达卡他韦、阿舒瑞韦和贝塞布韦固定剂量复方制剂治疗非肝硬化 HCV 基因 1 型感染患者。

Fixed-dose combination therapy with daclatasvir, asunaprevir, and beclabuvir for noncirrhotic patients with HCV genotype 1 infection.

机构信息

Texas Liver Institute, University of Texas Health Science Center, San Antonio.

Monash Health and Monash University, Melbourne, Australia.

出版信息

JAMA. 2015 May 5;313(17):1728-35. doi: 10.1001/jama.2015.3860.

DOI:10.1001/jama.2015.3860

PMID:25942723

Abstract

IMPORTANCE

The antiviral activity of all-oral, ribavirin-free, direct-acting antiviral regimens requires evaluation in patients with chronic hepatitis C virus (HCV) infection.

OBJECTIVE

To determine the rates of sustained virologic response (SVR) in patients receiving the 3-drug combination of daclatasvir (a pan-genotypic NS5A inhibitor), asunaprevir (an NS3 protease inhibitor), and beclabuvir (a nonnucleoside NS5B inhibitor).

DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, single-group, uncontrolled international study (UNITY-1) conducted at 66 sites in the United States, Canada, France, and Australia between December 2013 and August 2014. Patients without cirrhosis who were either treatment-naive (n = 312) or treatment-experienced (n = 103) and had chronic HCV genotype 1 infection were included.

INTERVENTIONS

Patients received a twice-daily fixed-dose combination of daclatasvir, 30 mg; asunaprevir, 200 mg; and beclabuvir, 75 mg.

MAIN OUTCOMES AND MEASURES

The primary study outcome was SVR12 (HCV-RNA <25 IU/mL at posttreatment week 12) in patients naive to treatment. A key secondary outcome was SVR12 in the treatment-experienced cohort.

RESULTS

Baseline characteristics were comparable between the treatment-naive and treatment-experienced cohorts. Patients were 58% male, 26% had IL28B (rs12979860) CC genotype, 73% were infected with genotype 1a, and 27% were infected with genotype 1b. Overall, SVR12 was observed in 379 of 415 patients (91.3%; 95% CI, 88.6%-94.0%): 287 of 312 treatment-naive patients (92.0%; 95% CI, 89.0%-95.0%) and 92 of 103 treatment-experienced patients (89.3%; 95% CI, 83.4%-95.3%). Virologic failure occurred in 34 patients (8%) overall. One patient died at posttreatment week 3; this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (<1%) leading to treatment discontinuation, including 2 grade 4 alanine aminotransferase elevations. The most common adverse events (in ≥10% of patients) were headache, fatigue, diarrhea, and nausea.

CONCLUSIONS AND RELEVANCE

In this open-label, nonrandomized, uncontrolled study, a high rate of SVR12 was achieved in treatment-naive and treatment-experienced noncirrhotic patients with chronic HCV genotype 1 infection who received 12 weeks of treatment with the oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir.

TRIAL REGISTRATION

clinicaltrials.gov Identifier: NCT01979939.

摘要

重要性

所有口服、无利巴韦林、直接作用抗病毒方案的抗病毒活性需要在慢性丙型肝炎病毒（HCV）感染患者中进行评估。

目的

确定接受达拉他韦（一种泛基因型 NS5A 抑制剂）、asunaprevir（一种 NS3 蛋白酶抑制剂）和 beclabuvir（一种非核苷 NS5B 抑制剂）三联药物组合治疗的患者的持续病毒学应答（SVR）率。

设计、地点和参与者：这是一项在美国、加拿大、法国和澳大利亚的 66 个地点进行的开放标签、单组、非对照国际研究（UNITY-1），于 2013 年 12 月至 2014 年 8 月进行。包括无肝硬化且为初治（n=312）或经治（n=103）且慢性 HCV 基因型 1 感染的患者。

干预措施

患者接受达拉他韦 30mg、asunaprevir 200mg 和 beclabuvir 75mg 的每日两次固定剂量联合治疗。

主要结局和测量

主要研究结局为初治患者的 SVR12（治疗后第 12 周 HCV-RNA <25IU/mL）。一个关键次要结局是经治队列中的 SVR12。

结果

初治和经治队列的基线特征相似。患者 58%为男性，26%为 IL28B（rs12979860）CC 基因型，73%感染基因型 1a，27%感染基因型 1b。总体而言，415 例患者中的 379 例（91.3%；95%CI，88.6%-94.0%）达到 SVR12：312 例初治患者中的 287 例（92.0%；95%CI，89.0%-95.0%）和 103 例经治患者中的 92 例（89.3%；95%CI，83.4%-95.3%）。总体发生病毒学失败 34 例（8%）。1 例患者在治疗后第 3 周死亡；这被认为与研究药物无关。发生 7 例严重不良事件，均被认为与研究治疗无关，有 3 例不良事件（<1%）导致停药，包括 2 例 4 级丙氨酸氨基转移酶升高。最常见的不良事件（发生于≥10%的患者）为头痛、疲劳、腹泻和恶心。