Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study
Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study
复制标题
DOI：
10.1016/s1473-3099(15)70060-5
复制
发表时间：
2015-07-01
影响因子：
56.3
通讯作者：
Dolan, Matthew
中科院分区：
文献类型：
--
作者：
Amin, Janaki;Becker, Stephen;Dolan, Matthew
ENCORE 1试验的第48周初步分析确定了与标准600 mg剂量相比，依法韦仑400 mg联合替诺福韦和恩曲他滨作为一线HIV治疗的病毒学非劣效性和安全性。这96周的后续试验评估的持久性，这种治疗的疗效和安全性超过96 weeks.Methods ENCORE 1是一个双盲，安慰剂对照，非劣效性试验在38个临床站点在13个国家。感染艾滋病毒的成年患者（≥ 16岁），既往未接受过抗逆转录病毒治疗，CD 4细胞计数为50-500个细胞/μ L，血浆HIV-1病毒载量至少为1000个拷贝/mL，随机分配（1：1）通过电子病例报告表接受固定剂量每日替诺福韦300 mg和恩曲他滨200 mg加依法韦仑400 mg每日或600 mg每日。参与者、医生和所有其他试验工作人员均对治疗分配设盲。根据基线时的HIV-1病毒载量（100 000拷贝/mL）对随机化进行分层。主要终点是第96周时两个治疗组中血浆HIV-1病毒载量低于200拷贝/mL的患者比例差异。如果通过改良的意向治疗分析，病毒载量差异的95% CI下限高于-10%，则认为治疗组非劣效。在改良的意向治疗、符合方案和非完成者=失败（NC = F）人群中评估非劣效性。按治疗组总结不良事件和严重不良事件。该研究注册于ClinicalTrials.gov，编号NCT 01011413。结果在2011年8月24日至2012年3月19日期间，636名合格参与者被招募并随机分配到两个治疗组（324名接受依法韦仑400 mg，312名接受依法韦仑600 mg）。接受至少一剂研究药物的意向治疗人群包括630例患者：依法韦仑400 mg组321例，依法韦仑600 mg组309例。585例患者（93%;依法韦仑400 mg组299例，600 mg组286例）完成了96周的随访。96周时，289在依法韦仑400 mg组的321例患者中，在依法韦仑600 mg组的309例患者中，90.6%的患者血浆HIV-1病毒载量低于200拷贝/mL（差异-0.6，95%CI-5.2至4.0; p = 0.72），这表明较低剂量的依法韦仑仍具有非劣效性。无论基线血浆病毒载量如何，均记录了阈值小于50和小于400拷贝/mL的非劣效性。依非韦伦400 mg组321例患者中有291例（91%）和600 mg组309例患者中有285例（92%）报告了不良事件（p = 0.48）。报告肯定或很可能与依法韦仑相关的不良事件的患者比例为依法韦仑400 mg组126例（39%），依法韦仑600 mg组148例（48%）（p = 0.03）。报告严重不良事件的患者数量在两组之间没有差异（p = 0.20）。解释我们的研究结果证实，依法韦仑400 mg不劣于标准剂量600 mg与替诺福韦和恩曲他滨联合作为初始HIV治疗超过96周。与600 mg剂量相比，400 mg剂量的依法韦仑报告的依法韦仑相关不良事件较少。这些结果支持依法韦仑400 mg的常规使用。利福平和依法韦仑400 mg联合给药需要进一步研究。
Background The week 48 primary analysis of the ENCORE1 trial established the virological non-inferiority and safety of efavirenz 400 mg compared with the standard 600 mg dose, combined with tenofovir and emtricitabine, as first-line HIV therapy. This 96-week follow-up of the trial assesses the durability of efficacy and safety of this treatment over 96 weeks.Methods ENCORE1 was a double-blind, placebo-controlled, non-inferiority trial done at 38 clinical sites in 13 countries. HIV-infected adult patients (>= 16 years of age) with no previous antiretroviral therapy, a CD4 cell count of 50-500 cells per mu L, and plasma HIV-1 viral load of at least 1000 copies per mL were randomly assigned (1: 1) by an electronic case report form to receive fixed-dose daily tenofovir 300 mg and emtricitabine 200 mg plus efavirenz either 400 mg daily or 600 mg daily. Participants, physicians, and all other trial staff were masked to treatment assignment. Randomisation was stratified by HIV-1 viral load at baseline ( 100 000 copies per mL). The primary endpoint was the difference in the proportions of patients in the two treatment groups with a plasma HIV-1 viral load below 200 copies per mL at week 96. Treatment groups were deemed to be non-inferior if the lower limit of the 95% CI for the difference in viral load was above -10% by modified intention-to-treat analysis. Non-inferiority was assessed in the modified intention-to-treat, per-protocol, and non-completer = failure (NC = F) populations. Adverse events and serious adverse events were summarised by treatment group. This study is registered with ClinicalTrials.gov, number NCT01011413.Findings Between Aug 24, 2011, and March 19, 2012, 636 eligible participants were enrolled and randomly assigned to the two treatment groups (324 to efavirenz 400 mg and 312 to efavirenz 600 mg). The intention-to-treat population who received at least one dose of study drug comprised 630 patients: 321 in the efavirenz 400 mg group and 309 in the efavirenz 600 mg group. 585 patients (93%; 299 in the efavirenz 400 mg group and 286 in the 600 mg group) completed 96 weeks of follow-up. At 96 weeks, 289 (90.0%) of 321 patients in the efavirenz 400 mg group and 280 (90.6%) of 309 in the efavirenz 600 mg group had a plasma HIV-1 viral load less than 200 copies per mL (difference -0.6, 95% CI -5.2 to 4.0; p = 0.72), which suggests continued non-inferiority of the lower efavirenz dose. Non-inferiority was recorded for thresholds of less than 50 and less than 400 copies per mL, irrespective of baseline plasma viral load. Adverse events were reported by 291 (91%) of 321 patients in the efavirenz 400 mg group and by 285 (92%) of 309 in the 600 mg group (p = 0.48). The proportions of patients reporting an adverse event that was definitely or probably related to efavirenz were 126 (39%) for efavirenz 400 mg and 148 (48%) for efavirenz 600 mg (p = 0.03). The number of patients who reported serious adverse events did not differ between the groups (p = 0.20).Interpretation Our findings confirm that efavirenz 400 mg is non-inferior to the standard dose of 600 mg in combination with tenofovir and emtricitabine as initial HIV therapy over 96 weeks. Fewer efavirenz-related adverse events were reported with the 400 mg efavirenz dose than with the 600 mg dose. These findings support the routine use of efavirenz 400 mg. The coadministration of rifampicin and efavirenz 400 mg needs further investigation.