In two phase 3 trials for first-line therapy in adults with HIV-1, doravirine showed non-inferior efficacy, a favourable safety profile, and a superior lipid profile to darunavir and efavirenz through to 48 and 96 weeks. Here we report 192-week results from both studies. DRIVE-FORWARD and DRIVE-AHEAD are multicentre, double-blind, randomised, active comparator-controlled, phase 3 trials of first-line antiretroviral treatment in adults with HIV-1. Eligible participants (aged ≥18 years) were naive to antiretroviral therapy, had plasma HIV-1 RNA 1000 copies per mL or more at screening, had no known resistance to any of the trial drugs, and had creatinine clearance 50 mL per min or more. DRIVE-FORWARD was conducted at 125 sites in 15 countries and compared doravirine (100 mg) with ritonavir-boosted darunavir (ritonavir [100 mg] and darunavir [800 mg]), each administered orally once daily with two nucleoside or nucleotide reverse transcriptase inhibitors (tenofovir disoproxil fumarate [300 mg] and emtricitabine [200 mg] or abacavir sulfate [600 mg] and lamivudine [300 mg]). DRIVE-AHEAD was conducted at 126 sites in 23 countries and compared doravirine (100 mg), lamivudine (300 mg), and tenofovir disoproxil fumarate (300 mg) with that of efavirenz (600 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), all administered orally once daily. DRIVE-FORWARD enrolment was between Dec 1, 2014, and June 1, 2020, and DRIVE-AHEAD enrolment was between June 10, 2015, and Aug 10, 2020. After the 96-week double-blind phase, eligible participants could enter an open-label extension and either continue doravirine or switch from comparator to doravirine for an additional 96 weeks. Efficacy (HIV-1 RNA <50 copies per mL) and safety assessments (adverse events and changes in laboratory parameters) were pooled. The DRIVE-FORWARD and DRIVE-AHEAD trials were registered with , and . Of 1494 participants treated in the double-blind phase (1261 [84%] male and 233 [16%] female), 550 continued doravirine and 502 switched to doravirine in the extension. Using the FDA snapshot approach, HIV-1 RNA less than 50 copies per mL was maintained in 457 (83%) of 550 participants who continued doravirine and 404 (80%) of 502 participants who switched to doravirine. Protocol-defined virological failure and development of resistance were low, occurring mainly before week 96. Two (<1%) of 550 participants who continued doravirine reported serious drug-related adverse events, and three (1%) who continued doravirine and one (<1%) of 502 who switched to doravirine discontinued due to drug-related adverse events. Participants continuing or switching to doravirine showed generally favourable lipid profiles, little weight gain, and small decreases in estimated glomerular filtration rates, with no discontinuations due to increased creatinine or renal adverse events. Favourable efficacy and safety profiles for doravirine at week 96 were maintained through to week 192 in participants who continued or switched to doravirine, supporting use of doravirine for long-term first-line HIV-1 treatment and for virologically suppressed adults switching therapy. Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

中文翻译：

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多拉韦林作为 HIV-1 成人一线治疗的安全性和有效性：DRIVE-FORWARD 和 DRIVE-AHEAD 3 期试验的开放标签扩展第 192 周结果

在针对成人 HIV-1 一线治疗的两项 3 期试验中，多拉韦林在 48 周和 96 周内显示出不劣于达芦那韦和依非韦伦的疗效、良好的安全性以及优于达芦那韦和依非韦伦的血脂状况。在此，我们报告了这两项研究的 192 周结果。 DRIVE-FORWARD 和 DRIVE-AHEAD 是针对成人 HIV-1 患者进行一线抗逆转录病毒治疗的多中心、双盲、随机、主动对照对照 3 期试验。符合条件的参与者（年龄≥18岁）未接受过抗逆转录病毒治疗，筛选时血浆HIV-1 RNA为1000拷贝/毫升或更多，对任何试验药物没有已知的耐药性，并且肌酐清除率为每分钟50毫升或更多。 DRIVE-FORWARD 在 15 个国家的 125 个地点进行，比较了多拉韦林 (100 mg) 与利托那韦增强的达芦那韦（利托那韦 [100 mg] 和达芦那韦 [800 mg]），每种药物每天口服一次，与两种核苷或核苷酸逆转录酶抑制剂一起给药（富马酸替诺福韦二吡呋酯 [300 mg] 和恩曲他滨 [200 mg] 或硫酸阿巴卡韦 [600 mg] 和拉米夫定 [300 mg]）。 DRIVE-AHEAD 在 23 个国家的 126 个地点进行，将多拉韦林（100 毫克）、拉米夫定（300 毫克）和富马酸替诺福韦二吡呋酯（300 毫克）与依非韦伦（600 毫克）、恩曲他滨（200 毫克）和替诺福韦进行比较富马酸二吡呋酯（300 mg），全部口服，每日一次。 DRIVE-FORWARD 注册时间为 2014 年 12 月 1 日至 2020 年 6 月 1 日，DRIVE-AHEAD 注册时间为 2015 年 6 月 10 日至 2020 年 8 月 10 日。经过 96 周的双盲阶段后，符合条件的参与者可以进入开放标签延伸，要么继续使用多拉韦林，要么从比较药物切换为多拉韦林，再持续 96 周。汇总疗效（HIV-1 RNA <50 拷贝/毫升）和安全性评估（不良事件和实验室参数的变化）。 DRIVE-FORWARD 和 DRIVE-AHEAD 试验已在 、 和 注册。在双盲阶段接受治疗的 1494 名参与者中（1261 名 [84%] 男性和 233 名 [16%] 女性），550 名继续使用多拉韦林，502 名在扩展中改用多拉韦林。使用 FDA 快照方法，继续使用多拉韦林的 550 名参与者中，有 457 名 (83%) 的 HIV-1 RNA 维持在每毫升以下 50 个拷贝，而改用多拉韦林的 502 名参与者中，有 404 名 (80%) 的 HIV-1 RNA 维持在每毫升以下。方案定义的病毒学失败和耐药性发展较低，主要发生在第 96 周之前。 550 名继续使用多拉韦林的参与者中，有两名 (<1%) 报告了严重的药物相关不良事件，三名 (1%) 继续使用多拉韦林，一名 (<1%) 继续使用多拉韦林，另一名 (<1%) 继续使用多拉韦林。 <1%）的 502 名改用多拉韦林的患者因药物相关不良事件而停药。继续或改用多拉韦林的参与者总体上表现出良好的血脂状况、体重增加很少、估计肾小球滤过率小幅下降，并且没有因肌酐增加或肾脏不良事件而停药。在继续或改用多拉韦林的参与者中，多拉韦林在第 96 周的良好疗效和安全性一直保持到第 192 周，支持使用多拉韦林进行长期一线 HIV-1 治疗和病毒学抑制成人转换治疗。 Merck Sharp & Dohme 是 Merck & Co 的子公司，位于美国新泽西州拉威。