Microbicide and PrEP Overview GCM Adolescent Consultation Durban, South Africa 5-6 Sept, 2007

1. Microbicide and PrEP OverviewGCM Adolescent ConsultationDurban, South Africa 5-6 Sept, 2007 Craig M. Wilson Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) University of Alabama at Birmingham

2. AVAILABLE 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 Interventions to Prevent HIV

4. Microbicides: Sites and Mechanisms • Mucosal surfaces • 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)

5. Microbicides: General Characteristics • 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. HIV Replication Cycle and Sites of Drug Activity Protease New HIV particles Capsid proteins and viral RNA CD4 Receptor Viral RNA Translation Integration Transcription Reverse Transcription Attachment and Fusion Uncoating Fusion Inhibitors • NRTIs • NNRTIs • Protease Inhibitors Nucleus Cellular DNA HIV Virions Reverse Transcriptase Integrase Unintegrated double stranded Viral DNA gag-pol polyprotein Integrated viral DNA Viral mRNA CCR5 or CXCR4 co-receptor 1 4 5 2 3 6 Assembly And Release Adapted:Levy JA. HIV and the Pathogenesis of AIDS. 2nd ed. Washington, DC: American Society for Microbiology; 1998:9-11 .

14. PrEP Study Designs • High risk populations with exposures for risk over defined period of time • 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)

15. 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

16. 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

17. 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

18. Summary Plenty of Challenges !