title: Serum miR-122 may serve as a biomarker for response to direct acting antivirals: effect of paritaprevir/R with dasabuvir or ombitasvir on miR-122 in HCV-infected subjects.
abstract: Circulating microRNAs (miRNA) have been intensely investigated as biomarkers in disease and therapy. Several studies have identified miR-122 as an important regulator of HCV replication. The effect of new therapies that directly target the HCV replication life cycle on circulating microRNA levels has not been elucidated. We performed expression profiling of circulating miRNA in serum in subjects treated with HCV direct-acting antiviral agents (DAAs). Serum miRNA levels were evaluated from two studies in HCV GT1-infected treatment-naïve subjects and prior nonresponders to pegylated interferon (pegIFN) and ribavirin (RBV) who received paritaprevir/ritonavir + dasabuvir + RBV for 12 weeks, and in treatment-naïve genotype (GT)1-3-infected subjects who received paritaprevir/ritonavir + ombitasvir ± RBV for 12 weeks. Over 100 different miRNA species were detected in serum. Of these, levels of miR-122 showed the most consistent change in response to treatment across all HCV genotypes. In all subjects, miR-122 showed an average four-fold reduction between baseline and week 2, and remained below baseline through post-treatment week 12 in subjects who achieved sustained virological response. In contrast, in subjects who did not achieve SVR, miR-122 levels began to return to baseline levels after the second week of treatment. The change in miR-122 levels was similar across genotypes, and was comparable with or without RBV. This is the first report comparing expression levels of circulating miRNA in HCV GT1-3 subjects treated with IFN-free combinations of DAAs. The results suggest that serum levels of miR-122 are reduced following treatment in subjects who achieve SVR, and correlate with HCV RNA levels across genotypes.
authors.affiliation: Department of Pharmacogenetics and Pharmacogenomics, Clinical Pharmacology, AbbVie, North Chicago, IL, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Waring
authors.affiliation: Department of Clinical Virology, AbbVie, North Chicago, IL, USA.
authors.forename: E O
authors.initials: EO
authors.lastname: Dumas
authors.affiliation: Department of Pharmacogenetics and Pharmacogenomics, Clinical Pharmacology, AbbVie, North Chicago, IL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Abel
authors.affiliation: Department of Clinical Virology, AbbVie, North Chicago, IL, USA.
authors.forename: E
authors.initials: E
authors.lastname: Coakley
authors.affiliation: Department of Clinical Virology, AbbVie, North Chicago, IL, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Cohen
authors.affiliation: Department of Pharmacogenetics and Pharmacogenomics, Clinical Pharmacology, AbbVie, North Chicago, IL, USA.
authors.forename: J Wade
authors.initials: JW
authors.lastname: Davis
authors.affiliation: Department of Clinical Virology, AbbVie, North Chicago, IL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Podsadecki
authors.affiliation: Department of Pharmacogenetics and Pharmacogenomics, Clinical Pharmacology, AbbVie, North Chicago, IL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dutta
mesh_terms: D015081:2-Naphthylamine; D000813:Anilides / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002219:Carbamates / Q000627:therapeutic use; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D016174:Hepacivirus / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000627:therapeutic use; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics; D011392:Proline / Q000031:analogs & derivatives; D013449:Sulfonamides / Q000627:therapeutic use; D014498:Uracil / Q000031:analogs & derivatives / Q000627:therapeutic use; D014633:Valine; D014779:Virus Replication / Q000235:genetics
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D015415:Biomarkers; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; C531907:MIRN122 microRNA, human; D047028:Macrocyclic Compounds; D035683:MicroRNAs; D013449:Sulfonamides; C586094:ombitasvir; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; C585405:paritaprevir
keywords: hepatitis C virus; miR-122; microRNA