All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study
All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study
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DOI：
10.1016/s0140-6736(14)61059-x
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发表时间：
2014-11-01
期刊：
影响因子：
168.9
通讯作者：
Noviello, Stephanie
中科院分区：
文献类型：
--
作者：
Manns, Michael;Pol, Stanislas;Noviello, Stephanie
背景：对于慢性丙型肝炎病毒（HCV）感染的无干扰素和无利巴韦林治疗存在未满足的需求。在这项研究中，我们评估了所有口服治疗与达卡他韦（NS 5A复制复合物抑制剂）加asunaprevir（NS 3蛋白酶抑制剂）在基因型1b感染的患者，包括那些高未满足的需求或肝硬化，或both.Methods我们做了这个3期，多队列研究（HALLMARK-DUAL）在116个网站在18个国家之间的2012年5月11日，2013年10月9日。患者为未接受过治疗的慢性HCV基因型1b感染成人;既往对聚乙二醇干扰素α联合利巴韦林无应答者;或医学上不适合、既往不耐受或不适合且不耐受聚乙二醇干扰素α联合利巴韦林。通过交互式语音应答系统和计算机生成的随机分配序列（按肝硬化状态分层）将初治患者随机分配（2：1比例），接受达卡他韦60 mg每日一次+阿那匹韦100 mg每日两次或安慰剂治疗12周。患者和研究中心对治疗分配和HCV RNA结果设盲，直至第12周结束。分配到达卡他韦加阿那匹韦的未治疗组继续开放标签治疗至第24周结束;分配到安慰剂组的参与者进入另一项达卡他韦加阿那匹韦研究。无应答者和不合格、不耐受或不合格和不耐受的患者接受开放标签的达卡他韦加阿舒那匹韦治疗24周。主要终点是治疗后第12周的持续病毒学应答。疗效分析仅限于给予达卡他韦加阿舒那匹韦的患者。该试验注册于ClinicalTrials.gov，编号NCT 01581203。结果该研究包括307名未经治疗的患者（205名接受达卡他韦加asunaprevir，102名接受安慰剂;所有随机分配的患者均接受预期治疗），205名无应答者和235名不合格，不耐受或不合格和不耐受的患者。达卡他韦联合阿那匹韦在初治队列中的182例（90%，95%CI 85-94）患者中提供了持续的病毒学应答，在无应答队列中为168例（82%，77-87），在不合格、不耐受或不合格和不耐受队列中为192例（82%，77-87）。严重不良事件发生在初治组12例（6%）患者中; 11例（5%）无应答者，16例（7%）不合格、不耐受或不合格和不耐受患者;导致停药的不良事件（最常见的是丙氨酸或天冬氨酸转氨酶可逆性升高）分别发生在6例（3%）、2例（1%）和2例（1%）患者中，没有死亡记录。3级或4级实验室检查异常并不常见，在未经治疗的患者中，达卡他韦联合阿那匹韦和安慰剂治疗的前12周内，转氨酶升高的发生率较低（
Background An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both.Methods We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2: 1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203.Findings This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85-94) patients in the treatment-naive cohort, 168 (82%, 77-87) in the non-responder cohort, and 192 (82%, 77-87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (