University of Alabama at Birmingham, Birmingham, AL, USA.
Nova Southeastern University, FL, USA.
Lancet. 2021 Dec 19;396(10267):1994-2005. doi: 10.1016/S0140-6736(20)32666-0. Epub 2020 Dec 9.
Phase 3 clinical studies showed non-inferiority of long-acting intramuscular cabotegravir and rilpivirine dosed every 4 weeks to oral antiretroviral therapy. Important phase 2 results of every 8 weeks dosing, and supportive modelling, underpin further evaluation of every 8 weeks dosing in this trial, which has the potential to offer greater convenience. Our objective was to compare the week 48 antiviral efficacy of cabotegravir plus rilpivirine long-acting dosed every 8 weeks with that of every 4 weeks dosing.
ATLAS-2M is an ongoing, randomised, multicentre (13 countries; Australia, Argentina, Canada, France, Germany, Italy, Mexico, Russia, South Africa, South Korea, Spain, Sweden, and the USA), open-label, phase 3b, non-inferiority study of cabotegravir plus rilpivirine long-acting maintenance therapy administered intramuscularly every 8 weeks (cabotegravir 600 mg plus rilpivirine 900 mg) or every 4 weeks (cabotegravir 400 mg plus rilpivirine 600 mg) to treatment-experienced adults living with HIV-1. Eligible newly recruited individuals must have received an uninterrupted first or second oral standard-of-care regimen for at least 6 months without virological failure and be aged 18 years or older. Eligible participants from the ATLAS trial, from both the oral standard-of-care and long-acting groups, must have completed the 52-week comparative phase with an ATLAS-2M screening plasma HIV-1 RNA less than 50 copies per mL. Participants were randomly assigned 1:1 to receive cabotegravir plus rilpivirine long-acting every 8 weeks or every 4 weeks. The randomisation schedule was generated by means of the GlaxoSmithKline validated randomisation software RANDALL NG. The primary endpoint at week 48 was HIV-1 RNA ≥50 copies per mL (Snapshot, intention-to-treat exposed), with a non-inferiority margin of 4%. The trial is registered at ClinicalTrials.gov, NCT03299049 and is ongoing.
Screening occurred between Oct 27, 2017, and May 31, 2018. Of 1149 individuals screened, 1045 participants were randomised to the every 8 weeks (n=522) or every 4 weeks (n=523) groups; 37% (n=391) transitioned from every 4 weeks cabotegravir plus rilpivirine long-acting in ATLAS. Median participant age was 42 years (IQR 34-50); 27% (n=280) female at birth; 73% (n=763) white race. Cabotegravir plus rilpivirine long-acting every 8 weeks was non-inferior to dosing every 4 weeks (HIV-1 RNA ≥50 copies per mL; 2% vs 1%) with an adjusted treatment difference of 0·8 (95% CI -0·6-2·2). There were eight (2%, every 8 weeks group) and two (<1%, every 4 weeks group) confirmed virological failures (two sequential measures ≥200 copies per mL). For the every 8 weeks group, five (63%) of eight had archived non-nucleoside reverse transcriptase inhibitor resistance-associated mutations to rilpivirine at baseline. The safety profile was similar between dosing groups, with 844 (81%) of 1045 participants having adverse events (excluding injection site reactions); no treatment-related deaths occurred.
The efficacy and safety profiles of dosing every 8 weeks and dosing every 4 weeks were similar. These results support the use of cabotegravir plus rilpivirine long-acting administered every 2 months as a therapeutic option for people living with HIV-1.
ViiV Healthcare and Janssen.
三期临床试验表明，长效肌内注射卡替拉韦和利匹韦林每四周一次给药与口服抗逆转录病毒疗法相比具有非劣效性。每八周一次给药的重要二期结果和支持性建模为该试验中每八周一次给药的进一步评估提供了依据，这有可能提供更大的便利。我们的目的是比较每 48 周时卡替拉韦和利匹韦林长效每八周一次给药与每四周一次给药的抗病毒疗效。
ATLAS-2M 是一项正在进行的、随机、多中心（13 个国家；澳大利亚、阿根廷、加拿大、法国、德国、意大利、墨西哥、俄罗斯、南非、韩国、西班牙、瑞典和美国）、开放性标签、三期 b 期、非劣效性研究，评估卡替拉韦和利匹韦林长效维持治疗每八周（卡替拉韦 600mg 加利匹韦林 900mg）或每四周（卡替拉韦 400mg 加利匹韦林 600mg）肌内注射用于治疗经验丰富的 HIV-1 感染者。新招募的合格个体必须接受过至少 6 个月的不间断的一线或二线标准护理方案治疗，且没有病毒学失败，并年满 18 岁。ATLAS 试验的合格参与者，包括口服标准护理组和长效组，必须在完成 52 周的比较期后，ATLAS-2M 筛查时血浆 HIV-1 RNA 小于 50 拷贝/ml。参与者按 1:1 的比例随机分配接受卡替拉韦和利匹韦林长效每八周或每四周一次给药。随机分组方案是通过 GlaxoSmithKline 验证的随机分组软件 RANDALL NG 生成的。主要终点是第 48 周时 HIV-1 RNA ≥50 拷贝/ml（Snapshot，意向治疗暴露），非劣效性边界为 4%。该试验在 ClinicalTrials.gov 注册，NCT03299049 号，正在进行中。
筛选于 2017 年 10 月 27 日至 2018 年 5 月 31 日进行。在筛选的 1149 人中，有 1045 名参与者被随机分配到每八周（n=522）或每四周（n=523）组；37%（n=391）从 ATLAS 中的每四周卡替拉韦和利匹韦林长效方案转为每八周方案。中位参与者年龄为 42 岁（IQR 34-50）；出生时为女性的占 27%（n=280）；白种人占 73%（n=763）。卡替拉韦和利匹韦林长效每八周一次给药与每四周一次给药相比非劣效（HIV-1 RNA ≥50 拷贝/ml；2%比 1%），调整后的治疗差异为 0.8（95%CI -0.6-2.2）。每八周组有 8 例（2%）和每四周组有 2 例（<1%）确认的病毒学失败（连续两次测量≥200 拷贝/ml）。在每八周组中，有 8 例（63%）的 5 例在基线时存在利匹韦林的非核苷类逆转录酶抑制剂耐药相关突变。两组的安全性特征相似，1045 名参与者中有 844 名（81%）出现不良事件（不包括注射部位反应）；无治疗相关死亡发生。
每八周和每四周给药的疗效和安全性特征相似。这些结果支持卡替拉韦和利匹韦林长效每两个月给药一次作为 HIV-1 感染者的治疗选择。
ViiV 医疗保健和杨森。
