1 “On Demand” Oral PrEP: Lessons Learned from Macaque ModelsANRS Satellite Symposium, July 2016 “On Demand” Oral PrEP: Lessons Learned from Macaque Models J. Gerardo García-Lerma Ph.D. Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of HIV/AIDS Prevention
2 Importance of macaque models for HIV prevention researchHistorically used to evaluate new PrEP and PEP interventions Possibility to model PrEP under highly controlled conditions (time of drug dosing, size of virus inoculum, route of virus exposure) Incorporate pharmacological measurements to understand correlates of protection Investigate factors that may potentially modify PrEP efficacy (i.e, circulating drug-resistant viruses, co-infection with other sexually transmitted infections, others) Provide proof of concept and inform on promising candidates for human trials
3 CDC repeat low virus dose macaque modelSimian HIV (SHIV) challenge containing an R5-tropic HIV envelope Macaques exposed to low and more physiologic doses of SHIV Virus exposures repeated over several months to model populations at high risk of HIV infection Design minimizes animal numbers and increases statistical power Protection defined by the degree infection is delayed or prevented Drug administered at human-equivalent doses defined through extensive PK assessments Early studies with oral FTC/TDF provided proof of concept of efficacy for daily Truvada PrEP
4 Proof of concept macaque PrEP study with daily FTC/TDFHuman doses of FTC and TDF administered orally mixed with food Animals exposed to SHIV rectally once a week for up to 14 weeks Untreated controls (n = 18) Daily FTC/TDF (n = 6) 2 4 6 8 10 12 14 25 50 75 100 Number of weekly rectal virus exposures % Uninfected macaques HR = 7.8, p = 0.008 Garcia-Lerma et al, PLoS Med 2008
5 Non-daily PrEP Deliver effective drug concentrations at mucosal sites and/or systemically at the time of potential HIV exposure when virus vulnerability is highest TRENDS in Pharmacological Sciences 2010
6 Efficacy of “Time driven” oral PrEP in macaques1 FTC/TDF dose (-3 days) 1 FTC/TDF dose (+2h) SHIV REPEATED FOR 14 WEEKS 100 3 days before/no post p > 0.05 3 days before/2h after HR = 15.4, p = 0.008 75 % Uninfected macaques 50 25 1 FTC/TDF dose (-3 days) SHIV REPEATED FOR 14 WEEKS Controls 2 4 6 8 10 12 14 Number of weekly rectal virus exposures Garcia-Lerma et al, Sci Transl Med 2010 Anderson et al, J Antimicrob Chemother 2014
7 Modeling “on demand” oral PrEP in macaquesFTC/TDF (-1 day) (+2h) SHIV % Uninfected macaques REPEATED FOR 14 WEEKS (-2h) (+1 day) 100 1 day before/1 day after HR = 6.6, p = 0.002 1 day before/2h after HR = 16.7, p = 0.006 2h before/1 day after HR = 4.1, p = 0.02 75 50 25 Controls 2 4 6 8 10 12 14 Number of weekly rectal virus exposures Garcia-Lerma et al, Sci Transl Med 2010
8 Increased efficacy of “on demand “ oral PrEP with double the dose of FTC/TDF100 Two doses 2h before and two doses 1d after HR = 16.7, p = 0.006 One dose 2h before and one dose 1d after HR = 4.1, p = 0.02 Two FTC/TDF doses (-2h) Two FTC/TDF doses (+1 day) SHIV REPEATED FOR 14 WEEKS 75 % Uninfected macaques 50 25 Controls 2 4 6 8 10 12 14 Number of weekly rectal virus exposures Garcia-Lerma et al, Sci Transl Med 2010
9 Efficacy of “on demand” PrEP against vaginal infectionPigtail macaques are preferred species Lunar menstrual cycle and changes in hormone levels similar to women; recapitulates potential fluctuations in susceptibility to HIV/SIV infection High susceptibility to SIV/SHIV without the use of exogenous progestins such as depo provera Understand how differences in drug penetration in rectal/vaginal tissues may affect PrEP efficacy TFV-DP 24h (fmols/mg tissue) FTC-TP 24h Vaginal 4 (4-5) 151 ( ) Rectal 166 (5-697) 72 (24-118) Lymphoid tissue 6 (3-17) 76 (25-115) Relative penetration VT:RT 0.02 2.10
10 Efficacy of “on demand” oral PrEP against vaginal SHIV infection in macaquesFTC/TDF (-1 day) (+2h) SHIV REPEATED FOR 4 FULL MENSTRUAL CYCLES Number of menstrual cycles % uninfected macaques 1 2 3 4 25 50 75 100 1 day before/2h after Controls Radzio et al., PLoS One 2012
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12 Summary The repeat low dose SHIV transmission model can be used to evaluate the efficacy of different PrEP regimens and modalities under well-controlled conditions Studies with oral FTC/TDF have provided proof of concept for daily and non-daily (time-driven, on demand) PrEP with Truvada and informed the design of human clinical trials Possibility to investigate other tenofovir prodrugs (i.e TAF) and evaluate potential interchangeability of FTC and 3TC Ability to investigate if the addition of integrase inhibitors can improve the window of protection with intermittent PrEP
13 ACKNOWLEDGEMENTS Division of HIV/AIDS Prevention, NCHHSTP, CDCJessica Radzio Mian-er Cong Wutyi Aung James Mitchell Debra Hanson Ron Otten Walid Heneine Tara Henning Ellen Kersh Janet McNicholl Angela Holder Amy Martin Chou-Pong Pau Division of Laboratory Sciences, NCEH, CDC Zsuzsanna Kuklenyik John Barr Gilead Sciences, Inc James Rooney Emory University Krisztina Hanley University of Colorado Peter Anderson National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of HIV/AIDS Prevention