University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Lancet Infect Dis. 2011 Dec;11(12):907-15. doi: 10.1016/S1473-3099(11)70196-7. Epub 2011 Sep 18.
Twice-daily raltegravir with once-daily tenofovir-emtricitabine is an effective initial antiretroviral regimen for patients with HIV-1. On the basis of pharmacokinetic data suggesting efficacy of once-daily raltegravir and because adherence is often improved with once-daily dosing, we aimed to compare these dosing schedules.
In our international, double-blind, randomised, phase 3 non-inferiority study, we enrolled antiretroviral-naive patients with HIV RNA loads of more than 5000 copies per mL and no baseline resistance to tenofovir or emtricitabine at 83 centres worldwide. We randomly allocated patients (1:1) by use of a computer-generated sequence to receive raltegravir once daily (two 400 mg tablets taken together every 24 h), or twice daily (one 400 mg tablet every 12 h), both in combination with once-daily co-formulated tenofovir 300 mg plus emtricitabine 150 mg. The primary outcome was virological response at 48 weeks (viral RNA loads <50 copies per mL) in patients who received at least one dose of study drug, counting non-completers as failure. We assessed non-inferiority in terms of the proportion of patients in both treatment groups who achieved the primary outcome, with a non-inferiority margin of -10%. This study is registered with ClinicalTrials.gov, number NCT00745823.
From Oct 15, 2008, to Nov 2, 2009, we randomly allocated 775 patients, of whom 382 (99%) of 386 patients in the once-daily group and 388 (99%) of 389 in the twice-daily group received at least one dose of study drug. At baseline, 304 (39%) of 770 treated patients had viral loads of more than 100,000 copies per mL and 188 (24%) had CD4 cell counts of fewer than 200 cells per μL. 318 (83%) of 382 patients in the once-daily group had virological response compared with 343 (89%) of 386 in the twice-daily group (difference -5·7%, 95% CI -10·7 to -0·83; p=0·044). Serious adverse events were reported in 26 (7%) of 382 once-daily recipients and 40 (10%) of 388 twice-daily recipients, and adverse events leading to discontinuation occurred in four (1%) patients in each group.
Despite high response rates with both regimens, once-daily raltegravir cannot be recommended in place of twice-daily dosing.
Merck.
拉替拉韦每日两次联合每日一次替诺福韦-恩曲他滨，是一种治疗 HIV-1 的有效初始抗逆转录病毒方案。基于药代动力学数据表明每日一次拉替拉韦的疗效，并且由于每日一次给药可提高依从性，我们旨在比较这两种给药方案。
在我们的国际、双盲、随机、3 期非劣效性研究中，我们在全球 83 个中心招募了 HIV RNA 载量超过 5000 拷贝/ml 且无基线对替诺福韦或恩曲他滨耐药的初治 HIV 感染者。我们使用计算机生成的序列以 1:1 的比例随机分配患者（每天一次接受拉替拉韦，每次 400mg 两片一起服用，每 24 小时一次）或每日两次（每次 400mg 一片，每 12 小时一次），两种方案均联合每日一次的固定剂量复方替诺福韦 300mg 加恩曲他滨 150mg。主要终点是接受至少一剂研究药物的患者在 48 周时的病毒学应答（病毒载量<50 拷贝/ml），将失访者计为失败。我们评估了两组患者中达到主要终点的比例，以 -10%作为非劣效性边界。本研究在 ClinicalTrials.gov 注册，编号为 NCT00745823。
从 2008 年 10 月 15 日至 2009 年 11 月 2 日，我们随机分配了 775 名患者，其中每日一次组的 386 名患者中的 382 名（99%）和每日两次组的 389 名患者中的 388 名（99%）至少接受了一剂研究药物。在基线时，770 名接受治疗的患者中有 304 名（39%）病毒载量超过 100000 拷贝/ml，188 名（24%）CD4 细胞计数低于 200 个/μL。每日一次组的 318 名患者（83%）有病毒学应答，而每日两次组的 343 名患者（89%）有病毒学应答（差异 -5.7%，95%CI -10.7 至 -0.83；p=0.044）。每日一次组的 382 名患者中有 26 名（7%）和每日两次组的 388 名患者中有 40 名（10%）报告了严重不良事件，每组各有 4 名（1%）患者因不良事件而停药。
尽管两种方案的应答率都很高，但不能推荐每日一次的拉替拉韦替代每日两次的给药方案。
默克公司。
