Microbicides - A New Frontier in HIV Prevention

Microbicides - A New Frontier in HIV Prevention

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 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 Slide 2 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? Slide 4 of 34 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 Slide 6 of 34 Diagnoses of HIV Infection among Adults and Adolescents, by Transmission Category, 20092013 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 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 Slide 9 of 34 Rene P, 21 yo man, referred by a partner who had syphilis What do you do? 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) 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 Slide 12 of 34 Antiretroviral Prevention: A Timeline 1995 PMPA effective in macaque 2006 HPTN-059 Phase 2

2005 HPTN-050 Phase 1 2007 TDF PrEP Study 2010 CAPRISA 004 Phase 2B 2010 iPrEX 2015 FACTS 001 2013 MTN-003 VOICE 2011 2015

2011 Partners iPerGay HPTN-052 PrEP 2015 2011 2011 PROUD FEM-PrEP TDF2 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 Slide 16 of 34 Key Components of These Trials HPTN 052 Partners PrEP iPrEX

VOICE & FEMPrEP 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 Key Components of These Trials HPTN 052

Partners PrEP iPrEX VOICE & FEMPrEP 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 18 of 34 Adherence & PrEP Efficacy % of blood samples with TFV detected HIV protection efficacy in randomized comparison 81% 75% TDF2 79% 62% iPrEx 51% 44%

FEM-PrEP 26% NS VOICE 28% NS Partners PrEP FTC/TDF arm 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 Clear dose-response relationship between evidence of PrEP use & efficacy Slide modified from J. Baeten Slide 19 of 34

Oral PrEP + ART as Prevention in High-Risk Serodiscordant Couples Partners Demonstration Project in Africa Oral daily TDF/FTC PrEP for HIVuninfected 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) HIV Incidence, Actual vs Expected Group Expected Actual Infected, n Incidence/100 PY (95% CI) 39.7 5.2 (3.7-6.9) 2

0.2 (0-0.9) 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. Slide 20 of 34 PrEP Safety Rates of death, serious adverse events, and laboratory abnormalities (including renal dysfunction) very low

PrEP well tolerated Not significantly different between those on PrEP and placebo 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 Immediate Infected, n Incidence/100 PY (90% CI) 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 Slide 18 of 34 Patterns of Pill Use on the Basis of Clinic Visits 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 Molina J-M et al. N Engl J Med 2015;373:2237-2246 Slide 24 of 34 Clinical Infect Dis, Sept 2015 Slide 25 of 34 PrEP in the Real World 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 Slide 26 of 34 PrEP and STIs in >600 MSM Kaiser Permanente San Francisco STI Incidence After 12 Months of PrEP Use 60% 50% 40% 33% 33% 28% 20% Expected HIV incidence with this STI incidence: 8.9% 6%

0% y n A I T S R ta c e I T lS l h C ia d y m a

G r o on a e rh li s i ph y S Volk et al. CID 2015 0% IV H Slide Slide 27 of 34

PrEP Demo Project (NIAID), n=557 30 % Positive 25 20 15 10 5 0 Screening 12 24 Visit Week 36 GC, CT or Syphilis Rectal GC or CT Pharyngeal GC

or CT 48 Cohen 2015, cidence = 0.43 cases / 100 py (95% CI 0.05-1.54) ISSTDR cidence (90 cases/100 py) stable across quarterly intervals (P> 0 of participants had at least one STI during follow-up pected, >75% of GC and >85% of CT infections were asymptomat 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 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 1 in 18 MSM were diagnosed with HIV within 1 year.** Syphilis No rectal STD or syphilis infection 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 Slide 30 of 34 Vaginal Rings for HIV Prevention Goal: reliable, long-lasting, womaninitiated 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 Thoughts & Next Steps Slide 31 of 34 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

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