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BackgroundCabotegravir (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 findingsHPTN 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 firs...

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Introduction The HIV Prevention Trials Network (HPTN) 083 trial demonstrated that long-acting cabotegravir (CAB-LA) was more effective than tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV prevention in cisgender men and transgender women who have sex with men. We characterized HIV infections that occurred in the blinded phase of HPTN 083. Methods Retrospective testing included HIV testing, viral load testing, quantification of study drugs and HIV drug resistance testing. Results Fifty-eight infections were evaluated, including 51 incident infections (12 CAB, 39 TDF/FTC). In many cases (5 CAB, 37 TDF/FTC), infection was associated with low or unquantifiable study drug concentrations. In four cases, infection occurred with on-time CAB-LA injections and expected plasma CAB concentrations. CAB exposure was associated with prolonged viral suppression and delayed antibody expression. In some cases, delayed HIV diagnosis resulted in CAB provision to participants with undetected infection, delayed antiretroviral treatment (ART), and emergence of drug resistance; most of these infections would have been detected earlier with viral load testing. Conclusions Early detection of HIV infection and prompt ART initiation could improve clinical outcomes in persons who become infected despite CAB-LA prophylaxis. Further studies are needed to elucidate the correlates of HIV protection in persons receiving CAB-LA.

Purpose of review Pre-exposure prophyalxis (PrEP) for HIV prevention is highly effective when taken as prescribed. Adherence to required dosing regimens for protection may pose challenges. Long Acting agents for HIV prevention may have the potential to improve adherence via favorable pharmacokinetics supportive of infrequent dosing. This review focuses on the potential benefits and considerations for the study and use of two long acting injectable agents, cabotegravir (GSK1265744 LA, CAB LA) and rilpivirine (TMC278 LA, RPV LA), for use as chemoprophylaxis for HIV prevention. Recent findings Oral RPV is FDA approved for HIV treatment (in combination with other antiretrovirals). Both CAB LA and RPV LA are currently in Phase 2a safety/tolerability/pharmacokinetic studies in anticipation and support of future efficacy evaluation. Both agents have favorable pharmacokinetics, and use is complicated by injection site reactions. Summary Long acting injectable formulations, if safe and well tolerated, may improve pharmacokinetic coverage of exposures to HIV infection. Complexities around safety, tolerability, and starting/stopping protocols require careful consideration.