Microbicide Research: A Promising HIV/AIDS Prevention Strategy for Women
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Microbicide Research: A Promising HIV/AIDS
Prevention Strategy for Women
Roberta Black, Ph.D.Division of AIDS, National Institute of Allergy
and Infectious DiseasesNational Institutes of Health
December 3, 2008
DHHS/NIH/NIAID
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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
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NIAID Topical Microbicide ProgramNIAID Topical Microbicide Program
o YearsWeeks
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 Individuals HIV Positive Individuals
DHHS/NIH/NIAID
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SuccessfulMicrobicide
Or Microbicide
Strategy
Lead IdentificationLead IdentificationAndAnd
OptimizationOptimization
Pipeline DevelopmentPipeline DevelopmentMultiple activities driven by Multiple activities driven by Milestones Milestones that that may occur sequentially or simultaneouslymay occur sequentially or simultaneously
Product Product EliminatedEliminated
Product RecycledProduct RecycledInto DiscoveryInto Discovery
Product recycled Product recycled In In
Pipeline Pipeline
LEADLEAD
Discovery Preclinical
Virology
Preclinical Studies
(Critical Path) Clinical Studies
I II IIIPilot
Studies Deployment
The Microbicide Development Pipeline
DHHS/NIH/NIAID
10,000cndts 250
51
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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
Successfulcompound
Or Strategy
Lead IdentificationLead IdentificationAndAnd
OptimizationOptimization
DiscoveryPreclinical Virology
Preclinical Studies
(Critical Path)Clinical Studies
I II IIIPilot
Studies Deployment
Successfulcompound
Or Strategy
Lead IdentificationLead IdentificationAndAnd
OptimizationOptimization
DiscoveryPreclinical Virology
Preclinical Studies
(Critical Path)Clinical Studies
I II IIIPilot
Studies Deployment
Three Areas of Emphasis
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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 ResearchBasic Biomedical Research
DHHS/NIH/NIAID
gp120V3
gp41
V1/2
Virus
Coreceptor CD4
Cell
UC781(Vaginal and Rectal)
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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 Non-Clinical Product DevelopmentDevelopment
EndometrialToxicity
Behavioral
DHHS/NIH/NIAID
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Microbicide Evolution
Nonoxynol-9
Nonspecific inhibitors
HIV specific inhibitors
1st Generation
2nd Generation
3rd Generation
4th Generation Combination Inhibitors
NRTNNRTCCR5
DHHS/NIH/NIAID
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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
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Trial initiated in February 2005Enrollment and follow up completeData analysis ongoingResults expected February 2009
HPTN 035: Phase II/IIb Trial of Vaginal Microbicides for the Prevention of HIV Infection in Women
STATUS
DHHS/NIH/NIAID
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Vaginal and Oral Interventions Vaginal and Oral Interventions
to Control the Epidemicto Control the Epidemic
MTN-003:The VOICE StudyMTN-003:The VOICE Study
Phase 2B, Safety and Phase 2B, Safety and Effectiveness Study Effectiveness Study
1% Tenofovir (PMPA) Gel1% Tenofovir (PMPA) Gel
Tenofovir DF (TDF) TabletTenofovir DF (TDF) Tablet
TDF/FTC (emtricitabine) TabletTDF/FTC (emtricitabine) Tablet
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MTN-003: The VOICE Study
TOTAL SAMPLE
(4200)
ORAL(2520)
TOPICAL(1680)
FTC/TDF(840)
TDF(840)
ORAL PLACEBO
(840)
PMPA GEL(840)
PLACEBO GEL(840)
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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
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PMPA Gel: Following a Classic Drug Development
Paradigm2006 2007 2008
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
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Discovery and development of new basic and preclinical science and concepts required to support/enhance microbicide clinical trialsSafety
Microbicides for prevention of other STIs Associated with enhancement of HIV transmission
Microbicides for use during pregnancyIncreased susceptibility of pregnant women
Tools for measuring adherence and acceptability
Additional Priority Areas
0 0.5
0
0.2
0.4
0.6
Optical Coherence Tomography (OCT)
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Discovery and development of new basic and preclinical science and concepts required to support/enhance microbicide clinical trialsSafety
Microbicides for prevention of other STIs Associated with enhancement of HIV transmission
Microbicides for use during pregnancyIncreased susceptibility of pregnant women
Tools for measuring adherence and acceptability
Additional Priority Areas
DHHS/NIH/NIAID
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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 How does NIAID make this all happen?all happen?
DHHS/NIH/NIAID
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Controlling the HIV Pandemic
PreventionPrevention
Anti-Retroviral Therapy
MicrobicidesHIV
Other STIsCombinations
Perinatal Perinatal Mother-to-child Mother-to-child
Transmission (MTCT)Transmission (MTCT)
VaccinesHIV
Other STIs
Antiretroviral TherapyPre-exposure Prophylaxis (PrEP)
Intervention StrategiesRisk reductionVoluntary counseling (VCT)
STI ReductionSTI ReductionHSV-2
Ultimate Goal: Multi-Component Prevention Strategy
DHHS/NIH/NIAID