NS5A抑制剂达卡他韦联合聚乙二醇干扰素和利巴韦林治疗丙型肝炎病毒4型的随机对照试验（COMMAND-4）
Randomized controlled trial of the NS5A inhibitor daclatasvir plus pegylated interferon and ribavirin for HCV genotype-4 (COMMAND-4).
作者信息
Hézode Christophe, Alric Laurent, Brown Ashley, Hassanein Tarek, Rizzetto Mario, Buti Maria, Bourlière Marc, Thabut Dominique, Molina Esther, Rustgi Vinod, Samuel Didier, McPhee Fiona, Liu Zhaohui, Yin Philip D, Hughes Eric, Treitel Michelle
机构信息
Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France.
出版信息
Antivir Ther. 2015 Aug 27;21(3):195-205. doi: 10.3851/IMP2985.
BACKGROUND
Treatment options for HCV genotype-4 (GT4) are limited. This Phase III study (COMMAND-4; AI444-042) evaluated the efficacy and safety of daclatasvir (DCV), a pan-genotypic HCV NS5A inhibitor, with pegylated interferon-α2a/ribavirin (PEG-IFN/RBV) in treatment-naive patients with HCV GT4 infection.
METHODS
Patients were randomly assigned (2:1; blinded) to treatment with DCV 60 mg (n=82) or placebo (n=42) once daily plus PEG-IFN 180 µg weekly and RBV 1,000-1,200 mg/day (weight-based) twice daily. DCV-treated patients with undetectable HCV RNA at weeks 4 and 12 (eRVR) received 24 weeks of DCV plus PEG-IFN/RBV; those without eRVR received an additional 24 weeks of PEG-IFN/RBV. All placebo-treated patients received 48 weeks of PEG-IFN/RBV. The primary end point was sustained virological response (SVR) at post-treatment week 12 (SVR12).
RESULTS
Patients were 75% IL28B non-CC and 11% had cirrhosis. SVR rates (HCV RNA < lower limit of quantitation [LLOQ]) at post-treatment week 12 or later (imputed to include patients missing SVR12 assessments but had SVR after post-treatment week 12) were 82% (67/82) with DCV plus PEG-IFN/RBV versus 43% (18/42) with PEG-IFN/RBV (P<0.0001). In DCV recipients, SVR12 rates were comparable across subgroups. The safety and tolerability profile of DCV plus PEG-IFN/RBV was comparable to that of PEG-IFN/RBV. Discontinuations due to adverse events occurred in 4.9% of patients receiving DCV plus PEG-IFN/RBV and 7.1% of patients receiving PEG-IFN/RBV.
CONCLUSIONS
In treatment-naive patients with HCV GT4 infection, DCV plus PEG-IFN/RBV achieved higher SVR12 rates than PEG-IFN/RBV alone. These data support DCV-based regimens for treatment of HCV GT4 infection, including all-oral combinations with other direct-acting antivirals (AI444-042; ClinicalTrials.gov NCT01448044).
背景
丙型肝炎病毒基因4型（GT4）的治疗选择有限。这项III期研究（COMMAND-4；AI444-042）评估了泛基因型丙型肝炎病毒NS5A抑制剂达克拉他韦（DCV）联合聚乙二醇化干扰素-α2a/利巴韦林（PEG-IFN/RBV）在初治丙型肝炎病毒GT4感染患者中的疗效和安全性。
方法
患者被随机分配（2:1；盲法）接受每日一次60 mg DCV治疗（n = 82）或安慰剂治疗（n = 42），同时每周一次接受180 μg PEG-IFN和每日两次1000 - 1200 mg（基于体重）的RBV治疗。在第4周和第12周丙型肝炎病毒RNA检测不到（eRVR）的接受DCV治疗的患者接受24周的DCV联合PEG-IFN/RBV治疗；无eRVR的患者再接受24周的PEG-IFN/RBV治疗。所有接受安慰剂治疗的患者接受48周的PEG-IFN/RBV治疗。主要终点是治疗后第12周的持续病毒学应答（SVR）（SVR12）。
结果
患者中75%为IL28B非CC型，11%有肝硬化。治疗后第12周或更晚时（推算包括错过SVR12评估但在治疗后第12周后获得SVR的患者）的SVR率（丙型肝炎病毒RNA <定量下限[LLOQ]），DCV联合PEG-IFN/RBV组为82%（67/82），而PEG-IFN/RBV组为43%（18/42）（P<0.0001）。在接受DCV治疗的患者中，各亚组的SVR12率相当。DCV联合PEG-IFN/RBV的安全性和耐受性与PEG-IFN/RBV相当。因不良事件停药的情况在接受DCV联合PEG-IFN/RBV治疗的患者中占4.9%，在接受PEG-IFN/RBV治疗的患者中占7.1%。
结论
在初治丙型肝炎病毒GT4感染患者中，DCV联合PEG-IFN/RBV获得的SVR12率高于单用PEG-IFN/RBV。这些数据支持基于DCV的方案用于治疗丙型肝炎病毒GT4感染，包括与其他直接作用抗病毒药物的全口服联合方案（AI444-042；ClinicalTrials.gov NCT01448044）。
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