Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, , Bethesda, Maryland, USA.
Gut. 2014 Jan;63(1):161-9. doi: 10.1136/gutjnl-2012-303852. Epub 2013 Feb 8.
Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C.
70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000-1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24 h before or 6 h after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10.
After 4 weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.5±0.5 log10 (p=0.009 vs controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting ISG induction by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological, response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs 22% non-responders, p=0.01; early virological response, 100% vs 68%, p=0.03; sustained virological response 83% vs 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC.
Ribavirin is a weak antiviral but its clinical effect seems to be mediated by a separate, indirect mechanism, which may act to reset IFN-responsiveness in HCV-infected liver.
利巴韦林可提高慢性丙型肝炎患者对聚乙二醇干扰素（PEG-IFN）的治疗反应，但作用机制仍存在争议。本研究旨在探讨利巴韦林治疗丙型肝炎的疗效相关因素及其作用机制。
70 例初治患者随机分为利巴韦林（1000-1200mg/d）或无治疗 4 周，随后采用 PEG-IFNα-2a 和利巴韦林标准剂量和疗程治疗。患者还随机分为在开始 PEG-IFN 前 24 小时或后 6 小时进行肝活检。采用微阵列评估肝组织基因表达，采用 nCounter 平台定量干扰素刺激基因（ISG）表达。采用 qPCR 在 PBMC 中评估 ISG 表达的时间变化，并检测血清 IP-10 水平。
利巴韦林单药治疗 4 周后，HCV 载量下降 0.5±0.5log10（p=0.009 与对照组相比），ALT 下降 33%（p<0.001）。利巴韦林预处理虽适度增强 PEG-IFN 诱导的 ISG，但不改变后续 PEG-IFN 和利巴韦林治疗的病毒学反应。然而，利巴韦林单药治疗的生化应答（而非病毒学应答）预测后续联合治疗的应答（生化应答快速病毒学应答率为 71%，非应答者为 22%，p=0.01；早期病毒学应答率为 100%，非应答者为 68%，p=0.03；持续病毒学应答率为 83%，非应答者为 41%，p=0.053）。利巴韦林单药治疗降低血清 IP-10 水平，但对 PBMC 中 ISG 表达无影响。
利巴韦林是一种弱抗病毒药物，但它的临床效果似乎是通过一种独立的间接机制介导的，该机制可能作用于重置 HCV 感染肝脏的 IFN 反应性。
