Background

In low-income and middle-income countries, affordable direct-acting antivirals are urgently needed to treat hepatitis C virus (HCV) infection. The combination of ravidasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, and sofosbuvir has shown efficacy and safety in patients with chronic HCV genotype 4 infection. STORM-C-1 trial aimed to assess the efficacy and safety of ravidasvir plus sofosbuvir in a diverse population of adults chronically infected with HCV.

Methods

STORM-C-1 is a two-stage, open-label, phase 2/3 single-arm clinical trial in six public academic and non-academic centres in Malaysia and four public academic and non-academic centres in Thailand. Patients with HCV with compensated cirrhosis (Metavir F4 and Child-Turcotte-Pugh class A) or without cirrhosis (Metavir F0–3) aged 18–69 years were eligible to participate, regardless of HCV genotype, HIV infection status, previous interferon-based HCV treatment, or source of HCV infection. Once daily ravidasvir (200 mg) and sofosbuvir (400 mg) were prescribed for 12 weeks for patients without cirrhosis and for 24 weeks for those with cirrhosis. The primary endpoint was sustained virological response at 12 weeks after treatment (SVR12; defined as HCV RNA <12 IU/mL in Thailand and HCV RNA <15 IU/mL in Malaysia at 12 weeks after the end of treatment). This trial is registered with ClinicalTrials.gov, number NCT02961426, and the National Medical Research Register of Malaysia, NMRR-16-747-29183.

Findings

Between Sept 14, 2016, and June 5, 2017, 301 patients were enrolled in stage one of STORM-C-1. 98 (33%) patients had genotype 1a infection, 27 (9%) had genotype 1b infection, two (1%) had genotype 2 infection, 158 (52%) had genotype 3 infection, and 16 (5%) had genotype 6 infection. 81 (27%) patients had compensated cirrhosis, 90 (30%) had HIV co-infection, and 99 (33%) had received previous interferon-based treatment. The most common treatment-emergent adverse events were pyrexia (35 [12%]), cough (26 [9%]), upper respiratory tract infection (23 [8%]), and headache (20 [7%]). There were no deaths or treatment discontinuations due to serious adverse events related to study drugs. Of the 300 patients included in the full analysis set, 291 (97%; 95% CI 94–99) had SVR12. Of note, SVR12 was reported in 78 (96%) of 81 patients with cirrhosis and 153 (97%) of 158 patients with genotype 3 infection, including 51 (96%) of 53 patients with cirrhosis. There was no difference in SVR12 rates by HIV co-infection or previous interferon treatment.

Interpretation

In this first stage, ravidasvir plus sofosbuvir was effective and well tolerated in this diverse adult population of patients with chronic HCV infection. Ravidasvir plus sofosbuvir has the potential to provide an additional affordable, simple, and efficacious public health tool for large-scale implementation to eliminate HCV as a cause of morbidity and mortality.

Funding

National Science and Technology Development Agency, Thailand; Department of Disease Control, Ministry of Public Health, Thailand; Ministry of Health, Malaysia; UK Aid; Médecins Sans Frontières (MSF); MSF Transformational Investment Capacity; FIND; Pharmaniaga; Starr International Foundation; Foundation for Art, Research, Partnership and Education; and the Swiss Agency for Development and Cooperation.

中文翻译：

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拉维达韦联合索磷布韦治疗无肝硬化或代偿性肝硬化慢性丙型肝炎感染患者 (STORM-C-1) 的疗效和安全性：一项两阶段、开放标签、多中心、单组 2/3 期试验的中期分析

背景

在低收入和中等收入国家，迫切需要负担得起的直接抗病毒药物来治疗丙型肝炎病毒 (HCV) 感染。ravidasvir 是一种泛基因型非结构蛋白 5A (NS5A) 抑制剂，它与 sofosbuvir 的组合在慢性 HCV 基因型 4 感染患者中显示出疗效和安全性。STORM-C-1 试验旨在评估 ravidasvir 加 sofosbuvir 在长期感染 HCV 的不同成人人群中的疗效和安全性。

方法

STORM-C-1是一项两阶段、开放标签、2/3期单臂临床试验，在马来西亚的六个公共学术和非学术中心以及泰国的四个公共学术和非学术中心进行。18-69 岁代偿性肝硬化（Metavir F4 和 Child-Turcotte-Pugh A 级）或无肝硬化（Metavir F0-3）的 HCV 患者有资格参加，无论 HCV 基因型、HIV 感染状态、既往基于干扰素的HCV 治疗，或 HCV 感染源。每天一次的拉维达韦（200 毫克）和索磷布韦（400 毫克）被开具处方，无肝硬化患者服用 12 周，肝硬化患者服用 24 周。主要终点是治疗后 12 周的持续病毒学应答（SVR12；在泰国定义为 HCV RNA <12 IU/mL，在马来西亚定义为治疗结束后 12 周时 HCV RNA <15 IU/mL）。

发现

2016 年 9 月 14 日至 2017 年 6 月 5 日期间，STORM-C-1 的第一阶段招募了 301 名患者。98 例 (33%) 患者感染基因 1a 型，27 例 (9%) 感染基因 1b 型，2 例 (1%) 感染基因 2 型，158 例 (52%) 感染基因 3 型，16 例 (5%) 感染基因 6 型感染。81 名 (27%) 患者出现代偿期肝硬化，90 名 (30%) 患者合并感染 HIV，99 名 (33%) 患者之前接受过基于干扰素的治疗。最常见的治疗紧急不良事件是发热 (35 [12%])、咳嗽 (26 [9%])、上呼吸道感染 (23 [8%]) 和头痛 (20 [7%])。没有因研究药物相关的严重不良事件导致死亡或治疗中断。在包含在完整分析集中的 300 名患者中，291 名（97%；95% CI 94–99）具有 SVR12。值得注意的是，81 名肝硬化患者中的 78 名（96%）和 158 名基因 3 型感染患者中的 153 名（97%）报告了 SVR12，其中包括 53 名肝硬化患者中的 51 名（96%）。HIV 合并感染或既往干扰素治疗对 SVR12 率没有影响。

解释

在第一阶段，拉维达韦加索非布韦在慢性 HCV 感染患者的多样化成人人群中有效且耐受性良好。Ravidasvir 加 sofosbuvir 有可能为大规模实施提供额外的负担得起、简单和有效的公共卫生工具，以消除 HCV 作为发病率和死亡率的原因。

资金

泰国国家科学技术发展署；泰国公共卫生部疾病控制司；马来西亚卫生部；英国援助；无国界医生组织（MSF）；MSF 转型投资能力；寻找; 发马; 斯塔尔国际基金会；艺术、研究、合作和教育基金会；和瑞士发展与合作署。