title: USP18 downregulation in peripheral blood mononuclear cells predicts nonresponse to interferon-based triple therapy in patients with chronic hepatitis C, genotype 1: a pilot study.
abstract: OBJECTIVE
  Patients with advanced liver fibrosis owing to chronic hepatitis C virus genotype 1 represent a difficult-to-treat group even if a protease inhibitor is added to pegylated interferon alpha and ribavirin. Therefore, only patients with a high chance of cure should be treated with interferon-based treatment.
  
  
  METHODS
  Expression of IFNG, IFNLR1, and interferon-sensitive genes CXCL9, IFI16, IFI27, ISG15, and USP18 in peripheral blood mononuclear cells was assessed before and during the initial 12 weeks of treatment. The studied group consisted of 26 treatment-experienced patients of average age of 50 years with advanced liver fibrosis compared to seven healthy volunteers. Fourteen patients were treated with pegylated interferon alpha 2b, ribavirin, and boceprevir and 12 patients with telaprevir. The overall sustained virological response (SVR) rate was 69% (18/26).
  
  
  RESULTS
  A significant difference in the initial expression (median, interquartile range [IQR]) of CXCL9 2.9×, IQR: 1.7-12.4 vs 1.2×, IQR: 0.5-1.8; (P=0.01) IFNG 7.3×, IQR: 1.7-32.6 vs 0.7×, IQR: 0.4-1.3; P=0.002 and USP18 3.7×, IQR: 2.1-7.7 vs 1.4×, IQR: 0.9-1.6; (P=0.03) was found between the SVR and non-SVR groups. Expression of all analyzed genes was progressively increasing during the first 12 weeks of therapy, but a significant difference between SVR and non-SVR group was found only in USP18 expression at week 12 (P=0.001). Initial expression of four genes predicted SVR in univariate analysis (CXCL9 [OR: 12.00, 95% CI: 1.21-118.89], IFI27 [OR: 12.00, 95% CI: 1.21-118.89], IFNG [OR: 10.50, 95% CI: 1.50-73.67], USP18 [OR: 21.00, 95% CI: 2.05-215.18]). In multivariate analysis, only the initial expression of USP18 was identified as a predictor of SVR (P=0.047).
  
  
  CONCLUSIONS
  Initial expression of USP18 and the course of its activation could be a reliable predictor of SVR achievement.
authors.affiliation: Department of Hepatogastroenterology, Resuscitation and Intensive Care, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Sona
authors.initials: S
authors.lastname: Frankova
authors.affiliation: Laboratory of Experimental Hepatology, Resuscitation and Intensive Care, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Jirsa
authors.affiliation: Department of Anesthesiology, Resuscitation and Intensive Care, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Dusan
authors.initials: D
authors.lastname: Merta
authors.affiliation: Laboratory of Experimental Hepatology, Resuscitation and Intensive Care, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Neroldova
authors.affiliation: Department of Internal Medicine, Central Military Hospital, First Medical School, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Urbanek
authors.affiliation: Department of Hepatogastroenterology, Resuscitation and Intensive Care, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Renata
authors.initials: R
authors.lastname: Senkerikova
authors.affiliation: Department of Hepatogastroenterology, Resuscitation and Intensive Care, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Julius
authors.initials: J
authors.lastname: Spicak
authors.affiliation: Department of Hepatogastroenterology, Resuscitation and Intensive Care, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Sperl
keywords: USP18; chronic hepatitis C; interferon-sensitive gene; protease inhibitor; virological response