1. How research Strengthens HIV care and prevention in resource constraint settings: Optimization of HIV Care Yazdan Yazdanpanah 1, Serge Paul Eholié 2 1-Service des maladies infectieuses et tropicales, Hôpital Bichat Claude Bernard, INSERM, Atip/avenir U738, Paris 2-Service des maladies infectieuses et tropicales, Hôpital Treichville, Site PACCI- ANRS, Abidjan, Côte d’Ivoire

2. The debate in 2000 “Is antiretroviral therapy possible in severely resource-constrained environments?”

3. “Setting realistic priorities for AIDS control in less-developed countries” “HAART Not affordable Poor people could not adhere: non-compliance Health systems in poor countries could not support: erratic supplies of drugs Not cost-effective Spread of drug-resistant strains of HIV Highly inequitable” Lancet 2000

4. AIDS 2002, 16:1363–1370 Supported by the ANRS and European Union Observational cohort studies Adherence to the HAART regimens was good Responses to treatment good and comparable to those in industrialized countries

5. in North American Studiesin African Studies Mills EJ, JAMA 2006 Concerns about sub- optimal adherence are not supported by the data and such concerns should not contribute to delayed access to care

6. The prevalence of resistant viruses = 11.8% AIDS 2003, 17 (suppl 3):S31–S38 Supported by the ANRS and European Union Observational cohort studies

7. Supported the use and funding of a generic fixed- dose in developing countries Lancet 2004; 364: 29–34

8. Goldie et al. N Engl J Med 2006 Supported by the ANRS, NIAID, Doris Duke Charitable Foundation Cost-effectiveness of cART = $ 1180/YLS < 3 x Côte d’Ivoire GDP/capita (708 $) = “cost-effective”

9. The Research Agenda What to start with? When to start? How should we monitor ART efficacy and what criteria for switching ART regimens? How should we improve –HIV testing (patients unaware of their status), –Linkage to care –Adherence interventions How should we avoid –Loss to follow-up –Medication stockout While scaling-up : how best to utilize available resources?

10. What to start with? Optimize and ideal regimen Convenience: Fixed dose combination, once a day, no food/liquid requirements; Compatibility: pregnant women, tuberculosis, HBV, HCV Potency/Efficacy Tolerability/safety Affordability Long term compliance Robsutness/Forgiveness (High genetic barrier) No overlapping resistance (chance for second line) WHO, Think Tank on HIV treatment optimization, Montreux, Switzerland, May 2012

11. What to start with? PI-based regimen was not superior to NNRTI at week 96 However, NNRTI-NRTI regimen was associated with a significantly higher rate of virologic failure and higher incidence of resistance mutations NNRTI vs. PI for HIV treatment (Low cost, FDC, tolerance vs. genetic barrier, emergence of resistance) Clumeck et al. CROI 2012 Lubumbashi trial,

12. Randomised controlled trials not always ideal Short term evaluation vs. Long term evaluation

13. In the case of two available regimens, the model inherently favored initiating with a NNRTI-based regimen and using a boosted PI-regimen subsequently. –NRTI options limited –the second PI- or NNRTI-based regimen efficacy similar to the addition of a single drug to an already resistant NRTI backbone. –PI monotherapy greater efficacy than NNRTI monotherapy AIDS 2007, 21:973–982 Supported by the ANRS, NIAID, Doris Duke Charitable Foundation

14. d4T vs Tenofovir (cost issue) Using tenofovir as part of first- line ART in India will improve survival, is cost-effective by international standards Clin Infect Dis 2010AIDS 2011

15. When to start? CD4 cell count 200-350 vs. < 200 CD4 cell count 350-550 vs. < 250

16. Trials exploring the benefits and risks of initiating ART at very high CD4 cell counts make more sense in low- resource than in rich countries. Clin Infect Dis 2012;54(5):714–23 Supported by the ANRS

17. Essai Temprano ANRS 12136 (N=2075); http://www.clinicaltrials.gov/ct2/show/NCT00495651 France, USA..., guidelines Essai START; http://www.clinicaltrials.gov/ct2/show/NCT00867048 Ongoing trials (Temprano, START) ? CD4 threshold to initiate ART in asymptomatic patients WHO guidelines « for a public health approach »

18. Strategies to monitor ART efficacy Lancet 2008 Archives Intern Med 2008 J AIDS 2010

19. 19 Lancet Infect Dis 2011; 11: 825–33 13 participants (6%) in the LAB group switched to second-line regimens whereas no participants in the CLIN group did so (p<0·0001) Supported by the ANRS

20. Low sensitivity of immunologic criteria: failures are missed, accumulation of resistance mutations. Low specificity and predictive values; large numbers of unnecessary ART switches = increased costs because of excess switches to more expensive ART 20 Clin Infect Dis 2011;53(12):1283–90

21. Viral load sites (South Africa, n = 18 706) Nonviral load sites (Zambia and Malawi, n = 80937) Failure on 1 st line but no switch 1,3%3,7% Switch to 2 nd line therapy 9,8%2,1% Loss to follow up9,2%15,3% Deaths4,3%6,3% AIDS 2011

22. Clinical trials : Substantial benefits for key outcomes favoring Biol vs. Clin Observational studies : more frequent switching, earlier switching, and switching at higher CD4 counts when comparing Biol vs. Clin Low to very low-quality of evidence

23. Clinical Infectious Diseases 2012;54(8):1187–95

24. M6: VF 21.8% M12: VF 23.% M24: VF 26.7% M36: VF 38% AIDS 2012

25. HIV care optimization HIV testing (patients unaware of their status) Linkage to care Pre-ART loss to follow-up Reduce the delay to start ART

26. AIDS 2011

27. Oral supervised self-testing was highly acceptable and accurate, Plos Med 2011 Promote HIV testing

28. “Whatever the next hottest, scientifically proven HIV treatment or prevention strategies are : –PreP –TasP they will share a common denominator for implementation: the HIV test. They all begin with learning one’s HIV status.” Walensky et al. Plos Med 2011

29. Plos Med 2011

30. After the introduction of point-of-care CD4, the proportion of loss to follow-up before initiation of antiretroviral treatment fell from 64% to 33% (OR 0·27, 95% CI 0·21-0·36)

31. HIV care optimization Adherence Loss to follow-up J Acquir Immune Defic Syndr 2011;56:e39–e44

32. “An old African proverb states that the growth of a deep-rooted tree cannot be stopped. Our tree - representing care and support for people living with HIV in LMIC – is well rooted in existing field experience and is therefore expected to grow.” Serge Paul Eholié