Towards a New Treatment Era ? Translating Results from START and TEMPRANO to Clinical Practice

1. Towards a New Treatment Era ? Translating Results from START and TEMPRANO to Clinical Practice Serge Paul EHOLIE1,2,3,Xavier ANGLARET,3,4 1- Department of Infectious and Tropical Diseases, Treichville University Hospital, Abidjan, Côte d’Ivoire 2- Department of Dermatology and Infectious Diseases, UFR des Sciences Médicales, University Félix HOUPHOUET-BOIGNY, Abidjan, Côte d’Ivoire 3- Programme PAC-CI, ANRS research site in Côte d’Ivoire 4- INSERM U1219, University of Bordeaux, France

2. When to start ART: Evolution of WHO guidelines for Low and Middle Income countries 2002 2006 2010 2013 CD4 ≤ 200 CD4 ≤ 200 Consider< 350 CD4 < 350 if TB CD4 ≤ 350 At any CD4 if TB/HBV CD4 ≤ 500 (Prioritize ≤ 350) At any CD4 if TB/HBV, pregnancy, serodiscordant couples

3. Moving towards the end of AIDS: Great achievements, ambitious targets… [ 35%] [ 50%] [ 10x] 17 milion (2016) [ 3x] WHO & UNAIDS reports , 2014 & 2015

4. Towards a new treatment Era ? When to start (1) The game changers

5. When to start ART ? Three recent Randomized Control Trial HPTN052: Cohen, NEJM 2011; 365:493-505 HPTN052: Grinsztejn, Lancet Infect Dis 2014; 14:281-90 TEMPRANO: TEMPRANO study group, NEJM 2015; 373:808-22 START: INSIGHT START study group, NEJM 2015; 373:795-807 All three trials had the same objective: To compare the efficacy of "early ART" vs. "deferred ART" in reducing severe morbidity* in adults with high CD4 counts** * Severe morbidity included all-cause death, tuberculosis, AIDS and non-AIDS cancers in the three trials **Baseline CD4 counts: HPTN052 350-550 /mm3 TEMPRANO 250-800 /mm3 START >500/mm3

6. HPTN052 Participants: 1761 54% in Africa (East/Southern) • TEMPRANO • Participants: 2056 • 100% in Africa (West) START Participants: 4651 21% Africa (mostly East/southern)

7. Hazard Ratio of severe morbidity : TEMPRANO 0.56 (0.41-0.76) N Engl J Med 2015;373:808-22.

8. Hazard Ratio of severe morbidity: START 0.43 (0.30-0.62) N Engl J Med 2015; 373:795-807.

9. Hazard Ratio of severe morbidity Hazard Ratio of HIV transmission HPTN052 0.73(0.52-1.03) 0.04 (0.01-0.27) N Engl J Med 2011; 365:493-505 Lancet Infect Dis 2014; 14:281-90

10. Towards a new treatment Era ? When to start (1) No more double standard in international guidelines ?

11. NEW REVISED NEW DIRECTIONS IN WHEN TO START NEW

12. Temporal Evolution of CD4 Criteria to Initiate ART in Asymptomatic HIV+ Adults (1996-2015)

13. IAS Temporal Evolution of CD4 Criteria to Initiate ART in Asymptomatic HIV+ Adults (1996-2015) DHHS EACS WHO With the courtesy of M Vitoria

14. No Double Standard anymore ! IAS Temporal Evolution of CD4 Criteria to Initiate ART in Asymptomatic HIV+ Adults (1996-2015) DHHS EACS WHO With the courtesy of M Vitoria

15. “Test, Treat, Retain, Respect, and Prevent” : a global action statement Abdool Karim , NEJM 2015

16. When to start in the guidelines When to start in the field ?

17. When to start in the guidelines When to start in the field ? 1. Empower physicians to follow international guidelines

18. Movement to ‘Treat All’ happening Policy uptake for adults and adolescents, July 2016 • 24% of all LMIC and 40% of fast track countries have adopted Treat All • By the end of 2016, more than half of all LMIC and 80% of fast track countries will have adopted Treat All With the courtesy of M. Doherty

19. Policy uptake to full implementation, July 2016 • Implementation is just getting underway and the majority of countries have not yet fully put the policy into practice for Treat All With the courtesy of M. Doherty

20. Policy uptake to full implementation, July 2016 • Implementation is just getting underway and the majority of countries have not yet fully put the policy into practice for Treat All The double (and even triple) standard is still there With the courtesy of M. Doherty

21. When to start in the guidelines When to start in the real life ? 2. No more limitation in financial resources

22. Percentage of African national budgets allocated to health - 2010 < 10%(n=19 [44.2%])

23. ≥15% (n=4 [9.3%]) <15% (n=20 [46.5%])

24. The funding gaps The funding GAPS 44/97 countries (%) , ART funding Gap exceeds 55% of the total resource requirements Dutta A, et Al, Plos Med, 2015

25. How limited financial ressourcesdangerouslyimpact clinical pratices Inadequate forecasting & supply... • Lack of ARV drugs • More patients in advanced stage • Need to prioritize

26. NEW REVISED NEW DIRECTIONS IN WHEN TO START NEW

27. NEW Clinicians should never be asked to prioritize ! REVISED NEW DIRECTIONS IN WHEN TO START NEW

28. The science has spoken. There can now be no excuse for inaction. Fauci, N Eng J Med 2015

29. There is no excuse for delay !!!! IAS Conference, Paris,2003

30. Towards a new treatment Era ? When to start (1) From policy making to the field in clinical practice

31. HIV Cascade in Subsaharan Africa (2013) 55% 61% 71% UNAIDS Gap Report 2014. http://www.unaids.org/en/resources/documents/2014/20140716_UNAIDS_gap_report

32. « Real world... » Raymond et al. HIV Drug Therapy Glasgow Congress 2014 With the courtesy of Y Yazdanpanah

33. « Real world... » • Testing and linkage to care are major issues, even in rich countries • Western Europe do better than U.S ... Raymond et al. HIV Drug Therapy Glasgow Congress 2014 With the courtesy of Y Yazdanpanah

34. HIV Cascade – Rwanda 2014 Nsanzimana, IAS 2015

35. Towards a new treatment Era ? When to start (1) Test ealier to treat earlier

36. 228 185 132 125 Lahuerta, Clin Infect Dis 2014

37. 228 185 132 125 Improvement but still late ART initiation Lahuerta, Clin Infect Dis 2014

38. Rwanda 284 Kenya 204 174 Mozambique 148 Tanzania Disparities between countries Lahuerta, Clin Infect Dis 2014

39. Adapted from: Plazy, BMC Infect Dis 2015

40. The new paradigm for HIV Testing Early ART Early HIV Diagnosis Target asymptomatic patients and/or at-risk people

41. Towards a new treatment Era? When to start (1) Does “Treat irrespective of CD4 count” reallymean “treat everyone” ?

42. Early ARTWillingness to accept or prescribe the treatment Belief or Trust in the treatment Patients Physicians

43. Among 743 eligible for ART (CD4 <200, 2009 SA guidelines) 148 (20%) refused to initiate ART Katz, AIDS 2011

44. Among 743 eligible for ART (CD4 <200, 2009 SA guidelines) 148 (20%) refused to initiate ART Katz, AIDS 2011

45. Early ARTWillingness to accept or prescribe the treatment Belief or Trust in the treatment Patients Physicians

46. 46,886 HIV-infected followed (2005) • LTNP (0.40%) • Elite LTNP (0.05%) • HIV controllers(0.22%) • Elite HIV controllers (0.15%) Grabar, AIDS 2009

47. (N=2056) Temprano ANRS 12136, N Eng J Med 2015; 373:808-822 Temprano ANRS 12136, N Engl J Med 2015

48. (N=2056) Temprano ANRS 12136, N Engl J Med 2015

49. Plasma HIV-1 RNA at 30 months in patient in the « deferred ART » group who did not start ART during trial follow-up Temprano, unpublished data

50. From “When to start” to “When not to start immediately ?” (“Treat everyone but…”) Public health approach vs. individualized HIV care Eholie, AIDS 2014