Lancet. 2014 Apr 26;383(9927):1474-1482. doi: 10.1016/S0140-6736(13)62187-X. Epub 2014 Feb 10.
The optimum dose of key antiretroviral drugs is often overlooked during product development. The ENCORE1 study compared the efficacy and safety of reduced dose efavirenz with standard dose efavirenz in combination with tenofovir and emtricitabine as first-line treatment for HIV infection. An effective and safe reduced dose could yield meaningful cost savings.
ENCORE1 is a continuing non-inferiority trial in HIV-1-infected antiretroviral-naive adults in 38 clinical sites in 13 countries. Participants (plasma HIV-RNA >1000 log10 copies per mL, CD4 T-cell count 50-500 cells per μL) were randomly assigned by a computer-generated sequence with a blocking factor of four (stratified by clinical site and by screening viral load) to receive tenofovir plus emtricitabine with either a reduced daily dose (400 mg) or a standard dose (600 mg) of efavirenz. Participants, physicians, and all other trial staff were masked to treatment group. The primary endpoint was the difference in proportions of participants with plasma HIV-RNA of less than 200 copies per mL at 48 weeks. Treatment groups were regarded as non-inferior if the lower limit of the 95% CI for the difference in viral load was less than -10% by modified intention-to-treat analysis. Adverse events were summarised by treatment. This trial is registered with ClinicalTrials.gov, number NCT01011413.
The modified intention-to-treat analysis consisted of 630 patients (efavirenz 400=321; efavirenz 600=309). 32% were women; 37% were African, 33% were Asian, and 30% were white. The mean baseline CD4 cell count was 273 cells per μL (SD 99) and median plasma HIV-RNA was 4·75 log10 copies per mL (IQR 0·88). The proportion of participants with a viral load below 200 copies per mL at week 48 was 94·1% for efavirenz 400 mg and 92·2% for 600 mg (difference 1·85%, 95% CI -2·1 to 5·79). CD4 T-cell counts at week 48 were significantly higher for the 400 mg group than for the 600 mg group (mean difference 25 cells per μL, 95% CI 6-44; p=0·01). We recorded no difference in grade or number of patients reporting adverse events (efavirenz 400=89·1%, efavirenz 600=88·4%; difference 0·75%, 95% CI -4·19 to 5·69; p=0·77). Study drug-related adverse events were significantly more frequent in the 600 mg group than in the 400 mg group (146% [47] vs 118 [37]), difference -10·5%, 95% CI -18·2 to -2·8; p=0·01) and significantly fewer patients with these events stopped treatment (400 mg=6 [2%], 600 mg=18 [6%], difference -3·96%, 95% CI -6·96 to -0·95; p=0·01).
Our findings suggest that a reduced dose of 400 mg efavirenz is non-inferior to the standard dose of 600 mg, when combined with tenofovir and emtricitabine during 48 weeks in ART-naive adults with HIV-1 infection. Adverse events related to the study drug were more frequent with 600 mg efavirenz than with 400 mg. Lower dose efavirenz should be recommended as part of routine care.
Bill & Melinda Gates Foundation, University of New South Wales.
在产品开发过程中，往往会忽略关键抗逆转录病毒药物的最佳剂量。ENCORE1 研究比较了在初治 HIV 感染的成年患者中，使用低剂量依非韦伦（每日 400mg）与标准剂量依非韦伦（每日 600mg）联合替诺福韦和恩曲他滨作为一线治疗的疗效和安全性。有效的、安全的低剂量可能会带来有意义的成本节约。
ENCORE1 是一项在 13 个国家的 38 个临床中心进行的、持续的非劣效性试验，纳入了 HIV-1 感染的初治、未接受过抗逆转录病毒治疗的成年患者。参与者（血浆 HIV-RNA>1000log10 拷贝/ml，CD4 T 细胞计数 50-500 个/μL）按照计算机生成的序列和四分组（按临床中心和筛查病毒载量分层）随机分配，接受替诺福韦和恩曲他滨联合每日 400mg 或 600mg 标准剂量的依非韦伦治疗。参与者、医生和所有其他试验工作人员均对治疗分组设盲。主要终点是治疗 48 周时血浆 HIV-RNA<200 拷贝/ml 的参与者比例。如果改良意向治疗分析的下限为病毒载量差异的-10%，则认为治疗组非劣效。不良事件按照治疗进行总结。本试验在 ClinicalTrials.gov 注册，编号为 NCT01011413。
改良意向治疗分析包括 630 名患者（依非韦伦 400mg 组=321 例，依非韦伦 600mg 组=309 例）。32%为女性，37%为非洲裔，33%为亚洲裔，30%为白种人。平均基线 CD4 细胞计数为 273 个/μL（标准差 99），中位数血浆 HIV-RNA 为 4.75log10 拷贝/ml（IQR 0.88）。治疗 48 周时，血浆 HIV-RNA<200 拷贝/ml 的参与者比例，依非韦伦 400mg 组为 94.1%，依非韦伦 600mg 组为 92.2%（差异 1.85%，95%CI-2.1 至 5.79）。400mg 组治疗 48 周时的 CD4 T 细胞计数明显高于 600mg 组（平均差异 25 个/μL，95%CI 6-44；p=0.01）。我们没有记录到任何在报告不良事件的患者中出现的等级或数量差异（依非韦伦 400mg 组为 89.1%，依非韦伦 600mg 组为 88.4%；差异 0.75%，95%CI-4.19 至 5.69；p=0.77）。研究药物相关不良事件在 600mg 组比 400mg 组更常见（146%[47]例比 118%[37]例），差异-10.5%，95%CI-18.2 至-2.8；p=0.01），且更少的患者因这些事件停药（400mg 组 6 例[2%]，600mg 组 18 例[6%]，差异-3.96%，95%CI-6.96 至-0.95；p=0.01）。
我们的研究结果表明，在初治 HIV-1 感染的成年患者中，与替诺福韦和恩曲他滨联合应用 48 周时，依非韦伦的低剂量 400mg 与标准剂量 600mg 相比是非劣效的。与 600mg 依非韦伦相比，与研究药物相关的不良事件在 400mg 依非韦伦组更为常见。建议将低剂量依非韦伦作为常规治疗的一部分。
比尔及梅琳达·盖茨基金会、新南威尔士大学。
