“International” TB treatment guidelines – The new WHO treatment recommendations

1. “International” TB treatment guidelines – The new WHO treatment recommendations Dr Dick Menzies Montreal Chest Institute McGill University, Canada

2. Overview of talk • Evidence based guidelines – why, and how? • The recent WHO TB treatment guidelines: • The questions • The evidence • The recommendations

3. Evidence-based guidelines – why? • “Old” WHO way - “Expert panels” • Group of experts meet to ‘discuss’ • Opinions exchanged – not always politely • Best/strongest/loudest/longest talker ‘wins’ • Lancet paper – VERY critical of process • “New” WHO way – guidelines committees • Evidence reviewed before hand – • Evidence presented by non-committee members • Recommendations based on evidence presented • Best evidence wins (much less room for opinion)

4. Evidence-based guidelines – How? • Step 1 – Ask the questions: • What is really wrong with current guidelines? • Patients fail, or die, or relapse? • What are the most important programmatic problems • Treatment is too long, or patients default • Step 2 – Involve the “evidence – gatherers” • These are different people. Not necessarily TB experts. Objective. Fair. Disciplined. Thorough. (good looking, smart….)

5. Evidence-based guidelines – How? • Step 3 – Conduct a systematic review • Develop selection criteria – FIRST • These are based on study methods • Search the published literature • All possibly relevant papers • Read MANY papers – select those that meet criteria – the right patients, the right methods • Step 4 – Meta-analysis • Produce an estimate of effect – how well does the drug/regimen work overall?

6. WHO treatment recommendations for new, and previously treated cases -The Questions • 1. In new cases: • How long should Rifampin be given? • What is the optimal schedule – ie what intermittency is optimal? • 2. Should treatment be modified for HIV-TB? • 3. What is the evidence for the current retreatment regimen? • How to treat INH resistance?

7. Systematic review and meta-analysis.Q1: Treatment of new cases • Estimate failure, relapse, or acquired drug resistance in previously untreated patients. • Duration of Rifampin • Intermittent therapy

8. Methods • Search strategy • Medline (1950-April 2008), EMBASE (1988-2008), Cochrane Central Register of Controlled Trials (through first quarter 2008) • Selection of studies by 2 reviewers 1 - titles and abstracts 2 - full-text articles – if disagreement then reviewed with 3rd reviewer

9. Criteria for Study selection • Published in English, French or Spanish • Randomized Trials only • Rifampin containing regimens • Standardized treatment (s) • New cases – no previous treatment • Bacteriologically confirmed • Initial diagnosis – culture positive • Failure and/or Relapse – culture positive • Drug Sensitivity testing: • PRE – in all • POST – in failures / relapses

10. Methods - Statistical Analysis • Pooled results across all studies • Each arm within each study = independent cohort • Random effects meta-analysis • I-squared statistic calculated to assess heterogeneity • meta-regression was used to adjust for other potentially confounding patient and treatment covariates: • Age, initial drug-resistance, DOT, completion of follow-up

11. Treatment of New cases Summary of study review and selection Identified from PubMed, EMBASE, Cochrane Database literature search: (after eliminating duplicates) 2215 titles 1978 titles excluded Titles retained for review of abstracts: 237 78 abstracts excluded after review 9 Reviews 25 Not RCT/Cohort (case control, prevalence, cross sectional design, program report) 1 Regimen not reported 8 Outcomes not by Regimen 17 No outcomes 4 Individualized treatment 4 Latent TB/Non M.TB Non pulmonary TB 3 MDR TB 2 Not drug therapy 135 additional full texts identified from references and reviews Full text reviewed: 301 109 were excluded after review 4 Reviews 4 Not RCT/Cohort (case control, prevalence, cross sectional design, program report) 8 Regimen not reported 16 Outcomes not by Regimen 30 No Outcomes 12 Individualized treatment 4 Latent TB/Non M.TB/Non pulmonary TB 1 MDR TB, 9 Not drug therapy 2 Mono-therapy 19 other 75 Reports included (57 Trials)

12. Rates of treatment failure or recurrence - randomized trial of rifampin throughout (2HRZE / 4HR) vs. rifampin for the first 2 months (2HRZE / 6HE) Lancet 2004; 364: 1244-51

13. HIV negative New cases Duration of Rifampin and Failure(17,000+ patients in 57 trials)

14. HIV negative New casesDuration of Rifampin and Relapse(17,000+ patients in 57 trials)

15. Duration of Rifampin and treatment outcomes in new cases (non-HIV)(17,000+ patients in 57 trials - Results of Meta-regression)

16. Duration of Rifampin – WHO recommendations • 2HRZE/4HR – the 6-month RIF regimen – “The regimen of first choice for all new cases” • 2HRZE/6HE – the 2-month RIF regimen – “Should be phased out as rapidly as possible”

17. Intermittent therapy • Possible because of long half life of drugs • And slow growth of M TB • Intermittent therapy does work • In-vitro (cultures only) • In animal studies • In humans – randomized trials • What is the lowest frequency? • How early can it start?

18. Systematic review and meta-analysis.Q1: Intermittent Treatment of new cases • Methods - Same search and selection as for duration of RIF

19. Intermittent regimens and Failure

20. Intermittent regimens and Relapse

21. Effect of Intermittent regimens(New cases – HIV negative)(Twice weekly dropped from analysis)

22. Intermittency and relapse: a meta-analysis. (Chang et al, Am J RespCrit Care Med. 2006; 174: 1153-58) Systematic review of 17 studies with 5,208 patients, and 200 relapse events. Higher risk if cavitation or 2 month culture positive Daily through-out – Lowest: RR= 1.0 Daily then 3X weekly: RR = 1.6 Daily then 2X weekly: RR = 2.8 3x weekly through-out: RR = 5.0 - greatest increase if cavitation or 2 month culture positive - Also greater if followed by 1X weekly Rifapentine

23. Intermittent therapy for TB in children – meta-analysis. (Ramesh Menon et al, Indian Pediatrics. 2009; May 20) Systematic review and meta-analysis – children less than 16. Four trials with 466 children Daily therapy had higher cure rates Twice weekly intermittent had Odds of cure: Per protocol: 0.27 (0.15, 0.51) Intention to treat: 0.66 (0.23, 1.84)

24. Summary - Intermittent therapy • Intermittent regimens facilitates DOT • Once weekly = totally unacceptable • Twice weekly = worse results • Thrice weekly = slightly worse • OK under ideal conditions • BUT – worse if HIV infected or drug resistant • Best is daily therapy in first two months • Then can switch to intermittent • If self-administered – give daily

25. Intermittent regimens – WHO recommendations • Daily through-out – considered the standard of care • Daily then intermittent 3X/week acceptable alternative • Thrice weekly ‘can be used – conditional’ • Twice weekly – should not be used

26. Q2: Treatment of HIV co-infected TB cases: Assess the impact on failure, relapse and death during treatment of active TB in HIV-infected patients of: • Duration of rifampin or rifabutin • Dosing schedule (daily vs. intermittent) in the initial intensive phase of therapy

27. Q2: HIV-TB treatment - methods • Same search strategy and methods of review • Except, studies included if: • RCT or Cohort studies • Included: • 6 Randomized trials • 21 Cohort studies

28. Adjusted incidence rate ratios (aIRR) of failure and relapse in HIVTB cases for Duration of Rifamycin

29. Adjusted incidence rate ratios (aIRR) of failure and relapse in HIVTB cases by Intermittency (dosing schedule)

30. Other studies: Efficacy of a 6-month vs 9-month intermittent regimen in HIV infected patients with TB – an RCT. (Swaminanthan et al, Am J RespCrit Care Med; 2010; 181: 743-51) 327 HIV-TB adults randomized to 6 vs 9 months therapy Bacteriologically confirmed relapse: Relapse with 9 months: 7% RR: 1.0 (reference) Relapse with 6 months: 15% RR: 2.0 (1.3, 3.2) Failure: 19 Patients failed - 15 developed acquired MDR, and 4 developed RIF Mono-Resistance If INH resistance 30% vs 5% if DS Failure with MDR if H resistant: 8.4 times more likely (2.2, 32)

31. WHO recommendations • No difference in duration – 6 months • 9 months if other risk factors for relapse • Avoid intermittent therapy initially • Interestingly in India…….. • Will move to 9 months for all HIV-TB • But initially 3 times weekly

32. Q3. Retreatment • Previously treated patients are more likely to have DR-TB. Treatment is more complex • Most likely – Mono-resistance (INH, or Strep) • Also poly-resistance (INH & EMB or INH & Strep) • And MDR-TB • Can one regimen treat all this? • WHO “Cat 2”. The standard retreatment regimen • 2SHRZE/1HRZE/5HRE

33. Q3. Questions for DR-TB treatment/ retreatment • Does standard therapy work – if mono- or poly-drug resistant? (Dogma “INH Mono-R is of no significance clinically”) • What is the evidence for the current retreatment regimen (Cat 2) • What is the treatment for INH mono-resistance?

34. Does standard initial therapy work – if drug resistance? FailureSystematic review of 57 studies with 20,000 patients.

35. Does standard initial therapy work – if drug resistance? RelapseSystematic review of 57 studies with 20,000 patients.

36. Does standard initial therapy work – if drug resistance? (Meta-regression)

37. What is the evidence for the current WHO standard retreatment (2SHRZE/1HRZE/5HRE) • Systematic review – all years • RCT or cohort studies

38. What is the evidence for the current WHO standard retreatment (2SHRZE/1HRZE/5HRE) • NO randomized trials found • 7 cohorts only – some quite small

39. Results of the WHO retreatment regimen in Mono-resistance to INH(2HRZES/1HRZE/5HRE)

40. Results of the WHO retreatment regimen in mixed drug resistant strains (No MDR)(2HRZES/1HRZE/5HRE)

41. What is the evidence for treatment of INH resistant TB • Systematic review – all patients with INH mono-resistance, or other DR-TB, or retreatment • All Randomized trials over past 50 years • Double blind, Controlled, • Standard regimens to each arm • Microbiologically confirmed outcomes • Failure and Relapse • Acquired drug resistance

42. The evidence for treatment of drug resistant TB RCT in Drug resistance / Re-treatmentNumber by decade when they started enrolment Note: To date NO phase 3 trial in MDR-TB

43. Intermittent therapy and Treatment outcomes - INH resistance (from multivariate meta-regression)

44. Number of drugs in initial phase to which strains sensitive - INH resistance(from multivariate meta-regression)

45. Q3. Retreatment – WHO recommendations • In the absence of any clear evidence: • Retreatment regimen retained for: • Relapse • Retrun after default • But, strong recommendation for Drug Sensitivity Testing for all previously treated patients • Evidence needed

46. Summary -The evidence based approach for Current WHO treatment guidelines • Well defined step-wise process • Lengthy evidence gathering • Which is rigorous and objective • Committee recommendation based on evidence • Reduces reliance on expert opinion • The major weakness of the process: • If the evidence is weak • Treatment of Drug resistant TB (retreatment) EVIDENCE IS NEEDED

47. Recent WHO treatment guidelines – Most important points: • Duration of RIF – 6 months minimum • 8-9 months if risk for relapse • Initial phase (2 months) – Daily preferred • Especially if HIV, or DR-TB • Continuation can be 3 times weekly • Avoid twice weekly • HIV-TB – preference for longer duration, daily therapy • Treatment of Drug resistant TB (retreatment) EVIDENCE IS NEEDED

48. Thank you!Teşekkürler!Merci!

49. Intermittent therapy and Treatment outcomes – with initial INH resistance (from multivariate meta-regression)

50. Effect of Intermittent regimens on Failure, Relapse, and ADRAcknowledgements • Initial design and planning: • Woojin Lew, Madhu Pai, Olivia Oxlade • Study review: • Woojin Lew, Dan Martin, Anita Paydar, Ian Martin • Data analysis: • Andrea Benedetti, Madhu Pai • Secretarial (tables, tables and more tables) • Anita Paydar and Ria Choe