Switch to fixed-dose doravirine (100 mg) and islatravir (0·25 mg) once daily in virologically suppressed adults with HIV-1 on bictegravir, emtricitabine, and tenofovir alafenamide: 48-week results of a phase 3, multicentre, randomised, controlled, double-blind, non-inferiority trial.

We aimed to assess the efficacy and safety of switching to doravirine (100 mg) and islatravir (0·25 mg) from bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed adults with HIV-1.

我们的目标是评估从 bictegravir、emtricitabine 和 tenofovir alafenamide 切换到 doravirine (100 mg) 和 islatravir (0·25 mg) 在 HIV-1 病毒学抑制成年患者中的疗效和安全性。

Methods

This phase 3, randomised, controlled, double-blind, non-inferiority trial was conducted at 49 research, community, and hospital-based clinics in six countries: Australia, Chile, Israel, Japan, the UK, and the USA.

这是一项第3阶段、随机、对照、双盲、非劣效试验，在澳大利亚、智利、以色列、日本、英国和美国的49个研究、社区和医院诊所进行。

Adults aged 18 years or older with HIV-1, who were virologically suppressed (with a viral load of HIV-1 RNA <50 copies per mL) for at least 3 consecutive months on bictegravir, emtricitabine, and tenofovir alafenamide and had no history of treatment failure or known resistance to doravirine, were eligible for the study.

年龄在18岁或以上的HIV-1成人患者，他们在过去三个月内使用比克替拉韦、恩曲他滨和替诺福韦阿拉芬酰胺治疗后病毒学抑制（HIV-1 RNA的病毒载量<50拷贝/毫升），并且没有治疗失败史或对多拉韦林已知耐药性，符合本研究的资格。

Participants were randomly assigned, in a 2:1 ratio according to a computer-generated randomisation schedule with a block size of three, to switch to oral doravirine (100 mg) and islatravir (0·25 mg) or to continue bictegravir, emtricitabine, and tenofovir alafenamide, once daily.

参与者按照2:1的比例，根据计算机生成的随机化计划，以三个为一个区块的大小，被随机分配到口服多拉韦林（100毫克）和伊司他韦（0.25毫克）组，或者继续使用比克替拉韦、恩曲他滨和替诺福韦阿仑酸酯，每日一次。

Participants, investigators, study staff, and sponsor personnel were masked to study treatment; sponsor personnel directly involved in this analysis were unmasked at week 48.

参与者、研究人员、研究工作人员和赞助方人员对研究治疗进行了遮蔽；直接参与此分析的赞助方人员在第48周时被解蔽。

The primary endpoint, which was assessed in all randomly assigned participants who received at least one dose of study treatment, was the percentage of participants with a viral load of 50 copies per mL or higher at week 48 according to the US Food and Drug Administration snapshot approach; non-inferiority would be concluded if the upper bound of the multiplicity-adjusted 95% CI for the treatment difference was less than 4%.

主要终点是在所有随机分配的参与者中评估的，这些参与者至少接受了一次研究治疗，并且根据美国食品药品监督管理局的快照方法，在第48周时，病毒载量为每毫升50拷贝或更高的参与者的百分比；如果治疗差异的多重校正95%置信区间的上限小于4%，则可得出非劣效性结论。

The trial is registered at ClinicalTrials.gov, NCT05630755, and is ongoing but closed to enrolment.

该试验已在ClinicalTrials.gov注册，注册号为NCT05630755，目前正在进行中，但已停止招募新参与者。

Results

Between Feb 17 and Nov 17, 2023, 585 individuals were screened, of whom 514 were randomly assigned and 513 treated: 342 participants were switched to doravirine (100 mg) and islatravir (0·25 mg) and 171 continued bictegravir, emtricitabine, and tenofovir alafenamide.

在2023年2月17日至11月17日期间，共有585名个体接受了筛查，其中514名被随机分配并接受了治疗：342名参与者改用多拉韦林（100毫克）和伊司他夫韦（0.25毫克），另外171名继续使用比克替拉韦、恩曲他滨和替诺福韦阿仑酸酯。

The median age of the 513 participants was 47 years (IQR 37-58), 403 (79%) were assigned male and 110 (21%) were assigned female at birth, 158 (31%) were Black or African American, and 117 (23%) were Hispanic, Latino, or Latina.

513名参与者的中位年龄为47岁（四分位数间距37-58），其中403名（79%）被分配为男性，110名（21%）出生时被分配为女性，158名（31%）为黑人或非裔美国人，117名（23%）为西班牙裔、拉丁裔或拉丁美洲裔。

At week 48, doravirine and islatravir showed non-inferiority to bictegravir, emtricitabine, and tenofovir alafenamide (viral load ≥50 copies per mL in five [1·5%] of 342 vs one [0·6%] of 171 participants) with a treatment difference of 0·9% (multiplicity-adjusted 95% CI -1·9 to 2·9).

在第48周时，多拉韦林和伊斯拉特拉韦与比克特格拉韦、恩曲他滨和替诺福韦阿拉芬酰胺相比显示出非劣效性（病毒载量≥50拷贝/毫升的患者分别为五例[1.5%]和一例[0.6%]），治疗差异为0.9%（多重校正的95%置信区间为-1.9至2.9）。

The rates of adverse events (74·6% [255 of 342 participants] vs 71·3% [122 of 171 participants]; difference 3·2 [95% CI -4·7 to 11·6]), treatment-related adverse events (10·2% [35] vs 9·4% [16]; 0·9 [-5·1 to 6·0]), serious adverse events (4·4% [15] vs 6·4% [11]; -2·0 [-7·1 to 1·9]), and discontinuations due to adverse events (2·9% [ten] vs 1·8% [three]; 1·2 [-2·3 to 3·9]) were similar in the doravirine and islatravir group and the bictegravir, emtricitabine, and tenofovir alafenamide group, and no deaths were reported.

不良事件的发生率（多拉韦林和伊斯拉特拉韦组为74.6% [255/342]，比克特格拉韦、恩曲他滨和替诺福韦阿拉芬酰胺组为71.3% [122/171]；差异为3.2 [95% CI -4.7至11.6]）、与治疗相关的不良事件（分别为10.2% [35]和9.4% [16]；差异为0.9 [-5.1至6.0]）、严重不良事件（分别为4.4% [15]和6.4% [11]；差异为-2.0 [-7.1至1.9]）以及因不良事件导致的停药率（分别为2.9% [十]和1.8% [三]；差异为1.2 [-2.3至3.9]）在多拉韦林和伊斯拉特拉韦组与比克特格拉韦、恩曲他滨和替诺福韦阿拉芬酰胺组之间相似，并且没有报告死亡病例。

interpretation

The combination of doravirine (100 mg) and islatravir (0·25 mg) has similar efficacy and safety profiles to bictegravir, emtricitabine, and tenofovir alafenamide, and could provide a two-drug, once daily, oral single-tablet option without an integrase strand-transfer inhibitor for adults who are virologically suppressed and want to switch to a different ART regimen.

多拉韦林（100毫克）与伊斯拉特韦（0.25毫克）的联合使用与比克替拉韦、恩曲他滨和替诺福韦阿法米具有相似的疗效和安全性，为病毒学抑制的成人提供了一种不含整合酶链转移抑制剂的双药、每日一次、口服单片剂选择，这些成人希望转换到不同的抗逆转录病毒治疗方案。

funding

Merck Sharp & Dohme, a subsidiary of Merck & Co.

默克夏普与多姆公司，默克公司的子公司。