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

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 respons

Genetic variation in TNFA predicts protection from severe bacterial infections in patients with end-stage liver disease awaiting liver transplantation

Background & Aims: Augmented susceptibility to infections increases mortality in patients with end-stage liver disease (ESLD). We sought to determine the contribution of selected genetic variants involved in inflammatory signalling downstream of the Toll-like receptor 4 (TLR4) to severe bacterial infections (SBIs) in patients with ESLD. Methods: We retrospectively assessed incidence of SBIs in 336 adult ESLD patients enlisted for orthotopic liver transplantation (OLT) and genotyped them for TLR4 c.+1196C/T, CD14 c.-159C/T, TNFA c. 238G/A, TNFA c. 863C/A, IL1B c. 31C/T and IL1RN variable number of tandem repeats allelic variants. Principal findings were validated in an independent cohort of 332 ESLD patients. Results: Thirty-four percent of patients from the identification cohort and 40% of patients from the validation cohort presented with SBI while enlisted for OLT. The presence of the variant allele TNFA c. -238A (rs361525) was associated with lower serum levels of TNF-alpha, and with significantly decreased risk of SBI in both cohorts. Multivariate analysis showed that the relative protection from SBI associated with this allele almost completely negated the increased susceptibility to SBI owed to advanced ESLD. Although not predictive of overall mortality, the presence of the TNFA c. -238A allele was associated with a complete prevention of SBI-related pre-transplant deaths. Conclusions: Our results suggest that genetic variability in inflammatory signalling is associated with the development of SBI in patients with ESLD. Specifically, we identified the importance of the TNFA c. -238A allele as a strong predictor of protection from SBI, and as a genetic marker associated with significantly improved pre-transplant survival in patients with SBI. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved