A Comparison of Daily and Non-daily
Pre-exposure Prophylaxis Dosing in Thai
Men Who Have Sex With Men, Bangkok
HPTN 067 / ADAPT Study
Timothy H. Holtz, Anupong Chitwarakorn, Marcel E. Curlin,
James Hughes, K. Rivet Amico, Craig Hendrix, Bonnie J.
Dye, Peter L. Anderson, Maoji Li, Vanessa Elharrar, Susan H.
Eshleman, Michael Stirratt, Robert M. Grant and the
Bangkok HPTN 067/ADAPT Study Team
July 20, 2015
249
screened
56 not enrolled*
HIV + rapid
Abnormal ALT/AST
Abnormal Ser Cr
Lab abnormality
HbV no immune
Other medical/mental
Not enrolled within window
Other
193
enrolled
15 not randomized
HIV + false
2/13.3%
HIV + in DOT 2/13.3%
Product hold 1/6.7%
Withdrew
1/6.7%
Lost contact 2/13.3%
Other
7/46.7%
*not mutually exclusive
DOT
Phase
178
randomized
Self-Administered Phase
60
Daily usage
59
Time-driven
usage
59
Event-driven
usage
11/19.6%
13/23.2%
7/12.5%
6/10.7%
11/19.6%
2/3.6%
5/8.9%
4/7.1%
Participant Demographics: Bangkok
Variable
Median age (years, IQR)
Age ranges
18-20
21-25
26-30
31-35
36-40
>40
Gender identity
Male
TGW
Race
Asian
Never married
Education
Completed college
In college, not completed
Unemployed
Student
% (N=178)
31 (27,34)
1%
21%
28%
30%
14%
6%
99%
1%
100%
97%
83%
6%
11%
9%
Coverage (PrEP Before and After Sex):
Daily vs. Time-Driven vs. Event-Driven
100%
90%
80%
Daily
85% 84%
Time-driven
74%
Event-driven
70%
60%
50%
40%
30%
19%
20%
11% 12%
10%
5%
1% 3%
3% 1% 3%
% only
post-sex dose
no
coverage
0%
% complete
coverage
% only
pre-sex dose
D/T p = 0.79, D/E p = 0.02, T/E p = 0.04, global p = 0.19
FTC/TDF Pills by Arm
9420
8285
Required tablets
Number of tablets
Tablets reported taken
4121
3713
1928
Daily
Required tablets:
Tablets actually taken:
Time-driven
2157
Event-driven
p < 0.001 for all comparisons (D/T, D/E, and T/E)
p < 0.001 for all comparisons (D/T, D/E, and T/E)
Adherence (Total pills taken/Total pills required):
Daily vs. Time-Driven vs. Event-Driven
D/T p < 0.42, D/E p < 0.001, T/E p < 0.001, global p < 0.001
Neuro and GI Symptoms / Side Effects
Side Effect reported
Daily
Time
Event
p value
% PPTs who experienced
any neurologic side effects
48%
46%
54%
0.64
% PPTs who experienced
any GI side effects
45%
34%
41%
0.46
Reports of Side Effects Over Time
HIV Incidence
• 2 seroconversions during the 6-week prerandomization weekly DOT study phase
– Both occurred at week 4
– Both had low levels of FTC detected and no
detectable TVF in plasma
– Both had low detectable levels of both FTC and
TVF in PBMC
– 2 of 193 participants over 22.9 person-years;
incidence 8.7% (1.1%–31.5%) during DOT phase
– 0 of 178 participants over 94.8 person-years;
incidence 0.0% (0.0%–3.9%) during selfadministered (SA) phase
Tenofovir diphosphate in PBMCs:
Proportion achieving detectable concentration
Time period
Study
Regimen
Daily (D)
Study
Regimen
Time (T)
Study
Regimen
Event (E)
Week 10
(with sex in the past 7
days)
100%
(n=31/31)
97%
(n=28/29)
93%
(n=28/30)
Week 30
(with sex in the past 7
days)
91%
(N=21/23)
95%
(N=18/19)
86%
(N=12/14)
Detectable >9.1 fmol/million PBMC
D/T p = 0.90, D/T p = 0.28, T/E p = 0.35, global p = 0.48
Median tenofovir diphosphate drug
concentration in PBMCs
Time period
Study
Regimen
Daily (D)
Study
Regimen
Time (T)
Study
Regimen
Event (E)
Week 10
(with sex in past 7 days)
(fmol/million cells)
81.1
(N=31)
35.3
(N=29)
26.4
(N=30)
Week 30
(with sex in past 7 days)
(fmol/million cells)
102.0
(N=23)
46.8
(N=19)
32.9
(N=14)
D/T p < 0.001, D/T p < 0.001, T/E p = 0.0495, global p < 0.001
Qualitative Component Methods
• 38 HPTN 067/ADAPT MSM participants
joined a qualitative evaluation: 32
participants joined in 6 focus-group
discussions (FGDs) and 6 attended keyinformant interviews (KIIs).
• Grounded theory and content analysis
were used to analyze the data.
Daily
regimen
Patterns of sex
• Have sex frequently
• Prefer not to plan for sex
• Do not have control over planning for sex with
sexual partners
• Self-perceived of having high HIV risk
Pros
• Easily taken, can take with daily vitamins
• Able to set tablet-taking time regardless of sex
• No need to carry tablets
• No need to disclose about PrEP use
Cons
• Concerns about long-term impacts and side effects
• Fear of being seen as being HIV-infected
• Difficult to use if sex were infrequent
• Difficulty to take daily for long period of time
• Routine change
• Tablet fatigue
• Affordability
Timedriven
regimen
Patterns of sex
• Have infrequent sex event
• Inability to plan sex / have no control over planning for
sex with sexual partners
Pros
• Fewer doses (less concerns about side effects)
• Able to choose the day to take tablets (2 doses/week)
• No need to plan for sex (keep few tablets in pocket for
post-sex dose after unexpected sex event)
Cons
• Difficulty in linking routine activity with 2 tablet-taking
days
• Complicated regimen (No more than 1 dose in a 2 hour
window)
• Need to carry few tablets at all times
• Difficult to hide tablets from sexual partners
• Planning for sex made sex no longer enjoyable
Eventdriven
regimen
Patterns of sex
• Have infrequent sex event
• Ability of sex planning / have control over
planning for sex with sexual partners
Pros
• Fewer doses (less concerns about side effects)
Cons
• Need sex planning
• Need to carry tablets at all times (pre/post-sex
dose)
• Difficult to hide tablets from sexual partners
• Regimen confusion (need to count by hours)
• Complicated regimen (No more than 1 dose in a
2 hour window)
Summary of Study Results
• Compared with the daily regimen, the time-driven
dosing regimens offered comparably high PrEP
coverage for sex acts with
– slightly less adherence
– fewer tablets required
• Among Thai MSM, adherence and drug
concentrations were highest in the daily arm
• TFV drug detection in PBMCs was high (>85%) in
all 3 arms at weeks 10 and 30 in this population
in Bangkok
– Indicates feasibility of non-daily regimens in this
population
Summary cont’d – Qualitative
• Daily dose was the easiest regimen without
the ability to plan for sex, but there were
concerns about long-term impact and
affordability
• Non-daily PrEP would be another choice
for those MSM who have infrequent sex
events, capacity to plan for sex, and ability
to take a post-sex dose
Poster presentation # WELBPE23
Conclusion
• Among those with few exposures, non-daily
dosing of PrEP could result in fewer tablets
required to achieve comparable coverage
– Importantly: coverage as defined in this study (1 or
more pills before & after sex) is not yet known to be
effective
– If proven effective in future research, non-daily
regimens could provide an alternative for those who
can adhere
• Study results offer additional support for
current CDC guidelines for daily dosing
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 Bangkok Study Team acknowledges:
Our HPTN 067 participants
Study staff at Silom Community Clinic @TropMed
DAIDS and NIMH
Thailand Ministry of Public Health
Epidemiology Branch, Division of HIV/AIDS Prevention, CDC
MSM Community Advisory Board
FHI 360
SCHARP
HPTN Laboratory Center
HPTN 067: Bangkok Site Staff
Supaporn Chaikummao
11/3/1954 – 31/5/2015
Pill-taking from Weekly Interview Log vs Pill Count Form
Number of Sex Acts Over Study
Follow-up by Study Arm, Weekly Interview
Average number of sex acts per week (excluding oral)
reported at weekly interviews by study arm
Period
D
T
E
Number of times had sex in
past 3 months at week 6
Mean
Median
Without a condom
13
10
0
17
10
0
10
6
0
Number of times had sex in
past 3 months at week 30
Mean
Median
Without a condom
14
10
0
13
10
0
9
6
0
Kruskall-Wallis p for difference between
three groups at week 30 = 0.023
• Over the span of
each previous 3
months, MSM in
our study had
sex on average
about once per
week (13 at
week 6, and 12
at week 30)
• Rarely if ever
without a
condom
Period
D
T
E
Number of sex partners
in past 3 months at
week 6
Mean
Median
5.9
3
10.8
3
4.5
3
Number of sex partners
in past 3 months at
week 30
Mean
Median
6.2
3
9.3
4
4.5
3
Kruskall-Wallis p for difference between
three groups at week 30 = 0.099
• Over the span
of each
previous 3
months, MSM
had on average
7 different sex
partners
Number of Sex Acts over Last 3 Months from CASI vs
Weekly Interview Log
Plasma Tenofovir Level by Number of Pills
Reported Taken in Prior Week
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
• Oral FTC/TDF PrEP is effective for preventing sexual
HIV infection when used daily
• Concerns about cost and side effects can limit
uptake
• Daily and non-daily regimens have not been
compared directly with respect to prophylactic
coverage for sexual exposure
• Less frequent oral dosing regimens might reduce
side effects and might favorably or unfavorably affect
adherence
• Daily FTC/TDF (Truvada) is currently FDA-approved
in U.S. for pre-exposure prophylaxis (PrEP) for HIV
prevention for populations at risk including men who
have sex with men (MSM)
ADAPT Study Primary Objective
• The HPTN 067 ADAPT trial Bangkok site, a phase 2,
randomized, open-label clinical trial of oral
emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)
PrEP was conducted among men who have sex with
men (MSM), and transgender women (TGW)
• To assess whether recommending non-daily usage of
oral FTC/TDF PrEP, compared with recommending
daily usage, will be associated with:
• Equivalent coverage of sex events with pre- and postexposure dosing
• Lower number of pills needed for coverage and fewer pills
used
• Decreased self-reported symptoms/side effects during 24
weeks of self-administered use
ADAPT Study Secondary Objectives
•
•
•
•
Assess safety of PrEP users
Assess adherence by study arm
Assess PrEP acceptability by arm
Evaluate potential influence of PrEP on
sexual risk behavior
• Assess drug levels of tenofovir,
emtricitabine, and their metabolites in
plasma and peripheral blood mononuclear
cells (PBMCs)
Methods: Eligibility
• MSM and TGW were eligible if:
– Male at birth, and
– Reported anal intercourse with another male 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 Design: Bangkok Site
Wk 0
Wk 34
(D) Daily- 1 tab daily
(T) Time driven- 1 tab twice a week plus 1 tab post-sex
(E) Event driven- 1 tab before and 1 tab after sex
FTC/TDF
D
MSM & TGW
Randomized
6 week
DOT
phase
No more than 2 dose daily and 7 doses/week
T
24 weeks
self-administered
dosing
Final
Study
Visit
E
From 07/12-08/13
Screened: 249
Enrolled: 193
Randomized: 178
Screen/Enrollment ratio
of 1.29
4
weeks
off
drug
Qualitative:
32 FGD and 6 KII:
Participants,
Staff
Sex coverage
Methods cont’d
• We contacted participants weekly to collect
dates/times of PrEP use (monitored
electronically by the Wisepill™ dispensing
device) and sex events
• Participants filled out a computer-assisted self
interview (CASI) about sexual behavior and
frequency at screening, 6, 10, and 30 weeks
• We collected plasma and PBMCs and
analyzed for tenofovir (TFV) and FTC and their
active metabolites at 10 and 30 weeks
• Participants who acquired HIV infection during
the study discontinued dosing and were
followed until study closure and referred for
post-trial care
Methods: Definitions
• Coverage for all arms was defined as >1 pill
taken in the 4 days before and >1 pill taken
in the 24 hours after sexual intercourse
• Adherence was defined as the proportion of
recommended pills taken for each regimen
Definition: Covered event
Coverage for all arms:
>1 pill taken in the 4 days before sex
>1 pill taken in the 24 hours after sex
>1 tablet
>1 tablet