西米普明与TMC647055/利托那韦联合或不联合利巴韦林以及JNJ-56914845在丙型肝炎病毒1型感染中的疗效、安全性和药代动力学
Efficacy, safety and pharmacokinetics of simeprevir and TMC647055/ritonavir with or without ribavirin and JNJ-56914845 in HCV genotype 1 infection.
作者信息
Bourgeois Stefan, Van Vlierberghe Hans, Moreno Christophe, Orlent Hans, Nevens Frederik, Arastéh Keikawus, Horsmans Yves, Schattenberg Jörn M, Buggisch Peter, Francque Sven, Vijgen Leen, Kakuda Thomas N, Hoeben Eva, Luo Donghan, Vandebosch An, Jacquemyn Bert, Van Remoortere Pieter, Verloes René
机构信息
Department of Gastroenterology & Hepatology, ZNA Antwerp, Antwerpen, Belgium.
Department of Hepatology and Gastroenterology, Universitair Ziekenhuis Gent, Ghent, Belgium.
出版信息
BMC Gastroenterol. 2017 Feb 10;17(1):26. doi: 10.1186/s12876-017-0580-2.
BACKGROUND
A Phase 2a, open-label study (NCT01724086) was conducted to assess the efficacy and safety of a once-daily, 2-direct-acting-antiviral-agent (2-DAA) combination of simeprevir + TMC647055/ritonavir ± ribavirin and of the 3-DAA combination of simeprevir + TMC647055/ritonavir + JNJ-56914845 in chronic hepatitis C virus genotype (GT)1-infected treatment-naïve and prior-relapse patients.
METHODS
The study comprised four 12-week treatment panels: Panel 1 (n = 10; GT1a) and Panel 2-Arm 1 (n = 12; GT1b): simeprevir 75 mg once daily + TMC647055 450 mg once daily/ritonavir 30 mg once daily + ribavirin 1000-1200 mg/day; Panel 2-Arm 2 (n = 9; GT1b): simeprevir 75 mg + TMC647055 450 mg/ritonavir 30 mg without ribavirin; Panel 3: simeprevir 75 mg + TMC647055 600 mg/ritonavir 50 mg with (Arm 1: GT1a; n = 7) or without (Arm 2: GT1b; n = 8) ribavirin; Panel 4: simeprevir 75 mg + TMC647055 450 mg/ritonavir 30 mg + JNJ-56914845 30 mg once daily (Arm 1: n = 22; GT1a/GT1b) or 60 mg once daily (Arm 2: n = 22; GT1a/GT1b). Primary endpoint was sustained virologic response 12 weeks after end of treatment (12 weeks of combination treatment; SVR12).
RESULTS
In Panel 1 and Panel 2-Arm 1, 5/10 and 6/12 (50%) GT1a/GT1b + ribavirin patients achieved SVR12, versus 3/9 (33%) GT1b without ribavirin patients in Panel 2-Arm 2. In Panel 3-Arm 1 and Panel 3-Arm 2, 6/7 (86%) GT1a + ribavirin and 4/8 (50%) GT1b without ribavirin patients, respectively, achieved SVR12. In Panel 4, 10/14 (71%) and 14/15 (93%) GT1a patients in Arms 1 and 2 achieved SVR12 compared with 8/8 and 7/7 (100%) GT1b patients in each arm, respectively. No deaths, serious adverse events (AEs), Grade 4 AEs or AEs leading to treatment discontinuation occurred.
CONCLUSIONS
The 2- and 3-DAA combinations were well tolerated. High SVR rates of 93% and 100% in GT1a- and GT1b-infected patients, respectively, were achieved in this study by combining simeprevir with JNJ-56914845 60 mg and TMC647055/ritonavir.
TRIAL REGISTRATION
NCT01724086 (date of registration: September 26, 2012).
背景
开展了一项2a期开放标签研究（NCT01724086），以评估simeprevir与TMC647055/利托那韦±利巴韦林的每日一次双直接抗病毒药物（2-DAA）联合用药方案，以及simeprevir与TMC647055/利托那韦加JNJ-56914845的三直接抗病毒药物（3-DAA）联合用药方案，用于初治和既往复发的慢性丙型肝炎病毒基因（GT）1型感染患者的疗效和安全性。
方法
该研究包括四个为期12周的治疗组：治疗组1（n = 10；GT1a）和治疗组2-臂1（n = 12；GT1b）：simeprevir每日一次75 mg + TMC647055每日一次450 mg/利托那韦每日一次30 mg + 利巴韦林1000 - 1200 mg/天；治疗组2-臂-2（n = 9；GT1b）：simeprevir 75 mg + TMC647055 450 mg/利托那韦30 mg，不用利巴韦林；治疗组3：simeprevir 75 mg + TMC647055 600 mg/利托那韦50 mg，使用（臂1：GT1a；n = 7）或不使用（臂2：GT1b；n = 8）利巴韦林；治疗组4：simeprevir 75 mg + TMC647055 450 mg/利托那韦30 mg + JNJ-56914845每日一次30 mg（臂1：n = 22；GT1a/GT1b）或每日一次60 mg（臂2：n = 22；GT1a/GT1b）。主要终点为治疗结束后12周（联合治疗12周）的持续病毒学应答（SVR12）。
结果
在治疗组1和治疗组2-臂1中，5/10和6/12（50%）的GT1a/GT1b + 利巴韦林患者实现了SVR12，而治疗组2-臂2中不使用利巴韦林的GT1b患者为3/9（33%）。在治疗组3-臂1和治疗组3-臂2中，分别有6/7（86%）的GT1a + 利巴韦林患者和4/8（50%）不使用利巴韦林的GT1b患者实现了SVR12。在治疗组4中，臂1和臂2中分别有10/14（71%）和14/15（93%）的GT1a患者实现了SVR12，而各臂中GT1b患者分别为8/8和7/7（100%）。未发生死亡、严重不良事件（AE）、4级AE或导致治疗中断的AE。
结论
2-DAA和3-DAA联合用药耐受性良好。本研究通过将simeprevir与60 mg JNJ-56914845以及TMC647055/利托那韦联合使用，在GT1a和GT1b感染患者中分别实现了93%和100%的高SVR率。
试验注册
NCT01724086（注册日期：2012年9月26日）。
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