1. Efficacy of “On Demand” PrEP The ANRS IPERGAY Trial
Jean-Michel Molina
Saint-Louis Hospital, University of Paris Diderot, Inserm U941, Paris, France 1

2. Relative Efficacy of Prevention Strategies
Reduction of HIV Transmission
Studies
Condoms in heterosexuals2
80%
Partners PrEP in discordant couples1
75%
Condoms in US MSM3
70%
TDF2 in men & women1
63%
Medical male circumcision1
54%
Bangkok PrEP in IDU
49%
44%
iPrEx in MSM1
CAPRISA 004 (1% TDF vaginal gel) in women1
39%
27%
Aspire / MTN 020 (Dapivirine ring)4
FEM-PrEP in women,5 VOICE (TDF/FTC, TDF vaginal gel), FACTS (TDF gel) in women6
Non significant*
Efficacy (%)
1. Adapted from Karim SS and Karim QA. Lancet 2011;378:e23–25; 2. Weller S and Davis K. Cochrane Database Syst Rev 2002:CD003255; 3. Smith DK et al. JAIDS 2015;68:337–344; 4. Baeten et al NEJM 2016; 5. van Damme L et al. NEJM 2012;367:411–422; 6. Marrazzo JM et al. NEJM 2014, Rees H, CROI 2015, Abs. 26LB

3. Interest in On Demand PrEP
Conflicting results from PrEP trials with oral daily TDF/FTC: Adherence « Achilles’ heel » of PrEP
More convenient dosing regimen: « On Demand »
Could improve adherence, safety and cost-effectiveness
Could provide an alternative to daily PrEP
Supported by animal models

4. Effect of a Double Dose of oral TDF/FTC (-2h, + 24h)
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Effect of a Double Dose of oral TDF/FTC (-2h, + 24h)
% Uninfected Macaques
100
Double dose oral TDF/FTC
(n = 6) HR : 16,7 p = 0.006 75 50
% Uninfected animals 25
Untreated Controls (n = 32) 2 4 6 8 10 12 14
Number of weekly rectal SHIV exposures
Garcia-Lerma et al.,Science Trans Med 2010, 14,14ra4 4

5. Double-Blinded Randomized Placebo-Controlled Trial
400 HIV negative 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 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
Follow-up visits: month 1, 2 and every two months thereafter with 4th generation HIV ELISA assays (combined Ab/Ag detection) on serum
Molina JM et al. NEJM 2015 5

6. IPERGAY : Sex-Driven iPrEP
2 tablets 2-24 hours before sex
1 tablet 24 hours later
1 tablet 48 hours after first intake
Friday
Saturday
Sunday
Monday
Tuesday
Wednesday
Thursday
4 pills of TDF/FTC taken over 3 days to cover one sexual intercourse

7. IPERGAY : Sex-Driven iPrEP
2 tablets 2-24 hours before sex
1 tablet every day during sexual activity
2 tablets after the last sexual intercourse
Friday
Saturday
Sunday
Monday
Tuesday
Wednesday
Thursday
On demand PrEP tells you How to Start and How to Stop PrEP

8. Adherence by Pill Count
Median number of pills/month (IQR):
15 pills (9-21)
TDF/FTC
Nb pills/month

9. Detection of TFV in Plasma
% of participants with TFV detected in plasma (548 samples from 113 participants)
100%
Placebo
TDF/FTC
100% 8
91%
88%
90%
85%
82% 40
83% 23
80% 44 46 33
70%
60%
Percentage of participants
50%
Overall detection:
86% in theTDF/FTC arm vs. 4% in the placebo arm
40%
30%
% détectabilité TFV tous suivis confondus post J0 (226 suivis) dans le bras GrB = 86%
20%
10% 5% 6% 4% 5% 5% 2% 3 3 2 2 0% 0% 2 0%
(56)
(57)
(51)
(56)
(49)
(52)
(42)
(44)
(37)
(40)
(22)
(26)
(8)
(8) M0
n=113 M1
n=107 M2
n=101 M4
n=86 M6
n=77 M8
n=48
M10
n=16

10. Detection of TVF and FTC in Rectal Tissue Biopsies
TFV 5 10 15 20 25 30
0.5
1.0
2.0
4.0
8.0
24.0
HIV Controls
on TDF/FTC
Time (hours)
FTC and TFV concentrations in rectal
tissue (ng/mg)

11. KM Estimates of Time to HIV-1 Infection (mITT Population)
0.00
0.10
0.20
0.04
0.02
0.08
0.06
0.14
0.18
0.16
0.12
Probability of HIV seropositivity
Log-rank test p=0.0022
Placebo
TDF/FTC 2 4 6 8 10 12 14 16 18 20 22 24
months from D0
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.
N at risk :
Placebo
201
142 74 55 42
TDF/FTC
199
141 82 58 43
Median follow-up of 9.3 months: 16 subjects infected 14 in placebo arm (incidence: 6.60 /100 PY) and 2 in TDF/FTC arm (0.91 /100PY)
86% relative reduction in the incidence of HIV-1 (95% CI : 40-98, p=0.002)
NNT to avert one HIV-infection: 18 (95% CI: 11-50)
Molina et al NEJM 2015

12. Randomized Double-Blinded vs. Placebo then Open-Label Extension
Randomized Double-Blinded vs. Placebo then Open-Label Extension
Feb 2012
Nov 2014
Jun 2016
HIV-negative MSM
Condomless Anal sex with > 2 partners in prior 6 months
Creat. Clearance > 60 mL/mn
HbS Ag negative
TDF/FTC
On Demand
Placebo
TDF/FTC
On Demand
Main messages:
The Caprisa study was conducted in KwaZulu-Natal, South Africa in a population of women 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.
Condoms, gels, tests for HIV and STIs, vaccinations for Hepatitis A and B, and peer counseling on risk reduction and adherence
Follow-up every two months 12

13. HIV Incidence (mITT Analysis)
Treatment
Follow-Up
Pts-years
HIV Incidence
per 100 Pts-years
(95% CI)
Placebo
212
6.60 ( )
TDF/FTC (double-blind)
219
0.91 ( )
TDF/FTC (open-label)
248
0.40 ( )
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.
Median Follow-up in Open-Label Phase 8.5 months ( )
1 single HIV-infection: Pt D/C PrEP - thought partner to be HIV negative
Molina et al CROI 2016 13 13

14. PK/PD Simulation of PrEP Efficacy in Rectal Tissue Using the IPERGAY Dosing Regimen
49 women received a single-dose of TDF and FTC with blood and rectal sampling over 48h.
PK/PD model using tissue concentrations of TFV, FTC, and competing endogenous nucleotides
CD4 T-cells used to identify 90% Effective Concentration (EC90) ratios of TVF-DP to dATP and FTC-TP to dCTP
First dose given 24h (A) or 2 h (B) before coitus
Percentage of the population achieving the EC90 in colorectal tissue
98% at coitus and for 240h
Time (h)
81% at coitus
100% 4h later
Time (h)
Cottrell ML et al. J Infect Dis 2016

15. Adverse Events Nb Participants (%) TDF/FTC n=199 Placebo n=201
All AEs
186 (93)
181 (90)
333 (92)
Severe AEs
20 (10)
17 (8)
14 (4)
Grade 3 or 4 AEs
19 (10)
15 (7)
24 (10)
AEs leading to Rx D/C 1*
1**
GI-related AEs
28 (14)
10 (5)
37 (10)
Nausea/vomiting 16 2 11
Abdominal pain 13 3 8
Diarrhea 6 20
*Venous thrombosis
**Decrease in plasma creatinine clearance from 81 to 76 ml/mn

16. PrEP Modalities Preferences among 1106 Young MSM Recruited by Facebook in 2015 in the US
Hall EW et al. J Med Intern Res 2016

17. PrEP Modalities Preferences among 1106 Young MSM Recruited by Facebook in 2015 in the US
Hall EW et al. J Med Intern Res 2016

18. Summary
On Demand PrEP with oral TDF/FTC is highly effective in high risk MSM
Low condom use did not undermine efficacy
Safety of On Demand PrEP was good
PrEP improved pleasure and removed fear during sexual activity
On Demand PrEP expands PrEP choices
On Demand PrEP gives guidance with regards to when to start and when to stop PrEP 18

19. PrEP “On Demand”

20. More on PrEP On Demand at Durban
BE SURE TO ATTEND!!!
More on PrEP On Demand
at Durban
Luis Sagaon Teyssier: Reported changes in PrEP and Condom use in MSM during the Open-label extension of the ANRS Ipergay study (Wednesday July 20, 12:30- 14:30 Poster WEPEC 263)
Isabelle Durand Zaleski: Cost-effectiveness of on Demand PrEP in MSM in the ANRS Ipergay study (Thursday July 21, Cost-Effectiveness and Modeling, Session Room 2: 16:30-18:30)
Efficacy of On Demand PrEP with TDF/FTC in the ANRS Ipergay open-label Extension Study (Wednesday July 20, Optimization Strategies, Session Room 1, 11:00-12:30)
PrEP Roll-out in France (Wednesday July 20, From Clinical Trials to Clinical Care, Session Room 7, 14:30- 17:00)

21. Community Engagement

22. Acknowledgments The Participants The Study Staff and Peer-Counselors
The Trial Scientific Committee
The DSMB
The Community Advisory Board
The ANRS Staff
INSERM SC10-US19 22 22