1. It’s Time for PrEP in Latin America and the Carribean
On Demand PrEP for MSM: Insights from the ANRS Ipergay and Prevenir Studies
Jean-Michel Molina
University of Paris and Saint-Louis Hospital, INSERM U944, France
It’s Time for PrEP in Latin America and the Carribean

2. Why Testing On Demand PrEP?
Alternative to daily PrEP if not willing/able to take a daily pill: will increase options for PrEP
Better safety due to less frequent drug exposure (kidneys, bones)
Improved cost-effectiveness
Convenient dosing regimen which may improve adherence and overall effectiveness

3. with TDF/FTC vs Placebo in MSM
Oral Daily PrEP
with TDF/FTC vs Placebo in MSM
PrEP adherence assessed by plasma drug levels only 50%
weeks
After a median follow-up of 14 months, 100 subjects became infected: in the TDF/FTC arm and 64 in the placebo arm
44% relative reduction in the incidence of HIV (95% CI : 15-63, p=0.005)
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.
Grant RM et al N Engl J Med, Nov 23, 2010. 3

4. On Demand PrEP with TDF/FTC or Placebo in MSM
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 On Demand
TDF/FTC On Demand
Condoms, gels, tests for HIV (using 4th generation assays) and STIs, PEP and vaccines for Hepatitis A and B, and peer counseling on risk reduction and adherence
Follow-up every two months
Molina JM et al NEJM 2015 4

5. Effect of a Double Dose of oral TDF/FTC (-2h, + 24h)
sgsfdgsfd
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
% Uninfected animals 50 25
Untreated Controls (n = 32) 2 4 6 8 10 12 14
83% Efficacy
Number of weekly rectal SHIV exposures
Garcia-Lerma et al.,Science Trans Med 2010, 14,14ra4 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
On demand PrEP tells you How to Start and How to Stop PrEP

7. On Demand Use of PrEP
TDF/FTC
Nb pills/month
Placebo
Nb pills/month
Participants took a median of 15 pills /month (IQR: 11-21) i.e. < 4 pills /week

8. Incidence of HIV-1 Infection
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
Mean follow-up of 12 months: 16 subjects infected (14 placebo, 2 in TDF/FTC)
Incidence: 6.6 vs 0.9/100 PY with placebo and TDF/FTC, respectively
86% relative reduction in the incidence of HIV-1 (95% CI : 40-98, p=0.002)
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.
Molina JM et al NEJM 2015

9. Daily PrEP with TDF/FTC in MSM (UK)
Multi-center Open-label randomized trial in GUM clinics
Immediate Daily Oral TDT/FTC
(n = 275)
HIV-negative Gay Men
and transgender women reporting unprotected anal intercourse with a man within last 90 days
Deferred Daily TDF/FTC by 12 months
(n = 269)
Primary endpoint: Time to accrual of 500 participants and retention
Other outcome measures: safety, adherence, risk compensation
All participants will be offered a risk reduction package : regular HIV testing, diagnosis and treatment of STIs, support to reduce high risk behavior including condoms, PEP.
Visits every 3 months with HIV testing using ELISA or rapid tests
S. Mc Cormack et al Lancet 2016 9

10. Efficacy of Daily PrEP in MSM in the UK
Group
No. of infections
Follow-up (PY)
Incidence (per 100 PY)
90% CI
Overall 23
465
5.0
3.5–6.9
Immediate 3
243
1.2
0.4–2.9
Deferred 20
222
9.0
6.1–12.8
Efficacy = 86% (90% CI: 64-96%) P-value=0.0001
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.
S. McCormack et al Lancet 2016 10

11. HIV Incidence (mITT Analysis)
Treatment
Follow-Up
Pts-years
HIV Incidence
per 100 Pts-years
(95% CI)
Placebo
212
6.60 ( )
On demand TDF/FTC (double-blind)
219
0.91 ( )
On demand TDF/FTC (open-label)
515
0.19 ( )
Median Follow-up in Open-Label Phase 18.4 months ( )
97% (95% CI: ) relative reduction vs. placebo
Molina et al Lancet HIV 2017 11 11

12. Adherence by Plasma TFV Levels
Percentage of participants
N participants
N samples
46%
14% 9%
69% 0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Blinded
OLE
199
1516
336
All visits* M6
55% 7%
71%
> 40 ng/mL (<24h)
]10-40] ng/mL (48-72h)
]1-10] ng/mL (<7 days)
Détectabilité seuil=1ng/mL
Phase aveugle : tous suivis confondus post J0 (1516 suivis de M1 à la visite T) dans le bras TRUVADA
Modele GEE = données répétées de M1 à VIST T(correlation des mesures entres les visites d’un même participant)
TDF Varie de 63% à 83% selon le suivi
TDF : pourcentage det 1 ng/mL calculé = % - estimé = 68,86% IC 95%=[64,24%; 73,14%]
FTC Varie de 69% à 92% selon le suivi
FTC : pourcentage det 1 ng/mL calculé = % - estimé = 76,19% IC 95%=[71,82%; 80,08%]

13. On Demand PrEP among Ipergay Participants Having Less Frequent Sex (Post-Hoc Analysis)
≤ 15 pills/month, systematically or often during sexual intercourse
Follow-Up (Person-Years)
Nb of Infections
Incidence Rate (for 100 Person-Years) p
Placebo
64.8 6
9.3 [3.4-20]
TDF/FTC
68.9
0.0 [0-5.4]
0.013
Median Nb sexual intercourse/month : 5 (IQR: 2-10) Median Nb pills/month : 9.5 (IQR: 6-13 ) i.e. < 2.5 pills /week
Antoni G, et al; 9th IAS, Paris, France, July 23-26, 2017; Lancet HIV submitted
Essai ANRS IPERGAY - Conseil Scientifique 24/01/2017

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. FTC and TFV concentrations in rectal
TFV and FTC in Rectal Tissue Biopsies Following a Double-Dose of TDF/FTC
FTC
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)
Fonsart et al JAC 2017

16. eGFR: TDF/FTC vs Placebo
Median of follow-up 9.4 months
eGFR change from baseline (mL/min/1.73m²)
Groups
Mean slope of eGFR decline per year
TDF/FTC: mL/min/1.73m²
Placebo: mL/min/1.73m²
P=0.27
In this figure, we reported the eGFR changes from baseline in the blind phase of the study. The median of follow up in the placebo and TDF/FTC groups was 9.4 months.
Using a linear mixed effect model, we modelized the mean slope of eGFR decline in each group over the study.
The mean slope of eGFR decline per year was mL per minute in the TDF/FTC group and -1,88mL/min in the placebo group
The slope of eGFR decline was not statistically different between the two arms.
Liegeon et al CROI 2019

17. Study Design Open-Label Prospective Cohort Study in the Paris Region
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
Creat. Clearance > 50 mL/mn
HbS Ag negative if On Demand
TDF/FTC Daily
TDF/FTC 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 regimens
Follow-up every 3 months with 4th Gen ELISA HIV test and plasma creatinine
STI screening at physicians’ discretion (Guidelines recommend every 3 months in MSM)
Condoms, gels, PEP, risk reduction and adherence counseling, Q on sexual behavior
On peut changer en cours d’étude 17

18. Baseline Characteristics
Characteristics (Median, IQR) or (n, %)
Daily
n = 724 (45.4%)
On Demand
n= 870 (54.6%)
P-value
Age (years)
36 (30-44)
0.10
MSM
708 (98)
865 (99.4)
Heterosexual men or women
7 (0.1)
5 (0.6)
<.01
Transgender
8 (1.1)
0 (0)
No regular sex partner
380 (53)
437 (51)
0.41
History of PrEP use
408 (56.5)
515 (59.2)
0.28
Use of Chemsex*
128 (17.7)
124 (14.3)
0.06
No. condomless sex acts in prior 4 weeks
3 (1-8)
2 (0-4)
<.001
No. sexual partners in prior 3 months
15 (7-25)
10 (5-15)
Only 3 women
* at last sexual intercourse : cocaine, GHB, MDMA, mephedrone..

19. HIV Incidence in First 1600 Pts Enrolled Treatment Follow-Up Pts-years
per 100 Pts-years
(95% CI)
TDF/FTC (Daily)
443
0 (0-0.8)
TDF/FTC (On Demand)
506
0 (0-0.7)
Mean Follow-up in this Open-Label Cohort: 7 months (SD: 4)
Incidence of study discontinuation: 3.3/100 PY
Incidence in Ipergay in Paris : 9,17/100 PY
85 HIV-infections averted*
* assuming an incidence of 9.17/100 PY as observed in the ANRS Ipergay study in Paris 19 19

20. Conclusions
Compelling evidence of the effectiveness and safety of On Demand oral PrEP with TDF/FTC among MSM
On demand PrEP gives guidance on how to start / stop PrEP
On demand oral PrEP expends PrEP options and may increase number of PrEP users
On demand oral PrEP needs to be tested in other populations

21. Acknowledgments
@jmmolinaparis 21 21