anneke Hesseling, Gary Maartens, Norbert Ndjeka, Michael Rich, H Simon Schaaf, Valérie Schwoebel, Shenjie Tang, Ye Tun, Kitty Van Weezenbeek, Francis Varaine, Irina Vasilyeva, Draurio Barreira Cravo Neto, Edward M Cox, Jennifer Furin, Brian Kaiser, Lindsay McKenna, Yadiul Mukadi, Eric Pelfrene, Anna Scardigli
Trial / study data: Challenge TB (Gunta Draviciene, Mavluda Makhmudova, Yulia Aleshkina); EndTBProject (Carole Mitnick, Michael Rich, Francis Varaine); Johnson & Johnson Services, Inc. (Tine De Marez, Chrispin Kambili); Otsuka (Marc Destito, Lawrence Geiter, Rajesh Gupta, Jeffery Hafkin, Keiso Yamasaki); STREAM Trial (Sarah Meredith, Andrew Nunn, Patrick Phillips, Ira D. Rusen); UNION (Antonio Piubello, Valérie Schwoebel, Arnaud Trébucq)
Observational data (surname of first authors for IPD 2018): Ahmad, Ahuja, Anderson, Bang, Barkane, Barry, Bonnet, Brode, Brust, Cegielski, Chan, Dheda, Fox, Gegia, Guglielmetti, Hughes, Isaakidis, Kempker, Koenig, Koh, Kvasnovsky, Lange, Laniado-Laborin, Leung, Marks, Migliori, Milanov, Ndjeka, O’Donnell, Palmero, Podewils, Riekstina, Rodrigues, Seo, Seung, Shim, Singla, Skrahina, Smith, Udwadia, van der Werf, Vasilyeva, Viiklepp, Yim
Funding: Russian Govt; USAID; support of ATS/CDC/IDSA and the European Respiratory Society and the Canadian Institutes of Health Research for compilation of earlier studies of the IPD 2018
WHO Regional and country offices
Many patients and national TB programmes