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Intermittent PrEP Opportunities and Challenges of Oral iPrEP

Intermittent PrEP Opportunities and Challenges of Oral iPrEP. CHU Saint Louis Paris. Jean-Michel Molina Department of Infectious Diseases Saint-Louis Hospital, INSERM U941 University of Paris 7, France. Conflicts of Interest. Research Grants: Merck, Sanofi

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Intermittent PrEP Opportunities and Challenges of Oral iPrEP

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

  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

  6. Time-Driven iPrEP

  7. Event-Driven iPrEP

  8. Time and Event-Driven iPrEP

  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

  11. 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/106 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

  12. 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

  13. Safety and Adherence to iPrEP in Kenya (IAVI E001) Adherence : MEMS Sexual activity: daily SMS and interviews 4-Month follow-up Daily oral TDF/FTC* (1 pill per day) (n =24) Daily oral Placebo* (1 pill per day) (n =12) 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 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 Mutua et al. PLoS ONE 2012 e33103

  14. PrEP Adherence Rates for Daily and Intermittent Regimens *Adjusted accounts for extra openings and extra pills taken out ** adherent to fixed dosing + post-coital dosing (SMS + MEMS) Mutua et al. PLoS ONE 2012 e33103

  15. 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

  16. What is the Evidence iPrEP Can Work ?

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

  18. TFV-DP Concentrations in IPrEx and STRAND Regression analysis in iPrEx: 90% reduction in HIV acquisition when TFV-DP>16 fmol/106 cells Predicted risk reduction: 76% with 2 pills / week 96% with 4 pills / week 99% with 7 pills/ week 16 * Anderson et al, Science Translational Medicine 2012 4:151ra125 * Visit when HIV was first discovered

  19. Ongoing Oral iPrEP Studies

  20. 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 Wk 24primary endpoint 6-week lead-in period 1 pill/week DOT before randomization 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) 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.

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

  22. 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)

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