1. Use of Antivirals in Prevention: Current Challenges and Controversies: Treatment for Prevention IAS 2011 Nancy Padian Senior technical consultant OGAC/PEPFAR UC Berkeley

2. Outline Review of the evidence Implementation Science Challenges – Burden on health systems – Testing and linkages to care – Eligibility – Adherence – Prioritizing distribution

3. Evidence for treatment for prevention

4. Ecological Studies and ART Population Level Benefit San Francisco (PloS One, 2010) British Columbia (Lancet, 2010) Ambiguous Benefit? Amsterdam France Australia

5. (Cohen et al, Current Opinion HIV 2011)

6. Modeling Population-Level ART Effects Cohen and Gay, CID 2010 1 st author (yr)Key assumptionsResults Blower (2000)Steady risk behavior levels; low resistance rate; 50% - 90% ART coverage substantial ↓in HIV incidence Lima (2008)75% - 100% ART coverage when CD4 < 200; stable adherence 37% - 62% ↓ in HIV incidence Granich (2009)Universal annual HIV testing & immediate treatment African HIV epidemic could be ended Law (2001)2X-10X ↓ in infectiousness; 40% - 70% ↑ in unsafe sex Behavioral disinhibition could limit preventive benefit Fraser (2004)Viral load suppression on ART limits transmission; 66% ↑ in risk behavior Behavioral disinhibition could limit preventive benefit Wilson (2008)Effective ART reduces viral load to < 10 copies / mL; decreased condom use Behavioral disinhibition could limit preventive benefit Baggaley (2006)Treatment of all w/ AIDS & pre-AIDS; decreased risk-taking Only small number of infections averted

7. HPTN 052 1763 discordant heterosexual couples (9 countries, 13 sites) Immediate ART 350-550cells/uL Deferred ART CD4 <250 AZT+3TC+EFV Endpoints: i) HIV transmission to partners ii) OIs and clinical events iii) ART toxicity Randomization

8. HPTN 052 Prevention Results  39 total infections, 35 in the delayed arm (p<.0001) – 28 linked infections (by 3 independent methods) 27 delayed arm 1 immediate arm o 17 of 27 infections in delayed arm occurred when the index participants’ CD4 was >350 – 7 unlinked infections 4 delayed arm (all now proven unlinked) 3 immediate arm (all now proven unlinked) – 4 infections still being analyzed (all in the delayed arm) – The details of 1/27 transmissions are being evaluated p<0.001

9. Effect of ART at Population Level Depends on: – durable and reliable HIV suppression – preventing transmitted resistance – dealing with acute HIV infection – numerous implementation issues

10. Implementation Science Challenges

11. Added Burden to Health System Human Resources – Task shifting Increased training Structural Resources Centralized and Decentralized care Increased Commodities – (e.g. test kits, drugs)

12. HIV testing and linkages to care Consider supply side interventions – PBF/P4P – CCT Develop service delivery models that: – Optimize testing uptake and increase demand – Optimize linkages to care and treatment – Protect patient rights and confidentiality – Examples Demand-side incentives Home-based, door-to-door testing Non-medical venues (hair salons, markets)

13. Knowledge of HIV Status among PLWH – Kenya 84% of HIV-infected adults did not know their status. 16% knew they were positive 28% reported last HIV-test negative 56% never tested for HIV KAIS, 2008

14. Gardner et al, CID. 2010: “ We estimate that only 19% of HIV-infected individuals in the United States have an undetectable HIV load.”

16. Barriers to Introducing & Scaling up Core Interventions for IDUs NSP – Police harassment – Administrative and pretrial detention without due process – Type of syringes distributed not always acceptable – High threshold policies and programmatic requirements constrain program and coverage Test – Stigma and discrimination – Testing in government-run facilities – Lack of confidentiality of test results – No or limited/inaccessible services available – Operational policies limit accessibility of testing (e.g. Only phlebotomists can administer test, limited use of rapid testing technologies, delay in receipt of positive results)

17. Barriers to Introducing & Scaling Up Core Interventions for IDUs Treat – ART Eligibility criteria excludes active IDUs from ART MAT often necessary before approval for ART initiation Stock outs of ART MAT not widely available – MAT Register with authorities before eligible for services Police harassment Information shared between health and law enforcement Lose rights to gainful employment, child custody High threshold policies and programmatic requirements constrain program and coverage Stock outs

18. Eligibility Right people, right drug concentration, right agent, right time Requires high uptake of frequent testing How to identify most contagious people early – Early, acute infection – Challenges linking asymptomatic people to care Need for acute infection incidence assay

19. Powers et al, Lancet 2011. Overall 38.4% of HIV transmissions in Lilongwe attributed to sexual contact with individuals with early infection

20. Adherence Innovative strategies for real time monitoring Less adherent-dependent doses Innovative delivery systems; long-acting, slow release Rings Implants Patches Better tolerated products

21. A cornerstone for combination prevention Behavior change – Adherence – Risk compensation condoms number of partners Links to: circumcision, PMTCT, PrEP, care, structural programs (especially for young women)

22. How to Prioritize Distribution Pregnant women Discordant couples Stigmatized and marginalized high risk groups – (e.g. FSW, IDU, HIV+) Children Challenge is how to ensure equity when treatment is not yet available to all who need it

23. Many Thanks!! Mike Cohen Wafaa El-Sadr Rich Needles