Hepatocellular Carcinoma and Hepatitis C Virus Treatments: The Bold and the Beautiful

Walaa Abdelhamed; Mohamed El-Kassas


J Viral Hepat. 2023;30(2):148-159. 

In This Article

Abstract and Introduction


The occurrence of hepatocellular carcinoma (HCC) is one of the most serious complications of hepatitis C virus (HCV) infection. Recently, effective antiviral medications have made sustained viral response (SVR) or cure a realistic therapeutic goal for most chronic HCV patients. Given HCV's tumorigenic propensity, it is not surprising that achieving SVR is helpful in preventing HCC. This review briefly summarizes and discusses the existing evidence on the relationship between hepatic carcinogenesis and viral eradication by antivirals, which is mainly divided into interferon-based and direct-acting antivirals (DAAs) based therapy. DAAs have changed the treatment landscape of chronic HCV, reaching high rates of SVR even in patients with advanced cirrhosis, with few contraindications and little side effects. Although some early reports suggested that DAA treatment increased the chance of HCC occurrence, more subsequent observational studies have refuted this theory. The probability of HCC recurrence after HCV eradication appears to be decreasing over time following SVR. Despite virological suppression/cure, individuals with liver cirrhosis are still at risk of HCC and should be monitored. There is a considerable need for markers/scores to predict the long-term risk of HCC in patients with HCV-related liver disease who attain SVR with direct-acting antivirals.


Hepatitis C virus (HCV) is a major serious global health issue, with approximately 70 million people currently infected.[1,2] HCV-related cirrhosis or hepatocellular carcinoma (HCC) results in the death of over 350,000 patients.[3] Although it takes chronic HCV patients about 20 years to develop cirrhosis, only 10 to 20% of people will reach cirrhosis over that time.[4–6] However, HCV-induced complications, like HCC development, are a slow process and are affected by various factors like the disease duration and HCV genotype.[7] Data from Western cohort studies reported that patients with HCV-induced cirrhosis who attained SVR have an annual risk of almost 2% for clinical disease progression and 1% for HCC development.[8]

Risk Factors of HCC Development in Chronic HCV-infected Patients

The occurrence of HCC is one of the most serious and lethal complications of HCV-related cirrhosis. Once cirrhosis is established in the context of HCV, HCC development occurs at an incidence rate of 1–4% annually.[9] The majority of HCC cases in Western countries and 34% of HCC cases in the United States are caused by chronic HCV infection.[10] Patients with HCV infection are 15–20 times more likely to develop HCC, with an annual incidence of (1%–4%) in cirrhotic patients over 30 years.[11] Over the past decade, deaths from HCC on top of post-hepatitis cirrhosis increased by 21.1%, while the number of HCC deaths unrelated to alcohol or HCV remained consistent.[12] Post-hepatitis C cirrhosis is responsible for 10–20% of virus-associated HCC,[13] while the rate of HCC in non-cirrhotic HCV-infected patients is 1% to 3% over 30 years.[14] The risk of HCV-induced HCC seems to be linked to the grade of necro-inflammation, but no evidence exists for a correlation between viral load and the risk of HCC.[15]

Antiviral Therapies and the Risk of Developing HCC in Patients With Chronic HCV Infection

HCV eradication using pegylated IFNα (Peg-IFNα)/ribavirin (RBV) was found to reduce the risk of development of HCC by 57–75%.[11] However, the outcome of direct-acting antivirals (DAAs) on the occurrence of HCC is controversial.[16–18] This review will highlight the impact of different antiviral therapies on the risk of developing HCC.

HCC in HBV and HIV Coinfections and Different Genotypes of HCV

The main variable influencing the risk for HCC in hepatitis B virus (HBV)-HCV coinfection is the HBV replication status. Co-infected patients with undetectable HBV DNA have the same risk of developing HCC as those who are just infected with HCV.[19] In contrast to people with latent HBV and HCV, HCV patients with active HBV replication have a 21% higher death rate and a risk of HCC that is twice as high.[19]

Additionally, compared to HCV patients, people with HIV-HCV coinfection had a much higher frequency of HCC, which usually occurs at a younger age. This rise is explained by increased HCV replication, a diminished HIV immunological response and faster development of cirrhosis.[20,21] Older age, cirrhosis and a low current CD4 cell count were all linked to a greater prevalence of HCC in a study including patients with HIV-HCV coinfection.[22] A large cohort of patients from the USA Veterans Affairs medical system showed that genotypes 1 and 3 of HCV virus were linked with an 80% greater risk of HCC.[23] HCV genotype 6 has also been linked to an increased risk of developing HCC, although less prevalent in developed countries.[24] Additionally, smoking and alcohol use were linked to the faster development of HCC in HCV-infected patients, most likely due to increased oxidative stress.[25]