Background

Long-acting cabotegravir and rilpivirine administered monthly or every 2 months might address the challenges associated with daily oral antiretroviral therapy. The ATLAS-2M week 48 results showed non-inferiority of long-acting cabotegravir and rilpivirine administered every 8 weeks compared with that of every 4 weeks. In this study, we report the efficacy, safety, and tolerability results from the week 96 analysis.

Methods

ATLAS-2M is a randomised, multicentre, open-label, phase 3b, non-inferiority trial conducted in 13 countries, evaluating the safety and efficacy of maintenance treatment with intramuscular injections of long-acting cabotegravir and rilpivirine, administered every 8 weeks versus every 4 weeks, to people living with HIV-1. Virologically suppressed adults with HIV-1, either already receiving intramuscular long-acting cabotegravir and rilpivirine every 4 weeks (ie, ATLAS study rollover participants) or oral standard of care, were randomly assigned (1:1), in an unblinded fashion, to receive either intramuscular long-acting cabotegravir (600 mg) and rilpivirine (900 mg) every 8 weeks (ie, the every 8-week dosing group) or intramuscular long-acting cabotegravir (400 mg) and rilpivirine (600 mg) every 4 weeks (ie, the every 4-week dosing group). Randomisation was generated using the GlaxoSmithKline-validated randomisation software RANDALL NG (version 1.3.3). The primary endpoint at week 48 was the proportion of participants with plasma HIV-1 RNA measurements of 50 copies per mL or more (ie, the US Food and Drug Administration [FDA] Snapshot algorithm), which has been published previously. Here, we present the week 96 results: the proportion of participants with plasma HIV-1 RNA measurements of less than 50 copies per mL (FDA Snapshot algorithm), with a non-inferiority margin of −10%; the proportion of participants with plasma HIV-1 RNA measurements of 50 copies per mL or more (FDA Snapshot algorithm), with a non-inferiority margin of 4%; the proportion of participants with protocol-defined confirmed virological failure (ie, two consecutive plasma HIV-1 RNA measurements ≥200 copies per mL); safety; pharmacokinetics; and tolerability. This study is registered with ClinicalTrials.gov, number NCT03299049, and is currently ongoing.

Findings

Between Oct 27, 2017, and May 31, 2018, a total of 1149 participants were screened; of whom, 1049 (91%) were randomly assigned and 1045 (91%) initiated treatment (522 in the every 8-week dosing group and 523 in the every 4-week dosing group). The median age was 42 years (IQR 34–50). 280 (27%) of 1045 participants were assigned female at birth and 764 (73%) were white. At week 96 (FDA Snapshot algorithm), 11 (2%) of 522 participants in the every 8-week dosing group and six (1%) of 523 in the every 4-week dosing group had an HIV-1 RNA measurement of 50 copies per mL or more, with an adjusted treatment difference of 1·0 (95% CI −0·6 to 2·5), meeting the prespecified non-inferiority threshold of 4%; 475 (91%) of 522 participants in the every 8-week dosing group and 472 (90%) of 523 in the every 4-week dosing group maintained an HIV-1 RNA measurement of less than 50 copies per mL, with an adjusted treatment difference of 0·8 (95% CI −2·8 to 4·3), which met the prespecified non-inferiority threshold of −10%. One participant in the every 8-week dosing group met the confirmed virological failure criterion since the week 48 analysis at week 88, resulting in a total of nine participants in the every 8-week dosing group and two in the every 4-week dosing group having confirmed virological failure. No new safety signals were identified, and no treatment-related deaths occurred. Injection site reactions were the most common adverse event, occurring in 412 (79%) of 522 participants in the every 8-week dosing group and 400 (76%) of 523 in the every 4-week dosing group. Most injection site reactions were grade 1 or 2 (7453 [99%] of 7557 in both groups), with a median duration of 3 days (IQR 2–5).

Interpretation

Long-acting cabotegravir and rilpivirine dosed every 8 weeks had non-inferior efficacy compared with that of every 4 weeks through the 96-week analysis, with both regimens maintaining high levels of virological suppression. These results show the durable safety, efficacy, and acceptability of dosing long-acting cabotegravir and rilpivirine monthly and every 2 months as maintenance therapy for people living with HIV-1.

Funding

ViiV Healthcare and Janssen Research & Development.

中文翻译：

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长效 cabotegravir 和 rilpivirine 每 2 个月在 HIV-1 感染成人 (ATLAS-2M) 中给药，96 周结果：一项随机、多中心、开放标签、3b 期、非劣效性研究

背景

每月或每 2 个月给药的长效卡博特拉韦和利匹韦林可能会解决与每日口服抗逆转录病毒治疗相关的挑战。ATLAS-2M 第 48 周的结果显示，与每 4 周相比，每 8 周给药一次的长效卡博特韦和利匹韦林的非劣效性。在这项研究中，我们报告了第 96 周分析的疗效、安全性和耐受性结果。

方法

ATLAS-2M 是一项随机、多中心、开放标签、3b 期、非劣效性试验，在 13 个国家进行，评估肌肉注射长效卡博特拉韦和利匹韦林维持治疗的安全性和有效性，每 8 周与每4 周，针对 HIV-1 感染者。病毒学抑制的 HIV-1 成人，无论是已经接受每 4 周肌肉注射长效卡博特拉韦和利匹韦林（即 ATLAS 研究翻转参与者）或口服标准护理，以非盲方式随机分配 (1:1)，每 8 周（即每 8 周给药组）接受肌内长效卡博特拉韦（600 毫克）和利匹韦林（900 毫克）或每 4 周肌内长效卡博特拉韦（400 毫克）和利匹韦林（600 毫克） (即，每 4 周一次的给药组)。使用 GlaxoSmithKline 验证的随机化软件 RANDALL NG（版本 1.3.3）生成随机化。第 48 周的主要终点是血浆 HIV-1 RNA 测量值为 50 拷贝/mL 或更多的参与者比例（即美国食品和药物管理局 [FDA] 快照算法），该算法之前已发表。在这里，我们展示了第 96 周的结果：血浆 HIV-1 RNA 测量值低于 50 拷贝/mL（FDA 快照算法）的参与者比例，非劣效性边际为 -10%；血浆 HIV-1 RNA 测量值为 50 拷贝/mL 或更多的参与者比例（FDA 快照算法），非劣效性为 4%；方案定义的确认病毒学失败的参与者比例（即，两次连续血浆 HIV-1 RNA 测量值≥200 拷贝/mL）；安全; 药代动力学；和耐受性。该研究已在 ClinicalTrials.gov 注册，编号为 NCT03299049，目前正在进行中。

发现

2017 年 10 月 27 日至 2018 年 5 月 31 日期间，共筛选了 1149 名参与者；其中，1049 人（91%）被随机分配，1045 人（91%）开始治疗（每 8 周给药组 522 人，每 4 周给药组 523 人）。中位年龄为 42 岁（IQR 34-50）。1045 名参与者中有 280 名（27%）出生时为女性，764 名（73%）为白人。在第 96 周（FDA 快照算法），每 8 周给药组的 522 名参与者中有 11 名 (2%) 和每 4 周给药组的 523 名参与者中有 6 名 (1%) 的 HIV-1 RNA 测量值为 50每毫升拷贝数或更多，调整后的治疗差异为 1·0（95% CI -0·6 至 2·5），满足预先设定的 4% 的非劣效性阈值；每 8 周给药组 522 名参与者中有 475 名（91%）和每 4 周给药组 523 名参与者中有 472 名（90%）保持 HIV-1 RNA 测量值低于 50 拷贝/mL，调整后的治疗差异为 0·8（95% CI -2·8 至 4·3），符合预先设定的非劣效性阈值 -10%。自第 88 周的第 48 周分析以来，每 8 周给药组的一名参与者符合确认的病毒学失败标准，导致每 8 周给药组共有 9 名参与者，每 4 周给药组有 2 名参与者确认病毒学失败。没有发现新的安全信号，也没有发生与治疗相关的死亡。注射部位反应是最常见的不良事件，发生在每 8 周给药组 522 名参与者中的 412 名（79%）和每 4 周给药组 523 名参与者中的 400 名（76%）。大多数注射部位反应为 1 级或 2 级（两组 7557 例中的 7453 例 [99%]），中位持续时间为 3 天（IQR 2-5）。

解释

通过 96 周的分析，每 8 周给药一次的长效卡博特拉韦和利匹韦林与每 4 周给药一次相比具有非劣效性，两种方案均保持高水平的病毒学抑制。这些结果表明，作为 HIV-1 感染者的维持治疗，每月和每 2 个月给药一次长效卡博特拉韦和利匹韦林具有持久的安全性、有效性和可接受性。

资金

ViiV 医疗保健和杨森研发。