Liver Abnormalities after Elimination of HCV Infection: Persistent Epigenetic and Immunological Perturbations Post-Cure.

Stephen J Polyak,I Nicholas Crispe,Thomas F Baumert

doi:10.3390/pathogens10010044

Abstract

Chronic hepatitis C (CHC) is a major cause of hepatocellular carcinoma (HCC) worldwide. While directly acting antiviral (DAA) drugs are now able to cure virtually all hepatitis C virus (HCV) infections, even in subjects with advanced liver disease, what happens to the liver and progression of the disease after DAA-induced cure of viremia is only beginning to emerge. Several large-scale clinical studies in different patient populations have shown that patients with advanced liver disease maintain a risk for developing HCC even when the original instigator, the virus, is eliminated by DAAs. Here we review emerging studies derived from multiple, complementary experimental systems involving patient liver tissues, human liver cell cultures, human liver slice cultures, and animal models, showing that HCV infection induces epigenetic, signaling, and gene expression changes in the liver associated with altered hepatic innate immunity and liver cancer risk. Of critical importance is the fact that these virus-induced abnormalities persist after DAA cure of HCV. These nascent findings portend the discovery of pathways involved in post-HCV immunopathogenesis, which may be clinically actionable targets for more comprehensive care of DAA-cured individuals.

Highlights

Hepatitis C virus (HCV) causes chronic infection and liver disease and infects an estimated 71 million people worldwide [1]
The award commemorates a decades-long quest; the virus was first described as non-A, non-B hepatitis by Alter and colleagues [3,4], discovered as HCV by Houghton and colleagues [5], and shown by Rice and colleagues that the RNA was infectious in vivo [6], resulting in effective antivirals, and eventually, cures for millions of patients
It was clear from the start that since HCV is an RNA virus that replicates exclusively in the cytoplasm of infected cells, patients could be cured of their infection

Summary

Introduction

Hepatitis C virus (HCV) causes chronic infection and liver disease and infects an estimated 71 million people worldwide [1]. This year, the Nobel Prize for Medicine was awarded to Harvey Alter, Michael Houghton, and Charlie Rice for the discovery of HCV [2]. The award commemorates a decades-long quest; the virus was first described as non-A, non-B hepatitis by Alter and colleagues [3,4], discovered as HCV by Houghton and colleagues [5], and shown by Rice and colleagues that the RNA was infectious in vivo [6], resulting in effective antivirals, and eventually, cures for millions of patients. Oral DAA regimens are available that can cure the majority of HCV infections, regardless of viral genotype and disease severity, two major limitations of earlier IFN-based therapy

What Happens to the Liver after Eradication of HCV?

Gene Expression and Signaling Changes

Findings

B: Changes in Signaling Networks