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

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

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

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

5. TB prevention: low transmission settings

6. _- HIV- HIV- TB Infectious TB Latent TB infection HIV+ TB Non-infectious TB Prevent reactivation HIV- HIV+

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

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 Sterling NEJM 2011;365:2155 non-inferior 9H: 15 TB cases 0.16/100pyrs 3RpH: 7 TB cases 0.07/100pyrs

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. --_-_--_- HIV- HIV- TB Infectious TB Latent TB infection HIV+ TB Non-infectious TB HIV- HIV+

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

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

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

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

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

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

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

22. Initial default and time to treatment: Thibela TB S-C- S-C+ S+C+ 0.00 0.25 0.50 0.75 1.00 proportion not on Rx 036912 follow-up time (months) median = 5.1 months median = 12 days Smear neg, culture neg Smear neg, culture pos Smear pos Churchyard et al, SA TB conference 2012

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

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

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

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 Cumulative TB incidence 6H36H In trial n=1995 6H 36H Samandari Lancet 2011;377:1588 43% reduction in TB p=0.047

32. Post-trial (no IPT) n=1678 6H 36H TB incidence post-trial: no difference for 36m vs. 6m INH arm Cumulative TB incidence 6H36H In trial n=1995 6H 36H Samandari CROI 2012 43% reduction in TB p=0.047 Hazard ratio 0.82 p=0.52

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

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

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

36. Thibela TB 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 Hostels +Mine shaft Cluster =

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

38. Thibela TB 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 Churchyard CROI 2012; Fielding CROI 2012

39. Thibela TB: individual analysis Baseline survey (n=15,609, 15 clusters) Employees (n=14,005, 15 clusters) Control clusters (n=6,397, 7 clusters ) Intervention clusters (n=7,608, 8 clusters) Control arm (n=6,263, 7 clusters) IPT arm (Started IPT) (n=4,646, 8 clusters) Excluded Did not start IPT (n=2,963) Excluded TB / IPT (n=134) Excluded Not employees (n=1,604) 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 0-9m9-18m>18m TB inc rate: control IPT 2.91 1.10 2.71 2.34 2.70 2.42 adjusted RR0.370.940.79

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 Rx duration to prevent 50% relapse H, isoniazid; R, rifampin; P, rifapentine; J, TMC207 H Months 123456 0 R RH PH 1/7 J Zhang et al, Am J Respir Crit Care Med 2011; 184:732 thanks to Eric Neurmberger for this slide Months post-infection Lung log 10 CFU Disease course in untreated mice

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- HIV- TB Infectious TB Latent TB infection HIV+ TB Non-infectious TB Improve CD4 count HIV- HIV+

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

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

51. IPT plus ART: Brazil Retrospective cohort, N=11,026 HIV+ clinic attendees, Brazil pyrsTB casesIRIRR (95% CI) Neither38651554.011.0 ART only116272211.900.48 (0.39-0.59) IPT only39551.270.32 (0.10-0.76) ART+IPT1253100.800.20 (0.09- 0.91) Golub AIDS 2007;21:1441 pyrsTB casesIR*IRR (95% CI) Neither38651554.011.0 ART only116272211.900.48 (0.39-0.59) IPT only39551.270.32 (0.10-0.76) ART+IPT1253100.800.20 (0.09-0.91) *per 100 pyrs

52. RCT of IPT plus ART: Cape Town Rangaka AIDS 2012 late breaker

53. Thibela TB Community-wide IPT did not improve TB control in South African gold mines What will it take? HostelsMine shaft Cluster

54. TB prevention in gold mines: what will it take? a) IPT for 9 months b) continuous IPT c) ART d) reducing treatment delay e) more sensitive diagnostics f) none of the above g) all of the above

55. Number of cases/100,000/year (true incidence) Reduce treatment delay Maximise ART coverage Better diagnostics Better preventive therapy Thibela TB modelling: need combination TB prevention Vynnycky, Sumner, Cox, White SA TB conference

56. Know your TB epidemic, know your TB response Conclusions

57. Low transmission settings Rifapentine / INH: simpler, shorter – awaiting data on effectiveness for HIV positive people

58. High TB transmission settings IPT has limited durability in Southern Africa continuous IPT for HIV+ people Combination TB prevention earlier treatment via better diagnostics improving systems to minimise treatment delay maximising ART coverage optimising TB preventive therapy

59. Thank you Gavin Churchyard, Violet Chihota, Aurum Institute Katherine Fielding, James Lewis, Peter Godfrey-Faussett, Emilia Vynnycky, Tom Sumner, Andy Cox, Richard White, LSHTM Chris Dye, WHO Taraz Samandari, CDC Dick Chaisson, Jonathan Golub, Neil Martinson, Johns Hopkins Tim Sterling, Vanderbilt University Funders: Bill and Melinda Gates Foundation Global Health Trials (UK MRC / Wellcome Trust / Department for International Development) No conflicts of interest to declare