Tail-Phase Safety, Tolerability, and Pharmacokinetics of Long-Acting Injectable Cabotegravir in HIV-Uninfected Adults: HPTN 077

Background: Long-acting injectable cabotegravir (CAB LA) is a novel integrase inhibitor in advanced clinical development for HIV treatment and HIV prevention. We investigated the terminal pharmacokinetics and safety of CAB LA after final injection as part of a Phase 2 study. Methods: We performed a randomized, double-blind placebo-controlled trial at 8 sites in the United States (US), sub-Saharan Africa, and Brazil. Participants, age 18-65, HIV-uninfected and at low-risk for HIV, were randomized 3:1 to CAB LA or placebo. Participants received CAB LA at one of two doses/intervals, which were aggregated for this analysis. The current analysis includes participants who received at least one injection and examines the tail phase (time from final injection to 52-76 weeks post-final injection). The outcomes were safety and pharmacokinetics. Safety was reported as incidence rates of grade 2 or higher adverse events. The apparent terminal phase half-life (t1/2app) and time to decay of CAB drug concentration to below the lower limit of quantification (LLOQ) were estimated using non-compartmental methods. Findings: Overall, 177 participants received at least one injection. Median age was 31 years, 66.1% were female, 69.5% were non-white, 52.5% were from the US. Rates of grade 2 or higher adverse events on CAB were higher in the injection phase compared to the tail phase. At one time point from 52-60 weeks and at 76 weeks after final injection, 22% and 13% of males, respectively, had detectable CAB concentrations; 63% and 48% of females had detectable CAB concentrations at those time points. The estimated median time from last injection to CAB concentration below the LLOQ was 43.7 (range 20-4-152.5) weeks for males and 67.3 (range 17.7-225.5) weeks for females. Terminal phase half-life was 33% longer for female sex at birth participants compared to male participants, and 31% longer for participants with body mass index (BMI) above vs. below the study median of 26. Interpretation: No new adverse events were observed with long-term follow-up. The long pharmacokinetic tail will need to be addressed in pivotal trials of treatment and prevention. Trial Registration: The trial was registered with ClinicalTrials.gov, number NCT02178800. This trial is completed. Funding Statement: National Institute of Allergy and Infectious Diseases (UM1AI068619, UM1AI068613, and, UM1AI068617) Declaration of Interests: RJL has received study medication, consulting fees and travel support from Gilead Sciences, and consulting fees and travel support from Merck, Inc. 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. 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. MAM received grant support through the NIH and received grant support through ViiV/GSK on work external to this study. ARR and DM are paid employees of ViiV Healthcare. CWH has research contracts with NIH, ViiV/GlaxoSmithKline, Gilead Sciences, and Merck through Johns Hopkins. Ethics Approval Statement: Local institutional review boards or ethics committees at each participating site granted ethics and regulatory approvals of the protocol and all participants provided written informed consent.