Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment

Abstract

Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. The lack of a readily accessible animal model system for HCV is a significant obstacle to understand the mechanisms of viral carcinogenesis. Traditionally, the primary prevention strategy of HCC has been to eliminate infection by antiviral therapy. The success of virus elimination by antiviral treatment is determined by the SVR when the HCV is no longer detectable in serum. Interferon-alpha (IFN-α) and its analogs, pegylated IFN-α (PEG-IFN-α) alone with ribavirin (RBV), have been the primary antiviral treatment of HCV for many years with a low cure rate. The cloning and sequencing of HCV have allowed the development of cell culture models, which accelerated antiviral drug discovery. It resulted in the selection of highly effective direct-acting antiviral (DAA)-based combination therapy that now offers incredible success in curing HCV infection in more than 95% of all patients, including those with cirrhosis. However, several emerging recent publications claim that patients who have liver cirrhosis at the time of DAAs treatment face the risk of HCC occurrence and recurrence after viral cure. This remains a substantial challenge while addressing the long-term benefit of antiviral medicine. The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. In addition to the potential oncogenic programming that drives HCC after viral clearance by DAAs, the current status of a biomarker development for early prediction of cirrhosis regression and HCC detection post viral treatment is discussed. Since DAAs treatment does not provide full protection against reinfection or viral transmission to other individuals, the recent studies for a vaccine development are also reviewed.

Keywords: DAA; ER stress; HCC; HCV; IFN; autophagy; direct-acting antiviral; endoplasmic reticulum stress; hepatitis C virus; hepatocellular carcinoma; interferon.

Figure 1

Progress in translational research that leads to significant breakthroughs in DAA-based antiviral drug development resulting in HCV cure. Reprinted from Semin Cell Dev Biol, Dash S, Aydin Y, Wu T. Integrated stress response in hepatitis C promotes Nrf2-related chaperone-mediated autophagy: a novel mechanism for host-microbe survival and HCC development in liver cirrhosis, Copyright (2019), with permission from Elsevier.

Figure 2

Hepatocellular carcinoma mechanisms related to chronic HCV infection are the combination of virus-mediated (direct), host-mediated (indirect), and host-related bystander effects.

Figure 3

Chronic HCV replication in liver cells induces a multifaceted stress response. The infection is initiated by the attachment and entry of the virus particle through several cell surface receptors. The HCV RNA binds to the ribosome and translates a single large polyprotein, which is processed into structural and non-structural proteins. Accumulation of viral proteins induces proliferation of ER-membranes and formation of membranous web structure. HCV replication in the membranous web produces many new genomic positive-strand and negative-strand RNA. Genomic HCV positive-strand RNA packages into complete infectious virus particles that release through the secretory pathway. Arrows show the emerging new DAAs targeting the viral protein and HCV replication cycle. Note: Adapted from Chapter 8, Figure 2 of Viral Polymerases: Structures, Functions and Roles as Antiviral Drug Targets, Dash S, Aydin Y, Stephens CM. In: Gupta SP, editor. Hepatitis C Virus NS5B RNA-Dependent RNA Polymerase Inhibitor: An Integral Part of HCV Antiviral Therapy, 211-235, copyright (2019), with permission from Elsevier.

Figure 4

Hepatic adaptive response to chronic HCV infection activates hepatocyte cell survival programming. HCV structural and non-structural proteins activate multiple cellular pathways.

Figure 5

Hepatic adaptive response to inflammatory stress progresses to cirrhosis. Blood supply to the liver by both the hepatic artery and the portal vein brings potential pathogens, including HCV. Kupffer cells and sinusoidal endothelial cells recognize HCV-derived pathogen-associated molecular pattern (PAMP). The activation of the innate immune response through Kupffer cells recruit new adaptive immune cells (CD4 and CD8 T cells) and B cells. Sustained inflammation can lead to liver fibrosis, cirrhosis, and HCC. Chronic hepatitis is a physiological adaptation that can be reversible after HCV cure. Pathological adaptation of the inflamed liver can lead to cirrhosis and HCC.

Figure 6

Sterile inflammation associated with host-related non-viral factors accelerates HCC progression during chronic HCV infection. Multiple host-related factors induce hepatic stress (ER stress) and low-grade inflammation in the liver. The most common causes of hepatic stress and inflammation include metabolic syndrome, type 2 diabetes, NAFLD associated with obesity and high-calorie diet, alcohol, gut microbiota, and autoimmune diseases. The bystander effect of inflammation associated with these non-viral causes can accelerate liver damage, persistent fibrosis, and HCC risk.