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Update on Pre-Exposure Prophylaxis: Never a Dull Moment

Update on Pre-Exposure Prophylaxis: Never a Dull Moment. Jeanne Marrazzo, MD, MPH Professor of Medicine University of Washington Seattle, Washington. From J Marrazzo , MD, at Los Angeles, CA: April 22, 2013, IAS-USA. . What is PrEP, and Why Might it Work?.

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Update on Pre-Exposure Prophylaxis: Never a Dull Moment

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  1. Update on Pre-Exposure Prophylaxis: Never a Dull Moment Jeanne Marrazzo, MD, MPHProfessor of MedicineUniversity of WashingtonSeattle, Washington From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA.

  2. 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! • Animal data is very supportive; stresses need for PEP component

  3. Evidence for PrEP Efficacy with Tenofovir-Based Regimens, 2012* • At time of FDA meeting Baeten J, Celum C. Current Opinion HIV AIDS, 2012

  4. FDA Antiviral Drugs Advisory Committee Meeting, May 10, 2012 • Recommended approval of daily TDF/FTC for HIV prevention in 3 groups: • MSM: 19-3 YES • HIV-uninfected partner in discordant couples: 19-2 YES • Other populations: 12:8 YES 16 July 2012

  5. Effect size (95% CI) OralFTC/TDF PrEPStudies FTC/TDF for HIV discordant couples (Partners PrEP) 75% (55; 87) FTC/TDF for young Heterosexuals (TDF-2) 63% (22; 83) FTC/TDF for MSM (iPrEx) 42% (15; 63) Wide confidence intervals outside of discordant couples, with lower limit <20% in iPrEx Efficacy 0 10 20 30 40 50 60 70 80 90 100%

  6. Effect size (95% CI) OralFTC/TDF PrEPStudies, 2012 FTC/TDF for women (FEM-PrEP) 6% (-69; 41) FTC/TDF for HIV discordant couples (Partners PrEP) 75% (55; 87) FTC/TDF for young heterosexuals (TDF-2) 63% (22; 83) FTC/TDF for MSM (iPrEx) 42% (15; 63) Efficacy 0 10 20 30 40 50 60 70 80 90 100%

  7. Divergent PrEP trial results: Contributions of Adherence + Biology? Adherence PrEP Efficacy • Biology* • Low genital drug levels (pK/pD) • Inflammation, STI • Acute HIV (high VL in partner) • Disrupted vaginal microbiome • Behavior • Frequency of anal vs. vaginal intercourse • Vaginal hygiene practices * These factors may make PrEP efficacy more sensitive to imperfect adherence Slide adapted from J. Baeten

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

  9. Candidate Drugs in PrEP Pipeline NNRTIs:Dapivirineintravaginal ring Effectiveness trials for dapivirine ring under way (MTN, IPM) 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 Integrase strand transfer inhibitors Macaque & humanized mice protected with topical & oral raltegravir (Dobard CROI 30; Neff PLoS ONE 2010); macaques protected with parenteral long-acting agent (GSK744) (Andrews CROI 2013) NRTIs:Tenofovir intravaginal ring (Smith CROI 2013) Phase IIB Phase II Phase I Animal Studies

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