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

Slides:



Advertisements
Similar presentations
9th Advanced HIV Course Aix-en-Provence 2011 Role of ARV as Prevention Martin Fisher Brighton and Sussex University Hospitals, UK.
Advertisements

Dr. Carol Odula (Obs./Gyn.) May 7 th 2013 Preparing for pre-exposure prophylaxis (PrEP) to prevent HIV infection.
Monica Gandhi MD, MPH Associate Professor and Women’s HIV Clinic provider, HIV/AIDS Division San Francisco General Hospital/ UCSF Safe Poz Love, U.S. Positive.
Maurice Cook ( EM Designs Group, Inc.) The End of AIDS Transmission? Robert M Grant, June 2012.
Preparing for pre-exposure prophylaxis (PrEP) to prevent HIV infection James Wilton Project Coordinator Biomedical Science of HIV Prevention
Journal Club Alcohol, Other Drugs, and Health: Current Evidence July–August 2013.
HIV in Texas: The Ways Forward Ann Robbins Manager of HIV/STD Prevention and Care Department of State Health Services.
Pre-Exposure Prophylaxis (PrEP) Initiative: Open Label Extension Robert M Grant, Peter L. Anderson, Vanessa McMahan, Albert Liu, K. Rivet Amico, Megha.
RISHA IRVIN, MD/MPH SAN FRANCISCO DEPT. OF PUBLIC HEALTH PREVENTION UMBRELLA FOR MSM IN THE AMERICAS (PUMA) Risk Compensation and Pre-Exposure Prophylaxis.
TasP is not enough Stipulated that TasP is effective in reducing infectiousness of the treated person – But much more is required. TasP requires effective.
HIV Prophylaxis: Following Occupational and Non-Occupational Exposure Nanik (Nayri) Hatsakorzian Pharm.D./MPH candidate 2014 Touro University, College.
A. D. Smith, 1 A. Muhaari 2 E. M. van der Elst 2 D. Kowuor, 2 A.Davies, 2 C Agwanda, 1 M. Price, 3 F. Priddy, 3 H. S. Okuku, 2 S.M. Graham, 4 E. J. Sanders.
Potential role of PEP, PrEP and ART for HIV Prevention among Men who have Sex with Men Frits van Griensven, PhD, MPH Division of HIV/AIDS Prevention US.
Extracellular and Intracellular Tenofovir DF and Emtricitabine Exposure in Mucosal Tissue after a Single Dose of Fixed-Dose TDF/FTC: Implications for Pre-exposure.
New York State Department of Health AIDS Institute June, 2014
HIV Science Update: From Rome to Addis – Biomedical Prevention Elly T Katabira, FRCP Department of Medicine Makerere University College of Health Sciences.
Are people living with HIV less likely to pass HIV to others if they are on treatment? Exploring the use of treatment as prevention James Wilton Project.
Use of Antivirals in Prevention Oral and Topical Prophylaxis
HPTN 067/ADAPT Background and Methods and Cape Town Results: Linda-Gail Bekker; James Hughes; Rivet Amico; Surita Roux; Craig Hendrix; Peter L. Anderson;
Maurice Cook ( EM Designs Group, Inc.) A Pill a Day To Keep HIV Away Robert M Grant, April 28, 2011.
Slide 1 of 9 From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. IAS–USA Jeanne Marrazzo, MD, MPH Professor of Medicine University of Washington.
N ORTHWEST AIDS E DUCATION AND T RAINING C ENTER PrEP 201: Beyond the Basics Joanne Stekler, MD MPH Associate Professor of Medicine University of Washington.
Making Pharmacological Sense of the Successes and Failures Among PrEP Clinical Trials Craig Hendrix, MD Johns Hopkins University.
Starting and Stopping PrEP: Lessons from Pharmacology David V. Glidden University of California at San Francisco IAS 2015, Vancouver 20 July 2015
Potential role of PEP, PrEP and ART for HIV Prevention among Men who have Sex with Men Frits van Griensven, PhD, MPH Division of HIV/AIDS Prevention US.
Looking back, looking forward: what we know and don’t know about oral PrEP and tenofovir gel for preventing HIV in women Jared Baeten MD PhD Departments.
Looking back, looking forward: what we know and don’t know about oral PrEP and tenofovir gel for preventing HIV in women Jared Baeten MD PhD Departments.
A PEP and PrEP Update Jeffrey D. Klausner, MD, MPH Black AIDS Institute-UCLA African-American University September 2014 Special thanks to Raphael Landovitz,
What Is Currently in the Pipeline & What is Ideal for an ARV-based Prevention Candidate? Carl W. Dieffenbach, Ph.D. Director, Division of AIDS, NIAID,
When Will Women Have Choices? Sharon Hillier University of Pittsburgh School and Medicine Microbicide Trials Network IAS, Washington DC, July 26, 2012.
Ethics in a new era Microbicides 2012 Preconference Bridget Haire.
ART: When to Start? – Case Discussion Roy M. Gulick, MD, MPH Professor of Medicine Chief, Division of Infectious Diseases Weill Medical College of Cornell.
Pragmatic Open-Label Randomised Trial of Pre-Exposure Prophylaxis: the PROUD study
Michael Hughes, MD Assistant Clinical Professor UCR Eisenhower Medical Associates.
N ORTHWEST AIDS E DUCATION AND T RAINING C ENTER CROI 2015: HIV Prevention Updates Ruanne V Barnabas, MBChB Dphil Global Health and Medicine University.
IAS July 1 The Caprisa 004 result in context Sheena McCormack Clinical Scientist MRC Clinical Trials Unit.
Microbicides and PrEP: Back to Basics Wednesday July 25, 2012 ADM Kashuba.
PrEP Update: The science, new tools, and next steps Dawn K. Smith MD, MS, MPH Division of HIV/AIDS Prevention, CDC “The findings and conclusions in this.
N ORTHWEST A IDS E DUCATION AND T RAINING C ENTER Pre-exposure Prophylaxis for HIV Prevention Efficacy and the importance of adherence Joanne Stekler,
Looking Ahead to MTN-017 Ross D. Cranston MD, FRCP Microbicide Trials Network IRMA.
Antiretrovirals for HIV Prevention: Progress and Challenges Kenneth H. Mayer, M.D. Brown/Miriam/Fenway.
HIV and Women Collaborating Across Borders to Advance the Health of Women IAS 2012 Gina M. Brown, M.D. July 22, 2012.
The tipping point: When do placebos become unethical? Bridget Haire.
#AIDS2016 Efficacy of “On Demand” PrEP in the ANRS IPERGAY Open-Label Extension Study JM. Molina, I. Charreau, B. Spire, L. Cotte, J.
Pre-exposure Prophylaxis (PrEP) for HIV Prevention: What’s the Future? Joanne Stekler, MD MPH Assistant Professor of Medicine University of Washington.
An overview of PrEP trials Bea Vuylsteke Institute of tropical Medicine, Antwerp, Belgium Marrakech, IUSTI 2016.
Review of Non-Daily PrEP Clinical Research and Experience
Timothy H. Holtz (CDC/DHAP / Thailand MOPH – US CDC Collaboration)
Regulatory Considerations for Approval: FDA perspective
PrEP for HIV Prevention
Efficacy of “On Demand” PrEP The ANRS IPERGAY Trial
What’s Next – and When: An Update on Injectable Prevention
Pharmacology Supports on Demand Dosing in MSM/TW
Module 4 (c) Stopping PrEP
On behalf of The MTN-020/ASPIRE Study Team
On Demand PrEP for Men at High Risk for HIV IPERGAY
UZ-UCSF Annual Research Day 8 April 2016
HPTN 067 ADAPT: A Phase 2 randomized open label trial of daily, twice weekly, and sex event PrEP dosing. Presented by Robert Grant, MD, MPH on behalf.
HIV and the ART of Prevention
22th International AIDS Conference
The Politics of PrEP The French Experience
Comparison of measures of adherence to HIV pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) and transgender women (TGW): results from.
AIDSACTIONBALTIMORE PREP UP TOWN HALL
Rectal Gels for PrEP Are They an Option?
100 Partners PrEP[5] Efficacy 75% Adherence 81% 80
José Bauermeister PhD, MPH University of Pennsylvania MTN BRWG Member
WHO technical brief on event-driven PrEP (ED-PrEP)
HIV Resistance in the Context of PrEP
It’s Time for PrEP in Latin America and the Carribean
Bob Holtkamp, Director of Prevention & Outreach
Presentation transcript:

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

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

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

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 ?

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

FridaySaturdaySundayMondayTuesdayWednesdayThursdayFridaySaturdaySunday Time-Driven iPrEP

FridaySaturdaySundayMondayTuesdayWednesdayThursdayFridaySaturdaySunday Event-Driven iPrEP

FridaySaturdaySundayMondayTuesdayWednesdayThursdayFridaySaturdaySunday Time and Event-Driven iPrEP

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

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

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 : 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) Rectal Tissue Blood Plasma TNF Concentration (ng/mL) Cervicovaginal Fluid Blood Plasma Time Post Dose (Days) TDF ng/ml or ng/g TDF ng/ml

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

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

Mutua et al. PLoS ONE 2012 e33103 MSM (n=67) and FSW (n=5) Aged 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)

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* (63-92) 92 (82-99) Intermittent Adherence Rate (%) (median, IQR) Overall unadjsuted** (63-78) Fixed doses (28-78) Post-coital doses (SMS + MEMS event) (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)

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

What is the Evidence iPrEP Can Work ?

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

TFV-DP Concentrations in IPrEx and STRAND Anderson et al, Science Translational Medicine :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

Ongoing Oral iPrEP Studies

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

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

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)