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TB prevention: new data, new approaches, new challenges

TB prevention: new data, new approaches, new challenges. Alison Grant London School of Hygiene & Tropical Medicine. Improving health worldwide. www.lshtm.ac.uk. TB prevention: breaking the cycle. --_-_--_-. HIV+. Infectious TB. HIV-. Latent TB infection. HIV- TB. HIV-. HIV+. HIV+

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TB prevention: new data, new approaches, new challenges

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  1. TB prevention: new data, new approaches, new challenges • Alison Grant • London School of Hygiene & Tropical Medicine Improving health worldwide www.lshtm.ac.uk

  2. TB prevention: breaking the cycle --_-_--_- HIV+ Infectious TB HIV- Latent TB infection HIV- TB HIV- HIV+ HIV+ TB Non-infectious TB slide courtesy Peter Godfrey-Faussett

  3. TB prevention: breaking the cycle --_-_--_- Prevent infection HIV+ Infectious TB HIV- Latent TB infection HIV- TB HIV- HIV+ HIV+ TB Non-infectious TB

  4. TB prevention: breaking the cycle --_-_--_- HIV+ Infectious TB HIV- Latent TB infection HIV- TB HIV- HIV+ Prevent disease HIV+ TB Non-infectious TB

  5. TB prevention: low transmission settings

  6. TB prevention: low transmission settings _- HIV+ Infectious TB HIV- Latent TB infection HIV- TB HIV- HIV+ Prevent reactivation HIV+ TB Non-infectious TB

  7. Effect of isoniazid preventive therapy (IPT) on TB for HIV+:meta-analysis of clinical trials Relative risk, 95% CI 1.0 Placebo Overall TST+ TST- Akolo 2010, Cochrane review

  8. Low TB transmission settings • most TB disease arises from latent infection • treatment of latent TB is central to TB elimination • INH x 9 months is long, completion rates are poor • shorter regimens preferable if effective, safe

  9. Rifapentine+INH vs. INH Sterling NEJM 2011;365:2155

  10. Rifapentine+INH vs. INH: results to 33 months 9H: 15 TB cases 0.16/100pyrs non-inferior 3RpH: 7 TB cases 0.07/100pyrs Sterling NEJM 2011;365:2155

  11. Rifapentine+INH vs. INH in HIV+ Sterling AIDS 2012

  12. Shorter preventive regimens under investigation • rifampicin x 4m vs. INH x9m • adults, TST+ or IGRA+ (excluding HIV+ on incompatible ART) • currently recruiting, high and low burden settings • rifapentine/INH daily x1m vs. INH daily x 9m • HIV+, TST≥5mm OR IGRA+ OR resident in high burden country • self-administered • started recruitment 2012

  13. TB prevention: high transmission settings

  14. TB prevention: high transmission settings --_-_--_- HIV+ Infectious TB HIV- Latent TB infection HIV- TB HIV- HIV+ HIV+ TB Non-infectious TB

  15. TB prevention: high transmission settings --_-_--_- HIV+ Infectious TB HIV- Latent TB infection HIV- TB HIV- HIV+ HIV+ TB Non-infectious TB

  16. TB prevention: high transmission settings --_-_--_- HIV+ Infectious TB HIV- Latent TB infection HIV- TB HIV- HIV+ HIV+ TB Non-infectious TB

  17. TB infection control is TB prevention MSF South Africa, Gilles van Cutsem and Colin Brown

  18. Earlier TB treatment is TB prevention symptomatic, seeks care symptomatic, does not seek care asymptomatic morbidity smear pos, culture pos smear neg, culture pos smear neg, culture neg infectiousness

  19. The long and winding road to TB treatment TB test sent Treatment start Attends health centre Has symptoms TB cured Infectious TB test result infectiousness

  20. Earlier test result is TB prevention…….. TB test sent Treatment start Attends health centre Has symptoms TB cured Infectious TB test result infectiousness

  21. …providing positive test results lead to treatment TB test sent Treatment start Attends health centre Has symptoms TB cured Infectious TB test result mind the gap….. infectiousness

  22. 1.00 0.75 proportion not on Rx 0.50 0.25 0.00 0 3 6 9 12 follow-up time (months) Initial default and time to treatment: Thibela TB S-C- Smear neg, culture neg median = 5.1 months S-C+ Smear neg, culture pos S+C+ Smear pos median = 12 days Churchyard et al, SA TB conference 2012

  23. Earlier testing is TB prevention TB test sent Treatment start Attends health centre Has symptoms TB cured Infectious TB test result infectiousness

  24. Southern Africa Zambia Western Cape 0 15 30 Km Western Cape Zambia 0 200 400 Km A community randomized trial of two interventions delivered to ~1,200,000 people while strengthening the existing health systems P. Godfrey-Faussett, H. Ayles, N. Beyers Map Source: Google Earth October 2007

  25. ZAMSTAR: two interventions • Total population 962,655 • 24 communities • Enhanced case finding (12 vs. 12): • community mobilisation • open access to sputum microscopy

  26. ZAMSTAR: two interventions • Total population 962,655 • 6 communities per arm • Enhanced case finding (12 vs. 12): • community mobilisation • open access to sputum microscopy • Household intervention (12. vs. 12) • TB patient as entry point to household • Screening for TB and HIV • Referral for treatment and care

  27. Household intervention reduced TB prevalence and transmission

  28. TB preventive therapy in high transmission settings --_-_--_- HIV+ Infectious TB HIV- Latent TB infection HIV- TB HIV- HIV+ Prevent reactivation HIV+ TB Non-infectious TB

  29. TB preventive therapy: high TB transmission settings • shorter regimens desirable • but is longer better?

  30. Botswana: IPT 36 vs. 6m Samandari Lancet 2011;377:1588

  31. 36m vs. 6m IPT: 43% less TB during trial In trial n=1995 43% reduction in TB p=0.047 Cumulative TB incidence 6H 36H 6H 36H Samandari Lancet 2011;377:1588

  32. TB incidence post-trial: no difference for 36m vs. 6m INH arm In trial n=1995 Post-trial (no IPT) n=1678 Hazard ratio 0.82 p=0.52 43% reduction in TB p=0.047 Cumulative TB incidence 6H 6H 36H 36H 6H 36H Samandari CROI 2012

  33. Soweto: novel TB preventive therapy regimens N=1148 HIV+, TST>5mm, not needing ART RIF/INH twice wkly x3m RPT/INH wkly x3m INH continuous INH x6m N=164 85% female median CD4 476 median FU 3.9y N=327 84% female median CD4 490 median FU 3.9y N=328 85% female median CD4 471 median FU 4.0y N=329 81% female median CD4 498 median FU 4.1y Martinson NEJM 2011;365:11

  34. Soweto study: HIV+, TST+ Martinson NEJM 2011;365:11

  35. Soweto study: HIV+, TST+ as treated analysis Martinson NEJM 2011;365:11

  36. Cluster = South African gold mines: TB case notifications <5000 per 100,000 per year Novel TB control strategies needed Thibela TB: cluster-randomised trial of community-wide IPT Thibela TB Hostels + Mine shaft

  37. Targeted vs. community-wide IPT High TB risk: TB contact HIV+ Offered IPT: High TB risk: everyone Offered IPT: everyone

  38. Cluster-randomised trial of community-wide IPT x 9m in 15 gold mines in South Africa (approx 80,000 people) No impact on TB incidence or prevalence at population level Thibela TB Churchyard CROI 2012; Fielding CROI 2012

  39. Thibela TB: individual analysis Baseline survey (n=15,609, 15 clusters) Excluded Not employees (n=1,604) Employees (n=14,005, 15 clusters) Control clusters (n=6,397, 7 clusters) Intervention clusters (n=7,608, 8 clusters) Excluded TB / IPT (n=134) Excluded Did not start IPT (n=2,963) Control arm (n=6,263, 7 clusters) IPT arm (Started IPT) (n=4,646, 8 clusters) Fielding CROI 2012

  40. Thibela TB: duration of IPT effect at individual level 63% reduction in TB incidence during 9m of intervention Fielding CROI 2012

  41. Why is IPT not durable in southern Africa? • ? High rates of TB reinfection • very difficult to measure • consistent with molecular epidemiology data from mines and elsewhere in southern Africa

  42. Why is IPT not durable in southern Africa? • ? high rate of reinfection • would explain why RH/RpH no better than IPT in Soweto

  43. Why is IPT not durable in southern Africa? • ? but if most TB in HIV+ is reinfection, why does TB incidence remain low among those TST neg at enrolment? Samandari Lancet 2011; 377:1588

  44. Why is IPT not durable in southern Africa? • ? but if most TB in HIV+ is reinfection, why does TB incidence remain low among those TST neg at enrolment? Samandari Lancet 2011; 377:1588

  45. Why is IPT not durable in southern Africa? • ? High rates of TB reinfection • consistent with molecular epi data from mines and elsewhere in southern Africa • very difficult to measure • ?IPT does not cure latent infection • very difficult to measure • consistent with data from mouse models

  46. Activity of TMC207 (J) in a mouse model of treatment for latent TB infection Disease course in untreated mice Rx duration to prevent 50% relapse H R RH PH1/7 Lung log10 CFU J 0 1 2 3 4 5 6 Months Zhang et al, Am J RespirCrit Care Med 2011; 184:732 thanks to Eric Neurmberger for this slide H, isoniazid; R, rifampin; P, rifapentine; J, TMC207 Months post-infection

  47. If reinfection, priority is to reduce transmission find and treat people with infectious TB (which we need to do anyway) If lack of cure with IPT alone, need better "preventive" regimens particularly where TB transmission is low shorter regimens operationally much easier to implement probably a bit of both either way, data support continuous IPT for HIV+ Implications of limited IPT durability

  48. TB prevention: addressing susceptibility --_-_--_- HIV+ Infectious TB HIV- Latent TB infection HIV- TB HIV- HIV+ Improve CD4 count HIV+ TB Non-infectious TB

  49. ART for TB prevention SutharPLoS Medicine 2012;9:e1001270

  50. ART for TB prevention: necessary but not sufficient Gupta PLoS ONE 2012;7:e34156

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