1. PREVENTION OF HIV-1 Myron S. Cohen, MD Institute for Global Health The University of North Carolina

2. Transmission of HIV-1 Biological Requirements Infectious Susceptibility Inoculum (concentration) Hereditary resistance Phenotypic factors Innate resistance Acquired (immune) resistance

3. semen SI HIV (T-tropic) NSI HIV (M-tropic) Lamina Propria Dendritic Cells CD4+ CCR5+ Α4 β7+ HIV-1 “SWARM” T cell CD4 CCR5 DC-SIGN migration to lymphoid organs 99% R5, 82% 1 variant.

4. HIV-1 Transmission Model Cohen et al, NEJM, 2011 Inoculum Mucosa Recipient Less fit, attenuated or stochastic event (R 0 <<1) Less fit virus (R 0 ~1) ~10 9 infection events >10 6 virions/ml plasma Time (days) 0 3 10 714-28 Defective virus X (Most fit virus R 0 >>1)

5. 10 -5 10 -4 10 -3 10 -2 10 -1 0 10 1 10 2 10 3 10 4 10 5 10 6 10 7 10 8 Transmission Virus Concentration in Extracellular Fluid or Plasma (Copies/ml) Time Post Exposure (days) 0510152030352540 455055606570 Reservoir Virus dissemination Transit eclipse ? T0T0 Acute Phase Reactants Days -5 to-7 Immune Complexes Day 9 Onset cytokines apoptosis, Day 7 Free Antibody, Day 13 CD8 T Cell Responses CTL Escape Autologous Neutralizing Antibody Autologous Neutralizing Antibody Escape Acute HIV-1 Infection Cohen et al, NEJM, 2011

6. Hollingsworth et al 2008 Hayes & White 2006* Pinkerton & Abramson 1996** Kretzschmar & Dietz 1998**† Xiridou et al 2004 Jacquez et al 1994 Abu-Raddad & Longini 2008† Salomon & Hogan 2008* Koopman et al 1997** Pinkerton 2007 Prabhu et al 2009 * Range of estimates reflects the proportion of all transmissions during an individual’s entire infectious period that occur during EHI. The extent to which this proportion corresponds with the proportion of all transmissions that occur during EHI at the population level will depend on the epidemic phase and the distribution of sexual contact patterns in the population. ** Transmission probabilities were drawn from the population category shown, but the reported estimates result from a range of hypothetical sexual behavior parameters that do not necessarily reflect a specific population. † The range of estimates shown was extracted from the endemic-phase portion of graphs showing the proportion of new infections due to EHI over calendar time. Powers et al 2010 Effect of Acute and Early HIV Infection on Spread Cohen et al, NEJM, 2011

7. Four Prevention Opportunities YEARS Treatment Of HIV Reduced Infectivity INFECTED YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms STDs Cohen et al, JCI, 2008 Cohen IAS 2008 HOURS Vaccines ART PrEP Microbicides EXPOSED (precoital/coital) 72h Vaccines ART PEP EXPOSED (postcoital)

8. ART to Prevent Sexual Transmission of HIV Post-exposure Prophylaxis (PEP) Pre-exposure prophylaxis (PrEP) Treatment of the infected person

9. Pre-Exposure Prophylaxis Study Effect CAPRISA (TDF Gel) 39-50% iPREX (Daily TDF) 44% FEM-PrEP (Daily TDF) Stopped Partners (TFV/TDF) >70% Botswana (TDF) >60% Others in Progress

10. Patterson, Cohen, Kashuba et al WAC 2010 Not Detected Concentration 24 Hours After a Single Dose of Truvada® TFV TFV-DP FTC FTC-TP

11. CAPRISA 004: TFV 1% Gel BAT24 Gel Cervicovaginal Fluid Gel Vaginal Tissue Tablet Cervicovaginal Fluid Tablet Blood Plasma Gel Blood Plasma Dumond, Kashuba et al 2007; Schwartz, Kashuba et al IAS 2009 Extracellular Tenofovir Concentrations

12. Pre-Exposure Prophylaxis? Differerences in studies -Gels vs. Pills? -Adherence? PrEP next steps -Infrastructure (testing requirements)? -Dosage schedules? -Different agents? -PrEP for whom?

13. Four Prevention Opportunities YEARS Treatment Of HIV Reduced Infectivity INFECTED YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms Cohen et al, JCI, 2008 Cohen IAS 2008 HOURS Vaccines ART PrEP Microbicides EXPOSED (precoital/coital) 72h Vaccines ART PEP EXPOSED (postcoital)

14. HIV “Treatment as Prevention”? Compelling biological plausibility: ART reduces HIV in genital secretions Five observational reports What is the magnitude and durability of ART for prevention? Does early ART (for prevention) benefit an HIV infected person? POSITIVE RESULTS: Bunnell (JAIDS, 2007) Sullivan (IAS 2008) Donnell (Lancet, 2010) Romero (BMJ, 2010) NEGATIVE RESULTS: Wang (IAS, JAIDS, 2010)

15. 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

16. HPTN 052 Modified April 28, 2011 (DSMB meeting #11) Recommendation: “Make the results available to the public (and study subjects) as soon as possible” HPTN 052 is ongoing with all HIV infected subjects offered ART, regardless of CD4 count

17. 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 PROVEN UNLINKED) –4 infections still being analyzed (ALL IN THE DELAYED ARM) –The details of 1/27 transmissions are being evaluated p<0.001

18. HPTN 052 Clinical Results  105 morbidity and mortality events (p<.01) –65 in delayed arm –40 in immediate arm  20 cases of extrapulmonary TB (p= 0.0013) –17 in delayed arm –3 in immediate arm  23 deaths (NS) –13 in delayed arm –10 in immediate arm

19. HPTN 052 Implications For discordant couples? For the Test and Treat Movement?

20. The Economist June 4, 2011

21. Treatment as Prevention The “Test and Treat” Movement THE HORSE IS OUT OF THE GATE Botswana cohort study (Essex, MP3) US HPTN 065 in NYC, DC, (El-Sadr) ANRS South Africa (Newell, Dabas) Combination Prevention Competition: –CDC September, 2011 –HPTN August, 2011

22. VACCINE COUNSELING ARV TREATMENT ARV TOPICAL PrEP STD TREATMENT? CIRCUMCISION ARV ORAL PrEP ACUTE HIV INFECTION? HIV Prevention