西美瑞韦联合聚乙二醇干扰素 α-2a 或 -2b 加利巴韦林治疗初治慢性丙型肝炎病毒基因 1 型感染患者（QUEST-2）：一项随机、双盲、安慰剂对照的 3 期临床试验。
Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial.
机构信息
Medizinische Hochschule Hannover, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany.
Service d'Hépatologie, Hôpital Beaujon, University Paris-Diderot and INSERM CRB3, Clichy, France.
出版信息
Lancet. 2014 Aug 2;384(9941):414-26. doi: 10.1016/S0140-6736(14)60538-9. Epub 2014 Jun 4.
BACKGROUND
Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerability of the combination of simeprevir, a one-pill, once-daily, oral HCV NS3/4A protease inhibitor versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin was assessed in treatment-naive patients with HCV genotype 1 infection.
METHODS
In the QUEST-2, phase 3 study, done at 76 sites in 14 countries (Europe, and North and South Americas), patients with confirmed chronic HCV genotype 1 infection and no history of HCV treatment were randomly assigned with a computer-generated allocation sequence in a ratio of 2:1 and stratified by HCV genotype 1 subtype and host IL28B genotype to receive simeprevir (150 mg once daily, orally), peginterferon alfa 2a (180 μg once weekly, subcutaneous injection) or 2b (according to bodyweight; 50 μg, 80 μg, 100 μg, 120 μg, or 150 μg once weekly, subcutaneous injection), plus ribavirin (1000-1200 mg/day or 800-1400 mg/day, orally; simeprevir group) or placebo (once daily, orally), peginterferon alfa 2a or 2b, plus ribavirin (placebo group) for 12 weeks, followed by just peginterferon alfa 2a or 2b plus ribavirin. Total treatment duration was 24 weeks or 48 weeks (simeprevir group) based on criteria for response-guided therapy (ie, HCV RNA <25 IU/mL undetectable or detectable at week 4 and undetectable week 12) or 48 weeks (placebo). Patients, study personnel, and the sponsor were masked to treatment assignment. The primary efficacy endpoint was sustained virological response at 12 weeks after the planned end of treatment (SVR12). Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01290679. Results from the primary (SVR12, week 60) analysis are presented.
FINDINGS
209 (81%) of 257 patients in the simeprevir group and 67 (50%) of 134 in the placebo group had SVR12 (adjusted difference 32·2%, 95% CI 23·3-41·2; p<0·0001). The incidences of adverse events were similar in the simeprevir and placebo groups at 12 weeks (246 [96%] vs 130 [97%]) and for the entire treatment (249 [97%] vs 132 [99%]), irrespective of the peginterferon alfa used. The most common adverse events were headache, fatigue, pyrexia, and influenza-like illness at 12 weeks (95 [37%) vs 45 [34%], 89 [35%] vs 52 [39%], 78 [30%] vs 48 [36%], and 66 [26%] vs 34 [25%], respectively) and for the entire treatment (100 [39%] vs 49 [37%], 94 [37%] vs 56 [42%], 79 [31%] vs 53 [40%], and 66 [26%] vs 35 [26%], respectively). Rash and photosensitivity frequencies were higher in the simeprevir group than in the placebo group (61 [24%] vs 15 [11%] and ten [4%] vs one [<1%], respectively). There was no difference in the prevalence of anaemia between the simeprevir and placebo groups (35 [14%] vs 21 [16%], respectively, at 12 weeks, and 53 [21%] vs 37 [28%], respectively, during the entire treatment).
INTERPRETATION
Addition of simeprevir to either peginterferon alfa 2a or peginterferon alfa 2b plus ribavirin improved SVR in treatment-naive patients with HCV genotype 1 infection, without worsening the known adverse events associated with peginterferon alfa plus ribavirin.
FUNDING
Janssen Infectious Diseases-Diagnostics.
背景
聚乙二醇干扰素（peginterferon）alfa 2a 或 2b 联合利巴韦林是丙型肝炎病毒（HCV）感染患者的标准治疗方法，但 HCV 基因型 1 感染患者的持续病毒学应答可能不理想。评估simeprevir（一种每日一次、口服的单一片剂 HCV NS3/4A 蛋白酶抑制剂）联合聚乙二醇干扰素 alfa 2a 或 2b 联合利巴韦林与安慰剂联合用于初治 HCV 基因型 1 感染患者的疗效、安全性和耐受性。
方法
在 QUEST-2 期、3 期研究中，在 14 个国家（欧洲、北美和南美）的 76 个地点进行，入组了确认患有慢性 HCV 基因型 1 感染且无 HCV 治疗史的患者，采用计算机生成的分配序列按 2:1 的比例随机分组，并按 HCV 基因型 1 亚型和宿主 IL28B 基因型分层，接受simeprevir（150mg，每日一次，口服）、聚乙二醇干扰素 alfa 2a（180μg，每周一次，皮下注射）或 2b（根据体重；50μg、80μg、100μg、120μg 或 150μg，每周一次，皮下注射），联合利巴韦林（simeprevir 组 1000-1200mg/天或 800-1400mg/天，口服；安慰剂组 1000-1200mg/天或 800-1400mg/天，口服）或安慰剂（每日一次，口服）、聚乙二醇干扰素 alfa 2a 或 2b 联合利巴韦林 12 周，然后仅接受聚乙二醇干扰素 alfa 2a 或 2b 联合利巴韦林。根据应答指导治疗的标准（即 HCV RNA <25IU/mL 不可检测或第 4 周可检测且第 12 周不可检测）或 48 周（安慰剂组）确定总治疗持续时间为 24 周或 48 周（simeprevir 组）。患者、研究人员和赞助商对治疗分配均不知情。主要疗效终点为治疗结束后 12 周的持续病毒学应答（SVR12）。分析采用意向治疗。该试验在 ClinicalTrials.gov 注册，编号为 NCT01290679。现将主要（SVR12，第 60 周）分析结果呈现。
结果
simeprevir 组 209 例（81%）和安慰剂组 67 例（50%）患者达到 SVR12（调整差异 32.2%，95%CI 23.3-41.2；p<0.0001）。simeprevir 组和安慰剂组在第 12 周（246 [96%] vs 130 [97%]）和整个治疗期间（249 [97%] vs 132 [99%]）的不良事件发生率相似，无论使用何种聚乙二醇干扰素 alfa 均如此。在第 12 周最常见的不良事件是头痛、疲劳、发热和流感样疾病（95 [37%] vs 45 [34%]，89 [35%] vs 52 [39%]，78 [30%] vs 48 [36%]，66 [26%] vs 34 [25%]），在整个治疗期间是头痛、疲劳、发热和流感样疾病（100 [39%] vs 49 [37%]，94 [37%] vs 56 [42%]，79 [31%] vs 53 [40%]，66 [26%] vs 35 [26%]）。在simeprevir 组比安慰剂组皮疹和光敏性的频率更高（61 [24%] vs 15 [11%]和 10 [4%] vs 1 [<1%]）。在第 12 周，simeprevir 组和安慰剂组的贫血发生率无差异（35 [14%] vs 21 [16%]，分别为 53 [21%] vs 37 [28%]，分别为整个治疗期间）。
结论
simeprevir 联合聚乙二醇干扰素 alfa 2a 或 2b 联合利巴韦林可提高初治 HCV 基因型 1 感染患者的 SVR，而不会加重与聚乙二醇干扰素 alfa 联合利巴韦林相关的已知不良事件。
资金来源
杨森传染病诊断学。
Zotero 插件