Efficacy of “On Demand” PrEP The ANRS IPERGAY Trial Jean-Michel Molina Saint-Louis Hospital, University of Paris Diderot, Inserm U941, Paris, France 1

Relative Efficacy of Prevention Strategies Reduction of HIV Transmission Studies Condoms in heterosexuals2 80% Partners PrEP in discordant couples1 75% Condoms in US MSM3 70% TDF2 in men & women1 63% Medical male circumcision1 54% Bangkok PrEP in IDU 49% 44% iPrEx in MSM1 CAPRISA 004 (1% TDF vaginal gel) in women1 39% 27% Aspire / MTN 020 (Dapivirine ring)4 FEM-PrEP in women,5 VOICE (TDF/FTC, TDF vaginal gel), FACTS (TDF gel) in women6 Non significant* 0 10 20 30 40 50 60 70 80 90 100 Efficacy (%) 1. Adapted from Karim SS and Karim QA. Lancet 2011;378:e23–25; 2. Weller S and Davis K. Cochrane Database Syst Rev 2002:CD003255; 3. Smith DK et al. JAIDS 2015;68:337–344; 4. Baeten et al NEJM 2016; 5. van Damme L et al. NEJM 2012;367:411–422; 6. Marrazzo JM et al. NEJM 2014, Rees H, CROI 2015, Abs. 26LB

Interest in On Demand PrEP Conflicting results from PrEP trials with oral daily TDF/FTC: Adherence « Achilles’ heel » of PrEP More convenient dosing regimen: « On Demand » Could improve adherence, safety and cost-effectiveness Could provide an alternative to daily PrEP Supported by animal models

Effect of a Double Dose of oral TDF/FTC (-2h, + 24h) sgsfdgsfd Effect of a Double Dose of oral TDF/FTC (-2h, + 24h) % Uninfected Macaques 100 Double dose oral TDF/FTC (n = 6) HR : 16,7 p = 0.006 75 50 % Uninfected animals 25 Untreated Controls (n = 32) 2 4 6 8 10 12 14 Number of weekly rectal SHIV exposures Garcia-Lerma et al.,Science Trans Med 2010, 14,14ra4 4

Double-Blinded Randomized Placebo-Controlled Trial 400 HIV negative MSM Condomless anal sex with > 2 partners within 6 m eGFR > 60 mL/mn Full prevention services* TDF/FTC before and after sex Full prevention services* Placebo before and after sex Main messages: The Caprisa study was conducted in KwaZulu-Natal, South Africa in a population of women 18-40 yo, that were sexually active and at high risk for contracting HIV. Sero-status, safety, sexual behaviour, gel and condom use were assessed monthly for 30 months. Women were requested to insert one dose of gel within 12 hours before sex and as soon as possible within 12 hours after sex. This dosing strategy was based on the data from monkey challenge studies and perinatal transmission studies. Background: Tenofovir (PMPA) was studied due to the effectiveness, safety, and long half life, along with the protective data in the monkey challenge studies. * Counseling, condoms and gels, testing and treatment for STIs, vaccination for HBV and HAV, PEP Follow-up visits: month 1, 2 and every two months thereafter with 4th generation HIV ELISA assays (combined Ab/Ag detection) on serum Molina JM et al. NEJM 2015 5

IPERGAY : Sex-Driven iPrEP 2 tablets 2-24 hours before sex 1 tablet 24 hours later 1 tablet 48 hours after first intake Friday Saturday Sunday Monday Tuesday Wednesday Thursday 4 pills of TDF/FTC taken over 3 days to cover one sexual intercourse

IPERGAY : Sex-Driven iPrEP 2 tablets 2-24 hours before sex 1 tablet every day during sexual activity 2 tablets after the last sexual intercourse Friday Saturday Sunday Monday Tuesday Wednesday Thursday On demand PrEP tells you How to Start and How to Stop PrEP

Adherence by Pill Count Median number of pills/month (IQR): 15 pills (9-21) TDF/FTC Nb pills/month

Detection of TFV in Plasma % of participants with TFV detected in plasma (548 samples from 113 participants) 100% Placebo TDF/FTC 100% 8 91% 88% 90% 85% 82% 40 83% 23 80% 44 46 33 70% 60% Percentage of participants 50% Overall detection: 86% in theTDF/FTC arm vs. 4% in the placebo arm 40% 30% % détectabilité TFV tous suivis confondus post J0 (226 suivis) dans le bras GrB = 86% 20% 10% 5% 6% 4% 5% 5% 2% 3 3 2 2 0% 0% 2 0% (56) (57) (51) (56) (49) (52) (42) (44) (37) (40) (22) (26) (8) (8) M0 n=113 M1 n=107 M2 n=101 M4 n=86 M6 n=77 M8 n=48 M10 n=16

Detection of TVF and FTC in Rectal Tissue Biopsies TFV 5 10 15 20 25 30 0.5 1.0 2.0 4.0 8.0 24.0 HIV Controls on TDF/FTC Time (hours) FTC and TFV concentrations in rectal tissue (ng/mg)

KM Estimates of Time to HIV-1 Infection (mITT Population) 0.00 0.10 0.20 0.04 0.02 0.08 0.06 0.14 0.18 0.16 0.12 Probability of HIV seropositivity Log-rank test p=0.0022 Placebo TDF/FTC 2 4 6 8 10 12 14 16 18 20 22 24 months from D0 Figure 2. Kaplan–Meier Estimates of Time to HIV Infection (Modified Intention-to-Treat Population). The cumulative probability of HIV acquisition is shown for the two study groups. The efficacy of preexposure prophylaxis with emtricitabine and tenofovir disoproxil fumarate (FTC–TDF) was 44%, as compared with placebo (P=0.005). The inset graph shows a more detailed version of the overall graph up to a probability of 0.10. N at risk : Placebo 201 142 74 55 42 TDF/FTC 199 141 82 58 43 Median follow-up of 9.3 months: 16 subjects infected 14 in placebo arm (incidence: 6.60 /100 PY) and 2 in TDF/FTC arm (0.91 /100PY) 86% relative reduction in the incidence of HIV-1 (95% CI : 40-98, p=0.002) NNT to avert one HIV-infection: 18 (95% CI: 11-50) Molina et al NEJM 2015

Randomized Double-Blinded vs. Placebo then Open-Label Extension www.ipergay.fr Randomized Double-Blinded vs. Placebo then Open-Label Extension Feb 2012 Nov 2014 Jun 2016 HIV-negative MSM Condomless Anal sex with > 2 partners in prior 6 months Creat. Clearance > 60 mL/mn HbS Ag negative TDF/FTC On Demand Placebo TDF/FTC On Demand Main messages: The Caprisa study was conducted in KwaZulu-Natal, South Africa in a population of women 18-40 yo, that were sexually active and at high risk for contracting HIV. Sero-status, safety, sexual behaviour, gel and condom use were assessed monthly for 30 months. Women were requested to insert one dose of gel within 12 hours before sex and as soon as possible within 12 hours after sex. This dosing strategy was based on the data from monkey challenge studies and perinatal transmission studies. Background: Tenofovir (PMPA) was studied due to the effectiveness, safety, and long half life, along with the protective data in the monkey challenge studies. Condoms, gels, tests for HIV and STIs, vaccinations for Hepatitis A and B, and peer counseling on risk reduction and adherence Follow-up every two months 12

HIV Incidence (mITT Analysis) Treatment Follow-Up Pts-years HIV Incidence per 100 Pts-years (95% CI) Placebo 212 6.60 (3.60-11.1) TDF/FTC (double-blind) 219 0.91 (0.11-3.30) TDF/FTC (open-label) 248 0.40 (0.01-2.25) Figure 2. Kaplan–Meier Estimates of Time to HIV Infection (Modified Intention-to-Treat Population). The cumulative probability of HIV acquisition is shown for the two study groups. The efficacy of preexposure prophylaxis with emtricitabine and tenofovir disoproxil fumarate (FTC–TDF) was 44%, as compared with placebo (P=0.005). The inset graph shows a more detailed version of the overall graph up to a probability of 0.10. Median Follow-up in Open-Label Phase 8.5 months (7.8-9.2) 1 single HIV-infection: Pt D/C PrEP - thought partner to be HIV negative Molina et al CROI 2016 13 13

PK/PD Simulation of PrEP Efficacy in Rectal Tissue Using the IPERGAY Dosing Regimen 49 women received a single-dose of TDF and FTC with blood and rectal sampling over 48h. PK/PD model using tissue concentrations of TFV, FTC, and competing endogenous nucleotides CD4 T-cells used to identify 90% Effective Concentration (EC90) ratios of TVF-DP to dATP and FTC-TP to dCTP First dose given 24h (A) or 2 h (B) before coitus Percentage of the population achieving the EC90 in colorectal tissue 98% at coitus and for 240h Time (h) 81% at coitus 100% 4h later Time (h) Cottrell ML et al. J Infect Dis 2016

Adverse Events Nb Participants (%) TDF/FTC n=199 Placebo n=201 All AEs 186 (93) 181 (90) 333 (92) Severe AEs 20 (10) 17 (8) 14 (4) Grade 3 or 4 AEs 19 (10) 15 (7) 24 (10) AEs leading to Rx D/C 1* 1** GI-related AEs 28 (14) 10 (5) 37 (10) Nausea/vomiting 16 2 11 Abdominal pain 13 3 8 Diarrhea 6 20 *Venous thrombosis **Decrease in plasma creatinine clearance from 81 to 76 ml/mn

PrEP Modalities Preferences among 1106 Young MSM Recruited by Facebook in 2015 in the US Hall EW et al. J Med Intern Res 2016

PrEP Modalities Preferences among 1106 Young MSM Recruited by Facebook in 2015 in the US Hall EW et al. J Med Intern Res 2016

Summary On Demand PrEP with oral TDF/FTC is highly effective in high risk MSM Low condom use did not undermine efficacy Safety of On Demand PrEP was good PrEP improved pleasure and removed fear during sexual activity On Demand PrEP expands PrEP choices On Demand PrEP gives guidance with regards to when to start and when to stop PrEP 18

PrEP “On Demand”

More on PrEP On Demand at Durban BE SURE TO ATTEND!!! More on PrEP On Demand at Durban Luis Sagaon Teyssier: Reported changes in PrEP and Condom use in MSM during the Open-label extension of the ANRS Ipergay study (Wednesday July 20, 12:30- 14:30 Poster WEPEC 263) Isabelle Durand Zaleski: Cost-effectiveness of on Demand PrEP in MSM in the ANRS Ipergay study (Thursday July 21, Cost-Effectiveness and Modeling, Session Room 2: 16:30-18:30) Efficacy of On Demand PrEP with TDF/FTC in the ANRS Ipergay open-label Extension Study (Wednesday July 20, Optimization Strategies, Session Room 1, 11:00-12:30) PrEP Roll-out in France (Wednesday July 20, From Clinical Trials to Clinical Care, Session Room 7, 14:30- 17:00)

Community Engagement

Acknowledgments The Participants The Study Staff and Peer-Counselors The Trial Scientific Committee The DSMB The Community Advisory Board The ANRS Staff INSERM SC10-US19 22 22