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

Abstract

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 4× 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.

Conflict of interest statement

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.

Figures

Fig 1. Study design.

(A) Cohort 1 (CAB LA 800 mg or 0.9% saline PBO IM every 12 weeks). (B) Cohort 2 (CAB LA 600 mg or 0.9% saline PBO IM every 8 weeks after an initial 4-week interval). CAB, cabotegravir; CAB LA, long-acting cabotegravir; IM, intramuscular; PBO, placebo; PO, by mouth; QD, once daily.

Fig 2. Study consort diagram.

*One participant excluded due to exclusionary condition at enrollment. AE, adverse event; CAB, cabotegravir; PBO, placebo; STI, sexually transmitted infection.

Fig 3. Study product discontinuation by cohort and arm (oral and injection phase).

n = 199 (Cohort 1 CAB = 82; Cohort 1 PBO = 28; Cohort 2 CAB = 69; Cohort 2 PBO = 20). AE, adverse event; CAB, cabotegravir; PBO, placebo.

Fig 4. Proportion of participants reporting an injection site reaction resulting from each injection visit.

(A) Proportion of Cohort 1 participants reporting any injection site reaction. (B) Proportion of Cohort 2 participants reporting any injection site reaction. AE, adverse event; CAB LA, long-acting cabotegravir; PBO, placebo.

Fig 5. CAB concentrations by sex at birth and cohort.

(A) Cohort 1 plasma CAB concentrations by sex at birth. (B) Cohort 2 plasma CAB concentrations by sex at birth. Shaded areas represent the 90% prediction interval for the model. Time points indicated in red denote visits at which injections were administered. Time 0 values represent plasma levels 1 week after last oral CAB dosing. PA-IC90 is the protein-adjusted concentration at which 90% inhibition of viral replication is achieved. CAB, cabotegravir.

Fig 6. Distribution of Cτ CAB concentrations relative to PA-IC90 by cohort and sex at birth and cohort and BMI (≥median versus <median).

(A) Distribution of Cτ CAB concentrations by cohort and sex at birth. (B) Distribution of Cτ CAB concentrations by cohort and BMI. PA-IC90 is the protein-adjusted concentration at which 90% inhibition of viral replication is achieved. BMI, body mass index; IM, intramuscular; Inj, injection; Q12W, every 12 weeks; Q8W, every 8 weeks.