HPTN 067/ADAPT
Background and Methods
and Cape Town Results:
Linda-Gail Bekker; James Hughes;
Rivet Amico; Surita Roux; Craig
Hendrix; Peter L. Anderson; Bonnie J.
Dye; Vanessa Elharrar; Michael J.
Stirratt; Robert M. Grant
Bekker et al, Poster 978LB, CROI Seattle 2015
Background
•
•
•
•
Oral FTC/TDF PrEP is effective for preventing HIV acquisition.1
– Protection after rectal exposure is estimated to be:
• Near 100% with use of 4+ tabs/week.2
• 84% with use of 2 to 3 tabs/week,2
– Full protection after vaginal exposure requires more PrEP use.3
Sex is often planned, and plans change over time.4
– PrEP provides benefit when used during seasons of risk.
– Such strategic PrEP use has been observed in MSM.2
– Measurement of adherence is challenging, especially when dynamic.5
Recommending PrEP dosing before and after sex leads to effective use
among MSM taking on average 16 tablets per month.7
Adapting PrEP regimens to match patterns of sex could increase strategic
PrEP use and minimize medication costs and side effects.
1. Grant NEJM 2010, Baeten NEJM 2012, Thigpen NEJM 2012, Choopanya Lancet 2013;
2. Grant Lancet Infec. Dis. 2014; 3. Cottrell (with Kashuba) R4P Cape Town, 2014;
4. van Griensven JIAS 2010; 5. Mutua PLoS One 2012, Kibengo PLoS One 2013;
6. Molina CROI Seattle 2015.
Bekker IAS2015, Vancouver, 2015
HPTN 067 Design
FTC/TDF
D
Randomized
Women
(incl. TGW)
& MSM
Daily- One tablet/day
Time driven- 1 tablet/2x week with a post sex boost
Event driven- 1 tablet pre-sex and 1 tablet post-sex
No more than 2 tablets daily or 7 tablets/week
Final
Study
Visit
Week 34
T
E
Sex coverage
Bekker IAS2015, Vancouver, 2015
Key
informant
interviews
and focus
groups
Harlem Prevention Center
179 HIV-uninfected at risk
MSM/TGW
NYC (Harlem), USA
Completed Dec 2014
Silom Community Clinic
178 HIV-uninfected at risk
MSM/TGW
Bangkok, Thailand
Completed March 2014
Emavundleni Prevention Centre
179 HIV-uninfected at risk WSM
Cape Town, South Africa
Completed June 2013
Bekker IAS2015, Vancouver, 2015
Outcomes
Primary:
• Coverage of sex events
• Number of tablets (required and taken)
• Self-reported side effects
Secondary:
• Adherence
• Safety
• Acceptability
• HIV infections
Bekker IAS2015, Vancouver, 2015
Definition: Covered sex 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
Bekker IAS2015, Vancouver, 2015
Review of results
from Cape Town
Bekker IAS2015, Vancouver, 2015
103 not enrolled*
294
screened
191
enrolled
12 not randomized
HIV + rapid 2/ 16.7%
Relocated 3/ 25%
Pregnant
1/ 8.3%
Lost contact 2/ 16.7%
Other
4/ 33.3%
DOT
Phase
HIV + rapid
Pregnant
Lab abnormality
Not Hep B immune
Other medical/mental
Low HIV risk
Withdrew consent
Not enrolled in window
Other
7/ 6.8%
3/ 2.9%
3/ 2.9%
29/ 28.2%
12/ 11.7%
26/ 25.2%
1/ 1%
14/ 13.6%
10/ 9.7%
179
randomized
Self-Administered Phase
60
Daily
usage
59
Timedriven
usage
60
Eventdriven
usage
Bekker IAS2015, Vancouver, 2015
Baseline Characteristics
• 100% Women
• Mostly young
– Age median 26
– Age range 18-52
•
•
•
•
80% never married
83% unemployed
99% black
Residing in or near
Crossroads area of Cape
Town
Bekker IAS2015, Vancouver, 2015
Coverage of Sexual Intercourse:
Cape Town
100%
90%
80%
Daily
75%
70%
60%
56%
Time-driven
52%
50%
Event-driven
40%
30%
30%
33%
21%
20%
9%
10%
8%
3%
1%
6%
7%
0%
% complete
coverage
% only
pre-sex dose
% only
post-sex dose
no
coverage
Sex event defined as vaginal or anal intercourse
Time vs Daily p = 0.0006, Event vs. Daily p < 0.0001, Time vs Event p = 0.46
Bekker IAS2015, Vancouver, 2015
FTC/TDF Tablets Required and
Tablets Taken by Arm
Number of tablets
9758
Required tablets
Tablets reported taken
7441
3629
2859
Daily
Required tablets:
Tablets actually taken:
Time-driven
2205
2002
Event-driven
p<0.0001 for all comparisons (D/T, D/E, and T/E)
p<0.0001 for all comparisons (D/T, D/E, and T/E)
Bekker IAS2015, Vancouver, 2015
Adherence to the Prescribed Regimen:
Cape Town
Time vs. Daily p = 0.002, Event vs. Daily p < 0.0001, Time vs. Event p < 0.0001.
Bekker IAS2015, Vancouver, 2015
HIV Incidence Outcomes
• 2 seroconversions during 6-week pre-randomization weekly DOT
study phase one tablet one time per week.
– Occurred at weeks 4 and 5.
– Incidence 8.9 / 100PY (2 / 22.6)
– No detectable drug in plasma at visits preceding seroconversion
for either participant.
• 5 seroconversions during 24-week self administered PrEP phase
– 2 in Time-Driven, 2 in Event-Driven, 1 in Daily
– Incidence 5.4 / 100PY (5 / 92.3)
– 3 had negligible drug levels at or before seroconversion
• 2 had detectable but low drug levels
Bekker IAS2015, Vancouver, 2015
Neuro and GI symptoms /
side effects
Side Effect reported
Daily
Time
Event
p-value
% PPTs who experienced
any Neurologic side effect
47%
14%
19%
0.07
% PPTs who experienced
any GI side effect
38%
31%
20%
0.08
Bekker IAS2015, Vancouver, 2015
Self-reported Neurological side
effects by arm during follow-up
Bekker IAS2015, Vancouver, 2015
Self-reported GI side effects by
arm during follow-up
Bekker IAS2015, Vancouver, 2015
TFV-DF in PBMCs:
% with TFV-DP > 9.1 fmol/M PBMC*
Time period
Study
Regimen
Daily (D)
Study
Regimen
Time (T)
Study
Regimen
Event (E)
Week 10
(with sex in the past 7 days)
81%
(33/41)
52%
(12/23)
54%
(20/37)
Week 30
(with sex in the past 7 days)
66%
(19/29)
46%
(11/24)
32%
(10/31)
*Indicative of at least 2 tablets per week.
Time vs Daily p = 0.01, Event vs Daily p = 0.002, Time vs Event p=0.63
Bekker IAS2015, Vancouver, 2015
Limitations
• Thresholds of adherence and drug concentrations required
for full protection after vaginal exposure are not yet known.
• Recent PK/PD modeling suggests that full protection from
vaginal exposure to HIV requires daily or near daily use.1
• The ADAPT trial participants were informed that daily oral
PrEP was effective but that non-daily dosing was unproven.
– Could have undermined adherence in the non-daily arms.
– Belief in efficacy is a strong facilitator of adherence.2
• Weekly telephone contact may have served as reminders.
1. Cottrell OA22.06. R4P Cape Town 2014;
2. Chemnasiri WELBPE23 IAS Vancouver 2015.
Bekker IAS2015, Vancouver, 2015
Conclusions
• The majority of young, predominately single, South African
women took oral PrEP when made available in an open label
study.
• Recommending daily dosing resulted in higher coverage of
sex events, higher drug concentrations, and higher
adherence.
• Daily dosing fosters habit formation, provides the most
forgiveness for occasional missed doses and does not require
planning for sex.
• These findings, and PK findings from vaginal tissues, support
current recommendations for daily use of oral FTC/TDF PrEP
in women.
Bekker IAS2015, Vancouver, 2015
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 Cape Town Study Team acknowledges key support and
contributions of the following:
HPTN 067 Participants and the African women they represent
Linda-Gail Bekker, Surita Ruoux, Elaine Sebastian and the Ema staff and CAB
HPTN 067 Protocol Team (including those at LC, LOC, SDMC and DAIDS)
Bekker IAS2015, Vancouver, 2015