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ANRS Satellite Symposium, July 2016
“On Demand” Oral PrEP: Lessons Learned
from Macaque Models
J. Gerardo García-Lerma Ph.D.
Laboratory Branch, Division of HIV/AIDS Prevention, Centers for
Disease Control and Prevention, Atlanta, GA, USA
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
Division of HIV/AIDS Prevention
Importance of macaque models for HIV prevention
research

Historically used to evaluate new PrEP and PEP interventions

Possibility to model PrEP under highly controlled conditions (time of drug
dosing, size of virus inoculum, route of virus exposure)

Incorporate pharmacological measurements to understand correlates of
protection

Investigate factors that may potentially modify PrEP efficacy (i.e,
circulating drug-resistant viruses, co-infection with other sexually
transmitted infections, others)
Provide proof of concept and inform on promising candidates for human trials
CDC repeat low virus dose macaque model

Simian HIV (SHIV) challenge containing an R5-tropic HIV envelope

Macaques exposed to low and more physiologic doses of SHIV

Virus exposures repeated over several months to model populations at
high risk of HIV infection
 Design minimizes animal numbers and increases statistical power
 Protection defined by the degree infection is delayed or prevented

Drug administered at human-equivalent doses defined through
extensive PK assessments

Early studies with oral FTC/TDF provided proof of concept of efficacy for
daily Truvada PrEP
Proof of concept macaque PrEP study with daily FTC/TDF

Human doses of FTC and TDF administered orally mixed with food

Animals exposed to SHIV rectally once a week for up to 14 weeks
% Uninfected macaques
100
75
50
Daily FTC/TDF (n = 6)
HR = 7.8, p = 0.008
Untreated controls
(n = 18)
25
0
0
2
4
6
8
10
12
14
Number of weekly rectal virus exposures
Garcia-Lerma et al, PLoS Med 2008
Non-daily PrEP

Deliver effective drug concentrations at mucosal sites and/or systemically
at the time of potential HIV exposure when virus vulnerability is highest
TRENDS in Pharmacological Sciences 2010
Efficacy of “Time driven” oral PrEP in macaques
1 FTC/TDF
SHIV dose (+2h)
REPEATED FOR
14 WEEKS
1 FTC/TDF
dose (-3 days)
SHIV
100
% Uninfected macaques
1 FTC/TDF
dose (-3 days)
3 days before/2h after
HR = 15.4, p = 0.008
75
50
3 days before/no post
p > 0.05
25
Controls
0
REPEATED FOR
14 WEEKS
0
2
4
6
8
10 12 14
Number of weekly rectal virus exposures
Garcia-Lerma et al, Sci Transl Med 2010
Anderson et al, J Antimicrob Chemother 2014
Modeling “on demand” oral PrEP in macaques
FTC/TDF
(-1 day)
FTC/TDF
SHIV (+2h)
REPEATED FOR
14 WEEKS
FTC/TDF
(-2h) SHIV
FTC/TDF
(+1 day)
REPEATED FOR
14 WEEKS
% Uninfected macaques
100
1 day before/2h after
HR = 16.7, p = 0.006
75
2h before/1 day after
HR = 4.1, p = 0.02
50
1 day before/1 day after
HR = 6.6, p = 0.002
25
Controls
0
0
FTC/TDF
(-1 day)
SHIV
FTC/TDF
(+1 day)
2
4
6
8
10 12 14
Number of weekly rectal virus exposures
REPEATED FOR
14 WEEKS
Garcia-Lerma et al, Sci Transl Med 2010
Increased efficacy of “on demand “ oral PrEP with double
the dose of FTC/TDF
Two FTC/TDF
doses (-2h)
SHIV
Two FTC/TDF
doses (+1 day)
REPEATED FOR
14 WEEKS
% Uninfected macaques
100
Two doses 2h before and
two doses 1d after
HR = 16.7, p = 0.006
75
50
One dose 2h before and
one dose 1d after
HR = 4.1, p = 0.02
25
Controls
0
0
2
4
6
8
10 12 14
Number of weekly rectal virus exposures
Garcia-Lerma et al, Sci Transl Med 2010
Efficacy of “on demand” PrEP against vaginal infection

Pigtail macaques are preferred species
 Lunar menstrual cycle and changes in hormone levels similar to women; recapitulates potential
fluctuations in susceptibility to HIV/SIV infection
 High susceptibility to SIV/SHIV without the use of exogenous progestins such as depo provera

Understand how differences in drug penetration in rectal/vaginal tissues may
affect PrEP efficacy
TFV-DP 24h
(fmols/mg tissue)
FTC-TP 24h
(fmols/mg tissue)
Vaginal
4 (4-5)
151 (145-179)
Rectal
166 (5-697)
72 (24-118)
Lymphoid tissue
6 (3-17)
76 (25-115)
Relative penetration VT:RT
0.02
2.10
Efficacy of “on demand” oral PrEP against vaginal SHIV
infection in macaques
SHIV
FTC/TDF
(+2h)
REPEATED FOR 4
FULL MENSTRUAL
CYCLES
1 day before/2h after
100
% uninfected macaques
FTC/TDF
(-1 day)
75
50
Controls
25
0
0
1
2
3
4
Number of menstrual cycles
Radzio et al., PLoS One 2012
Summary

The repeat low dose SHIV transmission model can be used to
evaluate the efficacy of different PrEP regimens and modalities
under well-controlled conditions

Studies with oral FTC/TDF have provided proof of concept for daily
and non-daily (time-driven, on demand) PrEP with Truvada and
informed the design of human clinical trials
 Possibility to investigate other tenofovir prodrugs (i.e TAF) and evaluate potential
interchangeability of FTC and 3TC
 Ability to investigate if the addition of integrase inhibitors can improve the
window of protection with intermittent PrEP
ACKNOWLEDGEMENTS
Division of HIV/AIDS
Prevention, NCHHSTP, CDC
Jessica Radzio
Mian-er Cong
Wutyi Aung
James Mitchell
Debra Hanson
Ron Otten
Walid Heneine
Tara Henning
Ellen Kersh
Janet McNicholl
Angela Holder
Amy Martin
Chou-Pong Pau
Division of Laboratory
Sciences, NCEH, CDC
Zsuzsanna Kuklenyik
John Barr
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
Division of HIV/AIDS Prevention
Gilead Sciences, Inc
James Rooney
Emory University
Krisztina Hanley
University of Colorado
Peter Anderson