Ezintsha, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Ezintsha, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Lancet HIV. 2020 Oct;7(10):e666-e676. doi: 10.1016/S2352-3018(20)30241-1.
ADVANCE compared the efficacy and safety of two antiretroviral first-line combinations (dolutegravir combined with emtricitabine and either tenofovir disoproxil fumarate or tenofovir alafenamide), with a third regimen (efavirenz combined with emtricitabine and tenofovir disoproxil fumarate) previously recommended by WHO. Here, we report the 96-week data for the study.
This randomised, open-label, non-inferiority phase 3 trial, was done at two research sites in Johannesburg, South Africa, after participant recruitment from 11 public health clinics also in Johannesburg. Eligible participants were aged 12 years or older with HIV-1 infection, who weighed at least 40 kg, had no antiretroviral exposure in the previous 6 months, with a creatinine clearance of more than 60 mL/min (>80 mL per min in individuals aged <19 years), and a plasma HIV-1 RNA concentration of 500 copies per mL or higher. Individuals who were pregnant or had tuberculosis were excluded. Participants were randomly assigned (1:1:1) by study staff using a computerised randomisation system. Randomisation was stratified by age (12 and <19 years and ≥19 years). Participants were randomly assigned to once-daily oral fixed-dose combination tenofovir alafenamide 25 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; once-daily oral fixed-dose combination tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; or once-daily oral fixed-dose combination of tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and efavirenz 600 mg. The primary efficacy endpoint was the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at week 48, which has been reported previously. Here, we report the key secondary efficacy endpoint of the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at the week 96 visit, assessed in all participants who received at least one dose of any study drug, with a prespecified non-inferiority margin of -10%. Safety data, including clinical, dual-energy X-ray absorptiometry and laboratory data, are also reported. This study was registered with ClinicalTrials.gov, NCT03122262.
Between Jan 17, 2017, and May 14, 2018, we screened 1453 individuals, of whom 1053 were enrolled: 351 participants were randomly assigned to the tenofovir alafenamide, emtricitabine, and dolutegravir group, 351 to the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 351 to the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group. All participants received at least one dose of study medication and were included in the primary analysis. At week 96, 276 (79%) of 351 participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group, 275 (78%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 258 (74%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group had achieved a plasma HIV-1 RNA concentration of less than 50 copies per mL. Non-inferiority was established in all three comparisons. The proportion of patients with protocol-defined virological failure at week 96 was low in all treatment groups. Participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group had fewer changes in bone density than the two other treatment groups. Mean weight gain was substantial (7·1 kg [SD 7·4] in the tenofovir alafenamide, emtricitabine, and dolutegravir group; 4·3 kg [6·7] in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 2·3 kg [7·0] in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group), and was greater among women than men. Ten (3%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group discontinued due to treatment-related adverse events, of which liver dysfunction (n=4) and rash (n=4) were most common.
Medium-term and long-term metabolic and clinical consequences of the considerable increase in bodyweight observed in participants given these antiretroviral regimens and the trajectory of this weight gain over time, especially among women, require further study.
USAID, Unitaid, South African Medical Research Council, ViiV Healthcare.
ADVANCE 研究比较了两种抗逆转录病毒一线治疗方案（多替拉韦联合恩曲他滨和替诺福韦二吡呋酯或替诺福韦艾拉酚胺）与此前世卫组织推荐的第三种方案（依非韦伦联合恩曲他滨和替诺福韦二吡呋酯）的疗效和安全性。在此，我们报告该研究的 96 周数据。
这项随机、开放标签、非劣效性 3 期临床试验在南非约翰内斯堡的两个研究地点进行，入组对象为来自约翰内斯堡 11 个公共卫生诊所的年龄 12 岁及以上、体重至少 40 kg、过去 6 个月内未接受过任何抗逆转录病毒治疗、肌酐清除率大于 60 mL/min（19 岁以下个体的肌酐清除率大于 80 mL/min）、血浆 HIV-1 RNA 浓度大于 500 拷贝/mL 的 HIV-1 感染者。排除妊娠或结核患者。由研究人员使用计算机随机化系统，按照 1:1:1 的比例将参与者随机分配到每天一次口服固定剂量复方替诺福韦艾拉酚胺 25 mg 和恩曲他滨 200 mg，以及每天一次口服多替拉韦 50 mg；每天一次口服固定剂量复方替诺福韦二吡呋酯 300 mg 和恩曲他滨 200 mg，以及每天一次口服多替拉韦 50 mg；或每天一次口服固定剂量复方替诺福韦二吡呋酯 300 mg、恩曲他滨 200 mg 和依非韦伦 600 mg。主要疗效终点是第 48 周时血浆 HIV-1 RNA 浓度小于 50 拷贝/mL 的参与者比例，该结果此前已报告。在此，我们报告了关键次要疗效终点，即在第 96 周时，所有接受至少一剂任何研究药物的参与者中，血浆 HIV-1 RNA 浓度小于 50 拷贝/mL 的参与者比例，非劣效性边界为-10%。还报告了安全性数据，包括临床、双能 X 射线吸收法和实验室数据。该研究在 ClinicalTrials.gov 注册，编号为 NCT03122262。
2017 年 1 月 17 日至 2018 年 5 月 14 日，我们筛查了 1453 名参与者，其中 1053 名入组：351 名参与者被随机分配到替诺福韦艾拉酚胺、恩曲他滨和多替拉韦组，351 名参与者被随机分配到替诺福韦二吡呋酯、恩曲他滨和多替拉韦组，351 名参与者被随机分配到替诺福韦二吡呋酯、恩曲他滨和依非韦伦组。所有参与者均至少接受一剂研究药物治疗，纳入主要分析。第 96 周时，替诺福韦艾拉酚胺、恩曲他滨和多替拉韦组 351 名参与者中有 276 名（79%），替诺福韦二吡呋酯、恩曲他滨和多替拉韦组 351 名参与者中有 275 名（78%），替诺福韦二吡呋酯、恩曲他滨和依非韦伦组 351 名参与者中有 258 名（74%）达到了血浆 HIV-1 RNA 浓度小于 50 拷贝/mL。所有三组比较均达到非劣效性。所有治疗组第 96 周时方案定义的病毒学失败比例较低。替诺福韦艾拉酚胺、恩曲他滨和多替拉韦组患者的骨密度变化较少。平均体重增加显著（替诺福韦艾拉酚胺、恩曲他滨和多替拉韦组为 7.1 kg[标准差 7.4]；替诺福韦二吡呋酯、恩曲他滨和多替拉韦组为 4.3 kg[6.7]；替诺福韦二吡呋酯、恩曲他滨和依非韦伦组为 2.3 kg[7.0]），女性比男性增加更多。替诺福韦二吡呋酯、恩曲他滨和依非韦伦组有 10 名（3%）参与者因治疗相关不良事件停药，其中肝功能障碍（n=4）和皮疹（n=4）最常见。
在接受这些抗逆转录病毒方案治疗的参与者中观察到的体重显著增加，以及尤其是女性参与者体重随时间的增加，对中期和长期的代谢和临床后果，需要进一步研究。
美国国际开发署、国际药品采购机制、南非医学研究理事会、辉瑞。
