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

After attending this presentation, participants will be able to: 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

Discussion HIV incidence: two snapshots & a case Slide 4 of 34 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?

One third of new HIV infections globally occur in young African women Slide 5 of 34 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 6 of 34 Diagnoses of HIV Infection among Adults and Adolescents, by Transmission Category, 2009–2013 — United States and 6 Dependent Areas Accounts for 81% of transmissions among men; increase highest in 25-34 y.o. 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. This slide presents the distribution of diagnoses of HIV infection among adults and adolescents diagnosed from 2009 through 2013, by transmission category, for the United States and 6 dependent areas.   The percentage of adults and adolescents with diagnosed HIV infection attributed to male-to-male sexual contact increased from 58% in 2009 to 65% in 2013. The percentages of diagnosed HIV infections attributed to injection drug use, male-to-male sexual contact and injection drug use, and heterosexual contact remained relatively stable (less than a 5% increase or decrease) from 2009 through 2013. A very small percentage of diagnosed infections each year were attributed to other transmission categories. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data are estimates. Estimated numbers resulted from statistical adjustment that accounted for reporting delays and missing transmission category, but not for incomplete reporting. Heterosexual contact is with a person known to have, or to be at high risk for, HIV infection. Other transmission categories include hemophilia, blood transfusion, perinatal exposure, and risk factor not reported or not identified.

Rene P, 20 yo man, referred by partner “who had syphilis” Slide 7 of 34 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

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

Rene P, 21 yo man, referred by partner “who had syphilis” Slide 10 of 34 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) PLEASE FORMAT AS ARS

Emphasized biobehavioral nature of the interventions needed Slide 11 of 34 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

Antiretroviral Prevention: A Timeline Slide 12 of 34 Antiretroviral Prevention: A Timeline 1995 PMPA effective in macaque 2006 HPTN-059 Phase 2 2010 CAPRISA 004 Phase 2B 2015 FACTS 001 2013 MTN-003 VOICE 2011 Partners PrEP 2015 iPerGay 2010 iPrEX 2005 HPTN-050 Phase 1 2007 TDF PrEP Study 2011 HPTN-052 2015 PROUD The efficacy of pre- and postexposure treatment with the antiviral compound (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) was tested against simian immunodeficiency virus (SIV) in macaques as a model for human immunodeficiency virus (HIV). PMPA was administered subcutaneously once daily beginning either 48 hours before, 4 hours after, or 24 hours after virus inoculation. Treatment continued for 4 weeks and the virologic, immunologic, and clinical status of the macaques was monitored for up to 56 weeks. PMPA prevented SIV infection in all macaques without toxicity, whereas all control macaques became infected. These results suggest a potential role for PMPA prophylaxis against early HIV infection in cases of known exposure. Science 2011 FEM-PrEP 2011 TDF2 10 10

Efficacy of Biomedical Interventions to Prevent HIV Acquisition: Evidence from Selected Randomized Clinical Trials Why important to review the evidence: because PrEP efficacy and safety in the real world depend critically on this understanding. Modified from Ambitious Treatment Targets: Writing the Final Chapter of the AIDS Epidemic, UNAIDS, 2014

Key Components of These Trials Slide 16 of 34 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

Key Components of These Trials Slide 17 of 34 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

Adherence & PrEP Efficacy Slide 18 of 34 % of blood samples with TFV detected HIV protection efficacy in randomized comparison Partners PrEP FTC/TDF arm 81% 75% TDF2 79% 62% iPrEx 51% 44% FEM-PrEP 26% NS VOICE 28% 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

Oral PrEP + ART as Prevention in High-Risk Serodiscordant Couples Slide 19 of 34 Oral PrEP + ART as Prevention in High-Risk Serodiscordant Couples 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 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 HIV Incidence, Actual vs Expected Group Infected, n Incidence/100 PY (95% CI) Expected 39.7 5.2 (3.7-6.9) Actual 2 0.2 (0-0.9) ART, antiretroviral therapy; FTC, emtricitabine; IRR, incident rate ratio; PrEP, pre-exposure prophylaxis; PY, patient-years; TDF, tenofovir DF; TFV, tenofovir. Baeten J, et al. CROI 2015. Abstract 24. Reproduced with permission.

Slide 20 of 34 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 22 of 34 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) HIV Incidence Group Infected, n Incidence/100 PY (90% CI) Immediate 3 1.3 (0.4-3.0) Deferred 19 8.9 (6.0-12.7) DMSB interrupted trial; recommended that all participants be offered PrEP Lancet 2015

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

Patterns of Pill Use on the Basis of Clinic Visits Figure 2 Patterns of Pill Use on the Basis of Clinic Visits during the Study Period. Shown are the number of doses of TDF-FTC (Panel A) and placebo (Panel B) that were taken during the 32-month study period (M1 through M32). Six categories of pill use per month were defined at each visit: no pill use or missing data, 1 to 4 pills, 5 to 11 pills, 12 to 18 pills, 19 to 25 pills, and 26 to 30 pills. Each colored bar represents a single patient; the length of follow-up varies according to the time of enrollment. Molina J-M et al. N Engl J Med 2015;373:2237-2246

Probability of HIV-1 Infection 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 Figure 3 Kaplan–Meier Estimates of the Probability of HIV-1 Infection. The cumulative probability of HIV-1 acquisition is shown for the two study groups in the modified intention-to-treat analysis. The inset shows the same data on an enlarged y axis. Molina J-M et al. N Engl J Med 2015;373:2237-2246

Clinical Infect Dis, Sept 2015 Slide 24 of 34 Clinical Infect Dis, Sept 2015 (95% CI 58-71)

PrEP in the “Real” World Slide 25 of 34 The Good News: No new HIV infections in over 600 PrEP initiators at Kaiser Permanente San Francisco No new HIV infections despite self-reported decreases in condom use – PrEP works Limitations of KP data: No control group Fewer condoms ≠ more HIV risk ? “PrEP-sorting” Undetectable viral loads Nuanced decisions about condoms Volk et al. CID 2015; Image courtesy J Volk

PrEP and STIs in >600 MSM Kaiser Permanente San Francisco Slide 26 of 34 Expected HIV incidence with this STI incidence: 8.9% (95% CI 58-71) Volk et al. CID 2015 Slide courtesy J. Volk

PrEP Demo Project (NIAID), n=557 Slide 27 of 34 Cohen 2015, ISSTDR 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

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

A Vicious Cycle: STDs predict future HIV Risk Slide 29 of 34 A Vicious Cycle: STDs predict future HIV Risk Rectal GC or CT 1 in 15 MSM were diagnosed with HIV within 1 year.* Primary or Secondary Syphilis 1 in 18 MSM were diagnosed with HIV within 1 year.** No rectal STD or syphilis infection NOTE: This slide has limitations because they are not exact comparisons. P&S Syphilis analysis uses case based surveillance data matching to get the hazard ratio and the annual incidence on the slide. The incidence for all men in the syphilis group was 1/20 within the year. As such, there is no data on syphilis negatives – this makes it a pretend cohort rather than a real cohort. Rectal GC/CT and the no STD category uses an STD clinic cohort that was then matched to HIV case registry data. It seems like a much more valid cohort analysis to me, since we have information on STD-negatives to compare it to. I used incidence among those negative for rectal infection and no syphilis in the past 2 years to get the 1/53 figure. The population for all of these groups was HIV-negative MSM, which is implied but not explicit on this slide. 1 in 53 MSM were diagnosed with HIV within 1 year.* *STD Clinic Patients, New York City. Pathela, CID 2013:57; **Matched STD/HIV Surveillance Data, New York City. Pathela, CID 2015:61

Vaginal Rings for HIV Prevention Slide 30 of 34 Vaginal Rings for HIV Prevention 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

Slide 31 of 34 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