Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study
Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study
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DOI：
10.1016/s0140-6736(15)00349-9
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发表时间：
2015-10-17
期刊：
影响因子：
168.9
通讯作者：
Greaves, Wayne
中科院分区：
文献类型：
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作者：
Roth, David;Nelson, David R.;Greaves, Wayne
背景4-5期慢性肾脏病患者的慢性丙型肝炎病毒（HCV）感染增加了死亡和肾移植失败的风险，但丙型肝炎和慢性肾脏病患者的治疗选择很少。本研究评估了HCV基因型1感染和4-5期慢性肾脏病患者的全口服无利巴韦林方案。方法在这项3期安全性随机研究和疗效观察研究中，HCV基因型1感染和慢性肾脏病患者（4-5期，有或无血液透析依赖）随机分配接受grazoprevir（100 mg，NS 3/4A蛋白酶抑制剂）和elbasvir（50 mg，NS 5A抑制剂;立即治疗组）或安慰剂（延迟治疗组），每日一次，持续12周。使用交互式语音应答系统集中进行随机化。另一个未随机化的患者队列接受相同的开放标签方案，并接受密集的药代动力学采样。主要疗效结局是联合立即治疗组和药代动力学人群治疗结束后12周（SVR 12）持续病毒学应答的非随机比较（有历史对照）。主要安全性结局是立即治疗组和延迟治疗组之间的随机比较。4周随访后（研究第16周），揭盲发生，延迟治疗组的患者接受了grazoprevir和elbasvir。使用二项式比例的精确检验，在双侧显著性水平（I类错误）0.0下检验主要疗效假设。使用分层Miettinen和Nurminen方法，以基线透析状态为分层，比较立即治疗组和延迟治疗组之间的安全性事件发生率。该研究在ClinicalTrials.gov注册，编号NCT 02092350。结果224例患者被随机分配到grazoprevir和elbasvir的立即治疗组（n=111）或延迟治疗组（n=113），11例被分配到强化药代动力学人群。总体而言，179例（76%）为血液透析依赖性，122例（52%）为HCV基因型1a感染，189例（80%）为HCV初治，14例（6%）为腹泻，108例（46%）为非洲裔美国人。在122例接受grazoprevir和elbasvir治疗的患者中，6例因非病毒学原因（死亡、失访[n=2]、不依从、患者退出和医生因暴力行为退出）从主要疗效分析中排除。合并的立即治疗组和强化药代动力学人群中没有患者，延迟治疗组中有5例（4%）患者因不良事件而停药。最常见的不良事件是头痛、恶心和疲劳，在接受活性药物和安慰剂药物的患者中发生频率相似。合并立即治疗组和强化药代动力学人群中的SVR 12为99%（95%CI 95.3-100.0; 115/116），与45%的历史对照相比，在治疗结束后12周复发一次，基于对血液透析中感染HCV的患者的临床试验中使用的基于干扰素的方案的荟萃分析。每日使用格拉佐匹韦和依巴斯韦治疗12周，不良事件发生率低，对感染HCV基因型1和4-5期慢性肾病的患者有效。
Background Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease.Methods In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0.0 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350.Findings 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95.3-100.0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis.Interpretation Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease.