Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome
Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome
复制标题
DOI：
10.1172/jci75938
复制
发表时间：
2014-08-01
影响因子：
15.9
通讯作者：
Kottilil, Shyamasundaran
中科院分区：
文献类型：
--
作者：
Meissner, Eric G.;Wu, David;Kottilil, Shyamasundaran
背景。丙型肝炎病毒 (HCV) 感染全球约 1.7 亿人，慢性感染者可能会导致肝硬化和肝细胞癌。治疗方法正在迅速从基于 IFN-α 的疗法发展到由直接作用抗病毒药物 (DAA) 组成的不含 IFN-α 的治疗方案，这些治疗方案在临床试验中证明了疗效和耐受性的改善。 DAA 治疗后病毒学复发是治疗失败的常见原因；然而，尚不清楚为什么会出现复发，也不清楚某些个体是否更容易出现复发性病毒血症。方法。我们使用 DAA 索磷布韦加利巴韦林 (SOF/RBV) 进行了一项临床试验，并对获得持续病毒学应答 (SVR) 或复发的患者的肝脏和外周血进行了详细的 mRNA 表达分析。 结果。无论治疗结果如何，治疗中的病毒清除都伴随着肝脏和血液中干扰素刺激基因（ISG）的快速下调。对 SVR 患者的治疗前和治疗结束 (EOT) 肝活检的配对分析表明，病毒清除伴随着 II 型和 III 型 IFN 表达的下降，但 I 型 IFN IFNA2 的表达却出乎意料地增加。实现 SVR 的患者的 EOT 肝活检中 ISG 的 mRNA 表达高于后来复发的患者。结论。这些结果表明，通过 EOT 恢复 I 型肝内 IFN 信号传导可能有助于根除 HCV 并预防 SOF/RBV 撤药后的复发。
BACKGROUND. Hepatitis C virus (HCV) infects approximately 170 million people worldwide and may lead to cirrhosis and hepatocellular carcinoma in chronically infected individuals. Treatment is rapidly evolving from IFN-alpha-based therapies to IFN-alpha-free regimens that consist of directly acting antiviral agents (DAAs), which demonstrate improved efficacy and tolerability in clinical trials. Virologic relapse after DAA therapy is a common cause of treatment failure; however, it is not clear why relapse occurs or whether certain individuals are more prone to recurrent viremia.METHODS. We conducted a clinical trial using the DAA sofosbuvir plus ribavirin (SOF/RBV) and performed detailed mRNA expression analysis in liver and peripheral blood from patients who achieved either a sustained virologic response (SVR) or relapsed.RESULTS. On-treatment viral clearance was accompanied by rapid downregulation of IFN-stimulated genes (ISGs) in liver and blood, regardless of treatment outcome. Analysis of paired pretreatment and end of treatment (EOT) liver biopsies from SVR patients showed that viral clearance was accompanied by decreased expression of type II and III IFNs, but unexpectedly increased expression of the type I IFN IFNA2. mRNA expression of ISGs was higher in EOT liver biopsies of patients who achieved SVR than in patients who later relapsed.CONCLUSION. These results suggest that restoration of type I intrahepatic IFN signaling by EOT may facilitate HCV eradication and prevention of relapse upon withdrawal of SOF/RBV.