Pragmatic Open-Label Randomised Trial of Pre-Exposure Prophylaxis: the PROUD study http://www.proud.mrc.ac.uk/ 1 1

PROUD Pilot GMSM reporting UAI last/next 90days; 18+; and willing to take a pill every day Randomize HIV negative MSM (exclude if treatment for HBV/Truvada contra-indicated) Risk reduction includes Truvada NOW Risk reduction includes Truvada AFTER 12M We created a randomised PrEP versus no-PrEP situation in the first year of follow-up. In the second year of follow-up, everyone has access to PrEP. Follow 3 monthly for up to 24 months Main endpoints in Pilot: recruitment and retention From April 2014: HIV infection in first 12 months 2 2

Baseline demographics1 Characteristics Immediate Deferred Age, median (IQR) 35 (30 – 43) 35 (29 – 42) Ethnicity White 80% 82% Born UK No 40% Education University 59% 60% Employment Full-time 70% 73% Sexuality Gay 96% 94% Current relationship No 53% 55% Recreational drug use2 Yes 76% 64% Presented in detail at IAS 2014 and R4P 2014 see www.proud.mrc.ac.uk Conference presentations 1 539/545 (99%) questionnaires returned 2 in the last 90 days

7 no HIV test after enrolled 1 HIV +ve at enrolment 276 assigned to IMMEDIATE 269 assigned to DEFERRED 2 HIV +ve at enrolment 7 no HIV test after enrolled 1 HIV +ve at enrolment 12 no HIV test after enrolled 267 contribute to effectiveness analysis 256 contribute to effectiveness analysis Participants could contribute the following to the person years of data for the main analysis, depending on which of these three timepoints came first. A full year before the protocol was changed The time up until they accessed PrEP which could be less than a year after the protocol change, as 139 participants on the deferred arm had not reached month 12 when we were advised to change to study protocol and offer everyone PrEP in October 2014. It could also be more than a year if they were in the deferred group and had defaulted from follow-up so came after 12 months to access PrEP The time up to their first HIV positive test. Calculation of person-years: From enrolment to the first of the following HIV test at m12, or HIV test at the time of access to PrEP, or diagnosis of HIV infection

Individual incident HIV infections Individual incident infections with the most recent HIV negative result, and the first positive HIV result The red bar indicates the time at which the window opened for the month 12 visit. There were 2 infections in the immediate and 6 in the deferred diagnosed at the first follow-up visit, all of whom could have caught HIV before enrolment. If they were all dropped the effectiveness there would still be a huge difference between the groups. Of the three immediate infections, one participant had a significant exposure in the week before enrolment which was too late for PEP. He took 15 doses of truvada before his HIV positive test. Although a sample taken 5 days later was negative for tenofovir in the plasma, this was as expected and the fact that he had the 184 minority mutation supports his story of taking Truvada. The second individual did not return after enrolment and was diagnosed at a different clinic. The third individual defaulted after three months and was later admitted to another hospital with a seroconversion illness. He told that hospital staff that he had not been taking PrEP for months and had no mutations.

HIV Incidence Efficacy =86% (90% CI: 58 – 96%) P value =0.0002 Group No. of infections Follow-up (PY) Incidence (per 100 PY) 90% CI Overall 22 453 4.9 3.4–6.8 Immediate 3 239 1.3 0.4–3.0 Deferred 19 214 8.9 6.0–12.7 Efficacy =86% (90% CI: 58 – 96%) P value =0.0002 Rate Difference =7.6 (90% CI: 4.1 – 11.2) Number Needed to Treat =13 (90% CI: 9 – 25) 86% reduction is greater than seen in placebo-controlled HIV prevention trials. The 90% confidence interval gives us 95% confidence around the lower bound of 58% reduction. The 95% lower bound is 52% - both exceed the 50% reduction we considered would make a useful impact on our epidemic. Rate difference is important for public health as it informs the number who would need to be treated. The number of gay men who need to be treated for one year to avert one infection is very low – only 13.

Conclusions HIV incidence in the population who came forward to access PrEP was much higher than predicted based on all MSM attending sexual health clinics Despite extensive use of PEP in the deferred period Our concerns about PrEP being less effective in the real world were unfounded MSM incorporated PrEP into existing risk reduction strategies which continued to include condom use There was no difference in STIs, which were common in both groups Clinics were able to adapt routine practice to incorporate PrEP

and the ANRS Ipergay Study Group On Demand PrEP with Oral TDF/FTC in MSM Results of the ANRS Ipergay Trial Molina JM, Capitant C, Spire B, Pialoux G, Chidiac C, Charreau I, Tremblay C, Meyer L, Delfraissy JF, and the ANRS Ipergay Study Group Hospital Saint-Louis and University of Paris 7, Inserm SC10-US019 Villejuif, Hospital Tenon, Paris, Hospital Croix-Rousse, Lyon, UMR912 SEAS Marseille, France, CHUM, Montreal, Canada and ANRS, Paris, France 8

Double-Blinded Randomized Placebo-Controlled Trial Study Design www.ipergay.fr Double-Blinded Randomized Placebo-Controlled Trial HIV negative high risk MSM Condomless anal sex with > 2 partners within 6 m eGFR > 60 mL/mn Full prevention services* TDF/FTC before and after sex Full prevention services* Placebo before and after sex Main messages: The Caprisa study was conducted in KwaZulu-Natal, South Africa in a population of women 18-40 yo, that were sexually active and at high risk for contracting HIV. Sero-status, safety, sexual behaviour, gel and condom use were assessed monthly for 30 months. Women were requested to insert one dose of gel within 12 hours before sex and as soon as possible within 12 hours after sex. This dosing strategy was based on the data from monkey challenge studies and perinatal transmission studies. Background: Tenofovir (PMPA) was studied due to the effectiveness, safety, and long half life, along with the protective data in the monkey challenge studies. * Counseling, condoms and gels, testing and treatment for STIs, vaccination for HBV and HAV, PEP End-point driven study : with 64 HIV-1 infections, 80% power to detect a 50% relative decrease in HIV-1 incidence with TDF/FTC (expected incidence: 3/100 PY with placebo) Follow-up visits: month 1, 2 and every two months thereafter 9

Ipergay : Event-Driven iPrEP 2 tablets (TDF/FTC or placebo) 2-24 hours before sex 1 tablet (TDF/FTC or placebo) 24 hours later 1 tablet (TDF/FTC or placebo) 48 hours after first intake Friday Saturday Sunday Monday Tuesday Wednesday Thursday

Study Flow-Chart Screened n=445 Randomized n=414 TDF/FTC n=206 Excluded n=31 (7%) Not meeting eligibility criteria n=11 Withdrew consent n=8 Lost to follow-up n=1 HIV-1 infection n=11 Randomized n=414 TDF/FTC n=206 Placebo n=208 Did not receive Rx n=7 Withdrew consent n=4 Lost to follow-up n=2 HIV-1 infection n=1 Did not receive Rx n=7 Withdrew consent n=2 Lost to follow-up n=3 HIV-1 infection n=2 Included in mITT analysis n=199 Included in mITT analysis n=201 D/C participation n=23 Withdrew consent n=11 Lost to follow-up n=7 Other n=5 D/C participation n=24 Withdrew consent n=15 Lost to follow-up n=6 Other n=3 Followed n=176 (88%) Followed n=177 (88%)

Baseline Characteristics Characteristics (Median, IQR) or (n, %) TDF/FTC n = 199 Placebo n = 201 Age (years) 35 (29-43) 34 (29-42) White 190 (95) 184 (92) Completed secondary education 178 (91) 177 (89) Employed 167 (85) 167 (84) Single 144 (77) 149 (81) History of PEP use 56 (28) 73 (37) Use of psychoactive drugs* 85 (44) 92 (48) Circumcised 38 (19) 41 (20) Infection with NG, CT or TP** 43 (22) 59 (29) Nb sexual acts in prior 4 weeks 10 (6-18) 10 (5-15) Nb sexual partners in prior 2 months 8 (5-17) 8 (5-16) * in last 12 months: ecstasy, crack, cocaine, crystal, speed, GHB/GBL ** NG: Neisseria gonorrhoeae, CT: Chlamydia trachomatis, TP: Treponema pallidum

HIV-1 Infection (mITT Population) KM Estimates of Time to HIV-1 Infection (mITT Population) Figure 2. Kaplan–Meier Estimates of Time to HIV Infection (Modified Intention-to-Treat Population). The cumulative probability of HIV acquisition is shown for the two study groups. The efficacy of preexposure prophylaxis with emtricitabine and tenofovir disoproxil fumarate (FTC–TDF) was 44%, as compared with placebo (P=0.005). The inset graph shows a more detailed version of the overall graph up to a probability of 0.10. Mean follow-up of 13 months: 16 subjects infected 14 in placebo arm (incidence: 6.6 per 100 PY), 2 in TDF/FTC arm (incidence: 0.94 per 100 PY) 86% relative reduction in the incidence of HIV-1 (95% CI: 40-99, p=0.002) NNT for one year to prevent one infection : 18 13 13

Adherence by Pill Count 100 90 Nb pills used / month 80 70 ]25-30] 60 ]18-25] Percentage of participants ]11-18] 50 ] 4-11] 40 ] 0 - 4 ] 30 0 : full bottles returned (all tablets) 20 missing : 294/2798 visits (10.5%) 10 Visits M1 M2 M4 M6 M8 M10 M12 M14 M16 M18 M20 M22 M24 M26 M28 M30 N part.. 382 352 315 288 236 190 162 143 128 115 105 93 88 72 63 45 Median number of pills/month (IQR): 16 pills (10-23) in the placebo arm and 16 pills (12-24) in the TDF/FTC arm (p=0.84) 48 participants (12%) received PEP 25 (13%) in the TDF/FTC arm and 23 (11%) in the placebo arm (p=0.73)

Conclusions In this population of high risk MSM, incidence of HIV-1 infection in the placebo arm was higher than expected “On Demand” oral PrEP with TDF/FTC was very effective with a 86% (95% CI: 40-99) reduction in HIV-incidence Adherence to PrEP was good supporting the acceptability of “on demand” PrEP Safety of “on demand” TDF/FTC was overall similar to placebo except for gastrointestinal AEs No evidence of risk compensation On demand PrEP: attractive alternative to daily PrEP in high risk MSM who do not use condoms consistently 15