PMID- 32280940 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231113 IS - 2589-5370 (Electronic) IS - 2589-5370 (Linking) VI - 21 DP - 2020 Apr TI - Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women. PG - 100303 LID - 10.1016/j.eclinm.2020.100303 [doi] LID - 100303 AB - BACKGROUND: Daily oral TDF/FTC is protective against HIV infection when used for pre-exposure prophylaxis (PrEP). However, daily adherence to oral PrEP is difficult for many; therefore, finding alternative PrEP strategies remains a priority. HPTN 076 evaluated the long-acting injectable form of rilpivirine (RPV), known as RPV LA for safety, pharmacokinetics and acceptability. METHODS: HPTN 076 (NTC 02165202) was a phase 2, double-blind, 2:1 randomized trial comparing the safety of 1200mg RPV LA (LA) to placebo (P). The study included a 28-day oral run-in phase of daily, self- administered oral RPV (25 mg), with directly observed oral dosing about six times. Of 136 enrolled sexually active, HIV-uninfected, low HIV-risk African (100) and US (36) adult women, injectable product was administered in two gluteal, intramuscular (IM) injections once every eight weeks to 122 participants following the oral run-in phase. A maximum of six injection time points occurred over a 48-week period. Acceptability, safety, tolerability and pharmacokinetic (PK) data were collected throughout the study. This paper includes primary endpoint data collected up to the week 52 post enrollment. FINDINGS: The median age of the enrolled population was 31 years (IQR: 25,38), median weight 75 kg (IQR: 64, 89), median body mass index (BMI) 30 (IQR: 27, 35), 46% married, 94% Black and 60% unemployed. A total of 122 (80 LA, 42 P) women received at least one injection and 98 (64 LA, 34 P) received all six injections. During the injection phase, three women withdrew from the study (2 LA, 1 P) and 16 women discontinued study product (10 LA, 6 P). Fourteen women (11 LA and 3 P) discontinued oral study product and did not enter the injection phase. Study product discontinuations were not significantly different between the two arms throughout. Of the product discontinuations in the injection phase, 8% in LA and 5% in P arm were due to adverse events (AEs), including one randomized to the P arm with prolonged QTc interval on EKG. The proportion of women who experienced Grade 2 or higher AEs during the injection phase as the primary outcome was not significantly different between the two arms [73.8%, 95% CI: (63.2%, 82.1%) for LA and 73.8%, 95% CI: (58.9%, 84.7%), p>0.99]. Transient Grade >/=2 liver abnormalities occurred in 14% of women in the LA arm compared with 12% in P arm. Three LA women (4%) developed Grade 3 injection site reactions compared with none in P arm. In participants who received at least 1 injection, the geometric mean of overall RPV trough concentrations (C(trough)) was 62.2 ng/mL. In participants who received all six injections, the geometric mean of C(Trough) through the injection phase and after the last injection were 72.8 ng/mL and 100.9 ng/mL, respectively. At week 52 (eight weeks after last injection), the geometric mean of RPV C(trough) was 75.0 ng/mL. At the last injection visit (Week 44), 80 % of women who answered acceptability questions strongly agreed that they would think about using- and 68% that they would definitely use a PrEP injectable in the future. INTERPRETATION: RPV LA IM injections every eight weeks in African and US women were safe and acceptable. Overall, despite more injection site reactions and pain in the participants receiving RPV LA the injections were well tolerated. Data from this study support the further development of injectable PrEP agents. CI - (c) 2020 Published by Elsevier Ltd. FAU - Bekker, L G AU - Bekker LG AD - The Desmond Tutu HIV Centre, University of Cape Town, South Africa. FAU - Li, S AU - Li S AD - Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. FAU - Pathak, S AU - Pathak S AD - Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. FAU - Tolley, E E AU - Tolley EE AD - FHI 360, Durham, NC, USA. FAU - Marzinke, M A AU - Marzinke MA AD - Johns Hopkins University, Baltimore, MD, USA. FAU - Justman, J E AU - Justman JE AD - ICAP at Columbia University, New York, NY, USA. FAU - Mgodi, N M AU - Mgodi NM AD - University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare, Zimbabwe. FAU - Chirenje, M AU - Chirenje M AD - University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare, Zimbabwe. FAU - Swaminathan, S AU - Swaminathan S AD - Rutgers New Jersey Medical School, Newark, NJ, USA. FAU - Adeyeye, A AU - Adeyeye A AD - DAIDS/NIAID/NIH, Rockville, MD, USA. FAU - Farrior, J AU - Farrior J AD - FHI 360, Durham, NC, USA. FAU - Hendrix, C W AU - Hendrix CW AD - Johns Hopkins University, Baltimore, MD, USA. FAU - Piwowar-Manning, E AU - Piwowar-Manning E AD - Johns Hopkins University, Baltimore, MD, USA. FAU - Richardson, P AU - Richardson P AD - Johns Hopkins University, Baltimore, MD, USA. FAU - Eshelman, S H AU - Eshelman SH AD - Johns Hopkins University, Baltimore, MD, USA. FAU - Redinger, H AU - Redinger H AD - Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. FAU - Williams, P AU - Williams P AD - Johnson and Johnson Global Public Health, Belgium. FAU - Sista, N D AU - Sista ND AD - FHI 360, Durham, NC, USA. CN - HPTN 076 Study Team LA - eng GR - UM1 AI069470/AI/NIAID NIH HHS/United States GR - UM1 AI068613/AI/NIAID NIH HHS/United States GR - UM1 AI069419/AI/NIAID NIH HHS/United States GR - UM1 AI069436/AI/NIAID NIH HHS/United States GR - U01 AI069436/AI/NIAID NIH HHS/United States GR - UM1 AI068617/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20200406 PL - England TA - EClinicalMedicine JT - EClinicalMedicine JID - 101733727 PMC - PMC7139112 OTO - NOTNLM OT - RPV LA as Pre exposure prophylaxis COIS- Linda-Gail Bekker serves on advisory boards and has received honoraria from Merck, GSK and Gilead. She has also been recipient of donated antivirals for clinical trials from Gilead. Craig W. Hendrix reports grants from NIH during the conduct of the study. He also reports grants from Gilead, ViiV/GSK, the Gates Foundation, and Merck, as well as personal fees and non-financial support from Merck, non-financial support from Gilead outside the submitted work. In addition, he has a patent US 10, 092, 509 B2 issued to Johns Hopkins University. Mark Marzinke reports grants from NIH during the conduct of the study and grants from NIH and ViiV/GSK outside the submitted work. Peter Williams reports other support from Johnson & Johnson, outside the submitted work. EDAT- 2020/04/14 06:00 MHDA- 2020/04/14 06:01 PMCR- 2020/04/06 CRDT- 2020/04/14 06:00 PHST- 2019/08/10 00:00 [received] PHST- 2020/02/18 00:00 [revised] PHST- 2020/02/18 00:00 [accepted] PHST- 2020/04/14 06:00 [entrez] PHST- 2020/04/14 06:00 [pubmed] PHST- 2020/04/14 06:01 [medline] PHST- 2020/04/06 00:00 [pmc-release] AID - S2589-5370(20)30047-X [pii] AID - 100303 [pii] AID - 10.1016/j.eclinm.2020.100303 [doi] PST - epublish SO - EClinicalMedicine. 2020 Apr 6;21:100303. doi: 10.1016/j.eclinm.2020.100303. eCollection 2020 Apr.