Baseline Intrahepatic and Peripheral Innate Immunity are Associated with Hepatitis C Virus Clearance During Direct‐Acting Antiviral Therapy

• DOI: 10.1002/hep.29921
• Publication Date: 2018-04-28T01:00:21Z
• Authors: Hawwa Alao; Maggie Cam; Chithra Keembiyeh...; Fang Zhang; Elisavet Serti; Daniel Suarez; Heiyoung Park; Nicolaas H. Fourie; Elizabeth C. Wright; Wendy A. Henderson; Qisheng Li; T. Jake Liang; Barbara Rehermann; Marc G. Ghany
• Keywords: Daclatasvir; Hepatitis C

Hepatitis C virus (HCV) infection induces interferon (IFN)-stimulated genes (ISGs) and downstream innate immune responses. This study investigated whether baseline on-treatment differences in these responses predict response versus virological breakthrough during therapy with direct-acting antivirals (DAAs). Thirteen HCV genotype 1b-infected patients who had previously failed a course of pegylated IFN/ribavirin were retreated asunaprevir/daclatasvir for 24 weeks. After pretreatment biopsy, randomized to undergo second biopsy at week 2 or 4 on therapy. Microarray NanoString analyses performed paired liver biopsies analyzed using linear mixed models. As biomarkers peripheral IFN responses, blood natural killer cells assessed phosphorylated signal transducer activator transcription 1 (pSTAT1) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression degranulation. Nine 13 (69%) achieved sustained 12 weeks off (SVR12), experienced breakthroughs between 12. Patients SVR12 displayed higher ISG levels frequency pSTAT1 TRAIL-expressing, degranulating samples than those breakthrough. Comparing gene from on-therapy biopsies, 408 (±1.2-fold, P < 0.01) differentially expressed. Genes down-regulated treatment predominantly ISGs. Down-regulation ISGs was rapid correlated RNA suppression. Conclusion: An enhanced signature is observed achieve compared experience breakthrough; the findings suggest that immunity may contribute clearance DAA by preventing emergence resistance-associated substitutions lead viral