Transcript n=12
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 Disclosures Advisory Boards: BMS, Gilead, GSK Janssen, Merck, ViiV Research Grants: Merck and Gilead 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) 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 Friday Saturday Sunday Monday Tuesday Wednesday Thursday Friday Saturday Sunday 4 pills of TDF/FTC taken over 3 days to cover one sexual intercourse How early after starting PrEP were participants protected in IPERGAY ? Effect of a Double Dose of oral TDF/FTC (-2h, + 24h) % Uninfected Macaques % Uninfected animals 100 Double dose oral TDF/FTC (n = 6) HR : 16,7 p = 0.006 75 50 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 TFV/FTC Plasma and Rectal PK after Single Dose Oral TDF/FTC Garcia-Lerma , Science Trans Med 2010, 14,14ra4 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 KM Estimates of Time to HIV-1 Infection (mITT Population) Probability of HIV seropositivity 0.20 Log-rank test p=0.0022 0.18 0.16 0.14 Placebo 0.12 0.10 0.08 0.06 TDF/FTC 0.04 0.02 0.00 0 N at risk : Placebo TDF/FTC 201 199 2 4 6 142 141 8 10 12 14 16 18 20 22 24 74 82 55 58 months from D0 42 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) 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 TFV and FTC Concentration in Rectal Tissue C o n c e n t r a t io n ( n g / m g ) 20 TFV FTC 15 10 5 10 0 .0 0 .5 1 .0 2 .0 4 .0 8 .0 2 4 .0 3Control 0 .0 T im e ( h o u r s ) Early detection of FTC in rectal tissue at high concentrations similar to HIVinfected patients on ART TFV is only detectable at 24h post drug intake at high concentrations Is the double-dose of TDF/FTC associated with increased PK exposure Dose-Proportional Increase in Plasma FTC PK Parameters Pharmacokinetic Parameters of FTC in HIV-infected* and Ipergay subjects Plasma Saliva Mean PK parameter 100 mg QD (n=8) 200 mg QD (n=8) 400 mg QD (n=12) 400 mg QD (n=12) Cmax (ng/ml) 880 1720 2906 558 Tmax (h) 0.93 2.00 2.10 2.80 35 47 80 31 AUC0-24 (hr.ng/ml) 3,980 8,000 16,527 3,253 T1/2 (h) 10.6 8.24 5.2 9.4 Cmin (ng/ml) * 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% Dose-Proportional Increase in Plasma TFV PK Parameters Pharmacokinetic Parameters of TFV in HIV-infected* and Ipergay subjects Plasma Saliva Mean PK parameter 75 mg QD (n=12) 150 mg QD (n=8) 300 mg QD (n=8) 600 mg QD (n=10) 600 mg QD (n=12) 600 mg QD (n=12) Cmax (ng/ml) 68.6 111 240 618 419 3.6 Tmax (h) 0.8 1.00 0.8 1.0 1.3 2.70 Cmin (ng/ml) ND 20 40 100 40 1.9 AUC0-24 (hr.ng/ml) 717 1,613 2,093 3.372 2,376 49 T1/2 (h) ND 12 11.9 13 11.2 ND *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% Are post-exposure doses needed Protection by SC TDF/FTC Given Before and/or After SHIV Exposure Garcia-Lerma , Science Trans Med 2010, 14,14ra4 Ex Vivo HIV-1 Infection 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 HIVinfection after intake of a double-dose of TDF/FTC Need for additional post-exposure doses 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 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