Download n=12

Coitally-Dependent TDF/FTC in MSM
Updates on PrEP Efficacy in IPERGAY
Jean-Michel Molina
and the ANRS Ipergay Study Group
Hospital Saint-Louis and University of Paris 7, Inserm U941,
Paris, France
Disclosures
 Advisory Boards: BMS, Gilead, GSK
Janssen, Merck, ViiV
 Research Grants: Merck and Gilead
Background
 PrEP trials in Europe and Canada have shown a
high incidence of HIV-infection (up to 9%) in high
risk MSM
 PROUD and IPERGAY have demonstrated similar
high effectiveness of PrEP with oral TDF/FTC (86%)
 IPERGAY is assessing coitally-dependent PrEP (2
pills before and 2 pills after sex)
 Participants in IPERGAY have frequent sex and
used on average 4 pills/week (15 pills/month)
IPERGAY : Sex-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
Friday
Saturday
Sunday
4 pills of TDF/FTC taken over 3 days to cover one sexual intercourse
How early after starting PrEP were
participants protected in IPERGAY ?
Effect of a Double Dose of
oral TDF/FTC (-2h, + 24h)
% Uninfected Macaques
% Uninfected animals
100
Double dose oral TDF/FTC
(n = 6) HR : 16,7 p = 0.006
75
50
25
Untreated Controls (n = 32)
0
0
2
4
6
8
10
12
14
Number of weekly rectal SHIV exposures
Garcia-Lerma et al.,Science Trans Med 2010, 14,14ra4
TFV/FTC Plasma and Rectal PK
after Single Dose Oral TDF/FTC
Garcia-Lerma , Science Trans Med 2010, 14,14ra4
Timing of Onset of Inferred
HIV Risk Reduction with TDF/FTC
Onset of action
99% risk reduction (69-100) after 5
daily doses and 96% (60-100) after 3
daily doses
Seifert S, et al. Clin Inf Dis. March 2015, 60: 804
KM Estimates of Time to
HIV-1 Infection (mITT Population)
Probability of HIV seropositivity
0.20
Log-rank test p=0.0022
0.18
0.16
0.14
Placebo
0.12
0.10
0.08
0.06
TDF/FTC
0.04
0.02
0.00
0
N at risk : Placebo
TDF/FTC
201
199
2
4
6
142
141
8
10
12 14 16 18 20 22 24
74
82
55
58
months from D0
42
43
Mean follow-up of 13 months: 16 subjects infected
14 in placebo arm (incidence: 6.6 /100 PY) and 2 in TDF/FTC arm (incidence: 0.9 /100PY)
86% relative reduction in the incidence of HIV-1 (95% CI : 40-98, p=0.0019)
Ipergay PK Sub-Study
 12 participants received a single double-dose of oral
TDF/FTC (600/400 mg) and PK sampling was performed
over 24 hours (T0, 0.5, 1, 2, 4, 8 and 24 hours)
 Plasma, PBMC, dried blood spots, saliva and rectal
biopsies were collected for PK analyses and ex vivo HIV-1
challenges
 Each participant had rectal biopsies collected at two time
points (including T0) with 2 participants per time point (0.5,
1, 2, 4, 8 and 24 hours)
 Rectal biopsies were exposed overnight to CCR5 tropic
HIV-1 and co-cultured with MT4-R5 cells over 11 days to
detect p24 Ag in supernatants
TFV and FTC Concentration
in Rectal Tissue
C o n c e n t r a t io n ( n g / m g )
20
TFV
FTC
15
10
5
10
0 .0
0 .5
1 .0
2 .0
4 .0
8 .0
2 4 .0 3Control
0 .0
T im e ( h o u r s )

Early detection of FTC in rectal tissue at high concentrations similar to HIVinfected patients on ART

TFV is only detectable at 24h post drug intake at high concentrations
Is the double-dose of TDF/FTC
associated with increased PK
exposure
Dose-Proportional Increase
in Plasma FTC PK Parameters
Pharmacokinetic Parameters of FTC in HIV-infected* and Ipergay subjects
Plasma
Saliva
Mean PK
parameter
100 mg QD
(n=8)
200 mg QD
(n=8)
400 mg QD
(n=12)
400 mg QD
(n=12)
Cmax (ng/ml)
880
1720
2906
558
Tmax (h)
0.93
2.00
2.10
2.80
35
47
80
31
AUC0-24 (hr.ng/ml)
3,980
8,000
16,527
3,253
T1/2 (h)
10.6
8.24
5.2
9.4
Cmin (ng/ml)
* Study FTC- 101 at steady-state: Wang LH et al AIDS Res Human Retrovir 2004
Mean in vitro IC90 estimate of FTC: 50 ng/ml
Mean AUC ratio of saliva / plasma : 22%
Dose-Proportional Increase
in Plasma TFV PK Parameters
Pharmacokinetic Parameters of TFV in HIV-infected* and Ipergay subjects
Plasma
Saliva
Mean PK
parameter
75 mg
QD
(n=12)
150 mg
QD
(n=8)
300 mg
QD
(n=8)
600 mg
QD
(n=10)
600 mg
QD
(n=12)
600 mg
QD
(n=12)
Cmax (ng/ml)
68.6
111
240
618
419
3.6
Tmax (h)
0.8
1.00
0.8
1.0
1.3
2.70
Cmin (ng/ml)
ND
20
40
100
40
1.9
AUC0-24 (hr.ng/ml)
717
1,613
2,093
3.372
2,376
49
T1/2 (h)
ND
12
11.9
13
11.2
ND
*Barditch-Crovo et al, Antimicrobial Agents Chemother 2001; 45:2733-9
Mean in vitro IC50 estimate of TFV: 10 ng/ml
Mean AUC ratio of saliva / plasma : < 10%
Are post-exposure doses needed
Protection by SC TDF/FTC Given
Before and/or After SHIV Exposure
Garcia-Lerma , Science Trans Med 2010, 14,14ra4
Ex Vivo HIV-1 Infection of
Rectal Biopsies
 10 participants had biopsies assessable at both time points
with 4 biopsies per time point and per participant
 Before drug intake all participants had at least 1 biopsy
infected (10/10) vs 6/10 after drug intake (p<0.07, Mac
Nemar test for clustered data)
 Using a quantitative infectivity score (0: no infection to 6:
infection detected at D4) median difference of mean scores:
1.38 (IQR: 0.25 -1.75), p<0.07, Wilcoxon sign rank test)
 Trend towards partial protection of rectal biopsies from HIVinfection after intake of a double-dose of TDF/FTC
 Need for additional post-exposure doses
Conclusions
 A double-dose of TDF/FTC is associated with rapid and
high concentrations of TVF and FTC in plasma
 FTC can achieve rapid and high concentrations in rectal
tissue and saliva
 Pre- and Post-exposure doses both appear to be critical for
providing full protection against HIV acquisition
 The effectiveness of coitally-dependent PrEP in people with
less frequent sex has yet to be demonstrated
 The IPERGAY study is ongoing open-label and will
hopefully provide additional information
Acknowledgments
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•
The Participants
The Study Staff and Peer-Counselors
The Trial Scientific Committee
The PK group: G. Peytavin, J. Fonsart, L. Goldwirt, B. Loze, M.
Taouk
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INSERM U941: S. Saragosti, F. Mamano, A. Hance, F. Clavel
INSERM SC10-US19
The DSMB and the Community Advisory Board
The ANRS Staff