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 Bekker IAS2015, Vancouver, 2015

HPTN 067 Design Final Study Visit Week 34 FTC/TDF Sex coverage Randomized D T E 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 Women (incl. TGW) & MSM Key informant interviews and focus groups Bekker IAS2015, Vancouver, 2015

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 Harlem Prevention Center 179 HIV-uninfected at risk MSM/TGW NYC (Harlem), USA Completed Dec 2014 Bekker IAS2015, Vancouver, 2015

Primary: Coverage of sex events Number of tablets (required and taken) Self-reported side effects Secondary: Adherence Safety Acceptability HIV infections Outcomes 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 Bekker IAS2015, Vancouver, 2015

Review of results from Cape Town Bekker IAS2015, Vancouver, 2015

294 screened 191 enrolled 103 not enrolled* HIV + rapid 7/ 6.8% Pregnant 3/ 2.9% Lab abnormality 3/ 2.9% Not Hep B immune 29/ 28.2% Other medical/mental12/ 11.7% Low HIV risk 26/ 25.2% Withdrew consent 1/ 1% Not enrolled in window 14/ 13.6% Other 10/ 9.7% 179 randomized 12 not randomized HIV + rapid 2/ 16.7% Relocated 3/ 25% Pregnant 1/ 8.3% Lost contact 2/ 16.7% Other 4/ 33.3% 60 Daily usage 59 Time- driven usage 60 Event- driven usage DOT Phase Self-Administered Phase Bekker IAS2015, Vancouver, 2015

100% Women Mostly young – Age median 26 – Age range % never married 83% unemployed 99% black Residing in or near Crossroads area of Cape Town Baseline Characteristics Bekker IAS2015, Vancouver, 2015

Coverage of Sexual Intercourse: Cape Town Sex event defined as vaginal or anal intercourse Time vs Daily p = , Event vs. Daily p < , Time vs Event p = 0.46 Bekker IAS2015, Vancouver, 2015

FTC/TDF Tablets Required and Tablets Taken by Arm Required tablets: p< for all comparisons (D/T, D/E, and T/E) Tablets actually taken: p< 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 < , Time vs. Event p < 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 reportedDailyTimeEventp-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 periodStudy 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

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. Limitations 1. Cottrell OA R4P Cape Town 2014; 2. Chemnasiri WELBPE23 IAS Vancouver Bekker IAS2015, Vancouver, 2015

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. Conclusions Bekker IAS2015, Vancouver, 2015

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 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