Division of Infectious Diseases, HIV-AIDS Unit, Geneva University Hospitals, Geneva, Switzerland.
TransVIHMI, University of Montpellier, IRD, INSERM, 34394 Montpellier, France.
Lancet HIV. 2020 Oct;7(10):e677-e687. doi: 10.1016/S2352-3018(20)30238-1.
Updated WHO guidelines recommend a dolutegravir-based regimen as the preferred first-line treatment for HIV infection and low-dose efavirenz (400 mg) as an alternative. We aimed to report the non-inferior efficacy of dolutegravir compared with efavirenz 400 mg at week 96.
We did a multicentre, randomised, open label, phase 3 trial in in three hospitals in Yaoundé, Cameroon, in HIV-1 infected antiretroviral-naive adults with an HIV RNA viral load of greater than 1000 copies per mL to compare dolutegravir 50 mg with efavirenz 400 mg (reference treatment), both combined with lamivudine and tenofovir disoproxil fumarate. The primary endpoint was the proportion with a viral load of less than 50 copies per mL at week 48 (10% non-inferiority margin). The study is registered with ClinicalTrials.gov, NCT02777229 and is ongoing.
Between July, 2016, and August, 2019, of 820 patients assessed, 613 were randomly assigned to receive at least one dose of study medication, with 310 in the dolutegravir group and 303 in the efavirenz 400 mg group. At week 96 in the intention-to-treat analysis, 229 (74%) of 310 patients receiving dolutegravir and 219 (72%) of 303 patients receiving efavirenz, achieved plasma HIV-1 RNA less than 50 copies per mL (difference 1·6%, 95% CI -5·4 to 8·6; p=0.66). Viral load suppression was reached significantly more rapidly in the dolutegravir group (p<0·001). Virological failure (>1000 copies per mL) was observed in 27 patients (eight in the dolutegravir group, among which, three women switched to efavirenz 600 mg because of the dolutegravir teratogeneicity signal, and 19 in the efavirenz 400 mg group). No acquired resistance mutations to dolutegravir were observed against 17 mutations to efavirenz with or without mutations to lamivudine and tenofovir disoproxil fumarate among the 19 efavirenz 400 mg participants with virological failure. Weight gain was greater in the dolutegravir group (median weight gain, 5·0 kg in the dolutegravir group and 3·0 kg in the efavirenz 400 mg group, p<0·001, and incidence of obesity, 22% in the dolutegravir group and 16% in the efavirenz 400 mg group, p=0·043). The incidence of new WHO HIV-related stage 3 and 4 events was similar in each group (12 [4%] in each group). The two groups had similar rates of serious adverse events (28 [9%] of 310 in the dolutegravir group and 21 [7%] of 303 in the efavirenz 400 mg group). 18 deaths were observed during the 96-week follow-up (eight in the dolutegravir group and ten in the efavirenz 400 mg group).
The non-inferior efficacy of the dolutegravir-based regimen and non-emergence of dolutegravir resistance at 96 weeks supports its use as a first-line regimen for antiretroviral-naive adults with HIV-1 infection. Viral load suppression was reached more quickly in the dolutegravir group and weight gain was significantly higher.
UNITAID and the French National Agency for AIDS Research.
世界卫生组织（WHO）更新后的指南推荐将基于多替拉韦的方案作为治疗人类免疫缺陷病毒（HIV）感染的首选一线治疗方法，同时将低剂量依非韦伦（400mg）作为替代方案。本研究旨在报告在第 96 周时，多替拉韦与依非韦伦 400mg 相比的非劣效疗效。
我们在喀麦隆雅温得的三家医院进行了一项多中心、随机、开放标签、3 期临床试验，纳入了 HIV-1 感染、初治、抗逆转录病毒药物治疗前 HIV RNA 病毒载量大于 1000 拷贝/ml 的成年患者，比较了多替拉韦 50mg 与依非韦伦 400mg（参考治疗），两者均与拉米夫定和富马酸替诺福韦二吡呋酯联合使用。主要终点是第 48 周时病毒载量小于 50 拷贝/ml 的比例（10%的非劣效性边缘）。该研究在 ClinicalTrials.gov 上注册，编号为 NCT02777229，正在进行中。
在 2016 年 7 月至 2019 年 8 月期间，对 820 名评估的患者进行了评估，其中 613 名患者被随机分配接受至少一剂研究药物，310 名患者接受多替拉韦治疗，303 名患者接受依非韦伦 400mg 治疗。在意向治疗分析中，在第 96 周时，310 名接受多替拉韦治疗的患者中有 229 名（74%）和 303 名接受依非韦伦 400mg 治疗的患者中有 219 名（72%）达到了血浆 HIV-1 RNA 小于 50 拷贝/ml（差异 1.6%，95%CI -5.4 至 8.6；p=0.66）。在多替拉韦组中，病毒载量抑制的达到速度明显更快（p<0.001）。在 27 名患者中观察到病毒学失败（>1000 拷贝/ml）（多替拉韦组 8 例，其中 3 例因多替拉韦的致畸性信号而转换为依非韦伦 600mg，依非韦伦 400mg 组 19 例）。在 19 例依非韦伦 400mg 治疗组病毒学失败的患者中，检测到了 17 种针对多替拉韦的耐药突变和 17 种针对依非韦伦的耐药突变，其中包括 19 例与拉米夫定和富马酸替诺福韦二吡呋酯无突变的患者。多替拉韦组的体重增加更为明显（多替拉韦组的中位数体重增加 5.0kg，依非韦伦 400mg 组为 3.0kg，p<0.001，肥胖的发生率，多替拉韦组为 22%，依非韦伦 400mg 组为 16%，p=0.043）。两组新发生的与 WHO 相关的 HIV 第 3 期和第 4 期事件的发生率相似（多替拉韦组和依非韦伦 400mg 组各 12 例[4%]）。两组严重不良事件的发生率相似（多替拉韦组 28 例[9%]，依非韦伦 400mg 组 21 例[7%]）。在 96 周的随访期间，观察到 18 例死亡（多替拉韦组 8 例，依非韦伦 400mg 组 10 例）。
第 96 周时多替拉韦方案的非劣效疗效和未出现多替拉韦耐药性支持将其作为 HIV-1 感染初治成年患者的一线治疗方案。多替拉韦组的病毒载量抑制更快达到，体重增加明显更高。
联合国艾滋病规划署和法国国家艾滋病研究署。
