Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial
Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial
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DOI：
10.1016/s0140-6736(12)60918-0
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发表时间：
2012-06-30
期刊：
影响因子：
168.9
通讯作者：
Kearney, Brian P.
中科院分区：
文献类型：
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作者：
DeJesus, Edwin;Rockstroh, Juergen K.;Kearney, Brian P.
背景HIV整合酶链转移抑制剂埃替拉韦（EVG）已与CYP 3A 4抑制剂考比司他（COBI）、恩曲他滨（FTC）和富马酸替诺福韦二异丙酯（TDF）共同配制成每日一次的单一片剂。我们比较了EVG/COBI/FTC/TDF与利托那韦增强（RTV）蛋白酶抑制剂方案阿扎那韦（ATV）/RTV+FTC/TDF作为HIV-1 infection.Methods的初始治疗，这3期，非劣效性研究招募了HIV-1 RNA浓度为5000拷贝/mL或更多和易感性阿扎那韦，恩曲他滨，替诺福韦初治患者。患者被随机分配（1：1）接受EVG/COBI/FTC/TDF或ATV/RTV+FTC/TDF加匹配的安慰剂，每天给药一次。通过交互式电话和网络应答系统访问计算机生成的随机序列进行随机化。患者、研究者和给予治疗、评估结局或分析数据的研究工作人员均对分配设盲。主要终点为48周后HIV RNA浓度≤ 50拷贝/mL（根据美国FDA快照算法），非劣效性界值为12%。该试验在ClinicalTrials.gov注册，编号NCT 01106586。结果筛选了1017名患者，入组了715名患者，并对708名患者进行了治疗（353名患者接受EVG/COBI/FTC/TDF治疗，355名患者接受ATV/RTV+FTC/TDF治疗）。对于主要结局，EVG/COBI/FTC/TDF非劣效于ATV/RTV+FTC/TDF（316例患者[89.5%] vs 308例患者[86.8%]，校正差异3.0%，95% CI -1.9%至7.8%）。两种方案均具有良好的安全性和耐受性; 13例（3.7%）患者与18例（5.1%）患者因不良事件而停止治疗。与接受ATV/RTV+ FTC/TDF的患者相比，接受EVG/COBI/FTC/TDF的患者肝功能检查结果异常的患者较少，空腹甘油三酯浓度的中位数增加较小（90 μ mol/L vs 260 μ mol/L，p=0.006）。到第2周，两个研究组的血清肌酐浓度中位值均出现小幅升高，同时肾小球滤过率估计值降低;它们通常在第8周稳定，并且直到第48周没有变化（中位数变化11 μ mol/L vs 7 μ mol/L）。解释如果给予监管批准，EVG/COBI/FTC/TDF将是第一个基于整合酶抑制剂的方案，每天给药一次，也是唯一一个配制成单一片剂用于初始HIV治疗的方案。
Background The HIV integrase strand transfer inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) into a once-daily, single tablet. We compared EVG/COBI/FTC/TDF with a ritonavir-boosted (RTV) protease inhibitor regimen of atazanavir (ATV)/RTV+FTC/TDF as initial therapy for HIV-1 infection.Methods This phase 3, non-inferiority study enrolled treatment-naive patients with an HIV-1 RNA concentration of 5000 copies per mL or more and susceptibility to atazanavir, emtricitabine, and tenofovir. Patients were randomly assigned (1: 1) to receive EVG/COBI/FTC/TDF or ATV/RTV+FTC/TDF plus matching placebos, administered once daily. Randomisation was by a computer-generated random sequence, accessed via an interactive telephone and web response system. Patients, and investigators and study staff who gave treatments, assessed outcomes, or analysed data were masked to the assignment. The primary endpoint was HIV RNA concentration of 50 copies per mL or less after 48 weeks (according to the US FDA snapshot algorithm), with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, number NCT01106586.Findings 1017 patients were screened, 715 were enrolled, and 708 were treated (353 with EVG/COBI/FTC/TDF and 355 with ATV/RTV+FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to ATV/RTV+FTC/TDF for the primary outcome (316 patients [89.5%] vs 308 patients [86.8%], adjusted difference 3.0%, 95% CI -1.9% to 7.8%). Both regimens had favourable safety and tolerability; 13 (3.7%) versus 18 (5.1%) patients discontinued treatment because of adverse events. Fewer patients receiving EVG/COBI/FTC/TDF had abnormal results in liver function tests than did those receiving ATV/RTV+FTC/TDF and had smaller median increases in fasting triglyceride concentration (90 mu mol/L vs 260 mu mol/L, p=0.006). Small median increases in serum creatinine concentration with accompanying decreases in estimated glomerular filtration rate occurred in both study groups by week 2; they generally stabilised by week 8 and did not change up to week 48 (median change 11 mu mol/L vs 7 mu mol/L).Interpretation If regulatory approval is given, EVG/COBI/FTC/TDF would be the first integrase-inhibitor-based regimen given once daily and the only one formulated as a single tablet for initial HIV treatment.