1. Jeanne M. Marrazzo, MD, MPH Professor of Medicine University of Washington Seattle, Washington A Shot in the Arm for HIV Prevention? Opportunities and Challenges in 2016 FORMATTED: 11/17/15 New Orleans, Louisiana: December 15-17, 2015

2. Slide 2 of 34 Learning Objectives After attending this presentation, participants will be able to: Discuss the approach to transitioning from PrEP to PEP Define contraindications to initiating antiretroviral PrEP Discuss accurate counseling messages for men who elect to use TDF-FTC as PrEP

3. Discussion  HIV incidence: two snapshots & a case  MSM in U.S.  Young women in sub-Saharan Africa  Understanding the evidence for new prevention options & implementation  Pre-exposure prophylaxis with antiretrovirals (PrEP)  Multipurpose prevention  Unintended consequences? Slide 4 of 34

4. One third of new HIV infections globally occur in young African women In context of ART scale up with 40% of HIV+ persons on ART & 6 million medical male circumcisions performed by end of 2013 Need to implement effective primary prevention strategies Slide 5 of 34

5. Diagnoses of HIV Infection among Adults and Adolescents, by Transmission Category, 2009–2013 — United States and 6 Dependent Areas Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays and missing transmission category, but not for incomplete reporting. a Heterosexual contact with a person known to have, or to be at high risk for, HIV infection. b Includes hemophilia, blood transfusion, perinatal exposure, and risk factor not reported or not identified. Accounts for 81% of transmissions among men; increase highest in 25-34 y.o. Slide 6 of 34

6. Rene P, 20 yo man, referred by partner “who had syphilis”  Considers himself healthy, no symptoms  HIV Ag-Ab test negative last week  Last syphilis serology negative 3 months ago  Two episodes of rectal gonorrhea last year  Moved to U.S. from Mexico last year  Sometimes uses meth on weekends  6 partners in last 3 months, some anonymous. Last unprotected sex 12 h ago Slide 7 of 34

7. Rene P, 21 yo man, referred by a partner “who had syphilis”  What do you do? Slide 9 of 34

8. Rene P, 21 yo man, referred by partner “who had syphilis”  Send confirmatory syphilis test (EIA, TPPA) before treating for syphilis  Treat him with BZN PCN 2.4 x 10-6 mu IM weekly for three weeks  Check plasma HIV viral load  Offer him TDF-FTC as PrEP and see him in 3 months  Treat now for sexual PEP (TDF/FTC/raltegravir) Slide 10 of 34

9. HIV Prevention in Clinical Care Settings: 2014 Recommendations of the International Antiviral Society-USA Panel: Emphasized biobehavioral nature of the interventions needed Marrazzo JM, Holtgrave DR, del Rio C et al, JAMA 2014 Free web access to the paper at jama.com Slide 11 of 34

10. Antiretroviral Prevention: A Timeline 1995 PMPA effective in macaque 2005 HPTN-050 Phase 1 2006 HPTN-059 Phase 2 2010 CAPRISA 004 Phase 2B 2010 iPrEX 2011 FEM-PrEP 2011 HPTN-052 2011 TDF2 2015 PROUD 2013 MTN-003 VOICE 2007 TDF PrEP Study 2015 FACTS 001 2015 iPerGay 2011 Partners PrEP Slide 12 of 34

11. Efficacy of Biomedical Interventions to Prevent HIV Acquisition: Evidence from Selected Randomized Clinical Trials Modified from Ambitious Treatment Targets: Writing the Final Chapter of the AIDS Epidemic, UNAIDS, 2014

12. Key Components of These Trials HPTN 052 Partners PrEP iPrEX VOICE & FEM- PrEP CAPRISA 004 Standard prevention “package”* ✔✔✔✔✔ Intensive adherence counseling ✔✔✔✔✔ Enrolled both members of discordant couples ✔✔ Study product use timed with likely HIV exposure ✔ Real-time biological marker of product adherence ✔ * Condoms, counseling, STI management Slide 16 of 34

13. Key Components of These Trials HPTN 052 Partners PrEP iPrEX VOICE & FEM- PrEP CAPRISA 004 Standard prevention “package”* ✔✔✔✔✔ Intensive adherence counseling ✔✔✔✔✔ Enrolled both members of discordant couples ✔✔ Study product use timed with likely HIV exposure ✔ Real-time biological marker of product adherence ✔ * Condoms, counseling, STI management Slide 17 of 34

14. Adherence & PrEP Efficacy % of blood samples with TFV detected HIV protection efficacy in randomized comparison Partners PrEP FTC/TDF arm 81%75% TDF279%62% iPrEx51%44% FEM-PrEP26%NS VOICE28%NS Clear dose-response relationship between evidence of PrEP use & efficacy Baeten et al N Engl J Med 2012 Grant et al N Engl J Med 2010 Van Damme et al N Engl J Med 2012 Thigpen et al N Engl J Med 2012 Slide modified from J. Baeten Slide 18 of 34

15. Oral PrEP + ART as Prevention in High-Risk Serodiscordant Couples Partners Demonstration Project in Africa –Oral daily TDF/FTC PrEP for HIV- uninfected partner in serodiscordant couple continued 6 mos beyond initiation of ART for infected partner –High-risk couples defined as younger age, fewer children, uncircumcised HIV-negative male, cohabitating, unprotected sex in past mo, high HIV-1 RNA in HIV-positive partner Interim analysis –> 95% of HIV-negative partners using PrEP –80% of HIV-positive partners have initiated ART; of these, > 90% with suppression  96% reduction in expected infections ‒IRR, expected vs observed: 0.04 (95% CI: 0.01- 0.19; P <.0001)  In pts with seroconversion, no TFV detectable in plasma at time of seroconversion – HIV-positive partner in 1 couple not on ART (high CD4+ count) – Other couple dissolved and HIV-negative partner in new relationship Baeten J, et al. CROI 2015. Abstract 24. Reproduced with permission. HIV Incidence, Actual vs Expected GroupInfected, n Incidence/100 PY (95% CI) Expected39.75.2 (3.7-6.9) Actual2 0.2 ( 0-0.9 ) Slide 19 of 34

16. PrEP Safety Rates of death, serious adverse events, and laboratory abnormalities (including renal dysfunction) very low Not significantly different between those on PrEP and placebo PrEP well tolerated Adverse effects occurred in minority of subjects GI adverse effects (e.g., nausea) more common in those receiving PrEP than placebo (< 10%, primarily during the first month only) PrEP safe during pregnancy (Mugo JAMA 2014) No reduction in contraceptive efficacy (Murnane AIDS 2014) Rare acquired resistance (about 3%); 12 infections averted for each case of resistance Slide 20 of 34

17. Randomized, open-label trial of daily oral TDF/FTC PrEP in HIV- MSM in 13 clinics in London –Immediate (n = 267) vs –Deferred for 12 mos (n = 256) Primary endpoint: HIV infection in 12 mos  86% reduction in risk seen over 60 wks with immediate PrEP (90% CI: 58% to 96%, P =.0002) –Number needed to treat to prevent 1 infection: 13 (90% CI: 9-25)  DMSB interrupted trial; recommended that all participants be offered PrEP HIV Incidence GroupInfected, n Incidence/100 PY (90% CI) Immediate31.3 (0.4-3.0) Deferred198.9 (6.0-12.7) Lancet 2015 Slide 22 of 34

18. Slide 18 of 34 NEJM 14 Dec 2015 Randomized double-blind trial of event-driven oral TDF/FTC* (n = 199) vs placebo (n = 201) (both with prevention services) in France – 2 tablets taken 2-24 hrs before sex – 1 tablet 24 hrs after sex – 1 tablet 48 hrs after first event-driven dose Primary endpoint: HIV seroconversion

19. Patterns of Pill Use on the Basis of Clinic Visits Molina J-M et al. N Engl J Med 2015;373:2237-2246

20. Probability of HIV-1 Infection Molina J-M et al. N Engl J Med 2015;373:2237-2246 86% reduction in risk in PrEP arm (95% CI: 40% to 99%, P =.002) Number needed to treat for 1 yr to prevent 1 infection: 18 Median of 16 pills taken per mo in each arm

21. Clinical Infect Dis, Sept 2015 Slide 24 of 34

22. The Good News:  No new HIV infections in over 600 PrEP initiators at Kaiser Permanente San Francisco Volk et al. CID 2015; Image courtesy J Volk PrEP in the “Real” World Slide 25 of 34

23. PrEP and STIs in >600 MSM Kaiser Permanente San Francisco Volk et al. CID 2015 Slide courtesy J. Volk Expected HIV incidence with this STI incidence: 8.9% Slide 26 of 34

24. HIV incidence = 0.43 cases / 100 py (95% CI 0.05-1.54) STI incidence (90 cases/100 py) stable across quarterly intervals (P> 0.1) 50.9% of participants had at least one STI during follow-up As expected, >75% of GC and >85% of CT infections were asymptomatic PrEP Demo Project (NIAID), n=557 Cohen 2015, ISSTDR Slide 27 of 34

25. Syphilis rates among MSM: timeline Peterman, 2015, Expert Rev Anti Infect Ther Syphilis rates among MSM will soon be similar to those in the early 1980s Slide 28 of 34

26. A Vicious Cycle: STDs predict future HIV Risk 1 in 15 MSM were diagnosed with HIV within 1 year.* 1 in 53 MSM were diagnosed with HIV within 1 year.* Rectal GC or CT 1 in 18 MSM were diagnosed with HIV within 1 year.** Primary or Secondary Syphilis No rectal STD or syphilis infection *STD Clinic Patients, New York City. Pathela, CID 2013:57; **Matched STD/HIV Surveillance Data, New York City. Pathela, CID 2015:61 Slide 29 of 34

27.  Goal: reliable, long-lasting, woman- initiated method to protect against HIV acquisition  ASPIRE (MTN-020) studied dapivirine, with complementary studies: IPM 027 (efficacy & safety) >25 completed phase I/II studies Results anticipated early 2016 Vaginal Rings for HIV Prevention Slide 30 of 34

28. Thoughts & Next Steps  PrEP works, when taken consistently, and is the most effective tool for preventing sexual HIV transmission we have so far  Only one ARV (TFV) available; data for women still limited  Critically dependent results coming up:  Intravaginal dapivirine ring  HPTN studies of long-acting ARV (cabotegravir, rilpivirine)  Rectal microbicide development  Combination product development  Antiretroviral + hormonal contraceptive Slide 31 of 34