Division of Infectious Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Orlando Immunology Center, Orlando, FL, USA.
Lancet HIV. 2017 Apr;4(4):e154-e160. doi: 10.1016/S2352-3018(17)30016-4. Epub 2017 Feb 15.
All recent treatment guidelines recommend integrase strand transfer inhibitors (INSTIs) as components of initial HIV therapy. Bictegravir, a novel, once-daily, unboosted INSTI, showed potent activity in a 10 day monotherapy study and has a high in-vitro resistance barrier. On the basis of these results, we did a phase 2 trial comparing bictegravir with dolutegravir.
In this randomised, double-blind, phase 2 trial, we recruited previously untreated adults (aged ≥18 years) with HIV-1 infections from 22 outpatient centres in the USA. Eligible patients had HIV-1 RNA concentrations of at least 1000 copies per mL, CD4 counts of at least 200 cells per μL, estimated glomerular filtration rates of at least 70 mL per min, and HIV-1 genotypes showing sensitivity to emtricitabine and tenofovir. We excluded patients if they were hepatitis B-co-infected or hepatitis C-co-infected, had new AIDS-defining conditions within 30 days of screening, or were pregnant. We randomly allocated participants (2:1) to receive oral once-daily 75 mg bictegravir or 50 mg dolutegravir with matching placebo plus the fixed-dose combination of 200 mg emtricitabine and 25 mg tenofovir alafenamide for 48 weeks. We randomly allocated participants via an interactive web system, stratified by HIV-1 RNA concentration. Investigators, patients, study staff giving treatment, collecting data, and assessing outcomes, and the funder were masked to treatment group. The primary outcome was the proportion of participants with plasma HIV-1 RNA concentrations of less than 50 copies per mL at week 24 according to the US Food and Drug Administration-defined snapshot algorithm. We included all participants receiving one dose of study drug in analyses. This trial is registered with ClinicalTrials.gov, number NCT02397694.
Between March 23, 2015, and May 21, 2015, we screened 125 patients, randomly allocating and giving study drug to 98 (65 received bictegravir plus emtricitabine and tenofovir alafenamide and 33 received dolutegravir plus emtricitabine and tenofovir alafenamide). At week 24, 63 (96·9%) of 65 in the bictegravir group had HIV-1 RNA loads of less than 50 copies per mL compared with 31 (93·9%) of 33 in the dolutegravir group (weighted difference 2·9%, 95% CI -8·5 to 14·2; p=0·50). Treatment-emergent adverse events were reported by 55 (85%) of 65 participants in the bictegravir plus emtricitabine and tenofovir alafenamide group versus 22 (67%) of 33 in the dolutegravir plus emtricitabine and tenofovir alafenamide group. The most common adverse events were diarrhoea (eight [12%] of 65 vs four [12%] of 33) and nausea (five [8%] of 65 vs four [12%] of 33). One participant taking bictegravir plus emtricitabine and tenofovir alafenamide discontinued because of a drug-related adverse event (urticaria) after week 24. No treatment-related serious adverse events or deaths occurred.
Bictegravir plus emtricitabine and tenofovir alafenamide and dolutegravir plus emtricitabine and tenofovir alafenamide both showed high efficacy up to 24 weeks. Both treatments were well tolerated. Administration of bictegravir, a novel, potent, once-daily INSTI designed to improve on existing INSTI options with the backbone of emtricitabine and tenofovir alafenamide, might provide an advantage to patients.
Gilead Sciences.
所有最近的治疗指南都推荐整合酶抑制剂（INSTIs）作为初始 HIV 治疗的组成部分。双替拉韦是一种新型、每日一次、无需增效的 INSTI，在为期 10 天的单药治疗研究中表现出强大的活性，并且具有很高的体外耐药屏障。基于这些结果，我们进行了一项比较双替拉韦与多替拉韦的 2 期试验。
在这项随机、双盲、2 期试验中，我们从美国 22 个门诊中心招募了以前未接受过治疗的成年人（年龄≥18 岁），携带 HIV-1 感染。符合条件的患者 HIV-1 RNA 浓度至少为 1000 拷贝/ml，CD4 计数至少为 200 个/μl，估计肾小球滤过率至少为 70ml/min，并且 HIV-1 基因型对恩曲他滨和替诺福韦敏感。如果患者合并乙型肝炎或丙型肝炎感染、在筛选后 30 天内出现新的艾滋病定义性疾病，或怀孕，则将其排除在外。我们通过一个互动的网络系统，按 HIV-1 RNA 浓度分层，将参与者随机分配（2:1）接受每日一次口服 75mg 双替拉韦或 50mg 多替拉韦，同时给予匹配的安慰剂加 200mg 恩曲他滨和 25mg 替诺福韦艾拉酚胺的固定剂量组合，持续 48 周。我们通过一个互动的网络系统，按 HIV-1 RNA 浓度分层，随机分配参与者。调查人员、患者、给予治疗的研究人员、收集数据和评估结果的人员以及资助者对治疗组均不知情。主要结局是根据美国食品和药物管理局定义的快照算法，在第 24 周时 HIV-1 RNA 浓度低于 50 拷贝/ml 的参与者比例。我们将所有接受一剂研究药物的参与者纳入分析。该试验在 ClinicalTrials.gov 注册，编号为 NCT02397694。
在 2015 年 3 月 23 日至 5 月 21 日期间，我们筛选了 125 名患者，随机分配并给予 98 名患者（65 名接受双替拉韦加恩曲他滨和替诺福韦艾拉酚胺，33 名接受多替拉韦加恩曲他滨和替诺福韦艾拉酚胺）研究药物。在第 24 周时，65 名接受双替拉韦治疗的患者中有 63 名（96.9%）HIV-1 RNA 载量低于 50 拷贝/ml，而 33 名接受多替拉韦治疗的患者中有 31 名（93.9%）（加权差异 2.9%，95%CI-8.5 至 14.2；p=0.50）。在接受双替拉韦加恩曲他滨和替诺福韦艾拉酚胺治疗的 65 名患者中，有 55 名（85%）报告了治疗相关不良事件，而在接受多替拉韦加恩曲他滨和替诺福韦艾拉酚胺治疗的 33 名患者中，有 22 名（67%）报告了治疗相关不良事件（腹泻：8 [12%] 名患者 vs 4 [12%] 名患者；恶心：5 [8%] 名患者 vs 4 [12%] 名患者）。一名接受双替拉韦加恩曲他滨和替诺福韦艾拉酚胺治疗的患者在第 24 周后因药物相关不良事件（荨麻疹）停止治疗。没有发生与治疗相关的严重不良事件或死亡。
双替拉韦加恩曲他滨和替诺福韦艾拉酚胺与多替拉韦加恩曲他滨和替诺福韦艾拉酚胺均在 24 周内显示出较高的疗效。两种治疗方法均具有良好的耐受性。双替拉韦是一种新型、每日一次、无需增效的 INSTI，旨在通过恩曲他滨和替诺福韦艾拉酚胺的骨干提高现有 INSTI 的疗效，可能为患者提供优势。
吉利德科学公司。
