Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study
Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study
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DOI：
10.1016/s1473-3099(15)00348-5
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发表时间：
2016-01-01
影响因子：
56.3
通讯作者：
McCallister, Scott
中科院分区：
文献类型：
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作者：
Mills, Anthony;Arribas, Jose R.;McCallister, Scott
背景 含有富马酸替诺福韦二吡呋酯的抗逆转录病毒疗法与肾毒性和骨矿物质密度降低有关。替诺福韦艾拉酚胺是一种新型替诺福韦前药，可将替诺福韦血浆浓度降低 90%，从而减少脱靶副作用。我们的目的是评估转用含有替诺福韦艾拉酚胺的治疗方案的患者与继续使用含有富马酸替诺福韦二吡呋酯的治疗方案的患者相比，疗效、安全性和耐受性是否不较差。 方法 在这项随机、主动对照、多中心、开放标签、非劣效性试验中，我们从吉利德在 19 个国家的 168 个地点进行的临床研究中招募了 HIV-1 感染的成年人。患者受到病毒学抑制（HIV-1 RNA < 50 拷贝/毫升），估计肾小球滤过率为每分钟 50 毫升或更高，并且在入组前至少 96 周正在服用四种含富马酸替诺福韦二吡呋酯的治疗方案之一。通过使用第三方计算机生成的序列，患者被随机分配 (2:1) 接受每日一次的单片治疗，其中含有埃替格韦 150 mg、考比司他 150 mg、恩曲他滨 200 mg 和替诺福韦艾拉酚胺 10 mg（替诺福韦艾拉酚胺组），或继续服用之前四种含富马酸替诺福韦二吡呋酯的方案之一（富马酸替诺福韦二吡呋酯组）持续 96 周。随机分组根据先前的治疗方案以六为一组进行分层。患者和治疗医生不会被告知指定的研究方案；结果评估人员在数据库锁定之前一直处于屏蔽状态。主要终点是接受至少一剂研究药物的患者在第 48 周时病毒载量无法检测到（HIV-1 RNA < 50 拷贝/毫升）的患者比例。非劣效裕度为 12%。这项研究已在 ClinicalTrials.gov 注册，编号为 NCT01815736。调查结果 2013 年 4 月 12 日至 2014 年 4 月 3 日期间，我们招募了 1443 名患者。 959 名患者被随机分配至替诺福韦艾拉酚胺组，477 名患者被随机分配至富马酸替诺福韦二吡呋酯组。第 48 周时，分配到替诺福韦艾拉酚胺组的 932 名患者 (97%) 和分配到富马酸替诺福韦二吡呋酯组的 444 名患者 (93%) 发现病毒抑制（调整后差异为 4. 1%，95% CI 1.6-6.7），分别有 10 名和 6 名患者出现病毒学失败。两组之间的不良事件数量相似，但替诺福韦艾拉酚胺组中与研究药物相关的不良事件更为常见（204 名患者 [21%] vs 76 名患者 [16%]）。与富马酸替诺福韦二吡呋酯组的患者相比，替诺福韦艾拉酚胺组的患者的髋部和脊柱骨矿物质密度以及肾小球滤过均显着改善。 解释：从含有富马酸替诺福韦二吡呋酯的方案转为含有替诺福韦艾拉酚胺的方案对于维持病毒抑制效果并不差，并且可以改善骨矿物质密度和肾功能。需要更长期的随访以更好地了解这些变化的临床影响。
Background Antiretroviral regimens containing tenofovir disoproxil fumarate have been associated with renal toxicity and reduced bone mineral density. Tenofovir alafenamide is a novel tenofovir prodrug that reduces tenofovir plasma concentrations by 90%, thereby decreasing off-target side-effects. We aimed to assess whether efficacy, safety, and tolerability were non-inferior in patients switched to a regimen containing tenofovir alafenamide versus in those remaining on one containing tenofovir disoproxil fumarate.Methods In this randomised, actively controlled, multicentre, open-label, non-inferiority trial, we recruited HIV-1-infected adults from Gilead clinical studies at 168 sites in 19 countries. Patients were virologically suppressed (HIV-1 RNA < 50 copies per mL) with an estimated glomerular filtration rate of 50 mL per min or greater, and were taking one of four tenofovir disoproxil fumarate-containing regimens for at least 96 weeks before enrolment. With use of a third-party computer-generated sequence, patients were randomly assigned (2: 1) to receive a once-a-day single-tablet containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg (tenofovir alafenamide group) or to carry on taking one of four previous tenofovir disoproxil fumarate-containing regimens (tenofovir disoproxil fumarate group) for 96 weeks. Randomisation was stratified by previous treatment regimen in blocks of six. Patients and treating physicians were not masked to the assigned study regimen; outcome assessors were masked until database lock. The primary endpoint was the proportion of patients who received at least one dose of study drug who had undetectable viral load (HIV-1 RNA < 50 copies per mL) at week 48. The non-inferiority margin was 12%. This study was registered with ClinicalTrials.gov, number NCT01815736.Findings Between April 12, 2013 and April 3, 2014, we enrolled 1443 patients. 959 patients were randomly assigned to the tenofovir alafenamide group and 477 to the tenofovir disoproxil fumarate group. Viral suppression at week 48 was noted in 932 (97%) patients assigned to the tenofovir alafenamide group and in 444 (93%) assigned to the tenofovir disoproxil fumarate group (adjusted difference 4 . 1%, 95% CI 1.6-6.7), with virological failure noted in ten and six patients, respectively. The number of adverse events was similar between the two groups, but study drug-related adverse events were more common in the tenofovir alafenamide group (204 patients [21%] vs 76 [16%]). Hip and spine bone mineral density and glomerular filtration were each significantly improved in patients in the tenofovir alafenamide group compared with those in the tenofovir disoproxil fumarate group.Interpretation Switching to a tenofovir alafenamide-containing regimen from one containing tenofovir disoproxil fumarate was non-inferior for maintenance of viral suppression and led to improved bone mineral density and renal function. Longer term follow-up is needed to better understand the clinical impact of these changes.