title: Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome.
abstract: 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-α-based therapies to IFN-α-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. TRIAL REGISTRATION. ClinicalTrials.gov NCT01441180.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Meissner
authors.forename: David
authors.initials: D
authors.lastname: Wu
authors.forename: Anu
authors.initials: A
authors.lastname: Osinusi
authors.forename: Dimitra
authors.initials: D
authors.lastname: Bon
authors.forename: Kimmo
authors.initials: K
authors.lastname: Virtaneva
authors.forename: Dan
authors.initials: D
authors.lastname: Sturdevant
authors.forename: Steve
authors.initials: S
authors.lastname: Porcella
authors.forename: Honghui
authors.initials: H
authors.lastname: Wang
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
authors.forename: John
authors.initials: J
authors.lastname: McHutchison
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Suffredini
authors.forename: Michael
authors.initials: M
authors.lastname: Polis
authors.forename: Stephen
authors.initials: S
authors.lastname: Hewitt
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prokunina-Olsson
authors.forename: Henry
authors.initials: H
authors.lastname: Masur
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Fauci
authors.forename: Shyamasundaran
authors.initials: S
authors.lastname: Kottilil
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage*; D054357:Chemokine CXCL10 / Q000097:blood; D004359:Drug Therapy, Combination; D010450:Endopeptidases / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D007372:Interferons / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D012254:Ribavirin / Q000008:administration & dosage*; D000069474:Sofosbuvir; D016896:Treatment Outcome; D043222:Ubiquitin Thiolesterase; D014542:Uridine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D054357:Chemokine CXCL10; D010450:Endopeptidases; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D012333:RNA, Messenger; D012254:Ribavirin; D000069474:Sofosbuvir; D043222:Ubiquitin Thiolesterase; D014542:Uridine Monophosphate; C114753:CXCL10 protein, human; C554158:IFNA2 protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579163:IFNL4 protein, human; C485560:USP18 protein, human