HPTN 067/ADAPT study: a comparison of daily and intermittent pre-exposure prophylaxis (PrEP) dosing for HIV prevention in men who have sex with men and transgender women in New York city
Mannheimer S. и др. «HPTN 067/ADAPT study: a comparison of daily and intermittent pre-exposure prophylaxis (PrEP) dosing for HIV prevention in men who have sex with men and transgender women in New York city» 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Vancouver, 2015. MOAC0305LB.
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HPTN 067/ADAPT study: a comparison of daily and intermittent pre-exposure prophylaxis (PrEP) dosing for HIV prevention in men who have sex with men and transgender women in New York city
1. 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
2. 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
3. • 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 FDA-
approved 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)
Introduction
4. 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
Primary Objective
5. • 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 ADAPT Study
Secondary Outcomes
6. 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
8. 359
screened
238
enrolled
121 not enrolled*
HIV + rapid 12% (N=14)
Lab abnormality 40%
Not enrolled within window 24%
Medical/mental comorbidity 12%
Withdrew consent 8%
Prohibited medication 1%
Low risk of HIV 1%
Other 7%
179
randomized
59 not randomized
HIV + rapid 2% (N=1)
Lost contact 56%
Incarcerated 12%
Withdrew 12%
Scheduling 7%
Relocated 5%
Comorbidities 5%
Product hold 2%
59
Daily
(D)
60
Time-driven
(T)
60
Event-driven
(E)
*More than one reason can be noted for reason not enrolled
HPTN 067 ADAPT: Harlem Site Schema
DOT
phase
Self administered phase
9. 179 participants randomized
• Mostly young (one third < 25, median age 30 y)
• MSM (98%)
• TGW (2%)
• Black (70%)
• Latino (25%)
• Unemployed (69%)
Baseline Characteristics
10. Coverage (PrEP Before and After Sex):
Daily vs. Time-Driven vs. Event-Driven
66%
24%
2%
8%
47%
30%
8%
15%
52%
29%
6%
13%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
% complete
coverage
% only
pre-sex dose
% only
post-sex dose
no
coverage
Daily
Time-driven
Event-driven
D/T and D/E p = 0.01; T/E p =0.47
11. FTC/TDF Tablets Required and
Tablets Taken by Arm
8249
3674
2572
5526
2468 2356
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
Daily Time-driven Event-driven
Numberoftablets
Required tablets
Tablets actually taken
Required tablets: p<0.0001 for all comparisons (D/T, D/E, and T/E)
Tablets actually taken: D/T and D/E p<0.0001; T/E p=0.33
12. Adherence: # required tablets actually taken
Total # tablets required
D/T and D/E p < 0.0001; T/E p = 0.16
13. 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
14. 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 post-
randomization
– 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%
15. Tenofovir diphosphate in Dried Blood Spots
Among Participants Reporting Sex in Prior 7 days
Week 10 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%
9% 11%
35%
57%
70%
48%
35%
19%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Daily Time-driven Event-driven
undetectable
low level
higher level
28%
39%
56%
22%
44%
28%
50%
17% 17%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Daily Time-driven Event-driven
undetectable
low level
higher level
16. Number of Sex Acts over Past 3 Months
At Week 30At Randomization
17. • Study not powered to determine efficacy
• 83% retention
• Results not generalizable to all U.S. MSM,
but represent an at-risk population
Limitations
18. • 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 post-
sex dosing
• Non-daily PrEP required fewer pills
• Side effects were seen with daily and non-
daily PrEP
• Daily PrEP arm participants achieved the
highest levels of tenofovir in dried blood spots
• No evidence of risk compensation seen
Summary
19. • 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 non-
daily PrEP in similar populations
Additional information:
Qualitative data from Harlem site (Poster # TULBPE21)
Conclusions
20. 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.
ACKNOWLEDGEMENTS
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
24. 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)
25. 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)
26. 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)
27. • 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 (half-
lives can be several weeks)
Methods / Definitions
28. Average number of sex acts per week (excluding oral)
reported at follow-up interviews by study arm
Thank you to the conference organizers for inviting me to present
I am presenting the results of the HPTN 067 ADAPT Study – a phase 2, open label study of intermittent emtricitabine/tenofovir-based PrEP
It has been well described that men who have sex with men in the US, particularly black MSM, are disproportionately affected by HIV
DAILY FTC/TDF (or Truvada) is currently FDA approved in the US for PrEP
HPTN 067 (ADAPT) in Harlem assessed the feasibility of NON-DAILY PrEP for MSM and transgender women
The primary objective of HPTN 067 was to assess whether non-daily PrEP (compared to daily) is associated with:
-Equivalent coverage of sex acts with pre- and post-exposure dosing
-Lower # of tablets
-Decreased side effects
The study was Not powered to determine efficacy
Secondary outcomes included
Safety
Adherence
Sexual risk behavior
Drug levels in plasma and dried blood spots
MSM & TGW eligible to enroll if
Male at birth,
Current HIV risk factors
Normal renal function ,
Excluded if HIV or hepatitis B infection
In HPTN 067 at Harlem, MSM and TGW participants were enrolled into an initial phase of weekly DOT and then were randomly assigned to 24 weeks of self-administered dosing according to one of three open-label FTC/TDF PrEP regimens:
Daily (D)
Time Driven: 1 tablet Twice weekly with a post-intercourse dose (T)
Event-driven: Before and after intercourse (E)
Tablets were stored and dispensed from a Wisepill electronic monitoring device that recorded each pillbox opening
Participants completed weekly interviews by phone or in person to review Wisepill data and collect self-reported pill taking and sexual behavior to help calculate coverage of sex acts
Participants were followed for a total of 34 weeks
359 individuals were screened, of whom 238 were enrolled from Jan 2013 thru May 2014
Many of those not enrolled were ineligible; reasons listed on the right including 12% who tested HIV+
Of the 238 enrolled into the 6 week DOT phase, 179 were randomized into the self-administered phase
Reasons for being enrolled into the DOT phase, but not being randomized into self-administered phase are listed on the left, including 1 participant who tested HIV+
The 179 randomized participants were mostly young (one third age 25 or younger),
98% were MSM, 2% transgender women, 70% Black and 25% latino
There were no significant differences in baseline demographics between study arms
Coverage of sex acts was one of the primary study endpoints:.
“Complete coverage” was defined as taking at least 1 PrEP tablet within 4 days before sex and at least 1 PrEP tablet with 24 hours after sex.
Daily arm participants reported complete coverage of 66% of sex acts, which was significantly higher than in the Time-driven and Event-Driven arms which had complete coverage for 47% & 52% of sex acts, respectively.
In cases of partial coverage of sex acts, participants in all 3 arms were more likely to complete the pre-sex dose / more likely to miss the post-sex dose.
Another primary outcome was the number of tablets required and taken
The number of tablets required, shown in blue, was calculated by the number required by each dosing regimen over study follow-up (adjusted by the #of reported sex acts for time- & event-driven arms0.
The number of required tablets differed significantly by arms- daily required the most, event-driven required the fewest tablets
The number of tablets actually taken (shown in red) were significantly lower in non-daily compared to Daily arms (no diff btwn Time & event)
Adherence to the assigned study arm dosing regimen was significantly higher in the daily arm, compared to the time-driven and event-driven arms
65% vs 46% vs 41%
Neurologic side effects (such as headache, dizziness) and Gastrointestinal side effects (such as nausea, diarrhea, bloating) were more frequently reported in the daily arm, but not significantly different when compared to the non-daily users.
Symptoms most often were MILD.
2 seroconversions occurred at the Harlem site: 1 during the DOT phase at week 4, and 1 during the self-administered phase in a Daily arm participant at week 18
In both cases there was no detectable drug at the visit preceding seroconversion, and little or no detectable drug at the seroconversion visit.
Higher level?
A greater proportion of Daily participants achieved higher range of TDF levels in Dried Blood Spots (>350 fmole);
-at week 10,the highest levels seen in 48% of daily participants, 35% of time-driven, 19% of event driven participants
No significant difference was seen in the number of sex acts from baseline to the end of the study
With participants reporting an average of one sex act a week
-not being powered for efficacy
-relied on self report for recall of sexual and pill taking behavior (informed by electronic monitoring data)
-83% retention
-not generalizable to all US MSM, but represent an at-risk population
In 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 post-sex dosing
-Non-daily PrEP required fewer pills
-Side effects were seen with daily and non-daily PrEP
-Daily PrEP arm participants achieved the highest levels of tenofovir in dried blood spots
-No evidence of risk compensation seen
- In conclusion
-Daily ftc/tdf based PrEP was feasible in this cohort of predominantly black US MSM in NYC
-Additional interventions may be needed to optimize PrEP adherence
-Additional studies needed to determine efficacy of non-daily PrEP in similar populations
Please visit our poster tomorrow for more qualitative data from our site
I’d like to thank the study funders, my collaborators, the Harlem community and most importantly our study participants
Protective- approx. 4 pills/week or 700 fmoles
remove
The regimens used in this trial and the definition of PrEP coverage was based on information that was available when the trial was designed in 2010. More current information suggests that higher concentrations of PrEP medications are required for protection from vaginal exposure to HIV, as would be afforded by daily oral dosing or any topical dosing.