1. HIV and Tuberculosis: science and implementation to turn the tide and reduce death Anthony D Harries The “Union”, Paris, France London School of Hygiene & Tropical Medicine, UK

2. 1.1 million people with HIV-TB 350,000 HIV-TB deaths WHO Global Tuberculosis Control 2011 Global Data for 2010

3. Over 80% of HIV-TB in sub-Saharan Africa WHO Global Tuberculosis Control 2011

4. Number of people receiving antiretroviral therapy in low- and middle-income countries, by region, 2002 – 2010

5. Of HIV-infected patients who start antiretroviral therapy (ART) in Africa 8% - 26% die in first year Often due to diagnosed and undiagnosed TB Lawn SD et al. AIDS 2008; 22: 1897 - 1908

6. Autopsies in HIV-positive persons dying on medical wards in Africa CountryPatients on ART Number autopsied Deaths due to TB Cote d’Ivoire 1 None93 44% Kenya 2 None75 51% Botswana 3 None104 40% South Africa 4 Some96 42% South Africa 5 All25 76% 1 Lucas et al, BMJ 1994; 308: 1531-3. 2 Rana et al, JAIDS 2000; 24: 23-9. 3 Ansari et al, IJTLD 2002; 6: 55-63. 4 Cohen et al. PLoS Medicine 2010; 7: e1000296. 5 Wong et al, XVIII Int AIDS Conference 2010

7. Mortality rates in HIV-infected smear- positive PTB patients before era of ART CountryCD4 count in HIV-positive patientsHIV-negative patients <200200-499500 or > Cote d’Ivoire: at 6 months 1 10%4%3%~1% Zaire: at 24 months 2 67%22%8%< 2% 1 Ackah et al, Lancet 1995; 345: 607-10; 2 Perriens et al, N Engl J Med 1995; 332: 779 – 84

8. 2012

9. Four spheres of work 1. Prevent TB by early ART and IPT 2. Find, diagnose and treat TB in PLHIV 3. Diagnose and treat HIV in TB 4. Deliver HIV-TB services

10. Prevent TB in persons with HIV: give early ART and IPT

11. Effect of ART on TB Incidence Rates: systematic review and meta-analysis Adapted from Suthar AB et al, PLOS Medicine 2012; 9: e1001270 IRR 0.35 [0.28-0.44] for all baseline CD4 counts

12. Malawi: TB case notification and ART Zachariah et al, IJTLD 2011; 15: 933-7

13. The current challenge in sub-Saharan Africa PLHIV start ART at CD4 cell counts of 100-150 cells/uL Most HIV-infected TB patients are diagnosed at CD4 cell counts of 150-200 cells/uL Thus, HIV diagnosis and ART are TOO LATE to prevent TB

14. 75% mortality reduction50% reduction in TB incidence Early versus Standard ART in HIV-infected adults in Haiti [Severe P et al, NEJM 2010; 362: 257-265] (Early = CD4 200-350; Standard= CD4<200 or AIDS

15. 96% reduced HIV transmission to HIV-negative partner 40% reduction in clinical events in HIV-infected persons – mainly related to EPTB (3 cases with early ART versus 17 with delayed ART) Early ART (CD4 350-500) versus Delayed ART (CD4 < 250)

16. Mathematical models predict huge TB prevention benefit from early ART Universal HIV testing and immediate start of ART in PLHIV TB incidence reduced by 48% in 5 years TB incidence reduced by 98% in 40 years 6 Million TB cases averted in 40 years Granich et al, Lancet 2009; 373: 48-57 Lancet 2009 Proc Nat Acad Sci USA 2010

17. Granich et al, 2011

18. ART duration (months) TB rate (per 100 PY) Updated CD4 (cells/uL) TB rate (per 100 PY) 0-1212.4≤ 10025.5 12-246.7101-20011.2 24-366.2201-3007.9 36-486.6301-5005.0 48-605.5501-7004.1 > 604.9> 7002.7 HIV-Uninfected TB rate (per 100 PY) 0.62 HIV-Infected

19. Isoniazid Preventive Therapy [IPT] Reduces overall TB risk by 33% Protective effect in those with positive tuberculin skin test (TST) where risk reduction is 64% (Akolo et al 2010) WHO Guidelines from 1998 – 2009 emphasised IPT in PLHIV with positive TST

20. WHO Global TB Report 2010 Challenges with scale up Process and assessment of TST Reliable exclusion of active TB

21. WHO Guidance for IPT: PLHIV with unknown or positive TST and who do not have TB should receive IPT TST not a requirement for starting IPT IPT for 6 months (strong recommendation) IPT for 36 months (conditional recommendation)

22. Post-trial (no IPT) n=1678 6H 36H Cumulative TB incidence in the in-trial & post- trial period by study arm for all participants Cumulative TB incidence P=0.04 P=0.52 6H36H 6m v 36 m IPT in trial n=1995 6H 36H Botswana IPT Study Samandari et al, Lancet 2011; 377: 1588 – 1598; Samandari et al, CROI 2012

23. Effect of IPT and ART in PLHIV TB incidence rates per 100 PY NoneIPT onlyART onlyART + IPT Brazil 1 4.01.31.90.8 South Africa 2 7.15.24.61.1 1 Golub et al, AIDS 2007; 21: 1441-8; 2 Golub et al, AIDS 2009; 23: 631-6 Await ANRS TEMPRANO (Cote d’Ivoire) & HAART-IPT (S Africa)

24. CHILDREN Lower TB prevalence in HIV- infected children than adults [Lucas et al 1996; Chintu et al 2002; Ansari et al 2003] Early ART reduces infant mortality and risk of TB from 20% to 8% per year [Violari et al, NEJM 2008, 359, 2233-44] IPT with ART does not further reduce TB risk (11% v 14%) [Madhi et al, NEJM 2011, 365, 21-31]

25. Find, diagnose and treat TB in persons with HIV

26. Standard TB Symptom Screening Tool Cough – current and of any duration Unintentional weight loss – in last 4 weeks Night sweats – in last 4 weeks Fever – in last 4 weeks Getahun H et al. PLoS Medicine 2011, 8: e1000391

27. Smear microscopy and chest x-ray Usual way of investigating for Tuberculosis Time consuming – Costly - Tests are insensitive

28. Sputum Specimen New TB diagnostic tools: Xpert MTB/Rif Sensitivities: Smear-positive PTB - 1 specimen = 98% Smear-negative PTB - 1 specimen = 72%; 3 specimens = 90% EPTB - different specimens = 81% (range 25% - 97%) Boehme et al, N Engl J Med 2010; 363: 1005-15: Lawn and Zumla, Exp Rev Anti-Infect Ther 2012 Other Specimen Diagnosis in under 2 hours

29. Urine LAM New TB diagnostic tools: Urine TB-LAM URINE SPECIMEN TB-LAM Dip-stick Determine TB-LAM test strips (diagnosis in 30 minutes) [ specificity 98%: sensitivity increases as CD4 count declines (~66% at CD4 < 100 cells/uL] Lawn et al, Lancet Infect Dis 2011; Dorman et al, CROI 2012

30. “Three I’s” in HIV care settings Intensified case finding (ICF) Isoniazid Preventive Therapy (IPT) Infection Control (IC) “TB diagnosis”

31. Two trials to investigate this intervention: PROMPT (EDCTP) and REMEMBER (ACTG network)

32. Diagnose and Treat HIV in TB

33. Presumptive or diagnosed TB Provider initiated HIV testing and counselling [PITC] If HIV- seropositive Start cotrimoxazole preventive therapy as soon as possible [25% - 46% mortality reduction] Start antiretroviral therapy as soon as possible [64% - 95% mortality reduction]

34. In 2010: Africa 59% Europe 80% HIV Testing for TB patients, all countries 2003-2010 WHO Global Tuberculosis Control 2011 New and retreatment TB cases in blue TB cases HIV tested in green

35. PITC for persons suspected of having TB and referral to HIV care and treatment Patients with suspected TB but negative sputum smears Zimbabwe: [12-month follow-up] 63% HIV-positive; 85% CD4 < 350 18% developed TB 12% died Only 15% were placed on ART MacPherson et al, IJTLD, 2011; 15: 1390-6

36. WHO 2010 ART Guidelines All HIV-positive TB patients eligible for ART, regardless of CD4 count ART initiated as soon as possible after the start of TB treatment

37. CAMELIA SAPIT STRIDE

38. Camelia Study in Cambodia ART start within 2-4 weeks reduces death in HIV-positive PTB, especially with CD4 counts < 50/uL IRIS is more frequent in the early start ART group Key Message

39. Two other ART-TB issues TB Meningitis Delay ART because IRIS within the central nervous system is dangerous Second line ART (PIs) RMP cannot be used Rifabutin (RFB) is safe and effective Need to reduce cost, work out optimum dosing schedules, introduce into FDC Loeliger et al, IJTLD 2011; 16: 6-15 Torok et al CID 2011, 52, 1374-83

40. Drug-resistant Tuberculosis Tugela Ferry, SAMDR-TBXDR-TB Number272382 HIV-infected %90%98% 1-month mortality40%51% 1-year mortality71%83% Gandhi et al, Am J Respir Crit Care Med 2010, 181: 80-6 ART and CPT: ART and CPT reduce mortality No RCTs done Same advice as for drug-sensitive TB

41. Deliver HIV-TB services: health facilities community

42. Health Facilities: co-location of TB and HIV clinics TB clinic ART clinic In clinics in separate geographical locations in South Africa, 11% of HIV- TB patients with CD4 < 50 started ART within 4 weeks of TB diagnosis Lawn et al, N Eng J Med 2012; 366: 474 Malawi - Salima District Hospital

43. Health Facilities: integrated HIV-TB clinics

44. Men Women Community HIV-Self Testing

45. DETECTB Zimbabwe Cluster-randomised trial 46 clusters ~120,000 adults Zambia and South Africa Cluster-randomised trial 24 clusters ~ 962,000 people South Africa Gold miners Cluster-randomised trial 15 clusters ~78,596 people Community Case Finding and Prevention

46. Community Multi-disease Campaigns Kenya (Lurambi) – HIV, malaria, diarrhoea

47. BOLD VISION Three Zero’s by 2015: Zero new infections Zero discrimination Zero AIDS-deaths

48. John Donne: “…any mans death diminishes me because I am involved in Mankinde; And therefore never send to know for whom the bell tolls; it tolls for thee….” Thanks to all who helped with the presentation Stephen Lawn Rony Zachariah Haileyesus Getahun Diane Havlir Taraz Samandari Elizabeth Corbett Helen Ayles Peter Godfrey-Faussett Eric Goemaere Reuben Granich Rod Escombe Gavin Churchyard

49. Anthony D Harries, Stephen D Lawn, Haileyesus Getahun, Rony Zachariah and Diane V Havlir New Article HIV and tuberculosis – science and implementation to turn the tide and reduce deaths Harries AD et al. J Int AIDS Soc 2012, 15:17396 available at www.jiasociety.org