title: IFI35, mir-99a and HCV genotype to predict sustained virological response to pegylated-interferon plus ribavirin in chronic hepatitis C.
abstract: Although, the treatment of chronic hepatitis C (CHC) greatly improved with the use of direct antiviral agents, pegylated-interferon (PEG-IFN) plus ribavirin remains an option for many patients, worldwide. The intra-hepatic level of expression of interferon stimulated genes (ISGs) and the rs12979860 CC genotype located within IFNL3 have been associated with sustained virological response (SVR), in patients with CHC. The aim of the study was to identify micro-RNAs associated with SVR and to build an accurate signature to predict SVR. Pre-treatment liver biopsies from 111 patients, treated with PEG-IFN plus ribavirin, were studied. Fifty-seven patients had SVR, 36 non-response (NR) and 18 relapse (RR). The expression of 851 human miRNAs and 30 selected mRNAs, including ISGs, was assessed by RT-qPCR. In the first group of patients (screen), 20 miRNAs out of the 851 studied were deregulated between NRs and SVRs. From the 4 miRNAs validated (mir-23a, mir-181a*, mir-217 and mir-99a), in the second group of patients (validation), 3 (mir-23a, mir-181a* and mir-99a) were down-regulated in NRs as compared to SVRs. The ISGs, studied, were accumulated in SVRs and IFNL3 rs12979860 CT/TT carriers compared respectively to NRs and CC carriers. Combining, clinical data together with the expression of selected genes and micro-RNAs, we identified a signature (IFI35, mir-99a and HCV genotype) to predict SVR (AUC:0.876) with a positive predictive value of 86.54% with high sensibility (80%) and specificity (80.4%). This signature may help to characterize patients with low chance to respond to PEG-IFN/ribavirin and to elucidate mechanisms of NR.
authors.affiliation: INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l'inflammation, BP 416, Paris, France; Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France; Service d'Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Estrabaud
authors.affiliation: INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l'inflammation, BP 416, Paris, France; Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France; Service d'Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Appourchaux
authors.affiliation: UMR745 INSERM, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.affiliation: Unité de santé publique, Hôpital Saint-Antoine, Assistance Publique Hôpitaux de Paris and UMR-S 707, UPMC Université Paris 06 & INSERM, Paris, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Carrat
authors.affiliation: INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l'inflammation, BP 416, Paris, France; Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France; Service d'Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Lapalus
authors.affiliation: INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l'inflammation, BP 416, Paris, France; Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France; Service d'Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lada
authors.affiliation: INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l'inflammation, BP 416, Paris, France; Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France; Service d'Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Michelle
authors.initials: M
authors.lastname: Martinot-Peignoux
authors.affiliation: INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l'inflammation, BP 416, Paris, France; Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France; Service d'Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boyer
authors.affiliation: INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l'inflammation, BP 416, Paris, France; Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France; Service d'Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.affiliation: UMR745 INSERM, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.affiliation: INSERM, UMR1149, Team «Viral hepatitis », Centre de Recherche sur l'inflammation, BP 416, Paris, France; Université Denis Diderot Paris 7, site Bichat, BP 416, Paris, France; Service d'Hépatologie, PMAD Hôpital Beaujon, 100 Bd du Général Leclerc, Clichy la Garenne, Clichy, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Tarik
authors.initials: T
authors.lastname: Asselah
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D005786:Gene Expression Regulation; D016679:Genome, Viral; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D006801:Humans; D007372:Interferons / Q000494:pharmacology / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; C085378:IFI35 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C561679:MIRN99 microRNA, human; D035683:MicroRNAs; D012254:Ribavirin; D007372:Interferons
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