Transcript Tenofovir Gel

Systemic vs. Topical PreExposure Prophylaxis (PrEP):
What Will VOICE and Other
Studies Tell Us?
Jeanne Marrazzo, MD, MPH
University of Washington
2011 HVTN Meeting
Discussion
• Microbicides as PrEP
• Potential advantages of & concerns with
topical delivery
• Evidence in humans, and ongoing studies
• What new delivery systems or agents are
being considered?
Pill
Gel / applicator
Vaginal film
Vaginal ring
Injectable
Topical PrEP: Why?
• Maximize local drug concentration at desired sites
• Minimize systemic toxicity
• Potentially rapid delivery to vulnerable tissues
without need for “loading” phase
• Potential for high barrier to resistance
• Enhanced user acceptability
Topical PrEP: Yes, But…
• Maximize local drug concentration at desired sites
– Ensure intracellular concentration of activated form of drug
is adequate
– Minimize adverse effects on local immune defense,
including anatomic barriers (no disruption) & microbiome
– Ideally, aim for cross-protection between vagina & rectum
with single-compartment dosing
• Minimize systemic toxicity
• Potentially rapid delivery to vulnerable tissues
without need for “loading” phase
• Potential for high barrier to resistance
• Enhanced user acceptability
Topical PrEP: Yes, But…
• Maximize local drug concentration at desired sites
– Ensure intracellular concentration of activated form of drug
is adequate
– Minimize adverse effects on local immune defense,
including anatomic barriers (no disruption) & microbiome
– Uncertainty about cross-protection between vagina &
rectum with single-compartment dosing
• Minimize systemic toxicity
– Minimal absorption desirable, but might limit local efficacy
• Potentially rapid delivery to vulnerable tissues
without need for “loading” phase
• Potential for high barrier to resistance
• Enhanced user acceptability
Topical PrEP: Yes, But…
• Maximize local drug concentration at desired sites
– Ensure intracellular concentration of activated form of drug
is adequate
– Minimize adverse effects on local immune defense,
including anatomic barriers (no disruption) & microbiome
– Uncertainty about cross-protection between vagina &
rectum with single-compartment dosing
• Minimize systemic toxicity
– Minimal absorption desirable, but might limit local efficacy
• Potentially rapid delivery to vulnerable tissues
without need for “loading” phase
– Pharmacokinetics still being defined; adequate protective
dose under study
• Potential for high barrier to resistance
• Enhanced user acceptability
Topical PrEP: Yes, But…
• Maximize local drug concentration at desired sites
– Ensure intracellular concentration of activated form of drug
is adequate
– Minimize adverse effects on local immune defense,
including anatomic barriers (no disruption) & microbiome
– Uncertainty about cross-protection between vagina &
rectum with single-compartment dosing
• Minimize systemic toxicity
– Minimal absorption desirable, but might limit local efficacy
• Potentially rapid delivery to vulnerable tissues
without need for “loading” phase
– Pharmacokinetics still being defined; adequate protective
dose under study
• Potential for high barrier to resistance
– Will topical ARV favor different resistance mutations?
• Enhanced user acceptability
Topical PrEP: Yes, But…
• Maximize local drug concentration at desired sites
– Ensure intracellular concentration of activated form of drug is
adequate
– Minimize adverse effects on local immune defense, including
anatomic barriers (no disruption) & microbiome
– Uncertainty about cross-protection between vagina & rectum
with single-compartment dosing
• Minimize systemic toxicity
– Minimal absorption desirable, but might limit local efficacy
• Potentially rapid delivery to vulnerable tissues without
need for “loading” phase
– Pharmacokinetics still being defined; adequate protective
dose under study
• Potential for high barrier to resistance
– Will topical ARV favor different resistance mutations?
• Enhanced user acceptability: better sex!
– But semen might affect product efficacy
MTN 001: Acceptability
• Likely future use, if effective:
– 93% oral tablet; 83% gel (p=0.002)
– Difference driven by lower, different US rates
• Preferences differed by location
Overall (%)
Africa (%)
US (%)
Vaginal Gel
28
42
14
Oral Tablets
57
40
72
Both liked equally
10
14
7
Both disliked
5
3
7
• Many African women said that the gel improved
sexual pleasure (qualitative interviews)
Hendrix C, CROI 2011
MTN 001: Qualitative Findings
End of Study In-depth Interviews
• Product preferences and barriers to use differed;
clear interest in both formulations
– Gel perceived by many women at Ugandan and
South African sites to improve sex
“Since I started using it, the love with my husband
increased…because he thinks I love him so much
yet it’s the gel.” - Uganda
• Side effects numerous, but subsided swiftly
• Strategies that integrate use into daily routine
critical to achieve high adherence
• Direct involvement of male partners regarded as
beneficial by many women
CAPRISA 004:
Pericoital 1% tenofovir gel
 Phase 2B trial in 889 women,
ages ≥18 years in Durban &
Vulindlela, South Africa
 Coitally dependent: gel within 12
hours before & 12 hours after sex,
max. 2 applications in 24 hours
 Study population: Young women
(mean age 23), unmarried, from
rural (69%) & urban (31%) settings
Abdool Karim et al, Science July 2010
 Completed 2010: Good safety
profile (↑ diarrhea compared to
placebo)
HIV Incidence in CAPRISA 004
No K65R resistance mutations among seroconverters
Abdool Karim, Q, et al. Science. 2010;329:1168-1174.
CAPRISA 004
HIV Incidence by Adherence
• High (> 80%) gel use, n = 336:
Tenofovir gel: 4.2%
Placebo gel: 9.3% P = .025
54% effective
• Intermediate (50%-80%), n = 181
Tenofovir gel: 6.3%
Placebo gel: 10.0% P = .343
38% effective
• Low (< 50%), n = 367
Tenofovir gel: 6.2%
Placebo gel: 8.6% P = .303
Abdool Karim, Q, et al. Science. 2010;329:1168-1174.
28% effective
CAPRISA 004: Impact of 1% tenofovir
gel on HSV-2 incidence
Tenofovir gel Placebo gel
n = 202*
n = 224*
# HSV-2 infections
Women-years of follow
up
HSV-2 incidence per
100 wy (95% CI)
*Note:
29
58
292.3
287.3
9.9
(6.6, 14.2)
20.2
(15.3, 26.1)
Excludes equivocal HSV-2 results at study exit
IRR = 0.49 (CI: 0.30, 0.78); P = .003
51% protection against HSV-2 by tenofovir gel (CI: 22% - 70%)
Abdool Karim Q, et al. AIDS 2010. Abstract TUSS0502.
One Effect of CAPRISA 004 Success
CAPRISA 004
What Didn’t We Learn?
• Whether women prefer the gel or the tablet
• Information on more frequent (daily) use
– Whether it is safe
– Whether it is more effective than pre- and postcoital dosing
• Information on use in adolescents
The VOICE Study
Tenofovir
Tablets
Tenofovir Gel
Truvada
Tablets
Which is effective?
Is each safe?
Which will women use?
Secondary Objectives:
Adherence/Behavioral Sexual/Intravaginal Practices
HIV Drug Resistance
PK/PD Models
Delayed HIV Seroconversion
Study Overview
• 5,029 women at 16 sites
• Accrual Sept 2009 – June 2011
• Inclusion: vaginal intercourse in past 3
months
• Average time on product 24 months (max 36)
• Planned completion 2012, results 2013
• Funded by NIAID/DAIDS, NIMH, NICHD
• Study products provided by CONRAD, Gilead
• Protocol co-chairs:
• Mike Chirenje, MD
• Jeanne Marrazzo, MD, MPH
VOICE Study Design
5,000 Women
Tablet
(3,000)
Truvada
(1,000)
Tenofovir
(1,000)
Vaginal Gel
(2,000)
Placebo Tablet
(1,000)
Tenofovir Gel
(1,000)
Five study groups
Placebo Gel
(1,000)
15 VOICE Sites – 5,029 women
• UGANDA: 322 women
– Makerere Univ./JHU, Kampala (1 site)
• ZIMBABWE: 630 women
– UZ-UCSF, Harare (1 site)
– UZ-UCSF, Chitungwiza (2 sites)
• SOUTH AFRICA: 4,077
women
Durban Area
– Medical Research Council (7 sites)
– CAPRISA eThekwini (1 site)
Johannesburg Area
– WRHI (1 site)
– PHRU Soweto (1 site)
Klerksdorp Area
– Aurum Institute (1 site)
VOICE: Contribution to Evidence Base
• Large number of person-years of follow-up
• Diverse population including
– Married women: may know partner’s HIV status
– Unmarried women (South Africa)
• Unlikely to know partner’s HIV status
• Likely impacts motivation to adhere to study product
– Young women (notable relative to Partners)
– Probable wider range of adherence given population
• Only trial that includes TFV gel arm
– If effective, will contribute pivotal data for licensure for
HIV & HSV-2 prevention indication
• Substudy (VOICE B) to examine BMD in oral arms
DSMB recommendations, Sept 2011
• The oral single-drug arm of TDF should be
stopped because of futility
– No safety concerns
• Unblind participants in the TDF arm have all
study products, both active and placebo,
discontinued as soon as possible
– Included VOICE B (BMD study) participants
• Continue the TDF/emtricitabine oral arm and
the TFV gel arm, with corresponding
placebos
Impact on Study Questions?
Some VOICE/VOICE B
Objectives
Impact of DSMB Outcome
Effectiveness of oral TDF
Answered – NOT EFFECTIVE IN
VOICE POPULATION
Safety of oral TDF
At least partially answered; no
safety concerns noted
Effectiveness of TDF/FTC
tablets, TFV gel
Not yet answered
Safety of TDF/FTC tablets, TFV
gel
Not yet answered, but no safety
concerns thus far
Impact of oral TDF on bone
density
Ability to answer questions was cut
short
Beyond VOICE: Next Steps for
TFV Gel?
• FACTS: Pericoital use in S. African
women
• Safety in pregnancy: MTN agenda
• Phase I/II studies of safety, acceptability
and PK of reformulated TFV gel for rectal
use: MTN agenda
• Examine HSV protection in VOICE
participants: underway
Candidate Drugs in PrEP Pipeline
Phase
IIB
Phase
II
Phase
I
• NNRTIs: Dapivirine intravaginal ring
• Effectiveness trials for dapivirine ring 2012 (IPM & partners)
• Entry inhibitors: Maraviroc with NRTI or NNRTI
• Oral maraviroc +/- FTC/TDF (HPTN 069)
• Maraviroc & dapivirine vaginal ring (IPM, MTN)
• NNRTIs: Rilpivirine (TMC 278), long-acting injectable
• Once monthly injections; in phase I safety studies in UK
• Broadly neutralizing monoclonal antibodies
Animal
Studies
• Integrase strand inhibitors
• Macaque & humanized mice protected with topical & oral
raltegravir (Dobard CROI 30; Neff PLoS One 2010)
Dapivirine ring
• Dapivirine is a nonnucleoside reverse
transcriptase inhibitor
• Flexible ring made of an
elastic silicone material
• Measures 56 mm (about 2
½”) in diameter and 7.7
mm (3/4”) thick
• Designed for 28-day use
• Will be compared to
placebo ring in the
ASPIRE study (start late
2012)
Topical PrEP?
• Move beyond tenofovir (dapivirine)
• Continue to advance the research agenda in pregnancy,
breastfeeding women, and for use with anal sex
• Combination multipurpose products
• Two HIV drugs combined with hormonal
contraception +/- targeting other infections (HSV)
• Combining PrEP with vaccines
• Oral and topical (rings, films, gels)
• Expansion & validation of biomarkers of efficacy/safety
• Critical for identifying which products to advance
ACKNOWLEDGMENTS
•
•
•
•
•
•
Connie Celum
Jared Baeten
Betsy Herold
Craig Hendrix
Lisa Noguchi
MTN is funded by NIAID (5U01AI068633),
NICHD and NIMH, all of the U.S. National
Institutes of Health
What is PrEP, and Why Might it Work?
• Definition: Provision of chemopreventive agent at vulnerable
site(s) prior to infection
• Rationale:
• Infection of healthy
mucosa requires
relatively large dose of
virus (10-6 to 10-8
particles)
• In theory, the right drug
could prevent founder
population from
establishing infection,
but time is of the
essence!
Garcia-Lerma JG, et al. Trends Pharmacol Sci. 2010
Tenofovir Gel Pregnancy Studies
MTN-002
•First microbicide study in pregnancy
 How does pregnancy affect drug absorption?
 Is the drug transferred to the fetus?
•Gel applied as one-time dose in 16 HIV-negative U.S.
women prior to scheduled C-section
•Results:
– Only small amounts of drug absorbed into mother’s
bloodstream, amniotic fluid and umbilical cord (fetal)
blood
Tenofovir Gel Pregnancy Studies
MTN Rectal Safety Studies

MTN-006
 Phase I safety, acceptability and drug absorption
study of vaginal tenofovir gel applied rectally in 18
HIV-negative adults at 2 U.S. sites
 Found safe but resulted in reformulation of the gel

MTN-007
 Phase I follow-up study to MTN-006
 60 HIV-negative men and women at 3 U.S. sites
 Study completed; results expected early 2012

MTN-017
 Planned Phase II study in MSM in U.S.,
South Africa (Cape Town), Thailand and Peru
• 1% TFV (30 mg) vs. 1% TFV &
5% FTC gels 30 minutes preSHIV challenge
• 4 arms: 2 no gel; 6 placebo (2%
HEC), 6 combo, 6 TFV
• 2x weekly low dose vaginal
challenge x 10 weeks
– No gel: 2/2 infected by 5
challenges
– Placebo: 5/6 infected w/ median
4.5 challenges (2.5 wks)
• TFV/FTC & TFV: total protection
through 20 challenges
• Detection of either in plasma of
protected macaques: 76%,
mean 30 minutes
• TDF (25 ng/ml) 0.01-0.03%
absorbed; FTC (70 ng/ml) 0.03%
Parikh U, J Virol Oct 2009
Characteristics of PrEP Trials Involving Women
Trial
Population /
Active Arm(s)
Heterosexual
FEM-PrEP
women
Daily TDF/FTC
TDF2
Partners
in
Prevention
VOICE
N (%)
Women
1,951
Heterosexual
men & women 550 (46)
Daily TDF/FTC
Serodiscordant
couples
Daily TDF or
TDF/FTC
Heterosexual
women
Daily TDF or
TDF/FTC
1,785
(38%)
P-Y
~1,100
?
Efficacy
Comments
0%
Concerns re
adherence, “high
risk” population
63%
Small no.
endpoints; subanalysis
TDF
W 68% (CI 29-85)
M 55% (CI 4-79)
F: 2,753
M: 4,587 FTC/TDF
W 62% (CI 19-82)
M 83% (CI 49-94)
5,029
(100)
F:8800*
Pending
Adherence very
high; median age
of women higher
than VOICE (30s)
Only trial to provide
data on TFV gel for
both HIV and HSV2 endpoints
CROI 2011
Microbicides in Vaginal Rings
#1001: Nel et al
•“Pharmacokinetic and Safety Assessment of Monthly Anti-HIV
Dapivirine Vaginal Microbicide Rings with Vaginal Dosing”
•Possible Phase 2B trial in works (though placebo window may
be closing)
Dapivirine = NNRTI, safe and well-tolerated
#1003: Singer et al
“An EVA Vaginal Ring Containing the NNRTI MIV-150 Protects
Against SHIV-RT Infection in vivo”
• 1/7 macaques challenged 24 hr & 2 weeks post-insertion
infected
• 1/2 challenged @ 24 hr and 2/2 @ 2wk control
macaques infected