Feasibility of Intermittent
PrEP Among US MSM:
Data from the Harlem Site
HPTN 067: ADAPT Study
Sharon Mannheimer, Yael Hirsch-Moverman, Avelino Loquere,
Julie Franks, James Hughes, San-San Ou, K. Rivet Amico, Craig
Hendrix, Bonnie J. Dye, Estelle Piwowar-Manning, Mark Marzinke,
Vanessa Elharrar, Michael Stirratt, Robert M. Grant for HPTN
067/ADAPT Harlem Study Team
July 20, 2015
Abstract MOAC0305LB
A Phase II, Randomized, Open-label,
Pharmacokinetic And Behavioral Study Of The Use
Of Intermittent Oral Emtricitabine/Tenofovir
Disoproxil Fumarate Pre-exposure Prophylaxis
(PrEP)
Alternative
Dosing to
Augment PrEP
Pill
Taking
Introduction
• Men who have sex with men (MSM) in the U.S.,
particularly young black MSM, are
disproportionately affected by HIV
• Daily FTC/TDF (Truvada®) is currently FDAapproved in U.S. for pre-exposure prophylaxis
(PrEP) for HIV prevention for populations at risk
including MSM
• HPTN 067 / ADAPT in Harlem, New York City,
assessed the feasibility of non-daily PrEP for U.S.
MSM and transgender women (TGW)
HPTN 067 ADAPT Study
Primary Objective
To assess whether recommending non-daily
oral FTC/TDF PrEP, compared with daily, is
associated with:
• Equivalent coverage of sex events with pre- and
post-exposure dosing
• Lower number of tablets needed
• Decreased self-reported symptoms/side effects
HPTN 067 ADAPT Study
Secondary Outcomes
• Safety and outcome of PrEP users
• Adherence
• Potential influence of PrEP on sexual / risk
behavior
• Drug levels of tenofovir, emtricitabine, and
their metabolites in plasma and dried blood
spots
HPTN 067 in Harlem: Eligibility
• MSM and TGW were eligible if:
– Male at birth, and
– Reported anal intercourse in the past 6 months, and
– Reported >1 other HIV risk factor in the past 6
months
– Normal renal function (CrCl > 70 ml/min)
• Exclusion criteria included:
–
–
–
–
–
–
HIV infection
Hepatitis B infection
Symptoms of acute HIV
Use of nephrotoxic drugs
Proteinuria or glucosuria or low serum phosphate
Recent PEP or PrEP use
HPTN 067 ADAPT Study Design:
Harlem Site
Wk 0
Wk 34
Daily (D)- 1 tab daily
Time driven (T)- 1 tab twice a week plus 1 tab post-sex
Event driven (E)- 1 tab before and 1 tab after sex
FTC/TDF
D
MSM & TGW
Randomized
6 week
DOT
phase
No more than 2 doses daily or 7 doses/week
T
24 weeks
self-administered
dosing
4
weeks
off
drug
Final
Study
Visit
E
Qualitative
substudy
Sex coverage
HPTN 067 ADAPT: Harlem Site Schema
359
screened
59 not randomized
HIV + rapid
2% (N=1)
Lost contact
56%
Incarcerated
12%
Withdrew
12%
Scheduling
7%
Relocated
5%
Comorbidities
5%
Product hold
2%
238
enrolled
121 not enrolled*
HIV + rapid
Lab abnormality
Not enrolled within window
Medical/mental comorbidity
Withdrew consent
Prohibited medication
Low risk of HIV
Other
DOT
phase
179
randomized
Self administered phase
59
60
60
Daily
(D)
Time-driven
(T)
Event-driven
(E)
*More than one reason can be noted for reason not enrolled
12% (N=14)
40%
24%
12%
8%
1%
1%
7%
Baseline Characteristics
179 participants randomized
•
•
•
•
•
•
Mostly young (one third < 25, median age 30 y)
MSM (98%)
TGW (2%)
Black (70%)
Latino (25%)
Unemployed (69%)
Coverage (PrEP Before and After Sex):
Daily vs. Time-Driven vs. Event-Driven
100%
Daily
Time-driven
Event-driven
90%
80%
70%
66%
60%
50%
52%
47%
40%
30% 29%
30%
24%
20%
15% 13%
8%
10%
2%
6%
8%
0%
% complete
coverage
% only
pre-sex dose
D/T and D/E p = 0.01; T/E p =0.47
% only
post-sex dose
no
coverage
FTC/TDF Tablets Required and
Tablets Taken by Arm
9000
8249
Number of tablets
8000
Required tablets
7000
Tablets actually taken
5526
6000
5000
3674
4000
3000
2468
2572
2356
2000
1000
0
Daily
Required tablets:
Tablets actually taken:
Time-driven
Event-driven
p<0.0001 for all comparisons (D/T, D/E, and T/E)
D/T and D/E p<0.0001; T/E p=0.33
Adherence: # required tablets actually taken
Total # tablets required
D/T and D/E p < 0.0001; T/E p = 0.16
Neuro and GI symptoms / side effects
Side Effect reported
Daily
Time
Event
global
p-value
% PPTs who experienced
any Neurologic side effect
24%
20%
18%
0.64
% PPTs who experienced
any GI side effect
39%
18%
28%
0.51
HIV Incidence Outcome
2 Seroconversions occurred at the Harlem site:
• 1 seroconversion during 6-week pre-randomization
weekly DOT study phase
– Occurred at Week 4
– No detectable drug at visits preceding or at seroconversion
visit
– 1 of 238 participants over 22.6 person-years
– Incidence 4.4%
• 1 seroconversion during 24-week post-randomization
self administered PrEP phase
– Occurred at Week 18 (Daily arm), 12 weeks postrandomization
– No detectable drug at visit preceding seroconversion
– very low level of TDF was detected only in dried blood spot
(not in plasma) at the seroconversion visit
– 1 of 179 participants over 83.1 person years
– Incidence 1.2%
Tenofovir diphosphate in Dried Blood Spots
Among Participants Reporting Sex in Prior 7 days
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
undetectable
low level
higher level
70%
57%
48%
35%
35%
19%
17%
9%
Daily
Time-driven
Week 10
11%
Event-driven
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
undetectable
low level
higher level
56%
50%
39%
28%
44%
28%
22%
Daily
17%
Time-driven
Week 30
p = 0.04 for global differences between all arms over entire follow-up
D/T p =0.07, D/E p=0.01, T/E p=0.36
17%
Event-driven
Number of Sex Acts over Past 3 Months
At Randomization
At Week 30
Limitations
• Study not powered to determine efficacy
• 83% retention
• Results not generalizable to all U.S. MSM,
but represent an at-risk population
Summary
• Daily dosing resulted in better coverage of
sex acts and better adherence
• Overall coverage of sex acts and PrEP
adherence suboptimal
• For non-daily PrEP, incomplete coverage of
sex acts was mostly related to lack of postsex dosing
• Non-daily PrEP required fewer pills
• Side effects were seen with daily and nondaily PrEP
• Daily PrEP arm participants achieved the
highest levels of tenofovir in dried blood spots
• No evidence of risk compensation seen
Conclusions
• Daily FTC/TDF-based PrEP was feasible in this cohort
of predominantly black U.S. MSM in New York City
• Additional interventions may be needed to optimize
PrEP adherence
• Additional studies needed to determine efficacy of nondaily PrEP in similar populations
Additional information:
Qualitative data from Harlem site (Poster # TULBPE21)
ACKNOWLEDGEMENTS
The HIV Prevention Trials Network is sponsored by the
National Institute of Allergy and Infectious Diseases,
the National Institute of Mental Health, and the National
Institute on Drug Abuse, all components of the
U.S. National Institutes of Health.
The HPTN 067 Harlem Study Team acknowledges:
Our participants
Study staff at Harlem Prevention Center and Bronx Prevention Center sites
Harlem Hospital Infectious Disease Community Advisory Board
The Harlem Community
ICAP
HPTN Leadership and Operations Center
HPTN Laboratory Center
HPTN Statistical and Data Management Center
Tenofovir diphosphate in Dried Blood Spots
Among Participants Reporting Sex in Prior 7 days
100%
90%
80%
70%
100%
undetectable
87%
85%
low level
protective level
60%
undetectable
80%
low level
70%
protective level
56%
60%
48%
50%
40%
35%
39%
40%
30%
17%
9%
10%
56%
50%
30%
20%
90%
39%
33%
33%
28%
20%
11%
4%
4%
Time-driven
Event-driven
0%
11%
6%
10%
0%
Daily
Week 10
D/T p = 0.03, D/E p=0.005, T/E p = 0.78
Daily
Time-driven
Week 30
Event-driven
Tenofovir plasma drug level data:
Proportion achieving detectable concentration
Percent detectable TFV
level
Study
Regimen
Daily (D)
Study
Regimen
Time (T)
Study
Regimen
Event (E)
% at Week 10 (with sex
in past 7 days) w/ TFV
level >0.31 ng/ml
74%
(N=27)
76%
(N=25)
64%
(N=33)
% at Week 30 (with sex
in past 7 days) w/ TFV
level >0.31 ng/ml
61%
(N=18)
56%
(N=18)
50%
(N=18)
Tenofovir plasma drug level data:
Proportion achieving higher concentration
Percent Detectable
(> 0.31 ng/mL)
Group
Study
Regimen
Daily (D)
Study
Regimen
Time (T)
Study
Regimen
Event (E)
% at Week 10 (with sex in
past 7 days) w/
TFV level >5 ng/ml
63%
(N=27)
72%
(N=25)
61%
(N=33)
% at Week 30 (with sex in
past 7 days) w/ TFV level
>5 ng/ml
56%
(N=18)
50%
(N=18)
39%
(N=18)
Tenofovir plasma drug level data: Median
TFV drug concentration
(ng/mL)
Study
Regimen
Daily (D)
Study
Regimen
Time (T)
Study
Regimen
Event (E)
At Week 10 (with sex in
the past 7 days),
Median
83
(N=27)
24
(N=25)
15
(N=33)
At Week 30 (with sex in
the past 7 days),
Median
31
(N=18)
11
(N=18)
1
(N=18)
Methods / Definitions
• Coverage for all arms was defined as >1 tablet taken
in the 4 days before and >1 tablet taken in the 24
hours after sexual intercourse
• Adherence was defined as the percentage of
recommended tablets taken for each regimen
• Plasma collected at weeks 4, 5, 6, 10, 18, and 30
and analyzed for tenofovir (TFV) and emtricitabine
(FTC) and their active metabolites (half-lives < 1 day)
• Dried Blood Spots (DBS) collected at weeks 4, 5, 6,
10, 18, and 30 - used to analyze intracelllular levels
of TFV and FTC metabolites in red blood cells (halflives can be several weeks)
Average number of sex acts per week (excluding oral)
reported at follow-up interviews by study arm
Plasma Tenofovir Level by Number of Pills
reported taken in prior week