雷迪帕韦和索非布韦联合利巴韦林治疗基因型 1 或 4 型丙型肝炎病毒感染和晚期肝病患者：一项多中心、开放标签、随机、2 期临床试验。
Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial.
机构信息
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Center of Infection Research (DZIF), Hannover-Braunschweig, Germany.
Centre Hepatobiliaire, Hôpital Paul Brousse, and Université Paris Sud, Villejuif, France.
出版信息
Lancet Infect Dis. 2016 Jun;16(6):685-697. doi: 10.1016/S1473-3099(16)00052-9. Epub 2016 Feb 18.
BACKGROUND
Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease.
METHODS
We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand. Cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned (1:1) using a computer-generated randomisation sequence to receive 12 or 24 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily (combination tablet), plus ribavirin (600-1200 mg daily). The primary endpoint was the proportion of patients achieving a sustained virological response 12 weeks after treatment (SVR12). All patients who received at least one dose of study drug were included in the safety analysis and all patients who received at least one dose of study drug and did not undergo liver transplantation during treatment were included in the efficacy analyses. Estimates of SVR12 and relapse rates and their two-sided 90% CI (Clopper-Pearson method) were provided. This exploratory phase 2 study was not powered for formal comparisons among treatment groups; no statistical hypothesis testing was planned or conducted. The trial is registered with EudraCT (number 2013-002802-30) and ClinicalTrials.gov (number NCT02010255).
FINDINGS
Between Jan 14, 2014, and Aug 19, 2014, 398 patients were screened. Of 333 patients who received treatment, 296 had genotype 1 HCV and 37 had genotype 4 HCV. In cohort A, among patients with genotype 1 HCV, SVR12 was achieved by 20 (87%, 90% CI 70-96) of 23 CTP-B patients with 12 weeks of treatment; 22 (96%, 81-100) of 23 CTP-B patients with 24 weeks of treatment; 17 (85%, 66-96) of 20 CTP-C patients (12 weeks treatment); and 18 (78%, 60-91) of 23 CTP-C patients (24 weeks treatment). In cohort B, among patients with genotype 1 HCV, SVR12 was achieved by 42 (93%, 84-98) of 45 patients without cirrhosis (12 weeks treatment); 44 (100%, 93-100) of 44 patients without cirrhosis (24 weeks treatment); 30 (100%, 91-100) of 30 CTP-A patients (12 weeks treatment); 27 (96%, 84-100) of 28 CTP-A patients (24 weeks treatment); 19 (95%, 78-100) of 20 CTP-B patients (12 weeks treatment); 20 (100%, 86-100) of 20 CTP-B patients (24 weeks treatment); one (50%, 3-98) of two CTP-C patients (12 weeks treatment); and four (80%, 34-99) of five CTP-C patients (24 weeks treatment). All five patients with fibrosing cholestatic hepatitis achieved SVR12 (100%, 90% CI 55-100). Among all patients with genotype 4 HCV, SVR12 was achieved by 14 (78%, 56-92) of 18 patients (12 weeks treatment) and 16 (94%, 75-100) of 17 patients (24 weeks treatment). Seven patients (2%) discontinued ledipasvir-sofosbuvir prematurely due to adverse events. 17 patients died, mainly from complications of hepatic decompensation.
INTERPRETATION
Ledipasvir-sofosbuvir and ribavirin provided high rates of SVR12 for patients with advanced liver disease, including those with decompensated cirrhosis before or after liver transplantation.
FUNDING
Gilead Sciences.
背景
对于患有丙型肝炎病毒（HCV）合并晚期肝病的患者，治疗选择有限。我们评估了利迪帕韦、索磷布韦和利巴韦林在 HCV 基因型 1 或 4 合并晚期肝病患者中的安全性和疗效。
方法
我们在欧洲、加拿大、澳大利亚和新西兰的 34 个地点进行了一项开放性标签研究。队列 A 包括未接受过肝移植的 Child-Turcotte-Pugh 分级 B（CTP-B）或 CTP-C 肝硬化患者。队列 B 包括移植后患者，这些患者要么没有肝硬化；要么 CTP-A、CTP-B 或 CTP-C 肝硬化；要么患有纤维性胆汁性肝炎。每组患者均采用计算机生成的随机序列按 1:1 比例随机分配接受 12 或 24 周的利迪帕韦（90mg）和索磷布韦（400mg）每日一次（联合片剂），加利巴韦林（600-1200mg 每日）治疗。主要终点是治疗后 12 周时获得持续病毒学应答（SVR12）的患者比例。所有接受至少一剂研究药物的患者均纳入安全性分析，所有接受至少一剂研究药物且治疗期间未接受肝移植的患者均纳入疗效分析。提供了 SVR12 和复发率及其 90%CI（Clopper-Pearson 方法）的估计值。这项探索性 2 期研究没有为各组之间的正式比较提供足够的效力；没有计划或进行任何统计假设检验。该试验在 EudraCT（编号 2013-002802-30）和 ClinicalTrials.gov（编号 NCT02010255）上注册。
结果
2014 年 1 月 14 日至 2014 年 8 月 19 日期间，共有 398 名患者接受了筛选。333 名接受治疗的患者中，296 名患有 HCV 基因型 1，37 名患有 HCV 基因型 4。在队列 A 中，在患有 HCV 基因型 1 的患者中，12 周治疗的 23 例 CTP-B 患者中有 20 例（87%，90%CI70-96）达到 SVR12；24 周治疗的 23 例 CTP-B 患者中有 22 例（96%，81-100）达到 SVR12；20 例 CTP-C 患者（12 周治疗）中有 17 例（85%，66-96）达到 SVR12；23 例 CTP-C 患者（24 周治疗）中有 18 例（78%，60-91）达到 SVR12。在队列 B 中，在患有 HCV 基因型 1 的患者中，无肝硬化的 45 例患者（12 周治疗）中有 42 例（93%，84-98）达到 SVR12；无肝硬化的 44 例患者（24 周治疗）中有 44 例（100%，93-100）达到 SVR12；30 例 CTP-A 患者（12 周治疗）中有 30 例（100%，91-100）达到 SVR12；28 例 CTP-A 患者（24 周治疗）中有 27 例（96%，84-100）达到 SVR12；20 例 CTP-B 患者（12 周治疗）中有 19 例（95%，78-100）达到 SVR12；20 例 CTP-B 患者（24 周治疗）中有 20 例（100%，86-100）达到 SVR12；2 例 CTP-C 患者（12 周治疗）中有 1 例（50%，3-98）达到 SVR12；5 例 CTP-C 患者（24 周治疗）中有 4 例（80%，34-99）达到 SVR12。所有 5 例纤维性胆汁性肝炎患者均达到 SVR12（100%，90%CI55-100）。在所有 HCV 基因型 4 患者中，18 例患者（12 周治疗）中有 14 例（78%，56-92）达到 SVR12，17 例患者（24 周治疗）中有 16 例（94%，75-100）达到 SVR12。7 例（2%）患者因不良反应提前停止使用利迪帕韦-索磷布韦。17 例患者死亡，主要死于肝失代偿并发症。
解释
利迪帕韦-索磷布韦和利巴韦林为患有晚期肝病的患者提供了高 SVR12 率，包括在肝移植前后失代偿的肝硬化患者。
资金来源
吉利德科学公司。
Zotero 插件