“On Demand” Oral PrEP: Lessons Learned from Macaque Models - PowerPoint Presentation

“On Demand” Oral PrEP: Lessons Learned from Macaque Models National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of HIV/AIDS Prevention J. Gerardo García-Lerma Ph.D. Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA ANRS Satellite Symposium, July 2016

Importance of macaque models for HIV prevention research Historically 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

CDC repeat low virus dose macaque model Simian HIV (SHIV) challenge containing an R5-tropic HIV envelope Macaques exposed to low and more physiologic doses of SHIVVirus 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 preventedDrug 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

Proof of concept macaque PrEP study with daily FTC/TDF Human 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) 0 2 4 6 8 10 12 14 0 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

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

Efficacy of “Time driven” oral PrEP in macaques 1 FTC/TDF dose (-3 days) 1 FTC/TDF dose (+2h) SHIV REPEATED FOR 14 WEEKS Controls 0 2 4 6 8 10 12 14 0 25 50 75 100 Number of weekly rectal virus exposures % Uninfected macaques 3 days before/2h after HR = 15.4, p = 0.008 Garcia-Lerma et al, Sci Transl Med 2010 Anderson et al, J Antimicrob Chemother 2014 3 days before/no post p > 0.05 1 FTC/TDF dose (-3 days) SHIV REPEATED FOR 14 WEEKS

Modeling “on demand” oral PrEP in macaques Controls 0 2 4 6 8 10 12 14 0 25 50 75 100 Number of weekly rectal virus exposures 1 day before/2h after HR = 16.7, p = 0.006 2h before/1 day after HR = 4.1, p = 0.02 FTC/TDF (-1 day) FTC/TDF (+2h) SHIV % Uninfected macaques REPEATED FOR 14 WEEKS FTC/TDF (-2h) FTC/TDF (+1 day) SHIV REPEATED FOR 14 WEEKS FTC/TDF (-1 day) FTC/TDF (+1 day) SHIV REPEATED FOR 14 WEEKS 1 day before/1 day after HR = 6.6, p = 0.002 Garcia-Lerma et al, Sci Transl Med 2010

Increased efficacy of “on demand “ oral PrEP with double the dose of FTC/TDF 0 2 4 6 8 10 12 14 0 25 50 75 100 Number of weekly rectal virus exposures % Uninfected macaques Two doses 2h before and t wo doses 1d after HR = 16.7, p = 0.006 Two FTC/TDF doses (-2h) Two FTC/TDF doses (+1 day) SHIV REPEATED FOR 14 WEEKS Controls One dose 2h before and one dose 1d after HR = 4.1, p = 0.02 Garcia-Lerma et al, Sci Transl Med 2010

Efficacy of “on demand” PrEP against vaginal infection Pigtail macaques are preferred speciesLunar 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 (fmols/mg tissue) Vaginal 4 (4-5) 151 (145-179) Rectal 166 (5-697) 72 (24-118) Lymphoid tissue 6 (3-17) 76 (25-115) Relative penetration VT:RT 0.02 2.10

Efficacy of “on demand” oral PrEP against vaginal SHIV infection in macaques Number of menstrual cycles % uninfected macaques 0 1 2 3 4 0 25 50 75 100 1 day before/2h after Controls FTC/TDF (-1 day) FTC/TDF (+2h) SHIV REPEATED FOR 4 FULL MENSTRUAL CYCLES Radzio et al., PLoS One 2012

Summary The repeat low dose SHIV transmission model can be used to evaluate the efficacy of different PrEP regimens and modalities under well-controlled conditionsStudies 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 trialsPossibility to investigate other tenofovir prodrugs (i.e TAF) and evaluate potential interchangeability of FTC and 3TCAbility to investigate if the addition of integrase inhibitors can improve the window of protection with intermittent PrEP

ACKNOWLEDGEMENTS National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of HIV/AIDS Prevention Division of HIV/AIDS Prevention, NCHHSTP, CDC Jessica Radzio Mian-er CongWutyi AungJames Mitchell Debra HansonRon OttenWalid Heneine Gilead Sciences, Inc James Rooney Tara Henning Ellen Kersh Janet McNicholl Angela Holder Amy Martin Chou-Pong Pau Division of Laboratory Sciences, NCEH, CDC Zsuzsanna KuklenyikJohn BarrEmory University Krisztina Hanley University of ColoradoPeter Anderson