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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

Authors Frankova S, Jirsa M, Merta D, Neroldova M, Urbanek P, Senkerikova R, Spicak J, Sperl J

Received 8 August 2015

Accepted for publication 15 October 2015

Published 17 December 2015 Volume 2015:11 Pages 1853—1861

DOI https://doi.org/10.2147/TCRM.S94010

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Hoa Le

Peer reviewer comments 3

Editor who approved publication: Professor Garry Walsh

Sona Frankova,1 Milan Jirsa,2 Dusan Merta,3 Magdalena Neroldova,2 Petr Urbanek,4 Renata Senkerikova,1 Julius Spicak,1 Jan Sperl1

1Department of Hepatogastroenterology, 2Laboratory of Experimental Hepatology, 3Department of Anesthesiology, Resuscitation and Intensive Care, Institute for Clinical and Experimental Medicine, 4Department of Internal Medicine, Central Military Hospital, First Medical School, Prague, Czech Republic

Background and aims: 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.
Patients and 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).
Conclusion: Initial expression of USP18 and the course of its activation could be a reliable predictor of SVR achievement.

Keywords:
chronic hepatitis C, interferon-sensitive gene, USP18, protease inhibitor, virological response

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