1. Intermittent PrEP Opportunities and Challenges of Oral iPrEP Jean-Michel Molina Department of Infectious Diseases Saint-Louis Hospital, INSERM U941 University of Paris 7, France CHU Saint Louis Paris

2. Conflicts of Interest  Research Grants: Merck, Sanofi  Advisory boards: Merck, Gilead, BMS, Janssen, ViiV  Travel/conference fees: AbbVie, BMS  Holding stock and personal relationship: none  PI of the ANRS Ipergay iPrEP trial

3. Current Status of Intermittent PrEP  Oral iPrEP is not approved and it use should be strongly discouraged until data are available  iPrEP different from “periodic” PrEP which is the starting and stopping of daily PrEP

4. Current Status of Daily Oral PrEP  Randomized trials: proof of concept that daily PrEP can reduce HIV incidence in high risk individuals  FDA approval of TDF/FTC for oral PrEP but current uptake is low, and no approval in other countries  Other trials using the same daily regimen have shown no efficacy: PrEP effectiveness in real life settings ?

5. The Challenge of Sustained Adherence to Daily PrEP  Only very high adherence to daily PrEP (>80%) associated with significant reduction of HIV incidence  Patients who have taken PrEP intermittently were not protected  Unsustainable daily PrEP adherence in adolescents and young women  Provide better support for adherence or assess more friendly regimens for long-term use

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9. What Do We Need to Know to Design iPrEP Regimens  Timing of HIV-infection following sexual exposure  PK of drugs in blood and tissues to achieve right drug concentration at the right place and at the right time  Assess people’s preference

10. Potential Benefits of iPrEP  Higher adherence to a more convenient dosing regimen  Higher adherence to iPrEP could improve efficacy: Intermittent use of TDF gel effective in Caprisa 004 when daily TDF gel ineffective in VOICE  Better safety due to lower drug exposure (kidneys, bones)  Lower risk of selecting drug resistance in case of HIV-infection  More cost-effective

12. TDF/FTC PK in Blood and Mucosal Tissue Single Dose TDF/FTC (LLOQ : 0.1ng/ml)  8 healthy men and 7 women  Blood and tissue concentrations of TDF and FTC quantified up to 14 days  Long half-lives : 47-49 hours  Cumulative exposure of rectal tissue to TDF > 30-fold higher vs. blood, only 4-fold higher for FTC  Cumulative exposure of cervical tissue to TDF 6-fold higher vs. blood, but > 40-fold higher for FTC Patterson K, et al. Sci Transl Med 3, 2011, 112re4 Time Post Dose (Days) 1000 100 10 1 0.1 0 2 681012414 Rectal Tissue Blood Plasma TNF Concentration (ng/mL) 1000 100 10 1 0.1 0 2 681012414 Cervicovaginal Fluid Blood Plasma Time Post Dose (Days) TDF ng/ml or ng/g TDF ng/ml

13. TDF PK in Blood and Mucosal Tissue Single Dose 300 mg TDF  6 healthy women, blood collected every 4 hours for the first 24h and up to 15 days  Long half-lives : 69 h TDF, 48h TVF-DP  TVF-DP peak 12h : 20 fmol/10 6 PBMC  Cumulative exposure of rectal tissue to TDF and TFV-DP > 30 and 120-fold higher respectively vs. vaginal tissue Louissaint et al. AIDS Res Human Retrovirus 2013,29

14. What Do Gays Men Think about iPrEP?  Online survey among 939 seronegative Gay men in France: 63% prefer « on demand » vs 25% daily PreP More interested by PrEP if unprotected anal sex (OR: 2.37, p<0.001)  Online survey in > 1000 seronegative Gay men in the US. Those most suitable for event-based PrEP were: older more educated more frequently used sexual networking more often reported sex with a not committed partner Capote et Pilule study, Adam P, Alexandre A. et al - Volk JE et al. J AIDS 2012, 61: 112

15. Mutua et al. PLoS ONE 2012 e33103 MSM (n=67) and FSW (n=5) Aged 18-49 yrs in Kenya Current or previous STI or Unprotected vaginal/anal sex or Transactional sex Daily oral TDF/FTC* (1 pill per day) (n =24) Daily oral Placebo* (1 pill per day) (n =12) Adherence : MEMS Sexual activity: daily SMS and interviews Intermittent oral TDF/FTC* (1 pill Monday Friday and 2h after sex) (n =24) Intermittent oral Placebo* (1 pill Monday, Friday and 2h after sex) (n =12) *Double blind vs. Placebo but Open-label daily vs. intermittent 4-Month follow-up Safety and Adherence to iPrEP in Kenya (IAVI E001)

16. PrEP Adherence Rates for Daily and Intermittent Regimens Dosing ScheduleActive N=48 Placebo N=24 Overall N=72 Daily Adherence Rate (%) (median, IQR) Overall unadjsuted Adjusted* 82 92 84 92 83 (63-92) 92 (82-99) Intermittent Adherence Rate (%) (median, IQR) Overall unadjsuted** 726868 (63-78) Fixed doses 563455 (28-78) Post-coital doses (SMS + MEMS event) 321926 (14-50) Post-coital doses within 2h (self report) 100 Mutua et al. PLoS ONE 2012 e33103 *Adjusted accounts for extra openings and extra pills taken out ** adherent to fixed dosing + post-coital dosing (SMS + MEMS)

17. Summary of IAVI E001  Adherence to coitally-dependent dosing may be difficult  SMS responses were low (23%) and may have impaired assessment of post-coital dosing adherence  in IAVI E002 trial in serodiscordant couples in Uganda SMS responses (80%) and adherence to iPrEP higher (91% twice- weekly, 45% post-coital)  Acceptability of PrEP was high and better with intermittent dosing (86%) despite challenges with the post-coital dosing  Safety was similar among all groups  Better methods to measure sexual activity and adherence to intermittent PrEP regimens

18. What is the Evidence iPrEP Can Work ?

19. Efficacy of iPrEP with TDF/FTC in the SHIV Macaque Model Garcia-Lerma, Science Trans Med 2010, 14,14ra4

20. TFV-DP Concentrations in IPrEx and STRAND Anderson et al, Science Translational Medicine 2012 4:151ra125 * Visit when HIV was first discovered * Regression analysis in iPrEx: 90% reduction in HIV acquisition when TFV-DP>16 fmol/10 6 cells Predicted risk reduction: 76% with 2 pills / week 96% with 4 pills / week 99% with 7 pills/ week 16

21. Ongoing Oral iPrEP Studies

22. Daily Truvada 1 tablet/d Regarless of sexual activity (n = 180) Time driven Truvada: 1 tablet 2 days/week + 1 post-exposure dose within 2 hours after sex (n = 180) High risk women and MSM (New York, Bangkok, Cape Town) Event driven Truvada: 1 tablet prior to sex + 1 post-exposure dose within 2 hours after sex (n = 180) Wk 24 primary endpoint Primary Objective: Is intermittent vs. daily dosing associated with equivalent coverage of sex events, lower number of pills used and decreased side effects R. Grant, F. Van Griensven, et al. HPTN 067/ADAPT (Alternative dosing to augment PrEP pill taking) Phase II, Randomized, Open-Label, Pharmacokinetic and Behavioral Study of the Use of Intermittent Oral PrEP with TDF/FTC 6-week lead-in period 1 pill/week DOT before randomization

23. IPERGAY Study Design High risk MSM Condomless anal sex with > 2 partners Full prevention services* TDF/FTC before and after sex (n=950) Full prevention services* placebo before and after sex (n=950)  Counseling, testing for STI, condoms, vaccination, PEP  Primary endpoint : HIV infection, 64 events expected  Incidence of HIV-infection: 3%PY, 50% efficacy, ~ 2000 pts Effectiveness of “on demand” PrEP Randomized placebo-controlled trial www.ipergay.fr

24. Conclusions  Oral iPrEP is a potentially interesting and promising strategy  Oral iPrEP should not be used outside research settings  Individuals reluctant to use daily PrEP should consider other preventive tools  More research is needed on iPrEP (PK and behavioral sciences)