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

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.

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

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%

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

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 < 0.0001; T/E p = 0.17, global p < 0.0001

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

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

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.

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.

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

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)

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

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.

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 www.ipergay.fr 15

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. www.ipergay.fr 16

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.

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; 29:1277-85.

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

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

The HPTN 067 Study Team would like to thank: Our HPTN 067 participants, Study staff at Silom Community Clinic @TropMed, 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

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

Extra Slides

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

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 = 0.0495, global p < 0.001