Baseline Amino Acid Substitutions in the NS5A ISDR and PKR Binding Domain of Hepatitis C and Different Fibrosis Levels and Levels of Development of Hepatocellular Carcinoma in Patients Treated with DAAs.

Stefania Paolucci,Roberto Gulminetti,Alice Fratini,Antonio Piralla,Paolo Sacchi,Stefano Novati,Fausto Baldanti,Federica Novazzi,Giorgio Barbarini,Annalisa De Silvestri,Renato Maserati

doi:10.3390/v12030255

Abstract

Variations in the interferon sensitivity-determining region (ISDR) within the NS5A region were related to the development of hepatocellular carcinoma (HCC) in patients infected with hepatitis C virus (HCV). The aim of the study was to investigate a relationship between ISDR/PKR substitutions and their association with liver fibrosis or HCC development. A total of 316 patients infected with HCV and treated with DAAs were evaluated. HCV RNA was quantified and sequenced before treatment. The liver fibrosis stage was assessed by transient elastography and equalized to METAVIR scores. Multivariate analysis showed that ≥3 substitutions in ISDR and ≥6 in PKR-bd were significantly associated with advanced fibrosis. Advanced fibrosis was observed in patients with higher substitutions in ISDR and PKR-bd. A higher correlation between advanced fibrosis and a high frequency of ≥3 substitutions in ISDR and ≥6 in PKR-bd was observed in patients infected with genotype 2c. In addition, in a higher proportion of HCC patients, advanced fibrosis (40.4% vs. 88.2%; p < 0.001) and ≥6 substitutions in PKR-bd (15.4% vs. 41.2%; p = 0.01) was observed. In conclusion, a higher number of substitutions in ISDR and PKR-bd were associated with advanced liver fibrosis, suggesting a use of like predictors for progression in the liver damage. A significantly higher number of PKR-bd substitutions was observed in HCC patients; in particular, in patients infected with HCV genotype 2c.

Highlights

Hepatitis C virus (HCV) infection is one of the main causes of hepatocellular carcinoma (HCC).Therapy to eradicate hepatitis C virus (HCV) prevents the progression of liver fibrosis [1,2,3] and the development of Viruses 2020, 12, 255; doi:10.3390/v12030255 www.mdpi.com/journal/virusesHCC [4,5,6]
The evaluation of variants of the HCV NS5A-interferon sensitivity-determining region (ISDR) and PKR-bd genes was performed at pretreatment in all 316 patients
The mean number of mutations observed in sustained virologic response (SVR) and failing-treatment patients was comparable

Summary

Introduction

Hepatitis C virus (HCV) infection is one of the main causes of hepatocellular carcinoma (HCC).Therapy to eradicate HCV prevents the progression of liver fibrosis [1,2,3] and the development of Viruses 2020, 12, 255; doi:10.3390/v12030255 www.mdpi.com/journal/virusesHCC [4,5,6]. Hepatitis C virus (HCV) infection is one of the main causes of hepatocellular carcinoma (HCC). Therapy to eradicate HCV prevents the progression of liver fibrosis [1,2,3] and the development of Viruses 2020, 12, 255; doi:10.3390/v12030255 www.mdpi.com/journal/viruses. HCC can develop even in patients with chronic hepatitis C who achieve sustained virologic response (SVR) [7,8]. Previous studies have shown that liver fibrosis is strongly associated with the development of HCC after SVR [9,10]. Patients at risk of HCC should continue to have close surveillance after SVR. It is important to determine which patients might have higher risk factors for HCC after SVR, and for how long they should be monitored

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