近日，英国伦敦帝国理工学院Graham S Cooke团队研究了支持消除丙型肝炎的治疗方案。这一研究成果于2025年5月7日发表在《柳叶刀》杂志上。

世卫组织建议使用三种抗病毒药物组合中的一种治疗丙型肝炎感染，疗程为8-12周。没有随机试验比较这些方案，高治愈率可能在较短的治疗时间内实现。该团队的目的是比较索非布韦-达卡他韦和索非布韦-维帕他韦治疗丙型肝炎感染的疗效与安全性，并评估潜在的新治疗策略。

研究组在越南的两家公立医院进行了一项多组、开放标签、随机对照非劣效性试验。患有慢性丙型肝炎感染和轻度至中度肝纤维化的成人（年龄≥18岁）符合条件。招募人员按中心和病毒基因型（1-5 vs 6）进行分层，1:1随机分配到索非布韦400 mg + 达卡他韦60 mg（索非布韦-达卡他韦）或索非布韦400 mg + 维帕他韦100 mg（索非布韦-维帕他韦）的口服固定剂量组合。参与者同时按因素随机分配到四种治疗策略中的一种：12周标准护理（SOC）；4周，每周一次皮下注射聚乙二醇化干扰素α -2a；诱导和维持治疗，先进行2周标准治疗，再进行10周治疗，每周5天；根据第7天的病毒载量，分别进行4、8或12周的反应引导治疗（RGT）。主要结局是治疗完成后12周的持续病毒学缓解（SVR），在所有可评估的参与者中进行分析，无论实际接受的治疗如何。该课题组人员为药物比较选择了5%的非劣效裕度，为治疗策略比较选择了10%的非劣效裕度。对所有随机受试者进行安全性评估。

在2020年6月19日至2023年5月10日期间，624名参与者被随机分配（470名[75%]男性，154名[25%]女性）。基因6型296例（47%），基因1-5型328例（53%）。609名（98%）参与者的主要结局是可评估的。索非布韦-达卡他韦组302例受试者中有294例（97%）发生SVR，索非布韦-维帕他韦组307例受试者中有292例（95%）发生SVR（风险差为2.2%，90%可信区间[CrI] - 0.2 ~ 4.8，在5%的非效性范围内；索非布韦-达卡他韦优于索非布韦-维帕他韦的概率为93%）。SOC组150例患者中有148例（99%）发生SVR， 4周抗病毒加干扰素组152例患者中有143例（94%）发生SVR（-4.5%, 90% CrI - 8.3 ~ - 1.3），诱导维持组152例患者中有151例（99%）发生SVR（0.6%, - 1.1 ~ 2.7）， RGT组155例患者中有144例（93%）发生SVR（- 5.7%, - 9.6 ~ - 3.3）；所有风险差异均在10%的非劣效性范围内。严重不良事件罕见，索非布韦-维帕他韦组313名参与者中有11名（4%），而索非布韦-达卡他韦组311名参与者中有6名（2%）；风险差异-1.6%（95% CrI -4·2至0.8） ，没有证据表明方案或策略之间存在差异，但与其他治疗策略相比，4周抗病毒+干扰素组的不良反应非常常见（与SOC组的风险差异为66.8%[59·2至74·0]；p<0·0001）。

研究结果表明，索非布韦-达卡他韦不逊于索非布韦-维帕他韦。新策略的疗效很好，这可能有助于为难以接触到的人群提供治疗方法。

附：英文原文

Title: Treatment options to support the elimination of hepatitis C: an open-label, factorial, randomised controlled non-inferiority trial

Author: Graham S Cooke, Le Manh Hung, Barnaby Flower, Leanne McCabe, Vu Thi Kim Hang, Vo Thi Thu, Dang Trong Thuan, Nguyen Thanh Dung, Le Thanh Phuong, Dao Bach Khoa, Nguyen Thi Chau An, Pham Ngoc Thach, Vu Thi Thu Huong, Dang Thi Bich, Nguyen Kim Tuyen, M Azim Ansari, Chau Le Ngoc, Vo Minh Quang, Nguyen Thi Ngoc Phuong, Le Thi Thao, Nguyen Bao Tran, Evelyne Kestelyn, Cherry Kingsley, Rogier Van Doorn, Motiur Rahman, Sarah L Pett, Guy E Thwaites, Eleanor Barnes, Jeremy N Day, Nguyen Van Vinh Chau, A Sarah Walker

Issue&Volume: 2025-05-07

Abstract:

Background

WHO recommends treating hepatitis C infection with one of three antiviral combinations for 8–12 weeks. No randomised trials have compared these regimens, and high cure rates might be achievable with shorter durations of therapy. We aimed to compare sofosbuvir–daclatasvir with sofosbuvir–velpatasvir, and to evaluate potential novel treatment strategies.

Methods

We conducted a multi-arm, open-label, randomised controlled non-inferiority trial in two public hospitals in Viet Nam. Adults (aged ≥18 years) with chronic hepatitis C infection and mild-to-moderate liver fibrosis were eligible. Recruitment was stratified by centre and viral genotype (1–5 vs 6) with 1:1 random allocation to an oral fixed-dose combination of sofosbuvir 400 mg plus daclatasvir 60 mg (sofosbuvir–daclatasvir) or sofosbuvir 400 mg plus velpatasvir 100 mg (sofosbuvir–velpatasvir). Participants were simultaneously factorially randomly assigned to one of four treatment strategies: 12 weeks’ standard of care (SOC); 4 weeks’ therapy with four weekly PEGylated interferon alfa-2a subcutaneous injections; induction and maintenance therapy with 2 weeks’ standard therapy followed by 10 weeks’ therapy 5 days a week; and response-guided therapy (RGT) for 4, 8, or 12 weeks determined by viral load on day 7. The primary outcome was sustained virological response (SVR) 12 weeks after treatment completion, analysed in all evaluable participants regardless of actual treatment received. We chose a 5% non-inferiority margin for the drug comparison, and a 10% non-inferiority margin for the treatment strategy comparisons. Safety was assessed in all randomised participants. This trial is registered with ISRCTN, 61522291, and is completed.

Findings

Between June 19, 2020, and May 10, 2023, 624 participants were randomised (470 [75%] were male and 154 [25%] were female). 296 (47%) had genotype 6 and 328 (53%) had genotypes 1–5. The primary outcome was assessable in 609 (98%) participants. SVR occurred in 294 (97%) of 302 participants in the sofosbuvir–daclatasvir group and 292 (95%) of 307 participants in the sofosbuvir–velpatasvir group (risk difference 2·2%, 90% credible interval [CrI] –0·2 to 4·8, within the 5% non-inferiority margin; 93% probability that sofosbuvir–daclatasvir is superior to sofosbuvir–velpatasvir). SVR occurred in 148 (99%) of 150 in the SOC group, 143 (94%) of 152 in the 4-week antiviral plus interferon group (–4·5%, 90% CrI –8·3 to –1·3), 151 (99%) of 152 in the induction–maintenance group (0·6%, –1·1 to 2·7), and 144 (93%) of 155 in the RGT group (–5·7%, –9·6 to –2·3); all risk differences were within the 10% non-inferiority margin. Serious adverse events were rare (11 [4%] of 313 participants in the sofosbuvir–velpatasvir group vs six [2%] of 311 in the sofosbuvir–daclatasvir group; risk difference –1·6% [95% CrI –4·2 to 0·8]) with no evidence of differences between regimens or strategies, but adverse reactions were very common in the 4-week antiviral plus interferon group compared with the other treatment strategies (risk difference vs SOC group, 66·8% [59·2 to 74·0]; p<0·0001).

Interpretation

Sofosbuvir–daclatasvir was non-inferior to sofosbuvir–velpatasvir. High efficacy was seen with novel strategies, which might help to inform approaches to treatment for harder-to-reach populations.

DOI: 10.1016/S0140-6736(25)00097-2

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00097-2/abstract