Ian McGowan MD DPhil FRCP University of Pittsburgh Pittsburgh, PA, USA Why We Need More than PrEP Expanding the HIV Prevention Toolbox in Africa Ian McGowan MD DPhil FRCP University of Pittsburgh Pittsburgh, PA, USA

Disclosure I have no financial relationships with a commercial entity producing, marketing, reselling or distributing healthcare related products and/or services.

Prevention Options for MSM & TGW Proven interventions Oral PrEP (Diagnosis and treatment of STIs) (Condoms) (Circumcision) Interventions under evaluation Long-acting antiretroviral agents Broadly neutralizing antibodies Rectal microbicides Vaccines

What Do People Want? “With a lack of understanding of their social and sexual lives and HIV risks, and with MSM being a hidden and stigmatized group in the region, optimized HIV prevention packages for southern African MSM are an urgent public health and research priority.” McNaghten A et al. 2014

The State of the Science

Rectal Microbicides

How Are They Applied?

Could a Rectal Microbicide Work? “HIV” (99mTc-SC) in Ejaculate “Microbicide”(111In-DTPA) CHARM-02 Study (Hiruy H et al. AIDS Res Hum Retroviruses 2015)

Rectal Microbicide Animal Models Humanized mouse Rhesus macaque

Rectal Microbicide Studies Completed studies Nonoxynol-9 HIVNET-008 UC781 RMP-01 Tenofovir 1% gel RMP-02/MTN-006 MTN-007 Project Gel CHARM-01 & CHARM-02 Maraviroc CHARM-03 Phase 2 MTN-017 Planned Phase 1 Studies MTN-026 MTN-033 MTN-037 MTN-039 DREAM-01 PREVENT-01

Questions to Consider Do we need rectal microbicides? Is tenofovir 1% gel the best candidate to move into later stage development? Is a vaginal applicator the best way to deliver a microbicide? What is the best dosing regimen? What is the best study design?

Priorities in Rectal Microbicide Research Pericoital use Extended efficacy (72 hours) Lubricant rather than applicator delivery Multipurpose products HIV, HPV, HSV, HCV Novel delivery systems Rectal douches Rectal inserts THSY08 The future of chemoprophylaxis: new concepts Abstract: THSY08 Thursday @ 14:30 – 16:00 Session Room 6

Long Acting Antiretroviral PrEP

Requirements for LA ARV Potency and PK profile allowing infrequent dosing (~ 2-3 months) Practical injection volume (~ 4mL) Stable formulation ideally without cold chain requirements Potential products TMC278 LA (Rilpivirine) GSK 744 (Cabotegravir)

Rilpivirine Levels in Plasma Persistence of rilpivirine following single dose of long-acting injection Abstract: TUAC0103 Tuesday @ 11:00 – 12:30 Session Room 11 1200 mg 600 mg 300 mg Jackson A et al. Clinical Pharmacology & Therapeutics 2014

HPTN-083 Study of Cabotegravir One month oral run in phase Exposure to LA PrEP every 2-3 months Two IM injections HPTN 083 is a study being done to evaluate the efficacy of the long-acting injectable agent, cabotegravir (CAB LA), for pre-exposure prophylaxis (PrEP) in HIV-uninfected men and transgender women who have sex with men (MSM and TGW). HPTN 083 will enroll approximately 4500 HIV-uninfected MSM and TGW at risk for acquiring HIV infection, ages 18 or older at sites in the Americas, Asia and South Africa. Status: Pending PrEP Cessation 12 months of Oral PrEP

Implantable Formulations Tenofovir alafenamide (TAF) implant Gunawardana M et al. Antimicrob Agents Chemother 2015 TAF biodegradable implant Van der Straten A USAID Grant In Progress

Broadly Neutralizing Antibodies

Broadly Neutralizing Antibodies HVTN 704 / HPTN-085 (The AMP Study) N = 2,700 This study will evaluate the safety and efficacy of the human monoclonal antibody (mAb) VRC-HIVMAB060-00-AB (VRC01) in preventing HIV-1 infection among men and transgender (TG) persons who have sex with men, in North and South America Timeline: March 2016 – September 2020 Participants will receive an intravenous (IV) infusion of 10 mg/kg of VRC01 over about 30 to 60 minutes at Weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, and 72. Companion study HVTN 703 in women in Africa

Vaccines

Vaccine Development HVTN 702 Phase 3 study in South Africa ALVAC-HIV (Clade C) Bivalent gp120 protein subunit vaccine (Clade C) MF59 adjuvant Phase 3 study in South Africa Men and women N= 5,400 Duration 3 years Timeline: Starting in November 2016 The HVTN 702 vaccine regimen consists of two experimental vaccines: a canarypox-based vaccine called ALVAC-HIV and a bivalent gp120 protein subunit vaccine with an adjuvant that enhances the body's immune response to the vaccine. Both ALVAC-HIV (supplied by Sanofi Pasteur) and the protein subunit vaccine (supplied by GSK) have been modified from RV144 to be specific to HIV subtype C, the predominant HIV subtype in southern Africa. In addition, the protein subunit vaccine in HVTN 702 is combined with MF59 (also supplied by GSK), a different adjuvant than the one used in RV144, in the hope of generating a more robust immune response. Finally, the HVTN 702 vaccine regimen will include booster shots at the one-year mark in an effort to prolong the early protective effect observed in RV144

Product Access Timelines Development Phase Potential Access Oral PrEP Licensed Kenya South Africa Vaccines Phase 3 2021? Broadly neutralizing antibodies Phase 2 N/A Rectal microbicides 2022? LA PrEP Phase 2B/3

Summary In the short term oral PrEP will be the most accessible HIV prevention product for African MSM and TGW Financial constraints may limit access to oral PrEP A safe and effective HIV vaccine would have the biggest public health benefit The future of LA PrEP and BNabs is uncertain due to costs and complexity of delivery Pericoital products including rectal microbicides could provide a more cost effective PrEP product