Background

In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies.

Methods

We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov, NCT02607930 and NCT02607956.

Findings

629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and tenofovir alafenamide, 325 to dolutegravir, emtricitabine, tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference −2·6%, 95% CI −8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (difference −1·9%, −7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (−0·1 vs −0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study.

Interpretation

These long-term data support the use of bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance.

Funding

Gilead Sciences.

中文翻译：

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固定剂量组合比克替拉韦、恩曲他滨和替诺福韦艾拉酚胺与含有多替拉韦的方案用于 HIV-1 感染的初始治疗：第 144 周来自两项随机、双盲、多中心、3 期、非劣效性试验。

背景

在两项 3 期研究的主要 48 周分析中，联合配制的比克替拉韦、恩曲他滨和替诺福韦艾拉酚胺在未接受过治疗的 HIV 感染者中并不劣于含有多替拉韦的方案。我们报告了这些研究的第 144 周有效性和安全性结果。

方法

我们进行了两项双盲、主动对照研究（现在处于开放标签扩展阶段）。研究 1 随机分配 (1:1) HLA-B*5701 阴性且无乙型肝炎病毒合并感染的成人接受联合配制的比替拉韦 50 mg、恩曲他滨 200 mg 和替诺福韦艾拉酚胺 25 mg，或联合配制的多替拉韦 50 mg、阿巴卡韦 600 mg和拉米夫定 300 毫克，每天一次。研究 2 随机分配 (1:1) 成人接受比克替拉韦、恩曲他滨和替诺福韦艾拉酚胺，或多替拉韦 50 mg 与联合配方的恩曲他滨 200 mg 和替诺福韦艾拉酚胺 25 mg。我们之前报告了主要终点的非劣效性。在这里，我们报告了第 144 周血浆 HIV-1 RNA 低于每毫升 50 拷贝的参与者比例的第 144 周次要结果，通过美国食品和药物管理局快照算法，以相同的方式分析。

发现

629 名参与者在研究 1 中被随机分配并接受治疗（314 名接受比克替拉韦、恩曲他滨和替诺福韦艾拉酚胺，315 名接受多替拉韦、阿巴卡韦和拉米夫定）和 645 名参加研究 2（327 名接受比克替拉韦、恩曲他滨和 5 替诺福韦替诺福韦拉米韦33 、恩曲他滨、替诺福韦艾拉酚胺）。在第 144 周时，比克替拉韦、恩曲他滨和替诺福韦艾拉酚胺在疗效方面不劣于含有多替拉韦的两种方案。在研究 1 中，比克替拉韦、恩曲他滨和替诺福韦艾拉酚胺组的 314 名参与者中有 256 名 (82%) 的血浆 HIV-1 RNA 低于每毫升 50 拷贝，而多替拉韦、阿巴卡韦和拉米夫定组的 315 名参与者中有 265 名 (84%)组（差异 -2·6%，95% CI -8·5 至 3·4）。在研究 2 中，320 名参与者中有 262 名 (82%) 的血浆 HIV-1 RNA 在比替拉韦、恩曲他滨、和替诺福韦艾拉酚胺组以及多替拉韦、恩曲他滨和替诺福韦艾拉酚胺组中的 325 个中的 273 个 (84%)（差异 -1·9%、-7·8 至 3·9）。在这两项研究中，直到第 144 周，没有参与者对研究药物产生治疗性耐药性。所有治疗方案均能很好地耐受额外暴露。比克替拉韦、恩曲他滨和替诺福韦艾拉酚胺组中没有参与者报告导致研究药物停药的不良事件，而多替拉韦、阿巴卡韦和拉米夫定组（研究 1）中的 315 名参与者中有 5 名（2%）和 6 名（2%） ) 比克替拉韦、恩曲他滨和替诺福韦艾拉酚胺组中的 320 例，而多替拉韦、恩曲他滨和替诺福韦艾拉酚胺组中的 325 例中的 6 例 (2%)（研究 2）。在研究 1 中，与10 毫克/分升相比；p=0·034)、直接 LDL（21 mg/dL对14 mg/dL；p=0·004）和总胆固醇与 HDL 的比率（-0·1对-0·3；p=0·007）在第 144 周；在研究 2 中未观察到各组之间的差异。在两项研究中，所有治疗组均观察到体重增加，任一研究的第 144 周体重与基线的中位变化均无差异。

解释

这些长期数据支持使用比克替拉韦、恩曲他滨和替诺福韦艾拉酚胺作为 HIV 感染者的安全、耐受性良好和持久的治疗方法，没有出现耐药性。

资金

吉利德科学。