#AIDS2016 Efficacy of “On Demand” PrEP in the ANRS IPERGAY Open-Label Extension Study JM. Molina, I. Charreau, B. Spire, L. Cotte, J. Chas, C. Capitant, C. Tremblay, D. Rojas-Castro, E. Cua, A. Pasquet, C. Bernaud, W. Rozenbaum, C. Delaugerre, V. Doré, S. Le Mestre, M.-C. Simon, J.-F. Delfraissy, L. Meyer and the ANRS IPERGAY Study Group Hospital Saint-Louis and University of Paris Diderot, Inserm SC10- US019 Villejuif, UMR912 SEAS Marseille, Hospital Croix-Rousse, Lyon, Hospital Tenon, Paris, APHP, CHUM, Montreal, Canada and AIDES, Paris, France

Disclosures of Interest Research grants: Merck and Gilead Advisory Boards : BMS, Merck, Gilead, Jassen, ViiV Shareholder: none

Background  ANRS IPERGAY: high effectiveness of PrEP with oral TDF/FTC taken « On Demand » in high risk MSM.  86% relative reduction in HIV-incidence in the TDF/FTC arm vs Placebo (95% CI: 40-98, P=0.002)  Trial was prematurely discontinued: overestimation of efficacy because of initial high adherence ?  We do not have long-term safety data  Open-label study extension pre-planned, and implemented only 8 days after the discontinuation of the placebo arm.  All participants were offered to continue follow-up and access to open-label TDF/FTC

Study Design 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 On Demand  Condoms, gels, tests for HIV (using 4th generation assays) and STIs, vaccinations for Hepatitis A and B, and peer counseling on risk reduction and adherence  Follow-up every two months Randomized Double-Blinded vs. Placebo then Open-Label Extension TDF/FTC On Demand Feb 2012 Nov 2014 Jun 2016

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

FridaySaturdaySundayMondayTuesdayWednesdayThursdayFridaySaturdaySunday 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 On demand PrEP tells you How to Start and How to Stop PrEP

months from D N at risk :Placebo TDF/FTC 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) Probability of HIV Infection Placebo TDF/FTC Log-rank test p= KM Estimates of Time to HIV-1 Infection (mITT Population) Molina et al NEJM % 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)

Open Label Study Extension Flow Chart mITT Analysis n=400 On FU Nov 2014 n=335 (84%) New Pts n=33 Started Open Label Extension n= = 362 Pts Completed FU June 30, 2016 n= 299 (83%) Discontinued FU n=63 Consent w/o n=34 Lost FU n=16 Other n=13 Screened n=445 Declined n=3 (0.9%) Non Eligible n=3 HIV Infection n=1 Returned n=1 Did not start PrEP n=45 HIV Infection VIH n=13 (3%)

OLE Baseline Characteristics * ecstasy, crack, cocaine, crystal, speed, GHB/GBL ** NG: Neisseria gonorrhoeae, CT: Chlamydia trachomatis, TP: Treponema pallidum, VH: viral hepatitis Pts Characteristics (Median, IQR) or (%) N= 362 Age (years)35 (29-43) White93% Completed secondary education91% Employed83% Single78% History of PEP use in prior 12 months36% Use of psychoactive drugs in prior 12 months*43% Circumcised21% Infection with NG, CT, TP or VH in prior 6 months**33% Nb sexual acts in prior 4 weeks9.5 (5-15) Nb sexual partners in prior 2 months7 (3-15)

HIV Incidence (mITT Analysis) 97% relative reduction vs. placebo Median Follow-up in Open-Label Phase 18.4 months (IQR: ) Treatment Follow-Up Pts-years HIV Incidence per 100 Pts-years (95% CI) Placebo (double-blind) ( ) TDF/FTC (double-blind) ( ) TDF/FTC (open-label) ( )

HIV-1 Infection A single HIV-infection during the Open-label Study Extension Participant randomized in the TDF/FTC arm (double-blind phase) Switch to the open-label extension 8 months later in November 2014 HIV-1 infection diagnosed 40 days later in December 2014 No PrEP use for months Stable relationship with a single partner TDF and FTC not detectable at time of HIV diagnosis No drug resistance mutation Antiretroviral therapy started 3 days later The stable partner was also found to be HIV-1 infected….

Adherence by Pill Count Median Nb pills/month: 18 (IQR: 11-25) M2 M4 M6 M8M10M12M14 M16M18M20

Adherence by Questionnaires PrEP use at the last sexual intercourse Double-blind phase: 1193 Q Open-Label Phase: 1617 Q % PrEP (min-max) Double-Blinded % (min-max) Open-Label % (min-max) P-Value Correct*42 (35-51)50 (46-53)0.007 Sub-Optimal29 (20-38)24 (16-31) No PrEP29 (22-39)26 (21-35) *At least one pill before and one pill after

> 40 ng/mL ]10-40] ng/mL ]1-10] ng/mL Adherence by Plasma TFV Levels

Adverse Events Nb Participants (%)TDF/FTC n=199 Placebo n=201 TDF/FTC OLE n=362 All AEs186 (93)181 (90)353 (98) Severe AEs20 (10)17 (8)40 (11) Grade 3 or 4 AEs19 (10)15 (7)40 (10) AEs leading to Rx D/C103* GI-related AEs28 (14) 10 (5)48 (13) Nausea/vomiting16214 Abdominal pain1339 Diarrhea8625 **Decrease in plasma creatinine clearance to 48, 71 and 76 ml/mn

Lab Abnormalities Nb Participants (%)TDF/FTC n=199 Placebo n=201 TDF/FTC OLE n=362 Grade 1 Creatinine35 (18%)19 (9%)57 (16%) Grade 2 Creatinine0 (0%)1 (1%)3 (1%) Proteinuria ≥ 2+11 (6%)9 (4%)30 (8%) Glycosuria ≥ 2+1 (1%)0 (0%) 2 (1%) All Grades ALAT33 (17%)26 (13%)85 (23%) Grade 3 or 4 ALAT1 (1%)4 (2%)7 (2%) 8 participants with creatinine clearance < 60 ml/mn at least once (2 double-blind and 7 Open-label)

Sexual Behavior Proportion Pts with Condomless Sex for Last Receptive Anal Intercourse No significant change in median Nb of partners or sexual acts during the open-label phase (P= 0.42 and P= 0.12) Double blinded P for Trend = D0D0

Sexually Transmitted Infections Double-Blind Median FU: 9.3 months n=400 Open-Label Median FU: 18.4 months n=362 Nb Pt (%)Nb Cases Nb Pt (%)Nb Cases Chlamydiae81 (20) (34)158 Gonorrheae88 (22) (32)175 Syphilis39 (10)4568 (19)77 HCV5 (1)5 5 All STIs147 (37) (58)415 Incidence rate of first STI 35.2 vs 40.6 per 100 PY in the double-blinded and OLE phases

Summary On Demand PrEP with oral TDF/FTC remained highly effective in high risk MSM as long as it was taken Safety of On Demand PrEP was good Low condom use in the open-label phase did not undermine efficacy No significant change in Nb partners or sex acts High rate of STIs needs to be addressed PrEP improved pleasure and removed fear during sexual activity Results of this study have led to PrEP approval in France with full reimbursement

PrEP “On Demand”

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) PrEP Roll-out in France (Wednesday July 20, From Clinical Trials to Clinical Care, Session Room 7, 14:30- 17:00) BE SURE TO ATTEND!! !

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

Community Engagement