在丙型肝炎病毒 1 型单感染和 HIV/丙型肝炎病毒共感染患者中，与利巴韦林联用或不联用，格拉瑞韦（MK-5172）和艾尔巴韦（MK-8742）治疗 8 周与 12 周的疗效和安全性：一项随机、开放标签的 2 期临床试验（C-WORTHY）。

Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial.

机构信息

Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France.

出版信息

Lancet. 2015 Mar 21;385(9973):1087-97. doi: 10.1016/S0140-6736(14)61793-1. Epub 2014 Nov 11.

DOI:10.1016/S0140-6736(14)61793-1

PMID:25467560

Abstract

BACKGROUND

Both hepatitis C virus (HCV) mono-infected and HIV/HCV co-infected patients are in need of safe, effective, all-oral HCV regimens. In a phase 2 study we aimed to assess the efficacy and safety of grazoprevir (MK-5172; HCV NS3/4A protease inhibitor) and two doses of elbasvir (MK-8742; HCV NS5A inhibitor) in patients with HCV mono-infection and HIV/HCV co-infection.

METHODS

The C-WORTHY study is a phase 2, multicentre, randomised controlled trial of grazoprevir plus elbasvir with or without ribavirin in patients with HCV; here, we report findings for previously untreated (genotype 1) patients without cirrhosis who were HCV mono-infected or HIV/HCV co-infected. Eligible patients were previously untreated adults aged 18 years or older with chronic HCV genoype 1 infection and HCV RNA at least 10 000 IU/mL in peripheral blood without evidence of cirrhosis, hepatocellular carcinoma, or decompensated liver disease. In part A of the study we randomly assigned HCV-mono-infected patients to receive 12 weeks of grazoprevir (100 mg) plus elbasvir (20 mg or 50 mg) with or without ribavirin (arms A1-3); in part B we assigned HCV-mono-infected patients to 8 or 12 weeks of grazoprevir (100 mg) plus elbasvir (50 mg) with or without ribavirin (arms B1-3) and HIV/HCV co-infected patients to 12 weeks of therapy with or without ribavirin. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL 12 weeks after end of treatment (SVR12). Randomisation was by presence or absence of ribavirin, 8 or 12 weeks of treatment, and dosage of elbasvir. Patients were stratified by gentoype 1a versus 1b. The patients, investigators, and study site personnel were masked to treatment group assignements but the funder was not. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01717326.

FINDINGS

218 patients with HCV mono-infection (n=159) and HIV/HCV co-infection (n=59) were enrolled. SVR12 for patients treated for 12 weeks with or without ribavirin ranged from 93-98% in mono-infected and 87-97% in co-infected patients. SVR12 rates in mono-infected and co-infected patients treated for 12 weeks without ribavirin were 98% (95% CI 88-100; 43/44) and 87% (95% CI 69-96; 26/30), respectively, and with ribavirin were 93% (95% CI 85-97; 79/85) and 97% (95% CI 82-100; 28/29), respectively. Among mono-infected patients with genotype 1a infection treated for 8 weeks, SVR12 was 80% (95% CI 61-92; 24/30). Five of six patients who discontinued early for reasons other than virological failure had HCV RNA less than 25 IU/mL at their last study visit. Virological failure among patients treated for 12 weeks occurred in seven patients (7/188, 4%) and was associated with emergence of resistance-associated variants to one or both drugs. The safety profile of grazoprevir plus elbasvir with or without ribavirin was similar in mono-infected and co-infected patients. No patient discontinued due to an adverse event or laboratory abnormality. The most common adverse events were fatigue (51 patients, 23%), headache (44, 20%), nausea (32, 15%), and diarrhoea (21, 10%).

INTERPRETATION

Once-daily grazoprevir plus elbasvir with or without ribavirin for 12 weeks in previously untreated HCV-mono-infected and HIV/HCV-co-infected patients without cirrhosis achieved SVR12 rates of 87-98%. These results support the ongoing phase 3 development of grazoprevir plus elbasvir.

FUNDING

Merck & Co, Inc.

摘要

背景

无论是丙型肝炎病毒（HCV）单感染还是 HIV/HCV 合并感染的患者，都需要安全、有效、全口服的 HCV 治疗方案。在一项 2 期研究中，我们旨在评估格拉瑞韦（MK-5172；HCV NS3/4A 蛋白酶抑制剂）和两种剂量的艾尔巴韦（MK-8742；HCV NS5A 抑制剂）在 HCV 单感染和 HIV/HCV 合并感染患者中的疗效和安全性。

方法

C-WORTHY 研究是一项多中心、随机对照的 2 期格拉瑞韦联合艾尔巴韦治疗 HCV 的临床试验，这里我们报告了既往未接受治疗（基因型 1）、无肝硬化、HCV 单感染或 HIV/HCV 合并感染患者的结果。符合条件的患者为年龄在 18 岁及以上、慢性 HCV 基因 1 感染且外周血 HCV RNA 至少为 10000IU/ml、无肝硬化、肝细胞癌或失代偿性肝病证据的既往未接受治疗的成年人。在研究的 A 部分，我们将 HCV 单感染患者随机分配至接受 12 周的格拉瑞韦（100mg）加艾尔巴韦（20mg 或 50mg）联合或不联合利巴韦林（A1-3 组）；在 B 部分，我们将 HCV 单感染患者随机分配至接受 8 或 12 周的格拉瑞韦（100mg）加艾尔巴韦（50mg）联合或不联合利巴韦林（B1-3 组），HIV/HCV 合并感染患者接受 12 周的治疗，联合或不联合利巴韦林。主要终点是治疗结束后 12 周时 HCV RNA 小于 25IU/ml 的患者比例（SVR12）。随机分组依据是否存在利巴韦林、治疗时间 8 或 12 周以及艾尔巴韦的剂量。患者按基因型 1a 与 1b 分层。患者、研究者和研究地点人员对治疗分组不知情，但资助者知情。分析采用意向治疗。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT01717326。

结果

218 例 HCV 单感染（n=159）和 HIV/HCV 合并感染（n=59）患者入组。接受 12 周治疗的患者中，有或无利巴韦林的 SVR12 率在单感染和合并感染患者中分别为 93-98%和 87-97%。无利巴韦林治疗 12 周的单感染和合并感染患者的 SVR12 率分别为 98%（95%CI 88-100；43/44）和 87%（95%CI 69-96；26/30），有利巴韦林的 SVR12 率分别为 93%（95%CI 85-97；79/85）和 97%（95%CI 82-100；28/29）。在接受 8 周治疗的基因型 1a 感染的单感染患者中，SVR12 为 80%（95%CI 61-92；24/30）。6 名因非病毒学失败原因提前停药的患者在最后一次研究就诊时 HCV RNA 均小于 25IU/ml。接受 12 周治疗的 188 例患者中，有 7 例（7/188，4%）发生病毒学失败，与一种或两种药物的耐药相关变异体的出现有关。有或无利巴韦林的格拉瑞韦加艾尔巴韦治疗的单感染和合并感染患者的安全性特征相似。无患者因不良事件或实验室异常而停药。最常见的不良事件是疲劳（51 例，23%）、头痛（44 例，20%）、恶心（32 例，15%）和腹泻（21 例，10%）。