April 11, 2012 Dick Menzies, MD Montreal Chest Institute, McGill University

MDR-TB, XDR-TB, and TDR-TB. Is this April 11, 2012 Dick Menzies, MD Montreal Chest Institute, McGill University MDR XDR TDR What s in a name? Dr Dick Menzies Le Chest (McGill, Montreal) 1

Disclaimer I have no financial conflicts of interest (sadly) Global TB Impact The World Health Organization estimates that: 1.6 million TB deaths. 8.8 million cases of new TB. 20 million persons living with active TB. 2 billion persons with latent or dormant infection. 200 million will develop active TB over next 20 years 2

Recent trends in Global TB: Global incidence increased rapidly in 1990 s Then by 0.4% annually 2000-2004 Now has levelled off or slight decline Globally number of cases still increasing slightly or levelled off High-income countries: Decreasing rates Former Soviet Union From 1990 until 2002 increased 12% / year Sub-Saharan Africa 1990-2004 Increasing 6% / year How much drug resistance is there? And how does this develop? 3

Rate of spontaneous mutations to different anti-tb drugs (From in-vitro experiments) Streptomycin 10-6 Isoniazid 10-6 -10-7 Rifampicin 10-8 -10-9 Ethambutol 10-7 -10-8 INH&Rif 10-14 4

Number of bacilli by clinical extent of disease Extent Quantity State Granuloma 103 latent TB Infiltrates 10 6- -107 AFB Neg Culture Pos Cavity 10 8-109 AFB +, ++ Many cavities, 10 10-1012 +++ Death 1013 rigor mortis Probability that resistance will develop by number of bacilli and of drugs Medication Quantity of Bacilli 10 6 10 8 10 10 10 12 Strep solo 50% 100% 100% 100% INH solo 10% 90% 100% 100% RIF solo 0% 10% 90% 100% INH&RIF 0% 0% 0% 10% 5

Treatment with Streptomycin alone, or PAS alone % Patients with resistance - Days after Tx started Source: Rieder, Interventions for TB control, IUATLD. Treating TB with one drug Improvement then worsening the fall and rise phenomenon Source: Toman Case Finding and Chemotherapy 6

Transient drug resistance during therapy with two or more drugs (effect of default) From Toman, Case Finding and Chemotherapy 13 Emergence of Drug resistance Single drug therapy inevitably leads to resistance Even two-drug therapy will often lead to resistance Irregular therapy also leads to selection of resistant strains: Low dose therapy will lead to DR All conditions are common in many countries Low quality drugs Inadequate regimens prescribed Patients have to buy meds = irregular and mono Poor follow-up = interrupted therapy (often many times) 7

TB treatment and Drug resistance a short history 1943 Streptomycin found to be active against M tuberculosis 1944 First clinical experience - Rapid improvement, but rapid development of resistance 1945-1970 15 new TB drugs developed, tested, and introduced. Concept of multi-drug therapy 1970 RIF introduced most effective TB drug MDR = Res to INH& RIF recognized in 1990 1971-2007 1 new TB drug developed, tested and introduced (FQN) Part 1 - MDR-TB 8

MDR-TB definition Resistance to INH and RIF Most effective and well tolerated TB drugs Before RIF was available, TB therapy was 18-24 months So given lack of new drugs Have to go back to the old drugs MDR-TB treatment Prolonged current minimum is 18 months Unpleasant current minimum is 6 months of injectable Toxic use second line drugs many more adverse effects Ineffective Cure rates 50-60% in 3 recent reviews 9

MDR treatment controversies Duration How long to treat? 12 months vs 18 vs 24 months Injectable 3-4 months vs 6 months or longer How many drugs? 3 vs 4 vs 5? Which drugs? Which injectable? 10

MDR treatment the evidence There are NO randomized trials Many cohorts with different approaches, populations and results Local experience shapes expert opinions And experience varies widely In the absence of evidence opinions get stronger First try: Classic meta-analysis of studies of MDR-TB treatment Three were completed in 2009-10 All based on observational studies Most cohorts received individualized therapy This made pooling of results difficult 11

Traditional systematic review in MDR-TB Characteristics and outcomes Variable Cohorts Default/ N treated Pooled default Estimate 95% CI % Female 0-28% 20 350/ 1878 19 14-25 28-36% 20 711/2511 19 15-23 36-100% 19 632/ 2639 21 15-27 Not reported 5 97/ 1018 9 2-15 Traditional systematic review in MDR-TB History and outcomes % prior treatment Cohorts Default/ N treated Pooled default Estimate 95% CI 0 33% 7 271/ 1170 16 9-22 33 67% 15 310/ 1378 21 14-29 67 100% 36 1140/ 4956 17 14-21 Not reported 6 69/ 542 26 18-33 12

Traditional systematic review in MDR-TB Treatment and outcomes % receiving fluoroquinolones Cohorts Death/ N treated Pooled death Estimate 95% CI 0 48% 12 92/ 1006 8 4-11 48 97% 12 286/ 1747 17 9-25 97% - 100% 10 128/ 1423 9 6-12 Not reported 22 475/ 3207 16 13-20 Problems of traditional systematic reviews in MDR-TB Treatment is individualized - in most series, and most patients. Patients are very different in same centre, and between centres Clinical characteristics (history, age, HIV) Drug resistance Hence can only analyze % with resistance, or % getting Drug X Can only detect very large effects 13

Second try: Individual Patient data meta-analysis Background Study initiated in response to WHO desire to update MDR treatment Expert group consulted to list the most important questions in MDR treatment 14

IPD Objectives Which are the most (and least) effective drugs for MDR-TB treatment? What is the optimal number of drugs? Overall (total) Intensive phase What is the optimal duration of treatment? Initial intensive phase (duration of Injectable) Total duration Methods 15

Study (data-set) Selection Study Eligible if: Included in one of 3 systematic reviews of MDR treatment Johnston (published 2009) Orenstein (published 2009) Akcakir (McGill MSc thesis, completed 2009) Inclusion criteria of these 3 reviews: Report of original data, published since 1970 At least one reported treatment outcome that conformed with established definitions for success, failure, relapse, death, or default All patients had bacteriological confirmation of TB, and confirmed INH and RIF resistance Studies excluded if only XDR-TB patients Data Collection Patient-level information Patient factors Treatment outcomes Age at time of diagnosis Sex HIV infection ART use Clinical factors Site of disease AFB smear results Culture results Chest X-ray (cavitations) Drug Sensitivity Testing (DST) - Initial & repeat First line DST results Second line DST results Treatment Factors Initial phase treatment regimen (drugs and duration) Continuation phase treatment regimen (drugs and duration) Modifications to treatment (in response to DST, or AE) Adverse events Surgical resection 16

Data Management Mapped and renamed original variables to common set of variables for pooled metaanalysis dataset Individual data dictionaries Completed variable extraction forms Authors contacted for missing data, clarify variables, verify certain results. Summary tables of clinical characteristics of the study population in each study compared with original publications Variables provided in few data sets were noted, but not analysed. Meta-analysis Random effects logistic regression to obtain the odds of cure for each drug - in all patients and among patients with MTB that was sensitive to drug of interest Multivariate approach: Pooled estimates calculated using PROC GLIMMIX in SAS a random effects logistic regression model Covariates: Age, Gender, HIV, Extent of disease (AFB smear/cxr cavities), and Past TB treatment (none, previous TB treatment, previous MDR-TB treatment) Heterogeneity examined using Forest plots, I 2, and τ 2 statistics 17

3 Systematic reviews identified Orenstein, Johnston, Akcakir 93 studies identified from 3 systematic reviews 67 individual cohorts 32 data sets included in this analysis, with 9898 patients Study Selection Excluded: 26 publications representing the same or overlapping cohorts Excluded - 35 cohorts 13 No author response 8 No longer have access to data 5 Inadequate outcome data 2 Refusals 2 No response following initial contact 2 No data on drug sensitivity testing 2 Data never sent 1 Cohort with less than 25 patients 9153 patients analyzed Excluded Patients 410 - XDR TB 127 - Extra-pulmonary TB 208 - No treatment info Patient Characteristics full data set 6742 (68%) male patients 6283 (63%) prior TB treatment 1193 (12%) HIV co-infection at MDR-TB diagnosis 16 patients received ART 9200 (93%) pulmonary TB 6425 (65%) AFB smear-positive 5081 (51%) cavitations on chest x-ray 18

Overall Treatment Outcomes Cure/completed - 4943 (54%) Failure - 746 (7%) Relapse - 90 (1%) (but only 11/32 (34%) studies reported) Death - 1614 (16%) Default - 2181 (22%) Which drugs? Drug-by-drug analysis First Line Agents Injectables Fluoro-Quinolones Group 4 Drugs Group 5 drugs 19

First Line Agents Pyrazinamide had minimal impact of borderline statistical significance for one outcome Ethambutol had no significant effects on any outcome First line drug vs. no first line drug Success vs. Fail/Relapse aor (95% CI) Success vs. Fail/Relapse/Death aor (95% CI) Success vs. Fail/Relapse/ Death/Default OR (95% CI) Pyrazinamide 1.2 (0.9, 1.7) 1.3 (1.1, 1.6) 1.1 (0.9, 1.4) Ethambutol 0.9 (0.7, 1.1) 0.8 (0.7, 1.0) 0.9 (0.8, 1.2) Injectables Kanamycin / Amikacin Capreomycin 20

Kanamycin only vs. Capreomycin only Kanamycin only Capreomycin only Total Cured 2572 733 Success vs. Fail/Relapse N 2884 841 Unadjusted 1.0 (ref) 0.5 (0.3, 0.7) Adjusted -- 0.5 (0.3, 0.7) Success vs. Fail/Relapse/Death N 3467 1018 Unadjusted 1.0 (ref) 0.5 (0.4, 0.7) Adjusted -- 0.6 (0.4, 0.8) Success vs. Fail/Relapse/Death/Default N 4495 1211 Unadjusted 1.0 (ref) 0.7 (0.6, 0.8) Adjusted -- 0.8 (0.6, 0.9) Kanamycin only vs. Capreomycin only In Kanamycin Sensitive* strains only Kanamycin only Capreomycin only Total Cured 2434 271 Success vs. Fail/Relapse N 2712 297 Unadjusted 1.0 (ref) 0.6 (0.4, 1.1) Adjusted -- 0.6 (0.3, 1.1) Success vs. Fail/Relapse/Death N 3267 349 Unadjusted 1.0 (ref) 0.7 (0.5, 0.96) Adjusted -- 0.8 (0.5, 1.1) Success vs. Fail/Relapse/Death/Default N 4247 425 Unadjusted 1.0 (ref) 0.7 (0.5, 0.9) Adjusted -- 0.8 (0.6, 1.05) *if patient missing Kanamycin DST result and < 10% fellow cohort members resistant, then imputed that patient was sensitive to Kanamycin 21

Kanamycin only vs. Capreomycin only, among only Kanamycin resistant patients Kanamycin only Capreomycin only Total Cured 48 405 Success vs. Fail/Relapse N 74 485 Unadjusted 1.0 (ref) 2.7 (1.6. 4.7) Adjusted 2.3 (1.2. 4.3) Success vs. Fail/Relapse/Death N 87 578 Unadjusted 1.0 (ref) 1.5 (0.8, 3.0) Adjusted -- 1.5 (0.8, 3.2) Success vs. Fail/Relapse/Death/Default N 114 678 Unadjusted 1.0 (ref) 1.6 (0.9, 2.8) Adjusted -- 1.6 (0.9, 2.9) Fluoro-quinolones Ofloxacin Later generation (Moxifloxacin, and Levofloxacin 22

Fluoro-Quinolones (FQ) Ofloxacin, Ciprofloxacin, and higher generation FQ were all superior to no FQ among FQ-sensitive patients FQ vs. no FQ Success vs. Fail/Relapse OR (95% CI) Success vs. Fail/Relapse/ Death OR (95% CI) Success vs. Fail/Relapse/ Death/Default OR (95% CI) Ofloxacin 2.5 (1.6, 3.9) 2.3 (1.4, 3.8) 2.0 (1.2, 3.3) High Quinolone 2.5 (1.6, 3.9) 2.7 (1.7, 4.3) 3.1 (2.0, 4.8) Fluoro-Quinolones (FQ) Higher generation FQs performed better than Ofloxacin across all 3 outcomes High FQ vs. Ofloxacin Success vs. Fail/Relapse OR (95% CI) Success vs. Fail/Relapse/Death OR (95% CI) Success vs. Fail/Relapse/ Death/Default OR (95% CI) 1.7 (1.1, 2.7) 2.0 (1.4, 3.1) 1.9 (1.3, 2.6) 23

Group 4 drugs PAS Cycloserine Ethionamide/Prothionamide Group 4 Drugs Ethionamide/Prothionamide was the most effective drug Cycloserine showed borderline effectiveness for one of the three outcomes Group 4 drug vs. no Group 4 drug Success vs. Fail/Relapse OR (95% CI) Success vs. Fail/Relapse/ Death OR (95% CI) Success vs. Fail/Relapse/ Death/Default OR (95% CI) Ethionamide/ 1.7 (1.3, 2.3) 1.7 (1.4, 2.1) 1.7 (1.5, 2.0) Prothionamide Cycloserine 1.1 (0.8, 1.7) 1.5 (1.0, 2.3) 1.5 (0.9, 2.2) PAS 0.9 (0.6, 1.4) 1.0 (0.8, 1.3) 1.1 (1.0, 1.4) 24

Group 5 drugs Clofazimine Thiacetazone Clarithromycin (or other Macrolides) Amoxy-Clavulanate Number of drugs and Duration Initial intensive phase (injectables) Continuation phase Total therapy 25

Effect of number of susceptible drugs in initial phase on Cure/complete vs fail/relapse I sq: 0 (0, 0.25) N of drugs Total treated Cured Pooled adjusted odds of cure N N N (%) OR (95% CI) 0-3 302 247 (82%) 1.0 Reference 4 470 427 (91%) 2.0 (1.3, 3.2) 5 806 732 (91%) 1.9 (1.2, 3.1) 6-10 809 745 (92%) 2.3 (1.2, 4.3) Effect of number of susceptible drugs in continuation phase on cure/complete vs fail/relapse I sq: 0 (0, 0.38) N of drugs Total treated Cured Pooled adjusted odds of cure N N N (%) OR (95% CI) 0-2 272 219 81% 1.0 reference 3 557 518 93% 2.5 (1.6, 3.8) 4 596 554 93% 2.7 (1.6, 4.4) 5-8 557 506 91% 1.9 (1.0, 3.7) 26

Duration of Initial Phase and Success vs. Fail/Relapse (ALL patients) Months N Adjusted Model 1.0 2.4 308 1.0 (reference) 2.5 3.9 1406 1.3 (0.5, 3.2) 4.0 5.4 453 2.3 (1.2, 4.2) 5.5 6.9 344 3.8 (2.0, 7.3) 7.0 8.4 172 4.8 (1.9, 11.8) 8.5 20.0 792 2.1 (1.2, 3.8) Total Duration of therapy and Success vs. Fail/Relapse (All patients) Months N Adjusted Model 6.0 12.4 778 1.0 (reference) 12.5 15.4 419 1.5 (0.6, 3.6) 15.5 18.4 1700 3.6 (1.5, 8.7) 18.5 21.4 655 5.2 (2.0, 11.5) 21.5 24.4 553 4.9 (2.1, 11.5) 24.5 27.4 313 11.7 (4.5, 30.2) 27.5 30.4 160 2.8 (1.0, 7.6) 30.5 36.0 89 1.2 (0.2, 5.8) 27

Conclusions of IPD Current Recommendations* Initial phase 3 6 months Continuation phase 18 24 months 3 5 additional drugs *2008 Emergency Update from WHO IPD Evidence Initial phase 7.1-8.5 months 4 effective drugs Continuation phase 18.6-21.5 months 3 effective drugs FQ especially later FQ Eto/Pto Kanamycin Part 2: XDR Setting: rural South Africa Incidence of TB 1,100 / 100,000 annually Or, 1.1% of total population develops TB each year!! >80% are HIV co-infected All TB drugs available Non-completion very common Outbreak: 80 HIV-TB patients at 1 hospital Same strain of TB = nosocomial outbreak Extensive drug resistance 79/80 die 28

Looking for XDR Definition of XDR = MDR plus resistance to FQ and at least one second line injectable Data- set established to study MDR-TB 9153 patients with MDR-TB 410 found to have XDR!! Cases going back to 1990 s Describing XDR How bad is it? What makes it bad? The FQ resistance The injectables Or both Data set had: 410 with XDR 424 with MDR and FQN resistance 1129 with Second line injectable resistance 29

Clinical characteristics of MDR patients with different resistance patterns. (From simple pooling across all studies) (Percentages are of patients in each group where information was available) XDR MDR- FQR MDR- INJR MDR only 405 424 1129 4776 Prior TB Therapy NONE 16% 19% 24% 20% FLD only 57% 64% 60% 73% SLD (MDR) 27% 17% 16% 7% Resection Surgery 17% 7% 13% 5% Serious AE 32% 43% 47% 29% Overall outcomes by MDR group XDR MDR-FQR MDR-INJR MDR only # of Studies 17 18 22 26 # of Patients 405 424 1129 4776 Pooled Outcomes Meta- analysis by study Cured 40% (27, 53) 48% (36, 60) 56% (45, 66) 64% (57, 72) Fail/Relapse 22% (15, 28) 18% (14, 21) 12% (9, 15) 4% (2, 6) Died 15% (8, 23) 11% (3, 19) 8% (3, 14) 8% (5, 11) Surgery 16% (8, 24) 12% (1,23) 16% (7, 24) 18% (12,24) SAE 7% (0.18) 11% (0.25) 9% (1, 17) 5% (0,10) 30

Number of likely effective drugs during initial phaseand odds of success Number XDR of drugs N aor (95% CI) 0-2 24 1.0 (reference) 3 47 4 46 1.9 (0.8, 4.3) 5 36 1.8 (0.5, 6.6) 6+ 20 4.9 (1.4, 16.6) Number of likely effective drugs during in continuation phase and odds of success Number XDR of drugs N aor (95% CI) 0-2 27 1.0 (reference) 3 32 3.3 (1.3, 8.5) 4 28 6.1 (1.4, 26.3) 5+ 17 2.3 (0.7, 7.6) 31

Impact of duration of Initial treatment on success vs Failure/Relapse Initial Duration XDR Months N aor (95% CI) 1-4.0 55 1.0 (reference) 4.1-6.5 41 6.1 (0.6, 62) 6.6-9.0 37 71.0 (5.2, 200) 9.1-20.0 77 5.1 (1.2, 21) Impact of Total duration of treatment on Odds of success vs Failure/Relapse Initial Duration XDR Months N aor (95% CI) 6.0-15.0 87 1.0 (reference) 15.1-20.0 79 2.0 (0.3,11.7) 20.1-25.0 61 5.5 (1.7, 17.6) 25.1-30.0 21 5.8 (1.3, 25.1) 32

Part 3: TDR Report from India: 6 patients resistant to all known TB drugs Poor outcomes Attracted HUGE media attention Usual doomsday sensationalist stories Bad press for Indian TB programme What is TDR? How to define? Depends on how much you test!! What are the outcomes? What determines prognosis? Resistance to which drugs? How to treat? 33

Looking for TDR Among the 400+ XDR patients there were many with Total Drug Resistance = resistant to all tested. Tried 3 different definitions: TDR1 XDR & resistant to Kana and Cap (and Sm if tested) TDR2 TDR1 & resistant to at least one Group 4 drug TDR3 TDR2 & resistant to EMB and/or PZA Definitions (used for analysis) Study population: 8955 DST for at least 1 FQN and 1 SLI: 6724 XDR: 405 (6% of MDR) TDR1: 68 TDR2: 48 TDR3: 42 (10% of XDR, 0.6% of MDR) Not TDR (but XDR): 301 34

Number of Drugs to which MTB organisms resistant by TDR groups (all have XDR) (1b) XDR but TDR1 TDR2 TDR3 Not TDR Total 301 68 48 42 5 9% 0% 10% 0% 6 31% 4% 27% 29% 7 31% 13% 8% 10% 8 18% 31% 6% 7% 9 10% 25% 4% 5% 10 1% 21% 35% 40% 11 0% 6% 8% 10% ODDS of Outcomes adjusted for individual characteristics - by TDR groups XDR but Not TDR TDR1 TDR2 TDR3 Total N 301 68 48 42 Cured 1.0 (reference) 0.4 (0.2, 0.8) 0.6 (0.2, 1.6) 0.5 (0.2, 1.7) Failed 1.0 (reference) 2.1 (1.0, 4.5) 1.8 (0.7, 4.7) 1.9 (0.7, 5.3) Died 1.0 (reference) 1.6 (0.6, 4.4) 1.7 (0.6, 4.9) 1.8 (0.6, 5.3) Failed or Died 1.0 (reference) 2.6 (1.2, 4.4) 2.6 (1.1, 6.7) 2.8 (1.0, 7.9) 35

Outcomes pooling across studies (standard metaanalysis) - by TDR groups XDR but Not TDR TDR1 TDR2 TDR3 Total N 301 68 48 42 Cured 43% (27, 58) 30% (17, 43) 34% (-, -)* 19% (0, 48) Failed 20% (15, 25) 29% (8, 50) 33% (-, -)* 26% (14, 38) Died 13% (6, 20) 18% (7, 29) 30% (18, 41) 35% (21, 50) Conclusions Treatment of drug-sensitive TB leads to MDR-TB Poor treatment leads faster and in more patients RIF containing regimens introduced in 1970 MDR described 20 years later Treatment of MDR-TB leads to XDR-TB Widespread treatment of MDR available since 2000 XDR described in 2006 (but present for years before) Treatment of XDR leads to TDR TDR described in 2011 (also present for years before Cure rates similar to historical spontaneous cure rates What's next? 36

Next steps New drugs at least two are needed TMC 207 (Tibotec) is the only one close to real use Others in pipeline at least 5 more years Better use of existing drugs High dose RIF Daily Rifapentine Other combinations Randomized trials Leadership Funding Collaboration Evidence base Phase 3 RCT in TB Number of Randomized trials of treatment in New cases by decade when they started enrolment 40 Number of studies 30 20 10 0 1950's 1960's 1970's 1980's 1990's 2000 Year study started Note: all but two of the RCT were publicly funded 37

40 Evidence base: Phase 3 RCT in Drug resistance / Re-treatment Number by decade when they started enrolment Number of studies 30 20 10 0 1950's 1960's 1970's 1980's 1990's 2000 Year study started To date no published RCT in MDR-TB We can do better!! Thank you Merci Gracias 38

Acknowledgements Melissa Bauer, Maria Graciela Holmes Delgado, Sandra Ramoutar, Lena Shah Andrea Benedetti The IPD Group The Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB, Members (in alphabetic order): D. Ashkin, S.Ahuja, M. Avendano, M. Bauer, M. Becerra, A. Benedetti, M. Burgos, R. Centis, E. Chan, C.Y. Chiang, F. Cobelens, H. Cox, E. Declercq, D. Enarson, D. Falzon, K. Flanagan, J. Flood, J. Furin, L. Garcia-Garcia, N. Gandhi, P. Hopewell, T. Holtz, S. Keshavjee, WJ.Koh, V. Leimane, C.C. Leung, J. Li, A.K. Maug, D. Menzies, G.B. Migliori, C.Mitnick, S.S. Munsiff, M. Narita, E. Nathanson, P. O Riordan, M. Pai, D. Palmero, G. Pasvol, J. Pena, C. Perez, MID Quelapio, H.T. Quy, A. Ponce-de-Leon, V. Riekstina, J. Robert, S. Royce, M. Salim, H.S. Schaaf, K.J. Seung, L. Shah, K.P. Shean, T.S. Shim, S.S. Shin, Y. Shiraishi, Jose Sifuentes-Osornio, G. Sotgiu, M. Strand, P. Tabarsi, T.E. Tupasi, M. Vargas, M. Van der Walt, T.S. Van der Werf, A. Van Deun, P. Viiklepp, W.W. Yew, J.J. Yim 39

Treatment Outcome Definitions Treatment Cure: completion of treatment and consistent (at least 5 consecutive) culture negative results for the final 12 months of treatment or if the last two cultures before the end of treatment had negative results. Treatment Completed: completion of the assigned treatment without meeting the definition for cure or failure Treatment Default: interruption of MDR-TB treatment for 2 or more consecutive months for any reason, 1 month before the planned end of treatment without meeting the definition for cure or failure. (Included patients who transferred out of program or whose outcome was simply unknown.) Treatment Failure: At least 1 positive culture after 6 months or 2 or more positive results of the 5 cultures in the final 12 months of treatment, or if there was a clinical decision to stop treatment due to poor response or adverse events. Death: Death from any cause during treatment. Merci / thanks 40