Antiretrovirals for HIV Prevention: Progress and Challenges Kenneth H. Mayer, M.D. Brown/Miriam/Fenway

HIV PREVENTION 2010 DECREASE SOURCE OF INFECTION Barrier protection Blood screening IDU harm reduction STI Treatment? Antiretroviral Therapy PMTCT Rx infected partners DECREASE HOST SUSCEPTIBILITY Barrier protection Infection Control Circumcision Vaccines? STI Treatment? PEP Oral PREP Topical Microbicides ALTER BEHAVIOR Condom and HIV testing promotion Individual interventions Couples interventions Community-based interventions Structural interventions (e.g., economic)

HOW ANTIRETROVIRALS CAN AFFECT HIV TRANSMISSION  PLASMA    SURVIVAL HIV  PLHIV  GENITAL TRACT  DURATION OF HIV INFECTIOUSNESS  TRANSMISSION  TRANSMISSION RELEVANT ISSUES: ACCESS, ADHERENCE, PREVENTION, STI RX.

Treatment as Prevention: Discordant Couples 2,993 couples were followed for a median of 512 days Sexual risk behaviors lower in those on ART (19% vs 25%, P<0.05) Both ART and change in behavior independently reduced HIV transmission Sullivan P. CROI 2009 HIV-free Survival of HIV- partners, by ARV status of HIV+ Partner Survival Probability Days Off ARV On ARV Censored Logrank P<.0001 Donnell, D. CROI, 2010: 1 linked transmission in Partners study from one person who had been on HAART for 18 days in a sample with 236 py f/u, compared to 2.23% incidence in untreated couples Over 90% decrease in HIV transmission with HAART

Can Antiretrorivals ↓ HIV Transmission?  HIV in several countries where treatment and prevention have been integrated, e.g. Brazil and Taiwan (Porco, AIDS, 2004; Fang, JID, 2004) Counter: Resistant HIV transmission (Imrie, JID, 1997; Little, NEJM, 2002; Angarano, AIDS, 2004) but prevalence may be decreasing because of HAART efficacy (Routy, AIDS, 2004) MSM: ↓ Community Viral Load, ↓ HIV incidence in SF (Das-Douglas, CROI, 2010, Session 10, 2/17) Counter: ↑ HIV incidence in Amsterdam MSM (Jansen, CROI 2010, Session 10, 2/17) HPTN 052 will answer whether starting earlier treatment can decrease HIV incidence But, Cell-Associated HIV is a major source of infectious virus (Anderson et al, AIDS, 2010)

HPTN 065 (TLC Plus) Testing, Linkage to Care, Treatment, Plus Lots More…. Test HIV Positive Adopt safer behaviors Enroll in Care Treat Maintain viral suppression Positive Prevention Testing Initiation of ART Linkage to care Adherence to ART Decrease in HIV Transmission

Why Antiretrovirals for 1° Prevention? Non-human primates –Multiple drugs have been shown to decrease HIV transmission pre or post exposure PMTCT, even single dose NVP to Mother/Infant was protective –? Enough time to lower VL in mother –? Direct infant benefit from antiretrovirals Occupational Post Exposure Prophylaxis (PEP) after percutaneous exposures –Associated with lower risk in HCW –AZT alone associated with 80% decrease –Not RCT, retrospective case-control MMWR 2005

Non-Occupational PEP Schechter et al, JAIDS, 2004 N=200 high risk Brazilian MSM –Followed over 24.2 months PEP (AZT/3TC) 4 day starter pack –28 day course 68 used PEP 109 times HIV incidence 2.9/100py –10 infected who did not use PEP (N=132) –Assumed partner was HIV-Uninfected –1 infection in a PEP user (N=68) –Risk Behavior Decreased Similar to SF experience (Martin et al, AIDS, 2004)

Study to assess most effective modality for topical ARV gels 1% TDF or 1% TDF/5% FTC gels in 23 macaques Gel (matrix + preservatives) clear, viscous, odorless, stable at 37° x 6 months 3 ml gel applied 30 mins before vaginal challenge with R5 virus inoculum (10 TCID 50 ) Challenges 2x/week for total 20 challenges Topical PrEP in Macaques with TDF or TDF/FTC no gel (n=2) placebo gel (n=9) FTC/TDF gel (n=6) TDF gel (n=6) % Protected Dobard C, et al, CROI, 2009; Dobard et al, CROI, 2010, poster 949 Challenges

What if PrEP “Works”? Block other steps in HIV life cycle, e.g. binding and integration? Develop drugs just for prevention? New Co-formulations: Generic PrEP? Topical vs. Oral: VOICE and beyond What is the optimal drug delivery system: gel, ring, suppository, diaphragm, injection, or pill? How to best dose: Fixed intervals vs. pre/post coital? PrEP and the immune system: adjuvant for vaccines? Special populations: youth, pregnant women

What if PrEP “Works”? Who should prescribe: How best to train providers? How will access be ensured in resource-limited settings? Prevention package: What is optimal counseling? How to often to monitor: safety labs, and test for new HIV infection/resistance? Home testing? How to facilitate best practices? New roles for ASO’s; use of new media to educate Will need enhanced surveillance for intended (decreased HIV incidence) and unintended (risk compensation, resistance) consequences