1. Coverage, Adherence, and Acceptability of Intermittent, Event (sex)-driven Oral PrEP in MSM
Timothy H. Holtz
(CDC/DHAP / Thailand MOPH – US CDC Collaboration)
and HPTN 067/ADAPT Study Team
MOSY08, IAS, Palais de Congrés, Paris, July 24, 2017
Division of Global HIV and TB, CDC, New Delhi, India

2. Conflicts of Interest
Research grants, advisory boards, travel funds, holding stock: No conflicts of interest to declare
Secondary: Site investigator for HPTN 067/ADAPT
I have no conflicts of interest.

3. Outline HPTN 067 results from Bangkok CRS and Harlem/NYC CRS
Coverage, adherence, drug levels
Seroconverters
Qualitative results from Bangkok
Acceptability of iPrEP
Dutch and Canadian demonstration models
IPERGAY
Assessing adherence with an intermittent regimen

4. Participant Demographics
Variable
Bangkok %
(N=178)
Harlem/NYC
(N=179)
Median age (years, IQR)
Age ranges
18-24
25-29
30-39
>40
31 (27,34) 
16%
27%
49% 8%
30 (23, 43)
30%
18%
21%
32%
Gender identity
Male
TGW
TG Queer
99% 1% -
97% 2%
Race
Thai
Black
White
Other
100%
70%
13%
26%
Latino
25%
Education
More than secondary
Secondary or less
94% 6%
42%
58%
Unemployed
11%
69%
Student 9%
19%
Anal intercourse without a condom
37%
77%

5. Bangkok Coverage (PrEP Before and After Sex): Daily vs. Time-Driven vs
Bangkok Coverage (PrEP Before and After Sex): Daily vs. Time-Driven vs. Event-Driven
D/T p = 0.79, D/E p = 0.02, T/E p = 0.04, global p = 0.19
Harlem/NYC Coverage (PrEP Before and After Sex): Daily vs. Time-Driven vs. Event-Driven

6. D/T and D/E p < 0.0001; T/E p = 0.17, global p < 0.0001
Adherence (Bangkok)
Adherence (Harlem/NYC)
85%
79%
65%
65%
47%
41%
D/T p < 0.42, D/E p < 0.001, T/E p < 0.001, global p < 0.001
D/T and D/E p < ; T/E p = 0.17, global p <

7. Bangkok: Tenofovir diphosphate in PBMCs Proportion achieving detectable concentration
Time period
Study Regimen
Daily (D)
Time (T)
Event (E)
Week 10
(with sex in the past 7 days)
100%
(n=31/31)
(n=29/29)
(n=30/30)
Week 30
96%
(N=22/23)
95%
(N=18/19)
93%
(N=13/14)
Detectable >5.2 fmol/million PBMC
D/T p = 0.93, D/E p = 0.88, T/E p = 0.95, global p = 0.99

8. New York: Tenofovir diphosphate in DBS 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

9. Seroconverter table HPTN 067
Case
Study Arm
HIV detected at study site
PrEP Exposure
Resistance to study drug 2
Acute at enrollment
Week 4
Once-weekly DOT only (4 doses)
M1841 3
Not detected 4
Infected by 6 weeks 8
Daily
Week 18
DOT plus daily PrEP; low adherence
Source: Sivay et al., JAIDS, 2017.

10. HPTN 067: Qualitative Component Methods - Bangkok
38 participants joined a qualitative evaluation: 32 participants joined in 6 focus-group discussions (FGDs) and 6 attended key-informant interviews (KIIs).
Grounded theory and content analysis were used to analyze the data.

11. Time-driven 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

12. Event-driven 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)

13. Summary of ADAPT Study Results in MSM
Among BKK MSM, coverage and adherence and drug concentrations were highest in the daily arm, whereas in NYC MSM/TG the overall coverage of sex acts and PrEP adherence was suboptimal
Compared with the daily regimen in BKK, the time-driven dosing regimens offered comparably high PrEP coverage for sex acts with slightly less adherence, and fewer tablets required
For non-daily PrEP in both sites, incomplete coverage of sex acts was mostly related to lack of post-sex dosing
BKK: TFV drug detection in PBMCs was high (>90%) in all 3 arms at weeks 10 and 30 in this population
Results indicate feasibility of non-daily regimens in some MSM populations
No evidence of risk compensation seen

14. Acceptability of intermittent (or sex-driven, non-daily) regimen
Dutch PrEP Demonstration Project 2016
237 MSM and TG screened, 198 initiated, 144 (73%) choose daily PrEP over iPrEP
Ppts choosing daily were younger, had multiple risk factors, and reported more AI partners
Hoornenborg et al. More ppts prefer daily PrEP. AMPrEP baseline data. IAC July 2016.
Clinique L’Actuel, Montréal, 2011–2017
1512 PrEP consultations, most 2014 and after
78% choose daily, 22% iPrEP
Ppts choosing daily were younger, higher number of casual partners, more likely to report serodiscordant partners, and less planned sex
Greenwald et a. Who opts for daily vs on-demand PrEP? Adherence 2017, June 2017.

15. ANRS IPERGAY Study Design
Effectiveness of “on demand” PrEP
Randomized placebo-controlled trial
High risk MSM
Condomless anal sex with > 2 partners
Full prevention services* TDF/FTC before and after sex (n=950)
Full prevention services* placebo before and after sex (n=950)
Counseling, testing for STI, condoms, vaccination, PEP
Primary endpoint : HIV infection, 16 events recorded (14 in placebo arm)
Relative risk reduction in HIV-infection: 86%; median of 15 pills/month 15

16. ANRS IPERGAY Adherence Results
Participant adherence to the prescribed regimen and/or condom use during “on demand” PrEP
43% reported PrEP use only during most recent sexual intercourse
29% reported both PrEP and condom use
12% reported condom use only
17% reported no PrEP or condom use (no change over study course)
Scheduled PrEP use (~coverage) reported by 59% of those reporting PrEP use during most recent intercourse
Overall, 83% ppts protected themselves by PrEP or condom use or both during the IPERGAY trial, with no increase in at risk sexual practices
Source: Sagaon-Teyssier et al. Uptake of PrEP and condom and sexual risk behavior among MSM during the ANRS IPERGAY trial. AIDS Care 2016. 16

17. What Do MSM Think about iPrEP?
Online survey among 939 seronegative gay men in France:
63% prefer « on demand » vs 25% daily PreP
More interested by PrEP if unprotected anal sex (OR: 2.37, p<0.001)
Online survey in >1000 seronegative gay men in the US; practical dosing of iPrEP would require MSM to be active < 3 days/wk, able to plan for sex; those most suitable for iPrEP were:
older
more educated
more frequently used sexual networking
more often reported sex with a non-committed partner
Capote et Pilule study, Adam P, Alexandre A. et al
Volk JE et al. J AIDS 2012, 61: 112
Online survey of 1106 seronegative MSM in Atlanta about likelihood of using PrEP methods:
62% said likely or somewhat likely to use « on demand » vs 51% daily PreP vs 53% daily injection
MSM expressed statistically significant interest in systemic PrEP and less likely to use rectal product (Wilcoxon p < 0.001)
Hall EW et al. J of Med Internet Res 2016; 18(5):e111.

18. Comparison of Adherence Measurement Tools
Strengths
Weaknesses
Subjective self-report
Easy to collect; inexpensive; reported nonadherence tends to be accurate
May overstate adherence due to social desirability and recall biases; discrepant with objective measures in multiple trials; unclear which self-reported measures are optimal
Objective clinic-based pill counts
Easy to collect, inexpensive
Susceptible to manipulation prior to clinic visit
Unannounced pill counts
More objective than clinic-based
Labor intensive, expensive, challenging to conduct, susceptible to manipulation, and disruptive to social context
Pharmacy refill
Easy to collect, objective measure of upper and lower ends of adherence
Requires close control over pharmacy use and record keeping, only provides maximal predicted adherence
Electronic adherence monitoring
Allows for assessment of patterns of use, historically has been more accurate measure
Requires adherence to the device used which may be limited due to stigma and inconvenience, subject to mis-classification, expensive, tech challenges
Drug levels
Highly sensitive to detecting use, reflects ingestion, drug levels correlate with HIV protection, hair and DBS given estimates over time
Impractical for routine use, plasma levels subject to manipulation, subject to behavioral and biologic variation, expensive
Source: Haberer et al. Defining success with HIV pre-exposure prophylaxis. AIDS 2015; 29:

19. How Best to Maximize Adherence? Reminders and Questionnaires:
SMS Reminders – can monitor both PrEP tablet-taking as well as sex events, incentives can also be included
Weekly check-ins – tablet-taking and events
Regular visits and key messaging

20. Conclusion
HPTN 067 study results offer additional support for current CDC/USPHS guidelines for daily dosing
Among MSM with fewer exposures and who can plan for sex, non-daily dosing of PrEP could result in comparable coverage
Limitations to intermittent dosing include loss of margin of forgiveness for missed doses
Non-daily regimens could provide an alternative for those who can adhere

21. The HPTN 067 Study Team would like to thank:
Our HPTN 067 participants, Study staff at Silom Community Harlem Health Ctr, DAIDS and NIMH, Thailand Ministry of Public Health, Epidemiology Branch - Division of HIV/AIDS Prevention at CDC, MSM Community Advisory Board, FHI 360, SCHARP, HPTN Labo Center, Albert Liu, L-G Bekker, and Jean-Michel Molina
silom
community
clinic

22. HPTN 067: Bangkok Site Staff
silom
community
clinic
HPTN 067: Bangkok Site Staff
Patrick J Flaherty
15/4/1970 – 12/5/2017

23. Extra Slides

24. Definitions: Coverage for all arms:
>1 pill taken in the 4 days before sex
>1 pill taken in the 24 hours after sex
>1 tablet
Adherence: # required tablets actually taken Total # tablets required

25. Median tenofovir diphosphate drug concentration in PBMCs - Bangkok
Time period
Study Regimen
Daily (D)
Time (T)
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 = , global p < 0.001