PMID- 30408115 OWN - NLM STAT- MEDLINE DCOM- 20190422 LR - 20231004 IS - 1549-1676 (Electronic) IS - 1549-1277 (Print) IS - 1549-1277 (Linking) VI - 15 IP - 11 DP - 2018 Nov TI - Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial. PG - e1002690 LID - 10.1371/journal.pmed.1002690 [doi] LID - e1002690 AB - BACKGROUND: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. METHODS AND FINDINGS: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18-65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4x PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. CONCLUSIONS: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. TRIAL REGISTRATION: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800. FAU - Landovitz, Raphael J AU - Landovitz RJ AUID- ORCID: 0000-0002-1442-714X AD - UCLA Center for Clinical AIDS Research and Education, Los Angeles, California, United States of America. FAU - Li, Sue AU - Li S AD - Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. FAU - Grinsztejn, Beatriz AU - Grinsztejn B AUID- ORCID: 0000-0003-3692-5155 AD - Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil. FAU - Dawood, Halima AU - Dawood H AD - Centre for the AIDS Programme of Research in South Africa, University of KwaZulu Natal, Durban, South Africa. FAU - Liu, Albert Y AU - Liu AY AUID- ORCID: 0000-0003-0320-823X AD - Bridge HIV, Population Health Division, San Francisco Department of Health, San Francisco, California, United States of America. FAU - Magnus, Manya AU - Magnus M AD - Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, George Washington University, Washington, District of Columbia, United States of America. FAU - Hosseinipour, Mina C AU - Hosseinipour MC AUID- ORCID: 0000-0003-2174-313X AD - UNC Project-Malawi, Lilongwe, Malawi. FAU - Panchia, Ravindre AU - Panchia R AD - Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, Soweto, South Africa. FAU - Cottle, Leslie AU - Cottle L AD - Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. FAU - Chau, Gordon AU - Chau G AD - Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. FAU - Richardson, Paul AU - Richardson P AD - School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America. FAU - Marzinke, Mark A AU - Marzinke MA AUID- ORCID: 0000-0003-1670-8786 AD - School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America. FAU - Hendrix, Craig W AU - Hendrix CW AUID- ORCID: 0000-0002-5696-8665 AD - School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America. FAU - Eshleman, Susan H AU - Eshleman SH AUID- ORCID: 0000-0002-4587-791X AD - School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America. FAU - Zhang, Yinfeng AU - Zhang Y AD - School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America. FAU - Tolley, Elizabeth AU - Tolley E AUID- ORCID: 0000-0002-9823-3675 AD - FHI360, Durham, North Carolina, United States of America. FAU - Sugarman, Jeremy AU - Sugarman J AD - School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America. AD - Berman Institute of Bioethics, Johns Hopkins University, Baltimore, Maryland, United States of America. FAU - Kofron, Ryan AU - Kofron R AD - UCLA Center for Clinical AIDS Research and Education, Los Angeles, California, United States of America. FAU - Adeyeye, Adeola AU - Adeyeye A AD - Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America. FAU - Burns, David AU - Burns D AD - Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America. FAU - Rinehart, Alex R AU - Rinehart AR AD - ViiV Healthcare, Durham, North Carolina, United States of America. FAU - Margolis, David AU - Margolis D AD - ViiV Healthcare, Durham, North Carolina, United States of America. FAU - Spreen, William R AU - Spreen WR AD - ViiV Healthcare, Durham, North Carolina, United States of America. FAU - Cohen, Myron S AU - Cohen MS AD - University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America. FAU - McCauley, Marybeth AU - McCauley M AD - FHI360, Durham, North Carolina, United States of America. FAU - Eron, Joseph J AU - Eron JJ AUID- ORCID: 0000-0002-4938-0644 AD - University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America. LA - eng SI - ClinicalTrials.gov/NCT02178800 GR - UM1 AI069423/AI/NIAID NIH HHS/United States GR - P30 AI094189/AI/NIAID NIH HHS/United States GR - UM1 AI069530/AI/NIAID NIH HHS/United States GR - UM1 AI068619/AI/NIAID NIH HHS/United States GR - UM1 AI068613/AI/NIAID NIH HHS/United States GR - U01 AI069424/AI/NIAID NIH HHS/United States GR - P30 AI050410/AI/NIAID NIH HHS/United States GR - UM1 AI068617/AI/NIAID NIH HHS/United States PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural DEP - 20181108 PL - United States TA - PLoS Med JT - PLoS medicine JID - 101231360 RN - 0 (Anti-HIV Agents) RN - 0 (Delayed-Action Preparations) RN - 0 (Pyridones) RN - HMH0132Z1Q (cabotegravir) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Anti-HIV Agents/*administration & dosage/adverse effects/blood/*pharmacokinetics MH - Brazil MH - Delayed-Action Preparations MH - Double-Blind Method MH - Drug Administration Schedule MH - Drug Monitoring MH - Female MH - HIV Infections/diagnosis/*prevention & control/transmission/virology MH - Humans MH - Injections, Intramuscular MH - Malawi MH - Male MH - Middle Aged MH - Pyridones/*administration & dosage/adverse effects/blood/*pharmacokinetics MH - Risk Assessment MH - Risk Factors MH - South Africa MH - Treatment Outcome MH - United States MH - Young Adult PMC - PMC6224042 COIS- RJL has received study medication, consulting fees and travel support from Gilead Sciences. He has received consulting fees and travel support from Merck, Inc. HD has received honoraria from Pfizer-South Africa, Novartis-South Africa, MSD-South Africa and Adcock Ingram for speaking engagements and has received travel support from Mylan-South Africa, Novartis-South Africa and Aspen-South Africa. AYL received research grants from NIH and has led studies in which study drug was donated by Gilead Sciences. DM and ARR are paid employees of ViiV Healthcare. WRS is a paid employee of ViiV Healthcare with stock in ViiV Healthcare and GlaxoSmithKline. CWH has research contracts with ViiV/GlaxoSmithKline and the NIH through Johns Hopkins and the University of Washington. MAM received grant support through the NIH, and received grant support through ViiV/GSK on work external to this study. JS is a member of Merck KGaA's Bioethics Advisory Panel and Stem Cell Research Oversight Committee; and he is a member of IQVIA's (formerly Quintiles) Ethics Advisory Panel. JJE is a consultant to Merck, Gilead Sciences, Janssen, and ViiV Healthcare; and he is an investigator on research contracts from ViiV Healthcare, Janssen, and Gilead Sciences. EDAT- 2018/11/09 06:00 MHDA- 2019/04/23 06:00 PMCR- 2018/11/08 CRDT- 2018/11/09 06:00 PHST- 2018/05/21 00:00 [received] PHST- 2018/10/08 00:00 [accepted] PHST- 2018/11/09 06:00 [entrez] PHST- 2018/11/09 06:00 [pubmed] PHST- 2019/04/23 06:00 [medline] PHST- 2018/11/08 00:00 [pmc-release] AID - PMEDICINE-D-18-01723 [pii] AID - 10.1371/journal.pmed.1002690 [doi] PST - epublish SO - PLoS Med. 2018 Nov 8;15(11):e1002690. doi: 10.1371/journal.pmed.1002690. eCollection 2018 Nov.