Serti Elisavet, Park Heiyoung, Keane Meghan, O'Keefe Ashley C, Rivera Elenita, Liang T Jake, Ghany Marc, Rehermann Barbara
Immunology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.
Gut. 2017 Apr;66(4):724-735. doi: 10.1136/gutjnl-2015-310033. Epub 2016 Jan 4.
Chronic HCV infection is characterised by innate immune activation with increased interferon-stimulated genes (ISG) expression and by an altered phenotype of interferon-responsive natural killer (NK) cells. Here, we asked whether a rapid reduction in viremia by daclatasvir (DCV) and asunaprevir (ASV) improves the response to pegylated interferon (PegIFN) in patients who had previously failed a standard course of PegIFN/ribavirin (RBV) therapy.
Twenty-two HCV-infected non-responders to previous PegIFN/RBV therapy were studied for IFN-responsiveness of NK cells during quadruple (QUAD) therapy with DCV, ASV, PegIFN and RBV. A direct comparison of early NK cell responses in PegIFN/RBV therapy and QUAD therapy was performed for seven patients using paired cryopreserved peripheral blood mononuclear cells (PBMC) from both treatment courses. As a validation cohort, nine DCV/ASV-treated patients were studied for their NK cell response to in vitro stimulation with IFNα.
The 24 h virological response to QUAD therapy correlated with an increase in signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1 (pSTAT1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in NK cells, and the STAT1/pSTAT1/TRAIL induction was greater during QUAD therapy than during previous PegIFN/RBV therapy. Successful QUAD therapy as well as successful IFN-free DCV/ASV regimen resulted in an improved functional NK cell response (degranulation and TRAIL expression) to in vitro stimulation with IFNα.
IFN-responsiveness can be improved by inhibiting HCV replication and reducing the HCV-induced activation of the innate immune response. This may provide a rationale for clinical trials of a brief period of direct acting antiviral therapy followed by PegIFN/RBV therapy to reduce the overall treatment costs in low-income and middle-income countries.
NCT01888900 and NCT00718172.
慢性丙型肝炎病毒（HCV）感染的特征是先天性免疫激活，干扰素刺激基因（ISG）表达增加，以及干扰素反应性自然杀伤（NK）细胞的表型改变。在此，我们探讨了对于先前标准疗程的聚乙二醇干扰素（PegIFN）/利巴韦林（RBV）治疗失败的患者，使用达卡他韦（DCV）和阿舒瑞韦（ASV）快速降低病毒血症是否能改善对PegIFN的反应。
对22名先前对PegIFN/RBV治疗无反应的HCV感染者，在接受DCV、ASV、PegIFN和RBV的四联（QUAD）治疗期间，研究NK细胞的干扰素反应性。使用来自两个治疗疗程的配对冻存外周血单个核细胞（PBMC），对7名患者在PegIFN/RBV治疗和QUAD治疗中的早期NK细胞反应进行直接比较。作为验证队列，研究了9名接受DCV/ASV治疗的患者的NK细胞对干扰素α体外刺激的反应。
对QUAD治疗的24小时病毒学反应与NK细胞中转录信号转导子和激活子1（STAT1）、磷酸化STAT1（pSTAT1）和肿瘤坏死因子相关凋亡诱导配体（TRAIL）表达的增加相关，并且在QUAD治疗期间STAT1/pSTAT1/TRAIL的诱导作用比先前的PegIFN/RBV治疗期间更强。成功的QUAD治疗以及成功的无干扰素DCV/ASV方案导致对干扰素α体外刺激的功能性NK细胞反应（脱颗粒和TRAIL表达）得到改善。
通过抑制HCV复制和减少HCV诱导的先天性免疫反应激活，可以改善干扰素反应性。这可能为在低收入和中等收入国家进行短期直接抗病毒治疗后再进行PegIFN/RBV治疗以降低总体治疗成本的临床试验提供理论依据。
NCT01888900和NCT00718172。
