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

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 (IFNα) 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.

The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance

“…The HCV relies on endoplasmic reticulum (ER) in the hepatocyte to produce viral proteins, thus causing the ER stress. The ER is an important organelle that helps to maintain normal functions of hepatocytes, such as the transportation of proteins and lipids and the synthesis of proteins [ 32 , 33 , 34 ]. As a result, injuring hepatocytes by HCV could lead to cirrhosis.…”

Tracking Down the Epigenetic Footprint of HCV-Induced Hepatocarcinogenesis

“…Studies found a correlation between lower risk of developing HCC following DAA treatment in patients without fibrosis compared to patients with existing fibrosis and cirrhosis before treatment [ 16 , 65 ]. In addition, cirrhosis is correlated with higher mortality rates in DAAs-treated patients, which increases in correlation with the stage of fibrosis [ 65 , 66 ]. Therefore, an intriguing question is whether the epigenetic signature is caused by indirect or etiology-specific mechanisms.…”

Changes of Gut-Microbiota-Liver Axis in Hepatitis C Virus Infection

“…Although cirrhotic liver in chronic HCV infected patients may progress to HCC development, HCV is classified as an indirect oncogenic virus based on the very low percentage of HCC development in HCV-infected patients and its inability to infect HCC cancer cells rather than normal hepatocytes [ 52 ]. Moreover, HCV is an RNA virus that is unable to be incorporated in the host genome, unlike the hepatitis B virus (HBV), and therefore, HCV is considered as an indirect oncogenic virus [ 53 ].…”