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Systemic vs. Topical Pre-Exposure Prophylaxis (PrEP): What Will VOICE and Other Studies Tell Us?

Systemic vs. Topical Pre-Exposure Prophylaxis (PrEP): What Will VOICE and Other Studies Tell Us?. Jeanne Marrazzo, MD, MPH University of Washington 2011 HVTN Meeting. Discussion. Microbicides as PrEP Potential advantages of & concerns with topical delivery

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Systemic vs. Topical Pre-Exposure Prophylaxis (PrEP): What Will VOICE and Other Studies Tell Us?

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  1. Systemic vs. Topical Pre-Exposure Prophylaxis (PrEP): What Will VOICE and Other Studies Tell Us? Jeanne Marrazzo, MD, MPH University of Washington 2011 HVTN Meeting

  2. Discussion • Microbicides as PrEP • Potential advantages of & concerns with topical delivery • Evidence in humans, and ongoing studies • What new delivery systems or agents are being considered? Vaginal ring Injectable Pill Gel / applicator Vaginal film

  3. Topical PrEP: Why? Maximize local drug concentration at desired sites Minimize systemic toxicity Potentially rapid delivery to vulnerable tissues without need for “loading” phase Potential for high barrier to resistance Enhanced user acceptability

  4. Topical PrEP: Yes, But… Maximize local drug concentration at desired sites Ensure intracellular concentration of activated form of drug is adequate Minimize adverse effects on local immune defense, including anatomic barriers (no disruption) & microbiome Ideally, aim for cross-protection between vagina & rectum with single-compartment dosing Minimize systemic toxicity Potentially rapid delivery to vulnerable tissues without need for “loading” phase Potential for high barrier to resistance Enhanced user acceptability

  5. Topical PrEP: Yes, But… Maximize local drug concentration at desired sites Ensure intracellular concentration of activated form of drug is adequate Minimize adverse effects on local immune defense, including anatomic barriers (no disruption) & microbiome Uncertainty about cross-protection between vagina & rectum with single-compartment dosing Minimize systemic toxicity Minimal absorption desirable, but might limit local efficacy Potentially rapid delivery to vulnerable tissues without need for “loading” phase Potential for high barrier to resistance Enhanced user acceptability

  6. Topical PrEP: Yes, But… Maximize local drug concentration at desired sites Ensure intracellular concentration of activated form of drug is adequate Minimize adverse effects on local immune defense, including anatomic barriers (no disruption) & microbiome Uncertainty about cross-protection between vagina & rectum with single-compartment dosing Minimize systemic toxicity Minimal absorption desirable, but might limit local efficacy Potentially rapid delivery to vulnerable tissues without need for “loading” phase Pharmacokinetics still being defined; adequate protective dose under study Potential for high barrier to resistance Enhanced user acceptability

  7. Topical PrEP: Yes, But… Maximize local drug concentration at desired sites Ensure intracellular concentration of activated form of drug is adequate Minimize adverse effects on local immune defense, including anatomic barriers (no disruption) & microbiome Uncertainty about cross-protection between vagina & rectum with single-compartment dosing Minimize systemic toxicity Minimal absorption desirable, but might limit local efficacy Potentially rapid delivery to vulnerable tissues without need for “loading” phase Pharmacokinetics still being defined; adequate protective dose under study Potential for high barrier to resistance Will topical ARV favor different resistance mutations? Enhanced user acceptability

  8. Topical PrEP: Yes, But… Maximize local drug concentration at desired sites Ensure intracellular concentration of activated form of drug is adequate Minimize adverse effects on local immune defense, including anatomic barriers (no disruption) & microbiome Uncertainty about cross-protection between vagina & rectum with single-compartment dosing Minimize systemic toxicity Minimal absorption desirable, but might limit local efficacy Potentially rapid delivery to vulnerable tissues without need for “loading” phase Pharmacokinetics still being defined; adequate protective dose under study Potential for high barrier to resistance Will topical ARV favor different resistance mutations? Enhanced user acceptability: better sex! But semen might affect product efficacy

  9. MTN 001: Acceptability • Likely future use, if effective: • 93% oral tablet; 83% gel (p=0.002) • Difference driven by lower, different US rates • Preferences differed by location • Many African women said that the gel improved sexual pleasure (qualitative interviews) Hendrix C, CROI 2011

  10. MTN 001: Qualitative FindingsEnd of Study In-depth Interviews • Product preferences and barriers to use differed; clear interest in both formulations • Gel perceived by many women at Ugandan and South African sites to improve sex “Since I started using it, the love with my husband increased…because he thinks I love him so much yet it’s the gel.” - Uganda • Side effects numerous, but subsided swiftly • Strategies that integrate use into daily routine critical to achieve high adherence • Direct involvement of male partners regarded as beneficial by many women

  11. CAPRISA 004: Pericoital 1% tenofovir gel • Phase 2B trial in 889 women, ages ≥18 years in Durban & Vulindlela, South Africa • Coitally dependent: gel within 12 hours before & 12 hours after sex, max. 2 applications in 24 hours • Study population: Young women (mean age 23), unmarried, from rural (69%) & urban (31%) settings • Completed 2010: Good safety profile(↑ diarrhea compared to placebo) Abdool Karim et al, Science July 2010

  12. HIV Incidence in CAPRISA 004 No K65R resistance mutations among seroconverters Abdool Karim, Q, et al. Science. 2010;329:1168-1174.

  13. CAPRISA 004 HIV Incidence by Adherence • High (> 80%) gel use, n = 336: Tenofovir gel: 4.2% Placebo gel: 9.3% P = .025 54% effective • Intermediate (50%-80%), n = 181 Tenofovir gel: 6.3% Placebo gel: 10.0% P = .343 38% effective • Low (< 50%), n = 367 Tenofovir gel: 6.2% Placebo gel: 8.6% P = .303 28% effective Abdool Karim, Q, et al. Science. 2010;329:1168-1174.

  14. CAPRISA 004: Impact of 1% tenofovir gel on HSV-2 incidence *Note: Excludes equivocal HSV-2 results at study exit IRR = 0.49 (CI: 0.30, 0.78); P = .003 51% protection against HSV-2 by tenofovir gel (CI: 22% - 70%) Abdool Karim Q, et al. AIDS 2010. Abstract TUSS0502.

  15. One Effect of CAPRISA 004 Success

  16. CAPRISA 004 What Didn’t We Learn? Whether women prefer the gel or the tablet Information on more frequent (daily) use Whether it is safe Whether it is more effective than pre- and post-coital dosing Information on use in adolescents

  17. The VOICE Study Tenofovir Tenofovir Gel Truvada Tablets Tablets Which is effective? Is each safe? Which will women use? Secondary Objectives: Adherence/Behavioral Sexual/Intravaginal Practices HIV Drug Resistance PK/PD Models Delayed HIV Seroconversion

  18. Study Overview • 5,029 women at 16 sites • Accrual Sept 2009 – June 2011 • Inclusion: vaginal intercourse in past 3 months • Average time on product 24 months (max 36) • Planned completion 2012, results 2013 • Funded by NIAID/DAIDS, NIMH, NICHD • Study products provided by CONRAD, Gilead • Protocol co-chairs: • Mike Chirenje, MD • Jeanne Marrazzo, MD, MPH

  19. 5,000 Women Tablet (3,000) Vaginal Gel (2,000) Truvada (1,000) Tenofovir (1,000) Placebo Tablet (1,000) Tenofovir Gel (1,000) Placebo Gel (1,000) VOICE Study Design Five study groups

  20. 15 VOICE Sites – 5,029 women • UGANDA: 322 women • Makerere Univ./JHU, Kampala (1 site) • ZIMBABWE: 630 women • UZ-UCSF, Harare (1 site) • UZ-UCSF, Chitungwiza (2 sites) • SOUTH AFRICA: 4,077 women Durban Area • Medical Research Council (7 sites) • CAPRISA eThekwini (1 site) Johannesburg Area • WRHI (1 site) • PHRU Soweto (1 site) Klerksdorp Area • Aurum Institute (1 site)

  21. VOICE: Contribution to Evidence Base • Large number of person-years of follow-up • Diverse population including • Married women: may know partner’s HIV status • Unmarried women (South Africa) • Unlikely to know partner’s HIV status • Likely impacts motivation to adhere to study product • Young women (notable relative to Partners) • Probable wider range of adherence given population • Only trial that includes TFV gel arm • If effective, will contribute pivotal data for licensure for HIV & HSV-2 prevention indication • Substudy (VOICE B) to examine BMD in oral arms

  22. DSMB recommendations, Sept 2011 • The oral single-drug arm of TDF should be stopped because of futility • No safety concerns • Unblindparticipants in the TDF arm have all study products, both active and placebo, discontinued as soon as possible • Included VOICE B (BMD study) participants • Continue the TDF/emtricitabine oral arm and the TFV gel arm, with corresponding placebos

  23. Impact on Study Questions?

  24. Beyond VOICE: Next Steps for TFV Gel? • FACTS: Pericoital use in S. African women • Safety in pregnancy: MTN agenda • Phase I/II studies of safety, acceptability and PK of reformulated TFV gel for rectal use: MTN agenda • Examine HSV protection in VOICE participants: underway

  25. Candidate Drugs in PrEP Pipeline NNRTIs:Dapivirineintravaginal ring Effectiveness trials for dapivirine ring 2012 (IPM & partners) Entry inhibitors: Maraviroc with NRTI or NNRTI Oral maraviroc +/- FTC/TDF (HPTN 069) Maraviroc & dapivirine vaginal ring (IPM, MTN) NNRTIs:Rilpivirine (TMC 278), long-acting injectable Once monthly injections; in phase I safety studies in UK Broadly neutralizing monoclonal antibodies Integrase strand inhibitors Macaque & humanized mice protected with topical & oral raltegravir(Dobard CROI 30; Neff PLoS One 2010) Phase IIB Phase II Phase I Animal Studies

  26. Dapivirine ring • Dapivirine is a non-nucleoside reverse transcriptase inhibitor • Flexible ring made of an elastic silicone material • Measures 56 mm (about 2 ½”) in diameter and 7.7 mm (3/4”) thick • Designed for 28-day use • Will be compared to placebo ring in the ASPIRE study (start late 2012)

  27. Topical PrEP? • Move beyond tenofovir (dapivirine) • Continue to advance the research agenda in pregnancy, breastfeeding women,and for use with anal sex • Combination multipurpose products • Two HIV drugs combined with hormonal contraception +/- targeting other infections(HSV) • Combining PrEP with vaccines • Oral and topical (rings, films, gels) • Expansion & validation of biomarkers of efficacy/safety • Critical for identifying which products to advance

  28. ACKNOWLEDGMENTS • Connie Celum • Jared Baeten • Betsy Herold • Craig Hendrix • Lisa Noguchi • MTN is funded by NIAID (5U01AI068633), NICHD and NIMH, all of the U.S. National Institutes of Health

  29. What is PrEP, and Why Might it Work? • Definition: Provision of chemopreventive agent at vulnerable site(s) prior to infection Garcia-Lerma JG, et al. Trends Pharmacol Sci. 2010 • Rationale: • Infection of healthy mucosa requires relatively large dose of virus (10-6 to 10-8 particles) • In theory, the right drug could prevent founder population from establishing infection, but time is of the essence!

  30. Tenofovir Gel Pregnancy Studies MTN-002 • First microbicide study in pregnancy • How does pregnancy affect drug absorption? • Is the drug transferred to the fetus? • Gel applied as one-time dose in 16 HIV-negative U.S. women prior to scheduled C-section • Results: • Only small amounts of drug absorbed into mother’s bloodstream, amniotic fluid and umbilical cord (fetal) blood

  31. Tenofovir Gel Pregnancy Studies

  32. MTN Rectal Safety Studies • MTN-006 • Phase I safety, acceptability and drug absorption study of vaginal tenofovir gel applied rectally in 18 HIV-negative adults at 2 U.S. sites • Found safe but resulted in reformulation of the gel • MTN-007 • Phase I follow-up study to MTN-006 • 60 HIV-negative men and women at 3 U.S. sites • Study completed; results expected early 2012 • MTN-017 • Planned Phase II study in MSM in U.S., • South Africa (Cape Town), Thailand and Peru

  33. 1% TFV (30 mg) vs. 1% TFV & 5% FTC gels 30 minutes pre-SHIV challenge • 4 arms: 2 no gel; 6 placebo (2% HEC), 6 combo, 6 TFV • 2x weekly low dose vaginal challenge x 10 weeks • No gel: 2/2 infected by 5 challenges • Placebo: 5/6 infected w/ median 4.5 challenges (2.5 wks) • TFV/FTC & TFV: total protection through 20 challenges • Detection of either in plasma of protected macaques: 76%, mean 30 minutes • TDF (25 ng/ml) 0.01-0.03% absorbed; FTC (70 ng/ml) 0.03% Parikh U, J Virol Oct 2009

  34. Characteristics of PrEP Trials Involving Women

  35. CROI 2011Microbicides in Vaginal Rings • #1001: Nel et al • “Pharmacokinetic and Safety Assessment of Monthly Anti-HIV Dapivirine Vaginal Microbicide Rings with Vaginal Dosing” • Possible Phase 2B trial in works (though placebo window may be closing) • Dapivirine = NNRTI, safe and well-tolerated • #1003: Singer et al “An EVA Vaginal Ring Containing the NNRTI MIV-150 Protects Against SHIV-RT Infection in vivo” • 1/7 macaques challenged 24 hr & 2 weeks post-insertion infected • 1/2 challenged @ 24 hr and 2/2 @ 2wk control macaques infected

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