title: Achieving sustained virologic response after interferon-free hepatitis C virus treatment correlates with hepatic interferon gene expression changes independent of cirrhosis.
abstract: Chronic hepatitis C virus (HCV) infection can now be treated with oral directly acting antiviral agents, either with or without ribavirin (RBV). Virologic relapse after treatment can occur, and in some studies was more common in cirrhotic subjects. We previously observed changes in hepatic immunity during interferon (IFN)-free therapy that correlated with favourable outcome in subjects with early liver disease. Here, we compared changes in endogenous IFN pathways during IFN-free, RBV-free therapy between cirrhotic and noncirrhotic subjects. mRNA and microRNA (miRNA) expression analyses were performed on paired pre- and post-treatment liver biopsies from genotype-1 HCV subjects treated with sofosbuvir/ledipasvir (SOF/LDV) for 12 weeks (n = 4, 3 cirrhotics) or SOF/LDV combined with GS-9669 or GS-9451 for 6 weeks (n = 6, 0 cirrhotics). Nine of ten subjects achieved a sustained virologic response (SVR), while one noncirrhotic subject relapsed. Hepatic IFN-stimulated gene expression decreased with treatment in the liver of all subjects, with no observable impact of cirrhosis. Hepatic gene expression of type III IFNs (IFNL1, IFNL3, IFNL4-ΔG) similarly decreased with treatment, while IFNA2 expression, undetectable in all subjects pretreatment, was detected post-treatment in three subjects who achieved a SVR. Only the subject who relapsed had detectable IFNL4-ΔG expression in post-treatment liver. Other IFNs had no change in gene expression (IFNG, IFNB1, IFNA5) or could not be detected. Although expression of multiple hepatic miRNAs changed with treatment, many miRNAs previously implicated in HCV replication and IFN signalling had unchanged expression. In conclusion, favourable treatment outcome during IFN-free HCV therapy is associated with changes in the host IFN response regardless of cirrhosis.
authors: Division of Infectious Diseases, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.|Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.|Critical Care Medicine Department, NIH Clinical Center, Bethesda, MD, USA.
authors: E G
authors: EG
authors: Meissner
authors: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.|St Joseph's Hospital and Medical Center, Department of Hepatology, Creighton University School of Medicine, Phoenix, AZ, USA.
authors: A
authors: A
authors: Kohli
authors: Genomics Unit, Research Technologies Section, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, USA.
authors: K
authors: K
authors: Virtaneva
authors: Genomics Unit, Research Technologies Section, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, USA.
authors: D
authors: D
authors: Sturdevant
authors: Genomics Unit, Research Technologies Section, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, USA.
authors: C
authors: C
authors: Martens
authors: Genomics Unit, Research Technologies Section, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, USA.
authors: S F
authors: SF
authors: Porcella
authors: Gilead Sciences Inc, Foster City, CA, USA.
authors: J G
authors: JG
authors: McHutchison
authors: St Joseph's Hospital and Medical Center, Department of Hepatology, Creighton University School of Medicine, Phoenix, AZ, USA.
authors: H
authors: H
authors: Masur
authors: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.|Division of Clinical Care and Research, Institute of Human Virology, University of Maryland, Baltimore, MD, USA.
authors: S
authors: S
authors: Kottilil
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D005260:Female; D020869:Gene Expression Profiling; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D007372:Interferons / Q000032:analysis*; D008297:Male; D035683:MicroRNAs / Q000032:analysis; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis; D017422:Sequence Analysis, DNA; D000072230:Sustained Virologic Response; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D035683:MicroRNAs; D012333:RNA, Messenger; D007372:Interferons
keywords: cirrhosis; endogenous interferons; hepatitis C virus; interferon-free therapy; treatment relapse