Research Article: Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial

Date Published: November 8, 2018

Publisher: Public Library of Science

Author(s): Raphael J. Landovitz, Sue Li, Beatriz Grinsztejn, Halima Dawood, Albert Y. Liu, Manya Magnus, Mina C. Hosseinipour, Ravindre Panchia, Leslie Cottle, Gordon Chau, Paul Richardson, Mark A. Marzinke, Craig W. Hendrix, Susan H. Eshleman, Yinfeng Zhang, Elizabeth Tolley, Jeremy Sugarman, Ryan Kofron, Adeola Adeyeye, David Burns, Alex R. Rinehart, David Margolis, William R. Spreen, Myron S. Cohen, Marybeth McCauley, Joseph J. Eron, Marie-Louise Newell

Abstract: 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 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 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population.ConclusionsIn 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 registrationClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800.

Partial Text: Oral tenofovir disoproxil fumarate (TDF)–based pre-exposure prophylaxis (PrEP) is highly effective for HIV prevention when taken as prescribed [1–5]. However, achieving and maintaining adherence rates sufficient for high-level protection against HIV is challenging for some individuals and populations [6–8]. Impediments to adherence with daily tablets may be as simple as forgetfulness but could involve more complicated reasons such as concerns about safety, stigma related to use, and potential harms if PrEP use is disclosed to sexual partners. Lessons learned from contraceptive technology suggest that an increased variety of product types for PrEP will increase the probability that at least 1 product will fit a given individual’s needs at a particular time [9]. For these reasons, there is interest in development and evaluation of HIV prevention agents that do not require daily adherence.

A total of 443 individuals were screened, and 200 participants were enrolled (Fig 2). The most frequent reasons for screening failure were not meeting the protocol’s low-risk or clinical inclusion criteria. One hundred ten participants were enrolled in Cohort 1 and were randomized 3:1 CAB to PBO (82 CAB and 28 PBO) from February 9, 2015, to September 16, 2015. Cohort 2 enrolled an additional 89 eligible participants (69 CAB and 20 PBO) from December 18, 2015, to May 27, 2016. Overall, the median age was 31 years (interquartile range [IQR] 24, 40); 132 (66%) were female at birth, with most female participants enrolled in Malawi, South Africa, and the US. The study population included 6 transgender men and 1 transgender woman. For analysis purposes, participants were identified by sex at birth. Participants were 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other. The demographics were similar between the 2 cohorts and were not significantly different between Cohort 1 and Cohort 2 (Table 1).

In HPTN 077, we administered 800 mg of CAB LA every 12 weeks (Cohort 1) or 600 mg of CAB LA every 8 weeks (after an initial 4-week injection interval; Cohort 2) or PBO to HIV-uninfected males and females in diverse geographic locations. This study builds on safety and pharmacokinetic findings of a previous phase 2a study of CAB LA in men in the US, using the 800 mg every 12 weeks dose only. We found that both doses/intervals were well tolerated. ISRs were very common, but infrequently led to injection discontinuation—at least with short-term injection sequences over 36 weeks. No other safety concerns were identified. Pharmacokinetics show that the 600 mg every 8 weeks dose used in Cohort 2 consistently met prespecified pharmacokinetic targets based on macaque models using a rectal SHIV challenge.

Source:

http://doi.org/10.1371/journal.pmed.1002690

 

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