1. PrEP Roll-Out In France Jean-Michel Molina Saint-Louis Hospital, University of Paris Diderot, Inserm U941, Paris, France

2. Disclosures of Interest Research grants: Merck and Gilead Advisory Boards : BMS, Merck, Gilead, Jassen, ViiV Shareholder: none

3. Reasons for PrEP Deferral in Europe PrEP approved in 2012 by US FDA and recommended by US CDC but: Uncertainty about real need Inconsistent efficacy across trials Questions regarding safety in healthy individuals Risk of selection of HIV resistance Impact on sexual behavior with reduction of condom use and increase in STIs Issues of cost and cost-effectiveness Implementation challenges

4. 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Year of Diagnosis 0 500 1000 1500 2500 2000 3000 Newly diagnosed HIV-infections 42% MSM 23% Foreign Heterosexual women 16% Foreign Heterosexual men 10% French heterosexual men 7% French heterosexual women 1% UDI 6600 new HIV-infections in France in 2014 INVS, December 2015 Increase in New HIV-infections in MSM

5. HIV Incidence (mITT Analysis) 97% relative reduction vs. placebo Median Follow-up in Open-Label Phase 18.4 months (17.5-19.1) Treatment Follow-Up Pts-years HIV Incidence per 100 Pts-years (95% CI) Placebo2126.60 (3.60-11.1) TDF/FTC (double-blind)2190.91 (0.11-3.30) TDF/FTC (open-label)5150.19 (0.01-1.08) Molina et al AIDS 2016, July 20, Durban, South Africa

6. Adverse Events Nb Participants (%)TDF/FTC n=199 Placebo n=201 TDF/FTC n=362 All AEs186 (93)181 (90)353 (98) Severe AEs20 (10)17 (8)40 (11) Grade 3 or 4 AEs19 (10)15 (7)40 (10) AEs leading to Rx D/C103* GI-related AEs28 (14) 10 (5)48 (13) Nausea/vomiting16214 Abdominal pain1339 Diarrhea8625 **Decrease in plasma creatinine clearance to 48, 71 and 76 ml/mn

7. Summary of Findings High incidence of HIV infection in high risk MSM in France, UK and Canada Daily and On Demand PrEP with oral TDF/FTC both highly effective in high risk MSM Low condom use did not undermine efficacy Safety of PrEP was good PrEP improved satisfaction and removed fear during sexual activity

8. Path to PrEP Access in Europe  eCDC comment on PrEP in Europe (April 30, 2015) : EU Members States should give consideration to integrating PrEP into their existing HIV prevention package for those most at-risk of HIV infection, starting with MSM.  WHO updated guidelines (October 2015): Oral PrEP should be offered as an additional prevention choice for people at substantial risk of HIV infection as part of combination prevention approaches.  EACS Guidelines (v8, october 2015): PrEP is recommended in HIV-negative MSM and transgender individuals who are inconsistent in their use of condoms. PrEP may be considered in HIV-negative heterosexual women and men.  Gilead submitted an application for TDF/FTC PrEP at EMA early 2016  Implementation projects in Europe: AMPrEP (Amsterdam) and Be-PrEP- ared (Antwerp)  PrEP was approved in France for temporary use with full coverage by the health care system (November 2015)

9. Recommendation of Temporary Use (RTU) for Truvada for PrEP ANSM (National Agency for Drug Safety) can authorize an RTU for a drug already approved, to be used for an indication different from its initial approval An RTU is granted for 3 years and can be renewed. An RTU for Truvada for PrEP was granted in November 2015, and was fully covered by the national health insurance Within the RTU, Truvada is indicated for PrEP in adults (> 18 years) at high risk of sexual HIV acquisition This has been effective since January 4, 2016

10. Who is Eligible for the Truvada RTU Adults (18 years or older) Negative HIV serologic assay (4th generation ELISA) No sign of primary HIV infection No recent HIV exposure (< 1 month) High risk of sexual HIV acquisition

11. High Risk of Sexual HIV Acquisition MSM or transgender individuals with: –Condomless anal sex with at least two different partners over the last 6 months –Episodes of STIs (syphilis, chlamydiae, gonorrhea, HBV, HCV) over the last 12 months –Multiple PEP treatments in the last 12 months –Use of drugs during sexual intercourse (cocaine, GHB, MDMA, etc…) Other persons at high risk of HIV acquisition on a case by case basis: –Sex workers exposed to condomless sex –Vulnerable persons exposed to condomless sex with people from a group with a high prevalence of HIV Person from areas/countries of high HIV prevalence Person with multiple sexual partners IVDU Persons having condomless sex with partners with genital ulcers, STIs, or bleeding that can increase their risk of HIV acquisition Other high risk situations of HIV acquisition

12. Who is Not Eligible for Truvada HIV Serologic assay positive or unknown Signs or symptoms of primary HIV-infection Creatinine clairance < 50 ml/mn Chronic HBV infection if PrEP used On Demand Breast-feeding Hypersensitivity to TDF or FTC or excipients

13. Dosing Regimens and Follow-up Dosing Schedule –Daily (1 pill a day) or On demand (only for MSM – Ipergay dosing regimen) Patients follow-up –Doctor visit (23 Euros - reimbursed 70%: 8 Euros per visit unless complementary insurance) –Baseline tests: HIV/HBV/HCV, tests for STIs (PCR 3 sites and syphilis), creatinine and ALT (190 Euros - reimbursed 60%: 83 Euros, 23 Euros if complementary insurance and free tests for STIs in STI clinic) –Test at Month 1 and every 3 months: HIV test, ALT and creatinine (23 Euros, 2 Euros to be paid, unless complementary insurance) –Tests for STIs as needed (at least once a year) Global Sexual Health –Referrals for psychiatry, addictology, proctology, sex therapy,

14. Requirements for the Truvada RTU Doctors should tell their patients that Truvada is prescribed through an RTU At ANSM’s request Gilead has opened a website (https://www.rtutruvada.fr) to collect information on PrEPhttps://www.rtutruvada.fr Doctors should report on this website –data on patients characteristics at treatment initiation, –modalities of PrEP use (daily or on demand), –incident HIV-infections, –drug-related adverse events, –pregnancies, Data analyzed by Gilead and reported to ANSM every 3 months.

15. PrEP Implementation in France in 2016 > 90 PrEP clinics have opened, initially in ANRS Ipergay sites (Paris, Lyon, Nice, Lille, Nantes) AIDES Website: http://www.aides.org/info- sante/prep http://www.aides.org/info- sante/prep TDF/FTC can be prescribed by hospital-based HIV specialists and STI clinics since June 2016 TDF/FTC can be obtained at private and hospital pharmacies Cumulative Nb Nb Doctors Nb Patients

16. Number of Subjects Registered per Region Haute Normandie Basse Normandie Bretagne Pays de la Loire Poitou- Charentes Aquitaine Midi-Pyrénées Languedoc- Roussillon Provence Alpes Côte d’Azur Centre Ile-de- France Bourgogne Picardie Nord Pas-de-Calais Champagn e Ardenne Lorraine Alsace Franche- Comté Rhône Alpes Auvergne Limousin > 500 > 10 > 1 > 100

17. Baseline Characteristics (Jan 2016- June 2016) Pts Characteristics (Median, IQR) or (%) N= 867 Age, years38 (30-44) French87% Male96.4% Female0.6% (n=6) Transgender0.3% (n=3) MSM96.4% Use of psychoactive drugs20.8% STIs in prior 12 months30% PEP use in last 12 months11.9% On Demand PrEP65.2%

18. PrEP “On Demand”

19. Two HIV Breakthrough Infections Patient 1: –Negative HIV serologic assay at PrEP initiation –HIV seroconversion at the next visit one month later –HIV PCR retrospectively found positive at baseline –Acute HIV-infection at PrEP initiation Patient 2: –Negative HIV serologic assay at PrEP initiation –HIV seroconversion at the next visit one month later –HIV RNA: 500 cp/ml with M184I RAM

20. PrEP Clinic at Paris St-Louis 408 patients came for a first visit since November 2015.

21. Baseline Characteristics Paris St-Louis (Nov 2015- June 2016) Pts Characteristics (Median, IQR) or (%) N= 396 MSM99.5% Age (years)37 French79% Completed secondary education82% Employed81% Single72% Informed by a friend39% Informed by internet25% Informed by AIDES19% Psychiatric follow-up22%

22. Baseline Characteristics A High Risk Population * past year: ecstasy, crack, cocaine, crystal, speed, GHB/GBL ** NG: Neisseria gonorrhoeae, CT: Chlamydia trachomatis, TP: Treponema pallidum Pts Characteristics (Median, IQR) or (%) N= 396 Ever used PrEP17% History of PEP use52% Use of psychoactive drugs* last 4 weeks44% Sex with an HIV-infected partner34% Infection with NG, CT or TP** last 2 years53% Nb condomless sexual acts in prior 4 weeks14 Nb sexual partners in prior 3 months11 Started PrEP at first visit87% On demand PrEP vs Daily63% 3 with HIV positive tests at screening (0.7%)

23. Two HIV Breakthrough Infections Patient 1: 30-year old MSM –45 sexual partners in prior 3 months, 30 condomless sexual intercourses in prior 4 weeks –Chemsex (cocaine, 4MEC, poppers) with STIs (chlamydiae, gonorrhea, HPV) –First visit: Nov 24, 2015: HIV serologic assay and PCR negative on Nov 17 –Ordered generic TDF/FTC online and started daily PrEP Dec 9 –Second visit Dec 28, 2015: HIV serologic test positive (WB: 4 bands) HIV RNA: 29,557 cp/ml with M184V RAM (bulk sequencing) TDF: 171 ng/ml in plasma –Started ART Jan 4, 2016 and fully suppressed 4 months later Patient 2: 37-year old MSM –20 sexual partners in prior 3 months, 60 condomless sexual intercourses in prior 4 weeks –Chemsex (cocaine, GHB, poppers), psychiatric follow-up and multiple STIs –First visit: Dec 1st, 2015: HIV serologic assay negative on Nov 27 –Daily TDF/FTC prescribed but too expensive and used TDF/FTC from an HIV-infected friend –Second visit March 17, 2016 to get « free » TDF/FTC through the RTU: Positive HIV serologic test on March 11 ( 6 bands on WB) HIV RNA: 29,557 cp/ml, no resistance Inconsistent adherence to TDF/FTC –Started ART March 25 and fully suppressed 2 months later

24. Challenges with PrEP Roll-Out  Dedicated nurses to provide information/appointment by email and tel  PrEP guide with prescription for tests for HIV and STIs sent by email  Organize outpatient clinic to meet the demand - Inform nurses and administrative personnel - Identify doctors willing to provide PrEP (> 10 doctors) - Increase offer: 10 consultations per week (2 to 3 from 6-10 pm)  PrEP can be started at first visit and patients seen at Month 1 and every 3 months  Adapt outpatient clinic for STI treatment (injections)  Peer-counseling by AIDES (PrEP adherence, risk reduction)

25. Lessons Learned in France  Close partnership with the community and strong political support have led to PrEP approval  Increase PrEP awareness among doctors and people at risk (MSM, transgender, and heterosexual migrants)  Adapt available resources to provide comprehensive sexual health care and meet the demand  Define best models of care and access points (hospitals, sexual health clinics, GP)  Monitor and evaluate PrEP implementation  High risk people self-select for PrEP: HIV-infection detected at screening or soon after PrEP initiation  Demonstrate the public health benefit of PrEP implementation: ANRS « PREVENIR » project

26. City Hall meeting, February 2016 Political Support from the City of Paris for HIV Prevention

27. Acknowledgments

28. Community Engagement