Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials
Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials
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DOI：
10.1016/s0140-6736(18)32462-0
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发表时间：
2019-01-12
期刊：
影响因子：
168.9
通讯作者：
Smith, Kimberly
中科院分区：
文献类型：
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作者：
Cahn, Pedro;Sierra Madero, Juan;Smith, Kimberly
研究背景有效的双药方案可以减少HIV-1抗逆转录病毒治疗（ART）的长期药物暴露和毒性。因此，我们的目的是评估的疗效和安全性的两种药物的方案相比，一个threedrug方案治疗HIV-1感染的ART-naive adults.Methods我们进行了两个相同的设计，多中心，双盲，随机，非劣效性，3期试验：GEMINI-1和GEMINI-2。这两项研究均在21个国家的192个中心进行。我们将参与者（≥ 18岁）HIV-1感染者，筛查HIV-1 RNA为500 000拷贝/mL或更低，并且未接受过ART。1）接受dolutegravir（50 mg）+lamivudine（300 mg）每日一次的两药方案或dolutegravir（50 mg）每日一次的三药方案加富马酸替诺福韦酯（300 mg）和恩曲他滨（200 mg）。两种药物方案均经口给药。我们对参与者和研究者进行了治疗分配的盲法：度鲁特韦作为单一实体片剂给药（类似于其商业制剂，除了薄膜颜色不同），拉米夫定片剂和富马酸替诺福韦二异丙酯和恩曲他滨片剂被包裹在胶囊中，以视觉上相互匹配。主要终点是意向治疗暴露人群中第48周时HIV-1 RNA低于50拷贝/mL的受试者比例，使用快照算法，非劣效性界值为-10%。对安全性人群进行了安全性分析。GEMINI-1和GEMINI-2已在ClinicalTrials注册。在2016年7月18日至2017年3月31日期间，两项研究的1441名参与者被随机分配接受两种药物方案（n=719）或三种药物方案（n=722）。在GEMINI-1意向治疗暴露人群中，第48周时，356名接受两种药物方案的参与者中有320名（90%）和358名接受三种药物方案的参与者中有332名（93%）的血浆HIV-1 RNA低于50拷贝/mL（校正治疗差异-2.6%，95%CI-6.7至1.5）;在GEMINI-2中，两种药物方案中360例患者中有335例（93%）和三种药物方案中359例患者中有337例（94%）实现了HIV-1 RNA低于50拷贝/mL（校正的治疗差异-0.7%，95% CI -4.3至2.9），显示两项研究的非劣效性界值为-10%（汇总分析：两药方案716例中655例[91%]，三药方案717例中669例[93%];校正治疗差异-1.7%，95%CI-4.4至1.1）。从数字上看，三药方案发生的药物相关不良事件多于两药方案（717例中的169例[24%] vs 716例中的126例[18%]）;很少有参与者因不良事件而停药（三药方案中的16例[2%]和两药方案中的15例[2%]）。GEMINI-2的两种药物方案组中报告了两例死亡，但均不被认为与研究药物有关。解释度鲁特韦加拉米夫定的非劣效性和相似的耐受性特征，在ART初治的成人中，48周时，指南推荐的三种药物方案支持其作为HIV-1感染患者的初始治疗。版权所有（c）2018 Elsevier Ltd.保留所有权利。
Background Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a threedrug regimen for the treatment of HIV-1 infection in ART-naive adults.Methods We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (>= 18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1: 1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of -10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials. gov, numbers NCT02831673 and NCT02831764, respectively.Findings Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-totreat- exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -2.6%, 95% CI -6.7 to 1.5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -0.7%, 95% CI -4.3 to 2.9), showing non-inferiority at a -10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference -1.7%, 95% CI -4.4 to 1.1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication.Interpretation The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guidelinerecommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. Copyright (c) 2018 Elsevier Ltd. All rights reserved.