Background

Previous work established non-inferiority of switching participants who were virologically suppressed from daily oral standard of care to monthly long-acting intramuscular injections of cabotegravir plus rilpivirine over 96 weeks following a cabotegravir plus rilpivirine oral lead-in. Here, we report an evaluation of switching participants from standard of care oral regimens to long-acting cabotegravir plus rilpivirine via direct-to-injection or oral lead-in pathways.

Methods

This study reports the week 124 results of the FLAIR study, an ongoing phase 3, randomised, open-label, multicentre (11 countries) trial. Antiretroviral therapy (ART)-naive participants who were virologically suppressed (HIV-1 RNA <50 copies per mL) during the 20-week induction phase with standard of care were randomly assigned (1:1) to continue the standard of care oral regimen or switch to long-acting cabotegravir plus rilpivirine (283 per group) in the 100-week maintenance phase. Randomisation was stratified by sex at birth and baseline (pre-induction) HIV-1 RNA (<100 000 or ≥100 000 copies per mL). Participants randomly assigned to long-acting therapy at baseline received a cabotegravir (30 mg) plus rilpivirine (25 mg) once daily oral lead-in for at least 4 weeks before first injection and could choose to continue long-acting cabotegravir (400 mg) plus rilpivirine (600 mg) every 4 weeks from week 100 or withdraw. At week 100, participants in the oral comparator ART group, in discussion with the investigator, could elect to switch to long-acting therapy (extension switch population), either direct-to-injection or with a 4 week oral lead-in (oral lead-in group), or withdraw. Week 124 endpoints included plasma HIV-1 RNA 50 or more copies per mL and less than 50 copies per mL (US Food and Drug Administration [FDA] Snapshot), confirmed virological failure (two consecutive HIV-1 RNA ≥200 copies per mL), and safety and tolerability. The study is registered at ClinicalTrials.gov, NCT02938520.

Findings

Screening occurred between Oct 27, 2016, and March 24, 2017. At week 100, 232 (92%) of 253 participants transitioned to long-acting cabotegravir plus rilpivirine in the extension phase (111 [48%] in the direct-to-injection group and 121 [52%] in the oral lead-in group; extension switch population). 243 (86%) of the 283 who were randomly assigned to the long-acting therapy group continued the long-acting regimen into the extension phase. One (<1%) participant in each extension switch group had 50 or more HIV-1 RNA copies per mL; 110 (99%) participants in the direct-to-injection group and 113 (93%) participants in the oral lead-in group remained suppressed (HIV-1 RNA <50 copies per mL) at the week 124 Snapshot. The lower suppression rates in the oral lead-in group were driven by non-virological reasons. For participants in the randomly assigned long-acting group, 227 (80%) of 283 participants remained suppressed; at the week 124 Snapshot, 14 (5%) participants had HIV-1 RNA 50 or more copies per mL, including five additional participants since the week 96 analysis. The remaining 42 (15%) participants in the randomly assigned long-acting group had no virological data. Adverse events leading to withdrawal were infrequent, occurring in three (1%) participants in the extension switch population (one in the direct-to-injection group and two in the oral lead-in group) after 24 weeks of cabotegravir plus rilpivirine therapy, and 15 (5%) participants in the randomly assigned long-acting group up to 124 weeks of therapy. No deaths occurred in the extension phase. Overall, cabotegravir plus rilpivirine adverse event type, severity, and frequency were similar across all groups. Injection site reactions were the most common adverse event, occurring after 914 (21%) of 4442 injections in the extension switch population and 3732 (21%) of 17 392 injections in the randomly assigned long-acting group. Injection site reactions were mostly classified as mild-to-moderate in severity and decreased in incidence over time. Four (2%) of 232 participants in the extension switch population and seven (2%) of 283 in the randomly assigned long-acting group withdrew due to injection-related reasons.

Interpretation

After 24 weeks of follow-up, switching to long-acting treatment with or without an oral lead-in phase had similar safety, tolerability, and efficacy, supporting future evaluation of the simpler direct-to-injection approach. The week 124 results for participants randomly assigned originally to the long-acting therapy show long-acting cabotegravir plus rilpivirine remains a durable maintenance therapy with a favourable safety profile.

Funding

ViiV Healthcare and Janssen Research & Development.

中文翻译：

---

在 HIV-1 感染成人中启动长效卡博特韦加利匹韦林直接注射或口服导入：开放标签 3 期 FLAIR 研究的第 124 周结果

背景

以前的工作确定了在 cabotegravir 加 rilpivirine 口服导入后的 96 周内，将病毒学抑制的参与者从每日口服护理标准转换为每月长效肌肉注射 cabotegravir 加 rilpivirine 的非劣效性。在这里，我们报告了通过直接注射或口服导入途径将参与者从标准护理口服方案转换为长效卡博特拉韦加利匹韦林的评估。

方法

本研究报告了 FLAIR 研究的第 124 周结果，这是一项正在进行的 3 期、随机、开放标签、多中心（11 个国家）试验。在标准护理的 20 周诱导期期间病毒学抑制（HIV-1 RNA <50 拷贝/mL）的抗逆转录病毒治疗 (ART) 初始参与者被随机分配 (1:1) 继续使用标准护理口服方案或在 100 周维持期改用长效 cabotegravir 加 rilpivirine（每组 283 个）。随机化按出生时的性别和基线（诱导前）HIV-1 RNA（<100 000 或 ≥100 000 拷贝/mL）进行分层。基线时随机分配到长效治疗的参与者在首次注射前每天一次口服导入卡博特拉韦（30 毫克）加利匹韦林（25 毫克）至少 4 周，并且可以选择继续长效卡博特拉韦（400 毫克）从第 100 周开始每 4 周加用利匹韦林（600 毫克）或退出。在第 100 周，口服对照 ART 组的参与者与研究者讨论后，可以选择转换为长效治疗（扩展转换群体），直接注射或 4 周口服导入（口服引入组），或退出。第 124 周的终点包括血浆 HIV-1 RNA 50 或更多拷贝/mL 和少于 50 拷贝/mL（美国食品和药物管理局 [FDA] 快照），确认病毒学失败（连续两次 HIV-1 RNA ≥200 拷贝/mL） ，以及安全性和耐受性。

发现

筛查于 2016 年 10 月 27 日至 2017 年 3 月 24 日之间进行。在第 100 周，253 名参与者中有 232 名 (92%) 在延长期过渡到长效卡博特韦加利匹韦林 (111 [48%] 在直接注射组和口服导入组 121 [52%]；扩展开关人群）。在被随机分配到长效治疗组的 283 人中，有 243 人（86%）继续使用长效治疗方案进入延长期。每个扩展开关组中的一名（<1%）参与者每毫升有 50 个或更多 HIV-1 RNA 拷贝；在第 124 周快照时，直接注射组的 110 名 (99%) 参与者和口服导入组的 113 名 (93%) 参与者仍然受到抑制（HIV-1 RNA <50 拷贝/mL）。口服导​​入组较低的抑制率是由非病毒学原因驱动的。对于随机分配的长效组的参与者，283 名参与者中有 227 名 (80%) 仍然受到抑制；在第 124 周快照中，14 名 (5%) 参与者每毫升的 HIV-1 RNA 拷贝数为 50 或更多，其中包括自第 96 周分析以来的另外五名参与者。随机分配的长效组中剩余的 42 名 (15%) 参与者没有病毒学数据。导致戒断的不良事件很少发生，在 cabotegravir 加 rilpivirine 治疗 24 周后，扩展开关人群中的三名 (1%) 参与者（一名在直接注射组，两名在口服导入组）发生，随机分配的长效组中的 15 名（5%）参与者接受了长达 124 周的治疗。延长期无死亡病例。总体而言，cabotegravir 加 rilpivirine 不良事件类型、严重程度、所有组的频率和频率相似。注射部位反应是最常见的不良事件，发生在延长开关组 4442 次注射中的 914 次（21%）和随机分配的长效组 17392 次注射中的 3732 次（21%）之后。注射部位反应的严重程度主要分为轻度至中度，并且随着时间的推移发生率下降。由于注射相关原因，延长转换人群的 232 名参与者中有 4 名 (2%) 和随机分配的长效组 283 名参与者中有 7 名 (2%) 退出。注射部位反应的严重程度主要分为轻度至中度，并且随着时间的推移发生率下降。由于注射相关原因，延长转换人群的 232 名参与者中有 4 名 (2%) 和随机分配的长效组 283 名参与者中有 7 名 (2%) 退出。注射部位反应的严重程度主要分为轻度至中度，并且随着时间的推移发生率下降。由于注射相关原因，延长转换人群的 232 名参与者中有 4 名 (2%) 和随机分配的长效组 283 名参与者中有 7 名 (2%) 退出。

解释

在 24 周的随访后，改用长效治疗（有或没有口服导入期）具有相似的安全性、耐受性和有效性，支持未来对更简单的直接注射方法的评估。最初随机分配到长效治疗的参与者的第 124 周结果显示，长效卡博特韦加利匹韦林仍然是一种持久的维持治疗，具有良好的安全性。

资金

ViiV 医疗保健和杨森研发。