1. Microbicide Research: A Promising HIV/AIDS Prevention Strategy for Women Roberta Black, Ph.D. Division of AIDS, National Institute of Allergy and Infectious Diseases National Institutes of Health December 3, 2008 DHHS/NIH/NIAID

2. Microbicide Products Purposes and Indications Singular indication product, e.g., HIV microbicide Combination sexual and reproductive health product, e.g., HIV microbicide + contraceptive Combination disease prevention product, e.g., HIV + HSV microbicide DHHS/NIH/NIAID

3. NIAID Topical Microbicide Program o Years Weeks Progression to AIDS To identify and support/facilitate development of safe, effective and acceptable topical microbicides to prevent HIV/AIDS and other STIs Overarching Goal Intervention Points for Microbicides in HIV Infection and Disease HIV Negative IndividualsHIV Positive Individuals DHHS/NIH/NIAID

4. Successful Microbicide Or Microbicide Strategy Lead Identification AndOptimization Pipeline Development Multiple activities driven by Milestones that may occur sequentially or simultaneously ProductEliminated Product Recycled Into Discovery Product recycled InPipeline LEAD Discovery Preclinical Virology Preclinical Studies (Critical Path) Clinical Studies I II III Pilot Studies Deployment The Microbicide Development Pipeline DHHS/NIH/NIAID 10,000 cndts 250 5 1

5.  Basic biomedical research  Foster basic science and preclinical pipeline studies  Nonclinical product development  Identify and advance the most promising approaches to clinical testing  Clinical evaluation  Evaluate safety, efficacy and acceptability in populations most in need NIAID Topical Microbicide Program DHHS/NIH/NIAID Three Areas of Emphasis

6.  Understand the basic biologic processes of the female reproductive tract and its interaction with seminal plasma  Define mechanisms of infection  Identify targets for microbicide discovery  Discover new microbicide candidates  HIV targets  STI targets  Cellular/tissue targets  Understand the interaction of microbicides with the tissues Basic Biomedical Research DHHS/NIH/NIAID gp120 V3 gp41 V1/2 Virus Coreceptor CD4 Cell UC781 (Vaginal and Rectal)

7.  Identify and help advance the most promising approaches to clinical testing  Feasibility – compatible with use as a microbicide?  Proof-of-concept – prevent HIV transmission in vitro and/or in vivo?  Develop and use relevant and predictive in vitro and in vivo safety, efficacy and adherence models to select the best candidates  Establish partnerships/collaborations among private sector, industry and NGOs with NIH and its grantees  Encourage and promote the integration of new expertise and technologies into the microbicide pipeline Non-Clinical Product Development Endometrial Toxicity Behavioral DHHS/NIH/NIAID

8. Microbicide Evolution Nonoxynol-9 Nonspecific inhibitors HIV specific inhibitors 1 st Generation 2nd Generation 3rd Generation 4th Generation Combination Inhibitors NRT NNRT CCR5 DHHS/NIH/NIAID

9.  Primary Objectives:  To evaluate the safety of BufferGel and 0.5% PRO 2000/5 Gel (P) when applied intravaginally by women at risk for sexually-transmitted HIV infection.  To estimate the effectiveness of these gels in preventing HIV infection.  Design: A phase II/IIb, four-arm, multisite, randomized, controlled, trial comparing BufferGel and 0.5% PRO 2000/5 Gel (P) with a placebo gel and with no treatment (condom only arm).  Population:Sexually active HIV-uninfected women  Sample Size: 3100 participants  Countries:Malawi, South Africa, USA, Zambia, Zimbabwe HPTN 035: Phase II/IIb Trial of Vaginal Microbicides for the Prevention of HIV Infection in Women SUMMARY DHHS/NIH/NIAID

10.  Trial initiated in February 2005  Enrollment and follow up complete  Data analysis ongoing  Results expected February 2009 HPTN 035: Phase II/IIb Trial of Vaginal Microbicides for the Prevention of HIV Infection in Women STATUS DHHS/NIH/NIAID

11. Vaginal and Oral Interventions to Control the Epidemic MTN-003:The VOICE Study Phase 2B, Safety and Effectiveness Study 1% Tenofovir (PMPA) Gel Tenofovir DF (TDF) Tablet TDF/FTC (emtricitabine) Tablet

12. MTN-003: The VOICE Study TOTAL SAMPLE (4200) ORAL (2520) FTC/TDF (840) TDF (840) ORAL PLACEBO (840) TOPICAL (1680) PMPA GEL (840) PLACEBO GEL (840)

13. Why a Head-to-Head Trial? Theoretical reasons to favor either approach for safety, acceptability, efficacy and/or selection of resistance –vaginal use may confer less systemic toxicity and less resistance –vaginal use may be more culturally acceptable –oral use is less closely linked to sexual practices, and can be administered by the woman without knowledge of her partner –NO HUMAN DATA Only head-to-head trial will answer questions

14. PMPA Gel: Following a Classic Drug Development Paradigm 200620072008 HPTN 050 Phase I Safety HPTN 059 Phase II Expanded Safety Male Tolerance Tissue PK MTN-001 Oral vs. Topical PK MTN-002 Pregnancy MTN-003 VOICE STUDY

15.  Discovery and development of new basic and preclinical science and concepts required to support/enhance microbicide clinical trials  Safety  Microbicides for prevention of other STIs  Associated with enhancement of HIV transmission  Microbicides for use during pregnancy  Increased susceptibility of pregnant women  Tools for measuring adherence and acceptability Additional Priority Areas Optical Coherence Tomography (OCT) DHHS/NIH/NIAID

16.  Discovery and development of new basic and preclinical science and concepts required to support/enhance microbicide clinical trials  Safety  Microbicides for prevention of other STIs  Associated with enhancement of HIV transmission  Microbicides for use during pregnancy  Increased susceptibility of pregnant women  Tools for measuring adherence and acceptability Additional Priority Areas DHHS/NIH/NIAID

17. 1.Grants  Unsolicited Grants  Specific Initiatives 2. Contracts  Microbicide-specific product advancement  Gap-filling resources for nonclinical development 3. Partnerships How does NIAID make this all happen? DHHS/NIH/NIAID

18. Controlling the HIV PandemicPrevention Anti-Retroviral Therapy Microbicides HIV Other STIs Combinations PerinatalMother-to-child Transmission (MTCT) Vaccines HIV Other STIs Antiretroviral Therapy Pre-exposure Prophylaxis (PrEP) Intervention Strategies Risk reduction Voluntary counseling (VCT) STI Reduction HSV-2 Ultimate Goal: Multi-Component Prevention Strategy DHHS/NIH/NIAID