Carlton-Smith C, Holmes J A, Naggie S, Lidofsky A, Lauer G M, Kim A Y, Chung R T
Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Department of Gastroenterology, St Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia.
J Viral Hepat. 2018 May;25(5):465-472. doi: 10.1111/jvh.12836. Epub 2017 Dec 27.
Interferon (IFN)-free direct-acting antiviral agents (DAAs) have revolutionized chronic hepatitis C virus (HCV) treatment; early studies suggest excellent efficacy in acute HCV. However, changes in innate immune responses during DAA therapy for acute HCV are unknown. We studied interferon-stimulated gene (ISG) expression and related cytokines/chemokines in HIV-infected patients with acute HCV receiving sofosbuvir plus ribavirin (SOF+RBV) as part of the A5327 clinical trial. ISG expression was determined from PBMCs, and circulating cytokines/chemokines were quantified from serum from study participants. The overall sustained virologic response (SVR) was 57%; all treatment failures were due to virologic relapse. Apart from NOS2a, baseline ISG/chemokine/cytokine levels were similar irrespective of treatment outcome. Downregulation of ISGs was observed at treatment week four and end of treatment (EOT), implicating HCV in establishing elevated ISGs early during HCV infection. Levels of many of these ISGs increased at post-treatment week 12 (PTW12) in relapsers only, coinciding with recurrent HCV RNA. Eleven ISGs were differentially expressed in responders vs relapsers. On-treatment viral suppression was also associated with a reduction in IP-10, CXCL11 and MIP-1β levels. In contrast, circulating IFN-α levels were significantly higher at EOT and PTW12 in responders vs relapsers. Upregulation of peripheral ISG expression is established early in the course of HCV infection during acute HCV infection, but did not predict subsequent treatment outcome with SOF+RBV. ISGs were downregulated during therapy and increased post-therapy in relapsers. IFN-α levels were higher in responders at EOT/PTW12, suggesting that impaired type I IFN production/secretion may contribute to relapse.
不含干扰素的直接抗病毒药物（DAA）彻底改变了慢性丙型肝炎病毒（HCV）的治疗方式；早期研究表明其对急性HCV疗效显著。然而，DAA治疗急性HCV期间先天免疫反应的变化尚不清楚。我们在A5327临床试验的一部分中，研究了接受索磷布韦加利巴韦林（SOF+RBV）治疗的HIV合并急性HCV感染患者中干扰素刺激基因（ISG）的表达及相关细胞因子/趋化因子情况。从外周血单核细胞（PBMC）中测定ISG表达，并从研究参与者的血清中定量循环细胞因子/趋化因子。总体持续病毒学应答（SVR）为57%；所有治疗失败均归因于病毒学复发。除了NOS2a，无论治疗结果如何，基线ISG/趋化因子/细胞因子水平相似。在治疗第4周和治疗结束时（EOT）观察到ISG下调，这表明HCV在HCV感染早期导致ISG升高。仅在复发者的治疗后第12周（PTW12），许多这些ISG的水平升高，与HCV RNA复发一致。11种ISG在应答者和复发者中差异表达。治疗期间的病毒抑制也与IP-10、CXCL11和MIP-1β水平降低有关。相比之下，应答者在EOT和PTW12时的循环干扰素-α水平明显高于复发者。在急性HCV感染期间，HCV感染过程早期外周ISG表达上调，但不能预测随后SOF+RBV的治疗结果。治疗期间ISG下调，复发者治疗后升高。应答者在EOT/PTW12时干扰素-α水平较高，表明I型干扰素产生/分泌受损可能导致复发。
