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

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.

背景
卡博特韦（Cabotegravir, CAB）是一种新型链转移整合酶抑制剂，正被开发用于HIV的治疗与预防。CAB有两种制剂形式：一是用于每日给药的速释口服片剂，二是用于肌内（intramuscular, IM）注射的长效注射混悬液（长效CAB [CAB LA]），该制剂在肌内注射后可实现药物的长期血浆暴露。HIV预防试验网络077号研究（HPTN 077）在巴西、马拉维、南非及美国的8个研究中心，评估了CAB LA在HIV阴性男性和女性中的安全性、耐受性及药代动力学特征。

研究方法与结果
HPTN 077是一项双盲、安慰剂对照的2a期临床试验。将HIV感染风险较低的18~65岁健康受试者按3:1的比例随机分配至CAB组或安慰剂（placebo, PBO）组。在初始口服给药阶段，受试者每日服用1片CAB或安慰剂片剂，持续4周。口服阶段无安全性顾虑的受试者可进入后续注射给药阶段：队列1：每12周接受1次CAB LA 800mg或安慰剂0.9%生理盐水肌内注射，共3个给药周期；队列2：前2次注射间隔4周，后续每次注射间隔8周，接受CAB LA 600mg或安慰剂肌内注射，共5个给药周期。
本研究的主要分析时段为受试者入组后的第5周至第41周，覆盖注射给药阶段，两个队列依次入组。研究的主要终点为安全性与耐受性，次要终点包括药代动力学指标及口服、注射阶段发生的不良事件。

2015年2月9日至2016年5月27日期间，本研究共筛查443名受试者，最终队列1纳入110名受试者，队列2纳入89名合格受试者。受试者人群特征如下：出生时被指派为女性者占66%，中位年龄31岁；非西班牙裔白人占27%，非西班牙裔黑人占41%，西班牙裔/拉丁裔占24%，亚裔占3%，混血/其他种族占6%；其中跨性别男性6名，跨性别女性1名。共有22名（11%）受试者停用口服研究药物，其中6名因临床或实验室检测发现的不良事件（adverse events, AEs）停药。在至少接受1次CAB LA注射的受试者中，队列1有80%、队列2有92%的受试者完成了全部注射疗程，注射疗程完成率与安慰剂组无显著差异。
注射部位反应（injection site reactions, ISRs）较为常见：接受CAB LA的受试者中，队列1有92%、队列2有88%报告出现任何类型的注射部位反应。此类反应多为1级（轻度）至2级（中度），仅1例注射部位反应（队列1）导致受试者停用研究药物。2级及以上的注射部位反应是唯一在CAB LA组较安慰剂组更常见的不良事件。CAB组共发生2例3级（重度）注射部位反应，两个队列各1例，但均未导致受试者停用研究药物。
6名受试者共确诊7例新发性传播感染。1名受试者在末次接受CAB LA注射后48周发生HIV感染：首次HIV检测呈反应性时及此前12周的随访访视中，血浆中均未检测到CAB。队列2（与队列1不同）的受试者均持续达到预先设定的药代动力学目标：至少95%的受试者的CAB谷浓度维持在PA-IC90以上，且80%的受试者谷浓度维持在4×PA-IC90以上。
本研究的局限性包括样本量较小、注射疗程较短以及研究人群为低感染风险人群。

结论
本研究显示，在所采用的剂量与给药间隔下，CAB LA具有良好的耐受性。注射部位反应较为常见，但极少导致受试者停用研究药物。每8周给药一次的600mg CAB LA方案可满足男女受试者的药代动力学目标。本研究观察到的安全性与药代动力学结果支持CAB LA的进一步开发，针对CAB LA用于HIV治疗与预防的有效性研究正在进行中。

试验注册
ClinicalTrials.gov注册信息：试验编号NCT02178800。