Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study
Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study
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DOI：
10.1016/s0140-6736(20)32666-0
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发表时间：
2020-12-19
期刊：
影响因子：
168.9
通讯作者：
Spreen, William
中科院分区：
文献类型：
--
作者：
Overton, Edgar T.;Richmond, Gary;Spreen, William
背景3期临床研究显示，长效肌内注射卡替拉韦和利匹韦林每4周给药一次，与口服抗逆转录病毒治疗相比，具有非劣效性。每8周一次给药的重要II期结果和支持性建模支持了本试验中每8周一次给药的进一步评价，这有可能提供更大的便利性。我们的目的是比较卡替拉韦加利匹韦林长效每8周给药与每4周给药的48周抗病毒疗效。（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），开放标签，3b期，在有治疗经验的HIV-1成人患者中，每8周一次（卡替拉韦600 mg+利匹韦林900 mg）或每4周一次（卡替拉韦400 mg+利匹韦林600 mg）肌内给药卡替拉韦+利匹韦林长效维持治疗的非劣效性研究。符合条件的新招募个体必须接受不间断的第一或第二口服标准治疗方案至少6个月，且无病毒学失败，年龄≥ 18岁。ATLAS试验的合格受试者（口服标准治疗组和长效治疗组）必须完成52周比较期，ATLAS-2 M筛查血浆HIV-1 RNA低于50拷贝/mL。受试者以1：1的比例被随机分配接受卡替拉韦加利匹韦林长效治疗，每8周一次或每4周一次。随机化时间表是通过葛兰素史克验证的随机化软件RANDALL NG生成的。第48周的主要终点是HIV-1 RNA ≥ 50拷贝/mL（快照，意向治疗暴露），非劣效性界值为4%。该试验注册于ClinicalTrials.gov，NCT 03299049，正在进行中。结果筛选于2017年10月27日至2018年5月31日进行。在筛选的1149名受试者中，1045名受试者被随机分配至每8周一次（n=522）或每4周一次（n=523）组; 37%（n=391）从ATLAS中的每4周一次卡替拉韦+利匹韦林长效治疗过渡。中位受试者年龄为42岁（IQR 34-50）; 27%（n=280）为女性出生; 73%（n=763）为白色人种。卡替拉韦加利匹韦林长效每8周一次非劣效于每4周一次给药（HIV-1 RNA >= 50拷贝/mL; 2% vs 1%），校正后的治疗差异为0.8（95% CI -0.6-2.2）。有8个（2%，每8周一次组）和2个（= 200拷贝/mL）。对于每8周一次组，8例患者中有5例（63%）在基线时对利匹韦林存在非核苷逆转录酶抑制剂耐药相关突变。给药组之间的安全性特征相似，1045名参与者中有844名（81%）有不良事件（不包括注射部位反应）;没有发生治疗相关的死亡。解释每8周给药一次和每4周给药一次的疗效和安全性特征相似。这些结果支持使用卡替拉韦加利匹韦林长效每2个月给药一次作为HIV-1感染者的治疗选择。
Background 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.Methods 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.Findings 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 (= 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.Interpretation 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.