Intermittent PrEP
Opportunities and Challenges
of Oral iPrEP
Jean-Michel Molina
Department of Infectious Diseases
Saint-Louis Hospital, INSERM U941
University of Paris 7, France
CHU Saint
Louis Paris
Conflicts of Interest
 Research Grants: Merck, Sanofi
 Advisory boards: Merck, Gilead, BMS,
Janssen, ViiV
 Travel/conference fees: AbbVie, BMS
 Holding stock and personal relationship: none
 PI of the ANRS Ipergay iPrEP trial
Current Status of Intermittent PrEP
 Oral iPrEP is not approved and it use should be
strongly discouraged until data are available
 iPrEP different from “periodic” PrEP which is the
starting and stopping of daily PrEP
Current Status of Daily Oral PrEP
 Randomized trials: proof of concept that daily PrEP
can reduce HIV incidence in high risk individuals
 FDA approval of TDF/FTC for oral PrEP but current
uptake is low, and no approval in other countries
 Other trials using the same daily regimen have
shown no efficacy: PrEP effectiveness in real life
settings ?
The Challenge of Sustained
Adherence to Daily PrEP
 Only very high adherence to daily PrEP (>80%)
associated with significant reduction of HIV incidence
 Patients who have taken PrEP intermittently were not
protected
 Unsustainable daily PrEP adherence in adolescents
and young women
 Provide better support for adherence or assess more
friendly regimens for long-term use
Time-Driven iPrEP
Friday
Saturday
Sunday
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday
Event-Driven iPrEP
Friday
Saturday
Sunday
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday
Time and Event-Driven iPrEP
Friday
Saturday
Sunday
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday
What Do We Need to Know to
Design iPrEP Regimens
 Timing of HIV-infection following sexual
exposure
 PK of drugs in blood and tissues to achieve
right drug concentration at the right place
and at the right time
 Assess people’s preference
Potential Benefits of iPrEP
 Higher adherence to a more convenient dosing
regimen
 Higher adherence to iPrEP could improve efficacy:
Intermittent use of TDF gel effective in Caprisa 004
when daily TDF gel ineffective in VOICE
 Better safety due to lower drug exposure (kidneys,
bones)
 Lower risk of selecting drug resistance in case of
HIV-infection
 More cost-effective
TDF PK in Blood and Mucosal Tissue
Single Dose 300 mg TDF
 6 healthy women, blood
collected every 4 hours for the
first 24h and up to 15 days
 Long half-lives : 69 h TDF, 48h
TVF-DP
 TVF-DP peak 12h : 20 fmol/106
PBMC
 Cumulative exposure of rectal
tissue to TDF and TFV-DP >
30 and 120-fold higher
respectively vs. vaginal tissue
Louissaint et al. AIDS Res Human Retrovirus 2013,29
What Do Gays Men Think about iPrEP?
 Online survey among 939 seronegative Gay men in France:
63% prefer « on demand » vs 25% daily PreP
 More interested by PrEP if unprotected anal sex (OR:
2.37, p<0.001)
 Online survey in > 1000 seronegative Gay men in the US.
Those most suitable for event-based PrEP were:
older
more educated
more frequently used sexual networking
more often reported sex with a not committed partner
Capote et Pilule study, Adam P, Alexandre A. et al - Volk JE et al. J AIDS 2012, 61: 112
Safety and Adherence to iPrEP
in Kenya (IAVI E001)
Adherence : MEMS
Sexual activity: daily SMS and interviews
4-Month
follow-up
Daily oral TDF/FTC*
(1 pill per day)
(n =24)
Daily oral Placebo*
MSM (n=67) and FSW (n=5)
Aged 18-49 yrs in Kenya
Current or previous STI or
Unprotected vaginal/anal sex
or Transactional sex
(1 pill per day)
(n =12)
Intermittent oral TDF/FTC*
(1 pill Monday Friday and 2h after sex)
(n =24)
Intermittent oral Placebo*
(1 pill Monday, Friday and 2h after sex)
*Double blind vs. Placebo but
Open-label daily vs. intermittent
(n =12)
Mutua et al. PLoS ONE 2012 e33103
PrEP Adherence Rates for
Daily and Intermittent Regimens
Dosing Schedule
Active Placebo
N=48
N=24
Overall
N=72
Daily Adherence Rate (%) (median, IQR)
Overall unadjsuted
82
84
83 (63-92)
Adjusted*
92
92
92 (82-99)
Overall unadjsuted**
72
68
68 (63-78)
Fixed doses
56
34
55 (28-78)
Post-coital doses (SMS + MEMS event)
32
19
26 (14-50)
100
100
100
Intermittent Adherence Rate (%) (median, IQR)
Post-coital doses within 2h (self report)
*Adjusted accounts for extra openings and extra pills taken out
** adherent to fixed dosing + post-coital dosing (SMS + MEMS)
Mutua et al. PLoS ONE 2012 e33103
Summary of IAVI E001
 Adherence to coitally-dependent dosing may be difficult
 SMS responses were low (23%) and may have impaired
assessment of post-coital dosing adherence
 in IAVI E002 trial in serodiscordant couples in Uganda SMS
responses (80%) and adherence to iPrEP higher (91% twiceweekly, 45% post-coital)
 Acceptability of PrEP was high and better with intermittent
dosing (86%) despite challenges with the post-coital dosing
 Safety was similar among all groups
 Better methods to measure sexual activity and adherence to
intermittent PrEP regimens
What is the Evidence
iPrEP Can Work ?
Efficacy of iPrEP with TDF/FTC
in the SHIV Macaque Model
Garcia-Lerma , Science Trans Med 2010, 14,14ra4
TFV-DP Concentrations
in IPrEx and STRAND
Regression analysis in
iPrEx: 90% reduction in
HIV acquisition when
TFV-DP>16 fmol/106 cells
16
Predicted risk reduction:
76% with 2 pills / week
96% with 4 pills / week
99% with 7 pills/ week
*
* Visit when HIV was first discovered
Anderson et al, Science Translational Medicine 2012 4:151ra125
Ongoing Oral iPrEP Studies
HPTN 067/ADAPT
(Alternative dosing to augment PrEP pill taking)
Phase II, Randomized, Open-Label, Pharmacokinetic
and Behavioral Study of the Use of Intermittent Oral
PrEP with TDF/FTC
6-week lead-in period
1 pill/week DOT
before randomization
High risk women
and MSM
(New York, Bangkok,
Cape Town)
Wk 24
primary endpoint
Daily Truvada 1 tablet/d
Regarless of sexual activity
(n = 180)
Time driven Truvada: 1 tablet 2 days/week
+ 1 post-exposure dose within 2 hours after sex
(n = 180)
Event driven Truvada: 1 tablet prior to sex
+ 1 post-exposure dose within 2 hours after sex
(n = 180)
Primary Objective: Is intermittent vs. daily dosing associated with equivalent
coverage of sex events, lower number of pills used and decreased side effects
R. Grant, F. Van Griensven, et al.
IPERGAY
Study Design
Effectiveness of “on demand” PrEP
Randomized placebo-controlled trial
• High risk MSM
• Condomless anal sex
with > 2 partners
Full prevention services*
TDF/FTC before and after sex
(n=950)
Full prevention services*
placebo before and after sex
(n=950)
 Counseling, testing for STI, condoms, vaccination, PEP
 Primary endpoint : HIV infection, 64 events expected
 Incidence of HIV-infection: 3%PY, 50% efficacy, ~ 2000 pts
www.ipergay.fr
Conclusions
 Oral iPrEP is a potentially interesting and
promising strategy
 Oral iPrEP should not be used outside research
settings
 Individuals reluctant to use daily PrEP should
consider other preventive tools
 More research is needed on iPrEP (PK and
behavioral sciences)