A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients.
A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients.
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DOI：
10.1097/qad.0000000000001817
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发表时间：
2018-07-17
期刊：
影响因子：
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通讯作者：
AMBER study group
中科院分区：
文献类型：
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作者：
Eron JJ;Orkin C;Gallant J;Molina JM;Negredo E;Antinori A;Mills A;Reynes J;Van Landuyt E;Lathouwers E;Hufkens V;Jezorwski J;Vanveggel S;Opsomer M;AMBER study group
旨在研究达芦那韦/考比司他/恩曲他滨/替诺福韦艾拉酚胺 (D/C/F/TAF) 800/150/200/10 mg 单片方案与达芦那韦/考比司他加恩曲他滨/富马酸替诺福韦二吡呋酯 (TDF)（对照）在未接受抗逆转录病毒治疗的情况下的疗效和安全性， HIV-1 感染的成年人。 3 期、随机、主动对照、双盲、国际、多中心、非劣效性研究 (NCT02431247)。 725 名参与者被随机分配 (1 : 1) 至 D/C/F/TAF (362) 或对照组 (363)。主要目标是证明 D/C/F/TAF 与对照相比，在 48 周时病毒载量百分比低于 50 拷贝/ml（FDA 快照分析）时具有非劣效性（10% 裕度）。第 48 周时，D/C/F/TAF 不劣于对照（分别为 91.4% 和 88.4% 的病毒载量<50 拷贝/ml；差异 2.7%；95% CI -1.6 至 7.1；P < 0.0001），分别有 4.4% 和 3.3% 的患者病毒载量大于或等于50 拷贝/毫升。两组均未观察到与达芦那韦或 TAF/TDF 耐药性相关的治疗突变。一名患者 (D/C/F/TAF) 被鉴定为 M184I/V，对恩曲他滨产生耐药性。 3 级和 4 级不良事件（5% vs. 6%）、严重不良事件（5% vs. 6%）和不良事件相关停药（2% vs. 4%）的发生率较低，且组间相似。 D/C/F/TAF 组尿蛋白/肌酐比值的平均下降幅度大于对照组（-22.42 vs. -10.34 mg/g，P = 0.033）。 D/C/F/TAF与对照相比，骨矿物质密度的平均百分比变化为0.21 vs. -2.73%，P < 0.0001（髋部），-0.68 vs. -2.38%，P = 0.004（腰椎），以及-0.26 vs. -2.97%，P < 0.0001 （股骨颈）。总胆固醇/HDL-胆固醇比值相对于基线的中位变化为 0.20 与 0.08，P = 0.036。 D/C/F/TAF 实现了较高的病毒学抑制率 (91.4%)，并且不劣于达芦那韦/考比司他和 F/TDF。 D/C/F/TAF 还证明了 TAF 与达芦那韦/考比司他联合使用的骨和肾脏安全性优势。
To investigate efficacy and safety of a single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg vs. darunavir/cobicistat plus emtricitabine/tenofovir disoproxyl fumarate (TDF) (control) in antiretroviral-treatment-naive, HIV-1-infected adults. Phase-3, randomized, active-controlled, double-blind, international, multicenter, noninferiority study (NCT02431247). Seven hundred and twenty-five participants were randomized (1 : 1) to D/C/F/TAF (362) or control (363). The primary objective was to demonstrate noninferiority of D/C/F/TAF vs. control for percentage viral load less than 50 copies/ml (FDA-snapshot analysis) at 48 weeks (10% margin). At week 48, D/C/F/TAF was noninferior to control (91.4 vs. 88.4% achieved viral load <50 copies/ml, respectively; difference 2.7%; 95% CI −1.6 to 7.1; P < 0.0001), with 4.4 vs. 3.3% of patients, respectively, having viral load greater or equal to 50 copies/ml. No treatment-emergent mutations associated with darunavir or TAF/TDF resistance were observed in either group. One patient (D/C/F/TAF) was identified with M184I/V conferring resistance to emtricitabine. Incidences of grades 3 and 4 adverse events (5 vs. 6%), serious adverse events (5 vs. 6%) and adverse event-related discontinuations (2 vs. 4%) were low and similar between groups. Mean decrease in urine protein/creatinine ratio was greater with D/C/F/TAF than control (−22.42 vs. −10.34 mg/g, P = 0.033). Mean percentage change in bone mineral density with D/C/F/TAF vs. control was 0.21 vs. −2.73%, P < 0.0001 (hip), −0.68 vs. −2.38%, P = 0.004 (lumbar spine), and −0.26 vs. −2.97%, P < 0.0001 (femoral neck). Median change from baseline in total cholesterol/HDL-cholesterol ratio was 0.20 vs. 0.08, P = 0.036. D/C/F/TAF achieved a high virologic suppression rate (91.4%) and was noninferior to darunavir/cobicistat with F/TDF. D/C/F/TAF also demonstrated the bone and renal safety advantages of TAF in combination with darunavir/cobicistat.