Switch to fixed-dose doravirine (100 mg) and islatravir (0·25 mg) once daily in virologically suppressed adults with HIV-1 on oral antiretroviral therapy: 48-week results of a phase 3, multicentre, randomised, open-label, non-inferiority trial.

We aimed to evaluate the efficacy and safety of switching from stable, oral antiretroviral therapy (ART) to the fixed combination of doravirine (100 mg) and islatravir (0·25 mg) in virologically suppressed adults living with HIV-1.

我们的目标是评估从稳定的口服抗逆转录病毒治疗(ART)切换到固定剂量组合的doravirine (100 mg)和islaviravir (0·25 mg)在病毒学抑制的HIV-1成年患者中的疗效和安全性。

Methods

This phase 3, randomised, active-controlled, open-label, non-inferiority trial was conducted at 53 research, community, and hospital-based clinics in eight countries: Australia, Canada, Colombia, Japan, South Africa, Switzerland, the UK, and the USA.

这项第三阶段、随机、活性对照、开放标签、非劣效试验在八个国 家的53个研究、社区和医院诊所进行：澳大利亚、加拿大、哥伦比亚、日本、南非、瑞士、英国和美国。

Adults (aged ≥18 years) with a viral load of fewer than 50 copies of HIV-1 RNA per mL on any oral, two-drug or three-drug ART regimen for at least 3 months, with no history of treatment failure, known resistance to doravirine, or active hepatitis B infection, were randomly assigned (2:1) according to a computer-generated randomisation schedule (block size three) to receive oral doravirine (100 mg) and islatravir (0·25 mg) once daily or to continue baseline ART for 48 weeks.

年龄≥18岁的成年人，使用任何口服、两药或三药抗逆转录病毒治疗方案至少3个月，且HIV-1 RNA载量低于每毫升50拷贝，没有治疗失败史、已知对多拉韦林耐药或活动性乙型肝炎感染，根据计算机生成的随机分配表（块大小为三）被随机分配（2:1），接受口服多拉韦林（100毫克）和伊斯拉特拉韦（0.25毫克）每日一次，或继续使用基础抗逆转录病毒治疗48周。

Randomisation was stratified by the anchor antiretroviral drug class (integrase strand-transfer inhibitor [INSTI], non-nucleoside reverse transcriptase inhibitor, or protease inhibitor) in the baseline regimen.

随机分组根据基线方案中的锚定抗逆转录病毒药物类别（整合酶链转移抑制剂[INSTI]、非核苷类逆转录酶抑制剂或蛋白酶抑制剂）进行分层。

The primary endpoint (assessed in all treated participants) was the percentage of participants with a viral load of 50 copies per mL or higher at week 48 (analysed 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（在所有接受治疗的参与者中评估）是第48周时病毒载量≥50拷贝/毫升的参与者百分比（根据美国食品药品监督管理局快照方法进行分析）；如果治疗差异的多重校正95%置信区间上限小于4%，则可得出非劣效性结论。

The safety analysis population included all randomly assigned participants who received at least one dose of study treatment.

安全性分析人群包括所有随机分配的参与者，他们至少接受了一次研究治疗。

The trial is registered at ClinicalTrials.gov, NCT05631093, and is ongoing but closed to enrolment.

该试验已在ClinicalTrials.gov注册，注册号为NCT05631093，目前正在进行中，但已停止招募新参与者。

Results

Between Feb 20 and Oct 24, 2023, 614 individuals were screened for eligibility, of whom 553 were randomly assigned to receive doravirine and islatravir (n=368) or baseline ART (n=185). 551 participants received at least one dose of allocated medication: 366 in the doravirine and islatravir group and 185 in the baseline ART group.

2023年2月20日至10月24日期间，共有614名个体接受了资格筛查，其中553人被随机分配接受多拉韦林和伊斯拉特韦（n=368）或基线抗逆转录治疗（n=185）。551名参与者至少接受了分配药物的一剂：多拉韦林和伊斯拉特韦组366人，基线抗逆转录治疗组185人。

Of these 551 participants, 332 (60%) were assigned male and 219 (40%) were assigned female at birth, and the median age was 51 years (IQR 41-59); 250 (45%) identified as Black or African American and 80 (15%) identified as Hispanic, Latino, or Latina.

在这551名参与者中，332人（60%）出生时被指定为男性，219人（40%）被指定为女性，中位年龄为51岁（四分位数间距41-59岁）；250人（45%）自认为是黑人或非裔美国人，80人（15%）自认为是西班牙裔、拉丁裔或拉丁美洲人。

Doravirine and islatravir showed non-inferiority at week 48, with viral loads of 50 copies per mL or higher in five (1·4%) of 366 participants versus nine (4·9%) of 185 participants on baseline ART (difference -3·6% [multiplicity-adjusted 95% CI -7·8 to -0·8]).

多拉韦林和伊斯拉特拉韦在第48周显示出非劣效性，366名参与者中有5人（1.4%）的病毒载量为50拷贝/毫升或更高，而在185名基线抗逆转录病毒治疗（ART）的参与者中有9人（4.9%）（差异-3.6% [多重校正后的95%置信区间-7.8到-0.8]）。

Treatment-related adverse events were more common with doravirine and islatravir (44 [12·0%] of 366 participants) than with baseline ART (nine [4·9%] of 185 participants; difference 7·2 [95% CI 2·2 to 11·6]).

与基线抗逆转录病毒治疗（ART）相比，多拉韦林和伊斯拉特拉韦相关的不良事件更为常见（366名参与者中有44人[12.0%]），而基线ART的185名参与者中有9人[4.9%]出现不良事件；差异为7.2 [95% CI 2.2到11.6]。

Rates were similar in the doravirine and islatravir group and the baseline ART group for any adverse event(79·5% [291 of 366 participants] vs 83·8% [155 of 185 participants]; difference -4·3 [-10·7 to 2·8]), serious adverse events (6·3% [23] vs 4·9% [nine]; 1·4 [-3·2 to 5·2]), and discontinuation due to adverse events (0·5% [two] vs 2·2% [four]; -1·6 [-4·9 to 0·2]).

在多拉韦林和伊斯拉特韦尔组与基线抗逆转录治疗组中，任何不良事件的发生率相似（79·5% [291/366参与者] 对比 83·8% [155/185参与者]；差异 -4·3 [-10·7至2·8]），严重不良事件的发生率相似（6·3% [23] 对比 4·9% [9]；1·4 [-3·2至5·2]），因不良事件而中断治疗的发生率相似（0·5% [2] 对比 2·2% [4]；-1·6 [-4·9至0·2]）。

One death occurred (in the baseline ART group) and was not considered treatment-related.

发生了一例死亡（在基线抗逆转录治疗组中），且被认为与治疗无关。

No participants discontinued treatment as a result of protocol-specified declines in CD4 cell or total lymphocyte counts.

没有参与者因协议规定的CD4细胞或总淋巴细胞计数下降而中断治疗。

interpretation

Doravirine and islatravir is efficacious and well tolerated and would represent the first non-INSTI-based, two-drug regimen for HIV-1 treatment.

多拉韦林和伊斯拉特韦是有效且耐受性良好的，这将代表首个非整合酶抑制剂(INSTI)为基础的HIV-1治疗的两药方案。

With increasing concern over the potential development of widespread INSTI resistance, this once-daily, oral, single-tablet regimen could be a potential option for people living with HIV-1 requiring a change to their antiretroviral regimen.

随着对潜在广泛整合酶抑制剂(INSTI)耐药性发展的日益关注，这种每日一次、口服、单片剂方案可能是需要改变抗逆转录病毒方案的HIV-1携带者的一个潜在选择。

The safety and efficacy findings support the ongoing development of islatravir, a drug with long-acting potential.

安全性和有效性的发现支持了具有长效潜力的药物Islatravir的持续开发。

funding

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

默克夏普和多姆公司，默克公司的子公司