Incidence of HIV-Infection with Daily or On Demand PrEP with TDF/FTC in the Paris Area: An Update of the Prevenir Study JM. Molina, J. Ghosn, M. Algarte-Genin, D. Rojas -Castro, L. Beniguel, G. Pialoux, C. Delaugerre, J-P. Viard, C. Katlama, C. Segouin, C. Pintado, P-M. Girard, J. Lourenco, M. Ohayon, S. Le Mestre, B. Spire, V. Doré, L. Assoumou, and D. Costagliola for the ANRS Prevenir Study Group Assistance Publique Hôpitaux de Paris, INSERM, Université de Paris, IPLESP, Coalition PLUS, AIDES, ANRS, SESSTIM, ORS PACA, France

Disclosures Research grants: Gilead Advisory Boards : Merck, Gilead, ViiV, Teva Shareholder: none 2

Background ANRS IPERGAY: high effectiveness of PrEP with oral TDF/FTC taken « On Demand » in high risk MSM. 86% relative reduction in HIV-incidence in the TDF/FTC arm vs placebo (95% CI: 40-98, P=0.002) 97% relative reduction in HIV-incidence in the TDF/FTC arm during the open-label extension (95% CI: 81-100) Limited data on real-world experience with On demand PrEP Confirm public health impact of PrEP on the HIV epidemic in Paris like in San Francisco and Australia Molina et al. NEJM 2015, Lancet HIV 2017

Study Design Open-Label Prospective Cohort Study in the Paris Region http://prevenir.anrs.fr/ Open-Label Prospective Cohort Study in the Paris Region n > 3,000 May 3rd 2017 May 31st 2020 HIV-negative high risk adults Inconsistent Condom use eGFR > 50 mL/mn HbS Ag negative if On Demand TDF/FTC Daily On Demand Show 15% reduction in new HIV diagnoses among MSM in the Paris Region Participants opted for either Daily or On Demand PrEP and could switch regimen Follow-up every 3 months with 4th Gen ELISA HIV test and plasma creatinine STI screening at physician’s discretion (Guidelines recommend every 3 months in MSM) Condoms, gels, risk reduction and adherence counseling, Q on sexual behavior On peut changer en cours d’étude 4

Study Objectives Primary Objective To show at 3 years > 15% reduction of new HIV diagnoses among MSM in Paris region in comparison with the numbers provided by the National Surveillance network in 2016 Secondary Objectives Participants characteristics Overall HIV incidence and by dosing regimen (Daily or On Demand) PrEP adherence and coverage of sex events (self-report, dried blood spots) Impact of social disparities and peer counseling on adherence and retention Sexual behavior (condom use, Nb of sexual acts, Nb of partners, STIs) Safety, tolerability ~ 3,000 pts to be enrolled (85% MSM) with the hypothesis of PrEP efficacy: 80% May 2, 2019: 3,057 pts enrolled across 26 sites

Baseline Characteristics Characteristics (Median, IQR) or (n, %) N = 3057 Age (years) 36 (29-44) Caucasian 2614 (85.5) MSM 3013 (98.7) Heterosexual men or women 30 (1.0) Transgender 13 (0.4) Bachelor’s degree 1863 (60.9) Employed 2113 (69.1) No regular sex partner 1681 (55.0) History of PrEP use 1706 (55.8) Use of Chemsex* 423 (13.8) On Demand dosing regimen 1499 (49.2) Nb condomless sex acts in prior 4 weeks 2 (0 - 5) Nb sexual partners in prior 3 months 10 (5 - 20) Mean duration of prior PrEP use 10 months Incidence of study discontinuation: 9 per 100 PY * at last sexual intercourse : cocaine, GHB, MDMA, mephedrone

Baseline Characteristics Characteristics (Median, IQR) or (n, %) Daily N=1546 (50.8%) On Demand N=1499 (49.2%) P-value Age (years) 35 (28 – 43) 36 (30 – 44) <.001 MSM 1513 (97.9) 1488 (99.3) 0.001 Heterosexual men or women 20 (1.3) 10 (0.7) Transgender 12 (0.8) 1 (0.1) Bachelor’s degree 902 (58.3) 958 (63.9) 0.004 Employed 1054 (68.2) 1057 (70.5) 0.660 No regular sex partner 870 (56.4) 803 (53.9) 0.165 History of PrEP use 844 (54.6) 858 (57.2) 0.142 Use of Chemsex* 218 (14.1) 204 (13.6) 0.715 No. condomless sex acts in prior 4 weeks 2 (0 – 6) 2 (0 – 4) No. sexual partners in prior 3 months 12 (6 - 25) 10 (5 - 15) Only 12 women (11 in daily and 1 in On demand); 18 heterosexual men (9 in daily and 9 in On demand) * at last sexual intercourse : cocaine, GHB, MDMA, mephedrone..

Dosing Regimen over Time Change between dosing regimen was allowed 15% change between visit half from daily to on demand and half from on demand to daily

Adherence to PrEP / Condoms PrEP / Condom use at last sexual intercourse 7685 times people had sex assessed in 2134 participants > M3 (n, %) Daily n = 3806 acts On Demand n = 3879 acts Total n= 7685 Total PrEP use 3705 (97.3) 3188 (82.2) 6893 (89.7) Correct use* 3613 (97.5) 3072 (96.4) 6685 (97.0) Suboptimal 92 (2.5) 116 (3.6) 208 (3.0) No PrEP 101 (2.7) 691 (17.8) 792 (10.3) Condoms 716 (18.8) 851 (21.9) 1567 (20.4) * According to the protocol, or at least one pill before (<24h) and one pill after sex (<24h)

HIV Incidence (mITT Analysis) Global HIV Incidence: 0.09/100 PY (95% CI: 0.01-0.33) (2 cases) Mean Follow-up of 8.7 months and 2208 Person-Years Rate of study discontinuation: 8.9/100 PY Treatment Follow-Up Pts-years HIV Incidence per 100 Pts-years (95% CI) P-value TDF/FTC (Daily) 1072.9 0.0 ( 0.0 – 0.3 ) 0.132 TDF/FTC (On Demand) 1132.7 0.2 ( 0.0 – 0.6 ) Incidence in Ipergay in Paris : 9,17/100 PY 143 HIV-infections averted* * assuming an incidence of 6.6/100 PY as observed in the Placebo group of the ANRS Ipergay study 10 10

HIV-Infected individuals Cases Sex, Age Date Started PrEP Date Enrolled in PREVENIR Last Neg. HIV Test Positive HIV Tests Comments Case 1 MSM 52 y April 2016 On demand Feb 2, 2018 Sept 4, 2018 Jan 2, 2019 HIV serology: positive Plasma : 6550 cp/mL No RAMs to TDF/FTC PrEP stopped 10 weeks before infection and condomless sex during this period Case 2 47 y June 2016 Daily June 10, 2017 Dec 6, 2018 Feb 18, 2019 Plasma : > 106 cp/mL No RAMs to TDF/FTC PrEP stopped 7 weeks before infection and condomless sex during this period

Sexual Behavior Numéro du poster de Luis: WEPED871 Increase of +43% at 3-month (P <0.001) Increase of +21% at 3-month (P <0.001) Decrease of -20% at 3-month (P <0.001) Increase of +15% at 3-month (P <0.001) Numéro du poster de Luis: WEPED871

Viral Hepatitis Infections 23 cases of viral hepatitis were diagnosed in 23 participants Daily 1072.9 Pts-years On Demand 1132.7 Pts-years No. Events Incidence per 100 PY (95% CI) No. Events Incidence per 100 PY (95% CI) All Viral Hepatitis 10 0.9 (0.5–1.7) 13 1.2 (0.6–2.0) HAV 0.0 (0–0.3) 1 0.1 (0–0.5) HCV 9 0.8 (0.4–1.6) 11 1.0 (0.5–1.7) HEV HBV Overall incidence rate of viral hepatitis 1.04 per 100 PY (0.66–1.56)

Incidence of Bacterial STIs 3026 2146 1701 1359 1001 674 Increase in incidence of +38% per year (P <0.001) Any STI +38% per year (P<0.001); Any chlamydia +36% per year (P<0.001); Any Gonorrhoea +34% per year (P<0.001); Any mycoplasma +13% per year (P=0.453); Syphilis +120% (P<0.001) Trends assessed in piecewise exponential survival models

Incidence of Bacterial STIs According to the PrEP Regimen Overall incidence rate of 86 per 100 PY (95% CI 82-90) Trends assessed in piecewise exponential survival models

Incidence of Anal CT/GC Incidence of Anal Gonorrhoea Increase of +47% per year (P <0.001) Increase of +48% per year (P <0.001) Overall incidence of 51 per 100 PY (95% CI 48-54) Overall incidence of 27 per 100 PY (95% CI 24-29) Trends assessed in piecewise exponential survival models

Adverse Events Daily 1072.9 Pts-years On Demand 1132.7 Pts-years Incidence Rate Ratio Daily vs On Demand (95% CI) No. Pts Incidence per 100 PY Drug-Related AEs 122 11.4 ( 9.4–13.6) 150 13.2 ( 11.2–15.5) 0.9 ( 0.7–1.1) Gastrointestinal 98 111 Asthenia 6 18 Cutaneous 5 7 Headache 8 Any Grade 3 or 4 AE 57 5.3 ( 4.0–6.9) 50 4.4 ( 3.3–5.8) 1.2 (0.8–1.8) Infections 27 30 Neuro-psychiatric Treatment D/C due to Drug-Related AE 0.0 (0–0.3) 3* 0.3 (0.0–0.8) 0.0 (0–2.6) *Vomiting (grade 3); Diarrhea (grade 1); Nausea/Headache/Dizziness (grade 1)

Lab Abnormalities All Grades ALAT 139 13.0 (10.9–15.3) 117 10.3 Daily 1072.9 Pts-years On Demand 1132.7 Pts-years Incidence Rate Ratio Daily vs On Demand (95% CI) No. Pts Incidence per 100 PY All Grades ALAT 139 13.0 (10.9–15.3) 117 10.3 (8.5–12.4) 1.3 (1.0–1.6) Grade 3 or 4 9 0.8 (0.4–1.6) 7 0.6 (0.3–1.3) 1.4 ( 0.4–4.3) Grade 1 Creatinine (>1.5 ULN) 165 15.4 (13.1 – 17.9) 177 15.6 (13.4–18.1) 1.0 (0.8–1.2) Creat. Clearance (50-70 ml/mn) 190 17.7 (15.3–20.4) 210 18.5 (16.1–21.2) ( 0.8 – 1.2) <50 ml/mn (0.4–1.5) 1.1 (0.4–3.0)

Summary Interim report of an open-label cohort study enrolling mostly MSM: 50% use Daily, 50% On demand PrEP Pts using Daily TDF/FTC have more partners, more condomless sex and a higher incidence of bacterial STIs High efficacy of Daily and On Demand PrEP in MSM: Only 2 HIV-infection in persons who have discontinued PrEP High and correct use of PrEP Good safety profile with both dosing regimens and only three participants with drug discontinuation due to gastro-intestinal AEs High retention rate High incidence of bacterial and viral STIs 19

Acknowledgments The Participants The Sites Investigators and Counselors The Trial Scientific Committee The Community Advisory Board The ANRS Staff INSERM IPLESP Paris Hospitals (APHP) University of Paris http://prevenir.anrs.fr/ 21 21