Transcript HIV Prevention Strategies: Update 2007 II

Microbicide and PrEP Overview
GCM Adolescent Consultation
Durban, South Africa
5-6 Sept, 2007
Craig M. Wilson
Adolescent Medicine Trials Network for HIV/AIDS
Interventions (ATN)
University of Alabama at Birmingham
Interventions to Prevent HIV
• AVAILABLE
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Behavior change (ABCs)
Condom promotion
MTCT interventions
IVDU risk reduction
STD control
Male circumcision
Post-exposure prophylaxis
• STILL UNPROVEN
– Vaccination
– Microbicides
– Pre-exposure
Prophylaxis
– Female condoms
– Treat infected partner
with antiretrovirals
– Abstinence only
programs
Microbicides: Sites and Mechanisms
• Mucosal surfaces
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Direct inactivation
Preservation of acidic environment
Enhancement/restoration of commensal flora
Physical barrier
• Tissue or Cell Surface
– HIV cell receptors or co-receptors
– Viral absorption or fusion
• Viral Surface
– Polyanionic polymers or envelope interacting agents
• Inside Cell
– Anti-retrovirals
(Review: Lancet 369:787, 2007)
Microbicides: General Characteristics
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Potent against most HIV and other STIs
Preserved activity in presence of seminal fluid
No effect on integrity of mucosal surfaces
No effect on commensal flora
Preserve or enhance low vaginal pH
Stable at tropical temperatures
Compatible with latex
Good acceptability: odor, color, taste,
Easy to use, low cost, long shelf life
Microbicides: Trials 1
• 60+ candidates in development
– One in Phase II/IIb and 3 in Phase III
– 11 in Phase I trials
• Nonoxynol (N-9) Trial
– African and Thai sex workers
– N-9 users with higher HIV infection rates (14.7 vs 10.3
per 100 person years)
– Evidence of increased mucosal irritation
Microbicides: Trials 2
• Cellulose Sulfate (Ushercell)
– Polyanion with broad STI activity
– 3 Phase I and a Phase II trial with promising results
– Two 2000+ Phase III trials stopped in 2007 when the
multi-country trial showed evidence of increased risk
• MIRA Trial (Padian et al Lancet on line 13 July, 2007)
– RCC trial comparing condom alone vs condom plus diaphragm with
readily available lubricant gel in South Africa and Zimbabwe
– N= 5045, age 18-49, follow up planned for up to 24 months
– HIV incidence of 4.1% vs 3.9% per 100 woman years in the
intervention vs control arms
Microbicides: Trials 3: Active
• BufferGel vs PRO2000 0.5% Phase IIb
– 6 country RCT (Malawi, S Africa, Tanzania, USA, Zambia,
Zimbabwe) N=3220
• PRO2000 0.5% vs 2.0% Phase III
– 6 country RCT, (Cameroon, S Africa, Tanzania, Uganda,
Zambia, Swaziland) N = 11,920
• Carragard Phase III
– South Africa 3 sites RCT, N = 6270
Microbicides: Summary
• Multiple products in late phase trials but
success needed in one of ongoing trials to
demonstrate proof of concept
• Will ultimately need multiple products
– extended daily use vs intermittent coitally dependent use
– contraceptive vs non-contraceptive
– product for rectal use
Adolescent Specific Issues for
Microbicides: Biological
• vaginal ecology and flora alteration
• douching/cleansing activities of population
• physical maturation/ectopy (non-issue if
sexually active)
• partner acceptability
Adolescent Specific Issues for
Microbicides: Trial Design
• Phase I/II studies:
– relatively intense biomedical sampling
– need sexually active populations
• Screening-in approaches
• parental permission approaches
• Phase II “Bridging” Studies
– “Bridging” design will depend on adult data
Pre-exposure Prophylaxis (PrEP)
• General proof of concept comes from animal
studies and MTCT ART interventions
• Previously not considered because of ART
toxicities or unfavorable pharmacokinetics
• Recent availability of ART with longer half-life
and lower toxicity profiles and lack of success
in other approaches have re-opened
considerations
HIV Replication Cycle and Sites of Drug Activity
Fusion
Inhibitors
NRTIs
NNRTIs
Protease Inhibitors
Nucleus
Cellular DNA
HIV Virions
Reverse
Transcriptase
Protease
Integrase
Capsid
proteins
and viral
RNA
CD4
Receptor
Viral RNA
Unintegrated
double stranded
Viral DNA
Integrated
viral DNA
CCR5
or
CXCR4
co-receptor
2
1
Attachment
and Fusion
Uncoating
New HIV
particles
3
Reverse
Transcription
Integration
Viral
mRNA
gag-pol
polyprotein
4
5
6
Transcription
Translation
Assembly
And Release
Adapted:Levy JA. HIV and the Pathogenesis of AIDS. 2nd ed. Washington, DC: American Society for Microbiology; 1998:9-11
PrEP Study Designs
• High risk populations with exposures for risk over
defined period of time
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Young females in southern Africa
Commercial sex workers
IVDU while engaging in care
Discordant couples
Young MSM in US
• Daily/continuous vs “coitally” dependent
• Single drug (tenofovir) vs combination
(tenofovir/FTC, Truvada)
PrEP Studies: Active
• Botswana
– male and female, age 18-29, daily tenofovir, N = 1200
• Multi-country eastern/southern Africa
– female, age >18, daily tenofovir
• India
– MSM, age > 18, daily truvada
• Multi-country
– discordant couples, age >18, truvada, vs tenofovir
• Multi-country eastern/southern Africa (development)
– Vaginal tenofovir vs PrEP microbicide
PrEP Study: Proposed
• Multi-country eastern/southern Africa plus US
– female, age 16-22, Africa
– male MSM, age 16-22, US
– episodic vs daily truvada
Adolescent Specific Issues for PrEP
• No biological issues
• Need sexually active populations
• screening in approaches
• parental permission approaches
• Need for behavioral studies around use
patterns
Summary
Plenty of Challenges !