mdr-tb a curable disease

8/14/2019 MDR-TB A Curable Disease

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The Threat and the Challenge of MDR-TB

A Curable Disease with a Proper Clinical and Operationa

Management

Prof. Jos A. CamineroLuna

Department of Pneumonology

University Hospital of Gran Canaria Dr. Negrn

Las Palmas de G.C. SPAIN

MDR-TB Unit Coordinator. The Union. France

44th Union World Conference

Paris, France, October 13, 2013


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Tuberculos isis certainly the

disease that has p rovoked

the mos t damage (diseases

and deaths ) to mankind

throughou t his tory . It has

caused death and disease foperhaps more than 3 m il lion

yearsand , as a ru le, has

affected the poorest strata ofsociety

J.A. Caminero. Eur Respir J 2004, 25: 895


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Amenoph is IV

and

Nefert i t i

(Deceased TB)

1360 b. c.


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Simn Bo lvar (1783-1830)Liberator of the Am ericas. Died of TB after a long i l lness


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Mycobacter ium tuberculos is

It is probably the infect ious agent that has

caused the greatest number of Deaths in

the History o f Humani ty

Today i t is st i l l considered as the 2nd

Greatest Murderer, ou t of all s ing lePathogens


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Fate of TB patients Without Treatment.

Ind ia 1961-68

2

3

4

5

6

Cured Positives Dead

* Grzybowski S, Enarson DA Bull Int Union Tuberc Lung Dis 1978;53(2):70-5.

%

TB Smear +

TB Smear -

*

*

*


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Two Genius of the Medic ine: Waskman and Flem ing


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Dr. Selman A. Waksman

- Discovered STREPTOMYCIN in 1943

- Together with his laboratory assistant A. Schatz


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Ma Z, Lienhard C. Clin Chest Med 30 (2009) 755768


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INH-PAS-SM


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ANTIMYCOBACTERIAL DRUGS

1. ISONIAZID 2. RIFAMPICIN3. PYRAZINAMIDE 4. ETHAMBUTOL

5. STREPTOMYCIN 6. CAPREOMYCINE

7. KANAMYCIN 8. AMIKACIN

9. ETHION.PROTHIONAMIDE 10. CYCLOSERINE-TER11. P.A.S. 12. THIACETAZONE

13. QUINOLONES: 14. CLOFAZIMIDE

- OFLOXACIN 15. Others:- LEVOFLOX. - GATIFLOXACIN - MOXIFLOX - MACROLIDES, CLAVULANATE., E

AT LEAST 4 FOR GOOD RETREATMENT!


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TB An INCURABLE

d isease ?

The Threatand the Fear o

MDR/XDR- TB


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It may affect over 10 million people world-wide

JAMA (2000)

MDR Tuberculosis A global pandemic BMJ (199

MDR a time bomb Am Rev Respir Dis (1985)

The Threato f MDR-TB?

Once liberated, it will be impossible to control...

WHO publicity (1997)

More fatal than AIDS Washington Post (1998)

It may destabilise Russian society NDCF (2000)


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Consequences of MDR/XDR-TB

Poor response to standardised treatment

Long duration of contagiousness

High risk of morbidity and mortality

Individualised treatment more costly

Diff icu l t management --> requ ires special ized Training


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The global TB situation, 2011

Estimated number ofcases, 2011

Estimated number ofdeaths, 2011

990,000*

(840,0001.1 million)

8.7 million

(8.39.0 million)

630,000

(460,000790,000)[of 12m prevalent cases]

All forms of TB

Multidrug-resistant

TB

HIV-associated TB 1.1 million

(1.01.2 million)

430,000(400,000460,000)

Source: WHO Global Tuberculosis Report 2012

* Excluding deaths attributed to HIV


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% of MDR among newTB cases (1994-2011 dat

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning t

status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boun daries. Dotted lines on maps represent approximate border lines for whi

may not yet be full agreement. WHO 2012. All rights reserved

Global average

3.7% (2.1 5.2%)


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% of MDR among previously treated TB cases (1994-2011 data

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of a

country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full

agreement.WHO 2012. All rights reserved

Global average

20% (13 26%)


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- Between November 2009 and December 2010, 156

consecutively diagnosed new and 68 previously treated TB

- MDR-TB was found in 35.3%(95% CI 27.742.8) of new patien

and 76.5%(95% CI 66.186.8) of those previously treated.

- Overall, nearly one in two patients enrolled had MDR-TB.

- Extensively drug-resistant TB was reported in 15 of the 107

MDR-TB patients (14.0%, 95% CI 7.320.7).


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High prevalence of chi ldhoo d mult i -drug resistant tuberculos is in

Johannesburg, South Afr ica: a cross s ect ional study

Lee Fairlie,Natalie C Beylis, Gary Reubenson, David P Moore,and Shabir A Madhi

BMC Infect Dis. 2011; 11: 28.

-1317 children were treated for TB in 2008

- DST was performed in 148 (72.5%) of the 204 children who had culture-confirmed

tuberculosis.

-The prevalence of isoniazid-resistance was 14.2% (n = 21) and the prevalence of

MDR-TB 8.8% (n = 13) (95%CI, 4.8-14.6%).

-The prevalence of HIV co-infection was 52.1%in children with drug

susceptible-TB and 53.9% in children with MDR-TB.

-Ten (76.9%) of the 13 children with MDR-TB received appropriate treatment and

four (30.8%) died at a median of 2.8 months (range 0.1-4.0 months) after

the date of tuberculosis investigation.


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Countries (84) reporting 1 XDR-TB case by Oct 2012


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TB An INCURABLE

d isease ?

The Threatand the Fear o

MDR/XDR- TB


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The Resistan t

M. tuberculos is

day by day is more

RESISTANT


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M tuberculos is vs

Human Specie

The Mil lenn ial Figh t

between 2Species


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Dr. Selman A. Waksman

- Discovered STREPTOMYCIN in 1943

- Together with his laboratory assistant A. Schatz

Mono - Res is tance


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INH-PAS-SM

Poly - Res is tance

M. TB Res is tan t to

2 or more Drugs


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RIFAMPICINA

Disco vered in 1963 by

Lepetit Labo ratories

Mult iDrug-Resistance

(MDR)

M. TB Res is tan t to ,

at least, H+R


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CONCLUSSIONS:

1. Only c ipro f loxac in , of loxac in , levof loxac in , sparf loxac in and

mo xif loxacin have been tested in randomized contro l led tr ia ls for

t reat ing tuberculo sis.

2 . We cannot recommend ciprof loxac in in t reating tubercu los is .

3 . Tr ials of newer f luoroquino lones for t reat ing tubercu los is are neededand are on -going .

4 . No di f ference has been d emonst ra ted between s parfloxac in and

of loxacin in d rug-resistant tuberculos is.

ExtensivelyDrug-Resistance

(XDR)

MDR-TB p lus

Res istance to FQand

1 SLDI(Kn , Ak, Cm)


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Ma Z, Lienhard C. Clin Chest Med 30 (2009) 755768

Already th ere are TB Cases with Resistance to al l these Drug s

Total ly-Drug Resistant (TDR-TB)?


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- In 2007, two patients with strains having resistance to all first and

second-line anti-TB drugs which were tested were reported from

Italy(1)

- In 2009, 15 TB patients in Iranwere reported to be resistant to all

anti-TB drugs tested (2)

- In December 2011, clinicians in Mumbai, India, described four

patients with TDR-TB (3). A few weeks later, the Times of India

reported another eight cases in Mumbai.

Total ly Drug Res istant (T.D.R.TB)

1) Migliori GB, et al. Euro Surveill. 2007 May;12(5):E070517.1

2) Velayati AA, et al. Chest. 2009 Aug;136(2):4205.

3) Udwadia ZF, et al. Clin. Infect. Dis. 2012 Feb 15;54(4):57981.


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1. Mono-Resistance2. Poly-Resistance

3. M.D.R.

4. X.D.R.

5. T.D.R.(Total ly Resistant TB)

The Batt lebetween the Human Species and M. tuberculos

Is DRTB an Incurable Epidemic ?

Notalways!! With adequate Management i t is curable,a lthough the poss ib i l ity of su ccess can decrease

notably


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Ma Z, et al. Lancet 2010; 375: 210009


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Pat ien ts w ith an Extensivepattern of Resistancehas always

exis ted , bu t w ith an Adequate

Cl in ical ManagementandEnough Resources a good Rate

o f Successis Poss ible


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Poss ibi l it ies to CureMDR/XDR-TB

Avai lable Evidence

1. His tor icEvidence (Pre-Rifamp. period )

2. CurrentEvidence

1. MDR-TB Patients (2 Meta-analysis)

2. XDR-TB Patients (1 Systematic Rev. and 1 Meta-analys


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The MDR/XDR-TB patien ts o f1950-70swere those w ith

Res is tance to H+S+PAS (thenthere was no t Rif nor Fq)


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USA. Schwartz Kn-Z-Eth-Cs 6-12 64 57 %JAMA 1962; 181:134

UK. Pines Z-Eth-Cs-Vi-Th 12-24 39 100 %Chest 1962; 53: 163

Morocco. Chicou Kn-Eth-Cs-Vi-P 4-12 31 67,7 %RevTuberc1962;26:867

USA. Kass Kn-Z-Eth-Cs 21-37 98 94,8 %Tubercle1965;46:151-80 E-Cm-Th

Germany. Schtz Eth-Cs-P 6 34 85 %PraxisPneum1964;18:288

Reference Drugs Fol low-up (m) N Cases Sm Con vers ion

Pre-RIFand Pre-Fq EraPatients with Resistance to INH+SMtreated with only 3 Drugs

Caminero JA. Int J Tuberc Lung Dis 2006, 10: 829-8


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Hungary. Bszrmenyi Z-Eth-Cs 3 31 51,6 %Tubercle 1965;46:143

USA. Lester Kn-Z-Eth-Cs- 6-60 146 83.5 %AmRevRespirDis1968;97:392-8

Poland. Zierski Z-Eth-Cs 3-9 65 92,4 %Tubercle 1964;45:96

Czechosl. Tousek Z-Eth-Cs 60-84 55 96 %Tubercle 1967;48:27

Spain. March Z-Eth-Cs-Vi-E 6-18 33 93,4 %RevClinEsp1968;109:117

Reference Drugs Fol low-up (m) N Cases Sm Con vers ion

Pre-RIFand Pre-Fq EraPatients with Resistance to INH+SMtreated with only 3 Drugs



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Poss ibi l it ies to CureMDR/XDR-TB

Avai lable Evidence

1. Histo r ic Evidence (Pre-Rifamp. period )

2. CurrentEvidence

1. MDR-TB Patients (2 Meta-analysis)

2. XDR-TB Patients (1 Systematic Rev. and 1 Meta-analys


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- Systematic search (to December 2008) 36 met inclusion

criteria, representing 31 treatment programmes from

21 Countries

- 62% [95% CI 5767] successfu l outcom es

-13% [917] defaulted

-11% [913] died

-2% [14] were transferred ou t

September 2009


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- 34 cl inical repo rts (mean 250 patients) met th e inclus ion c ri ter ia.

- The prop ort ion o f pat ients treated successfu l ly impro ved when:

- Treatment durat ion was at least 18 month s

- Patients r eceived DOT throu gho ut treatment

- Studies that combined both factors had sign i f icant ly higher pooledsuccess propor t ions (69%)than oth er studies of treatment

outcomes (58%)

-Individual izedtreatment regim ens had high er treatment su ccess (64%)than

standardized regimens (54%), al though the dif ference w as not sign i f icant

-Treatment approach es and stu dy m ethodolo gies were heterogeneous across stu dies.

- Many important variables, including patients HIV status, were inconsistently reported

between stu dies.

MDR-TB Treatment in Children


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- Systematic review and meta-analysis reviewed treatment outcomes for

children with MDR-TB.

- Eight studies, which reported outcomes on 315 patients, contributed to t

database.

- Average duration of treatment ranged from 6 months to 34 ms.

- The pooled estimate for treatment success(defined as a composite of cuand completion) was 81.7%with death in 5.9%, and default in 6.2% of

patients.

- Adverse reactions occurred in 39.1% of the children, the most common o

which were nausea and vomiting followed by hearing loss, psychiatriceffects and hypothyroidism.

Ettehad D, Schaaf HS, Seddon JA, Cooke GS, Ford N. Treatment outcomes for children with multidrug-resistant

tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2012;12:449-56.

MDR TB Treatment in Children


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-Longertreatment duration and delayed sputum smear conversionwere reported in

most studies among XDR-TB patients.

-Median time to sputum Smearconversionranged 4156 days in MDR-TB patient

while it ranged 88110 days in XDR-TB cases.

-The median time to Culture conversionranged 5899 days in MDR-TB cases; it

was substantially different in XDR-TB patients, ranging 60195 days.


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Sotgiu G. Eur Respir J 2009; 33: 871-88

- Very d i f ferent Outcomes


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- 13 observational stu dies covering 560 patients:

- 43.7%(95% CI, 32.8%54.5%) favorable ou tcomes

- 20.8% (95% CI, 14.2%27.3%) Died .

- Studies in wh ich a higher proport io n of pat ients received alater-generat ion f luoroquinolonereported a higher

pro po rt ion o f favo rable treatment ou tcomes (p= .012)


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With each 10% increase in

the proportion of patients

receiving a later-

generationfluoroquinolone, there was

a 4% increase in the

proportion of patients with

favorable outcomes.

Jacobson et al. CID 2010; 51 (Ju


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Patients w ith an Extensivepattern of

Resistancehas always existed, bu t w ithAdequate Clinical Managementand

Enough Resources a good Rate of

Successis Poss ible

The Clinical Managementof MDR orXDR-TB Patien ts is Key

MDR/XDR TB Clinic al Management


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-There are no Clinical Trialscom par ing d i fferent

Regimen and Drugs

-There areon ly personalexperiences and

pub l icat ions show ing very di f ferent resul ts

-The most important Recommendat ions / Guidel ines

have changed in the last decades and

are no t in agreement

-Current ly there are very controvers ia lissues, som et im

wi th no agreement

MDR/XDR-TB Clinic al ManagementMany ControversialIssues to Address


MDR/XDR-TB Clinical Management.


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1. How to appro ach Diagnosiso f MDR? Reliabi l i ty of DS

2. How Many Drugsto Treat MDR-TB ?

3. RationalUse of the FLD and SLD

5. Ro le of Surgeryin MDR-TB Treatmen t

ControversialIssues

4. Leng th o f the Injectable(Intensive phase)

6. Ap proach to the Ideal Regime in MDR-TB

Standardizedvs Individual izedRegim es


M tuberculosis Resistance


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M. tuberculosis Resistance

In TB, drug resistanceis

always the result of poor casemanagementof drug

sensitive tuberculosis cases


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The first priority to fight against

MDR/XDT-TB is to strengthen the

NTPwith a good management of

the susceptible TB


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- 37 studies were inc luded. Inappropr iate treatment regimens

were prescr ibed in 67% of stud ies.

- The percentage of pat ients receiv ing inapprop r iate regimens

varied betw een 0.4% and 100%.

- In 19 studies the qual i ty of treatment regimen report ing was

low


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Even for countries with

unlimited resources, thetime to generatea MDR-

TB case is less than thetime required to cureit

PRIORITIES in a National


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PRIORITIESin a National

Tubercu los is Prog ramme (NTP)

1. To Avo id MDR-TB

4. To Avo id XDR-TB



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1. To Avo id MDR-TB

4. To Avo id XDR-TB


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THE BEST WAY TO AVOID MDR-TB (1)

To Give the best ini t ial treatment when the

patient p resents TB fo r the first t ime.

2 HRZE / 4 HR-Adv isable Daily, at least in the Intensive Phase, bu t preferable along al

the treatment

-EMB(or Intensive Phase) along all the treatment if Smear +at the end

of th e 2 month, or u nt i l kn ow ing Suscept ib i l i ty H+R


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Direct ly Observed

Treatmentisfundamental to

prevent Resistance

emergence

THE BEST WAY TO AVOID MDR-TB (2)



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1. To Avo id MDR-TB

4. To Avo id XDR-TB

THE BEST WAY TO AVOID XDR TB (1)


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THE BEST WAY TO AVOID XDR-TB (1)

- Select ion of th e Best SLD Regimen according the

Class if icat ion of the MDR-TB (New, never receiv ing previous lySLD and receiv ing previous ly SLD)

- To support in the select ion of this Regimen is essent ia

to know the poss ib le Resistance to Fq+SLDI in MDR-TB

- Survei l lanceto address the best SLD Regimen

- Genotype SLD in al l the MDR-TB patients p reviou s to s tarthe SLD Regimen

THE BEST WAY TO AVOID XDR TB (2)


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Direct ly Observed

Treatmentisfundamental to

prevent Resistance

emergence

THE BEST WAY TO AVOID XDR-TB (2)

Conclusions


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1. MDR/XDR-TB is a global threatand a world challenge

2. With adequate clinical and operational management, all the TB

cases has a chance to be cured, even those with very extensive

pattern of resistance

3. The first priority to fight against MDR/XDT-TB is to strengthen

the NTPwith a good management of the susceptible TB

mdr-tb a curable disease

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