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

Abstract

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

Characterization of changes in intrahepatic immune cell populations during HCV treatment with sofosbuvir and ribavirin

“…Whether individual differences in the nature of interaction between Kupffer cells and CD8+ cells can explain variability in the magnitude of hepatic transaminase elevation observed in patients with HCV infection requires further study. While intriguing, changes that correlated with reduced hepatic inflammation were not found to differ by treatment outcome, consistent with the notion that gross changes in hepatic inflammation may associate with a reduction in HCV burden by DAA suppression rather than with events associated with viral elimination . We were unable to assess changes in HCV‐specific immune cells in the liver in the context of this study due to lack of sample availability amenable to cellular extraction and functional analysis, and thus cannot correlate our findings with those showing restoration of peripheral anti‐HCV CD8+ T‐cell function during therapy …”

Hepatitis C Virus Manipulates Humans as its Favorite Host for a Long‐Term Relationship

“…Increased HCV‐specific memory T cells persist in spontaneously resolved infections. Success of DAA treatment for HCV eradication and the nature of the host immune status associated with virus recovery were recently reported . Available information suggests that the baseline innate immune response contributes to a successful DAA therapy.…”

“…Success of DAA treatment for HCV eradication and the nature of the host immune status associated with virus recovery were recently reported. (44)(45)(46) Available information suggests that the baseline innate immune response contributes to a successful DAA therapy. DAA treatment may result in expansion of lymphocytes and redifferentiation toward effector-like phenotype.…”

Revisiting the Paradox of Interferon‐Stimulated Gene Expression as a Predictor of Hepatitis C Virus Treatment Response, a Decade Later

“…(1) Induction of type III IFNs is the predominant antiviral pathway and driver of ISG induction, which render hepatocytes refractory to further type I IFN action, (6) conceptually supported by the observation that blocking type III IFN enhances the antiviral activity of exogenous IFN-α. (5) Interestingly, in the current issue of Hepatology, Alao et al, from the National Institutes of Health, (7) demonstrate that hepatic ISG expression is a favorable predictor of response to direct-acting antivirals (DAAs) and that transcription of ISGs is down-regulated rapidly (within 4 weeks) following initiation of DAAs. All patients were genotype 1b-infected, had failed therapy with PEG-IFN-α /ribavirin, and were treated with asunaprevir (NS3 protease inhibitor) and daclatasvir (an NS5A inhibitor) for 24 weeks.…”

“…Interestingly, in the current issue of H epatology , Alao et al, from the National Institutes of Health, demonstrate that hepatic ISG expression is a favorable predictor of response to direct‐acting antivirals (DAAs) and that transcription of ISGs is down‐regulated rapidly (within 4 weeks) following initiation of DAAs. All patients were genotype 1b–infected, had failed therapy with PEG‐IFN‐α /ribavirin, and were treated with asunaprevir (NS3 protease inhibitor) and daclatasvir (an NS5A inhibitor) for 24 weeks.…”