Coitally-Dependent TDF/FTC in MSM Updates on PrEP Efficacy in IPERGAY

1. Coitally-Dependent TDF/FTC in MSM Updates on PrEP Efficacy in IPERGAY Jean-Michel Molina and the ANRS Ipergay Study Group Hospital Saint-Louis and University of Paris 7, Inserm U941, Paris, France

2. Disclosures Advisory Boards: BMS, Gilead, GSK Janssen, Merck, ViiV Research Grants: Merck and Gilead

3. Background PrEP trials in Europe and Canada have shown a high incidence of HIV-infection (up to 9%) in high risk MSM PROUD and IPERGAY have demonstrated similar high effectiveness of PrEP with oral TDF/FTC (86%) IPERGAY is assessing coitally-dependent PrEP (2 pills before and 2 pills after sex) Participants in IPERGAY have frequent sex and used on average 4 pills/week (15 pills/month)

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

5. How early after starting PrEP were participants protected in IPERGAY ?

6. 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) 0 0 2 4 6 8 10 12 14 Number of weekly rectal SHIV exposures Garcia-Lerma et al.,Science Trans Med 2010, 14,14ra4

7. TFV/FTC Plasma and Rectal PK after Single Dose Oral TDF/FTC Garcia-Lerma , Science Trans Med 2010, 14,14ra4

8. Timing of Onset of Inferred HIV Risk Reduction with TDF/FTC Onset of action 99% risk reduction (69-100) after 5 daily doses and 96% (60-100) after 3 daily doses Seifert S, et al.Clin Inf Dis. March 2015, 60: 804

9. KM Estimates of Time to HIV-1 Infection (mITT Population) 0.20 Log-rank test p=0.0022 0.18 0.16 0.14 Placebo 0.12 0.10 Probability of HIV seropositivity 0.08 0.06 TDF/FTC 0.04 0.02 0.00 months from D0 0 2 4 6 8 10 12 14 16 18 20 22 24 N at risk : Placebo 201 142 74 55 42 TDF/FTC 199 141 82 58 43 Mean follow-up of 13 months: 16 subjects infected 14 in placebo arm (incidence: 6.6 /100 PY) and 2 in TDF/FTC arm (incidence: 0.9 /100PY) 86% relative reduction in the incidence of HIV-1 (95% CI : 40-98, p=0.0019)

10. Ipergay PK Sub-Study 12 participants received a single double-dose of oral TDF/FTC (600/400 mg) and PK sampling was performed over 24 hours (T0, 0.5, 1, 2, 4, 8 and 24 hours) Plasma, PBMC, dried blood spots, saliva and rectal biopsies were collected for PK analyses and ex vivo HIV-1 challenges Each participant had rectal biopsies collected at two time points (including T0) with 2 participants per time point (0.5, 1, 2, 4, 8 and 24 hours) Rectal biopsies were exposed overnight to CCR5 tropic HIV-1 and co-cultured with MT4-R5 cells over 11 days to detect p24 Ag in supernatants

11. TFV and FTC Concentration in Rectal Tissue Early detection of FTC in rectal tissue at high concentrations similar to HIV-infected patients on ART TFV is only detectable at 24h post drug intake at high concentrations 1 Control

12. Is the double-dose of TDF/FTC associated with increased PK exposure

13. Dose-Proportional Increasein Plasma FTC PK Parameters Pharmacokinetic Parameters of FTC in HIV-infected* and Ipergay subjects Plasma Saliva * Study FTC- 101 at steady-state: Wang LH et al AIDS Res Human Retrovir 2004 Mean in vitro IC90 estimate of FTC: 50 ng/ml Mean AUC ratio of saliva / plasma : 22%

14. Dose-Proportional Increasein Plasma TFV PK Parameters Pharmacokinetic Parameters of TFV in HIV-infected* and Ipergay subjects Plasma Saliva *Barditch-Crovo et al, Antimicrobial Agents Chemother 2001; 45:2733-9 Mean in vitro IC50 estimate of TFV: 10 ng/ml Mean AUC ratio of saliva / plasma : < 10%

15. Are post-exposure doses needed

16. Protection by SC TDF/FTC Given Before and/or After SHIV Exposure Garcia-Lerma , Science Trans Med 2010, 14,14ra4

17. Ex Vivo HIV-1Infection of Rectal Biopsies 10 participants had biopsies assessable at both time points with 4 biopsies per time point and per participant Before drug intake all participants had at least 1 biopsy infected (10/10) vs 6/10 after drug intake (p<0.07, Mac Nemar test for clustered data) Using a quantitative infectivity score (0: no infection to 6: infection detected at D4) median difference of mean scores: 1.38 (IQR: 0.25 -1.75), p<0.07, Wilcoxon sign rank test) Trend towards partial protection of rectal biopsies from HIV- infection after intake of a double-dose of TDF/FTC Need for additional post-exposure doses

18. Conclusions A double-dose of TDF/FTC is associated with rapid and high concentrations of TVF and FTC in plasma FTC can achieve rapid and high concentrations in rectal tissue and saliva Pre- and Post-exposure doses both appear to be critical for providing full protection against HIV acquisition The effectiveness of coitally-dependent PrEP in people with less frequent sex has yet to be demonstrated The IPERGAY study is ongoing open-label and will hopefully provide additional information

19. Acknowledgments The Participants The Study Staff and Peer-Counselors The Trial Scientific Committee The PK group: G. Peytavin, J. Fonsart, L. Goldwirt, B. Loze, M. Taouk INSERM U941: S. Saragosti, F. Mamano, A. Hance, F. Clavel INSERM SC10-US19 The DSMB and the Community Advisory Board The ANRS Staff