Mode of action of the virus

Life cycle of HCV

The hepatitis C virus genome is composed of positive polarity single-stranded RNA contained within a capsid, which is contained within a lipid envelope.

The viral particle attaches itself to receptors on the hepatocyte (liver cell) via glycoproteins in its envelope. The virus enters the hepatocyte via endocytosis (fusion between the viral envelope And the cellular membrane).

This is followed by decapsidation, which releases viral RNA into the cell cytoplasm. In the endoplasmic reticulum, the released RNA is converted into polyprotein by mechanisms within the hepatocyte (ribosomes and cellular proteins). Next, the viral replication complex is formed and viral particles are assembled before extracellular vesicles are released.

The proteins involved in this process include, among others, the following:

  • NS3/4 are involved in the formation of the replication complex;
  • NS5B is involved in replication;
  • NS5A is involved in the encapsidation of the viral genome.

These proteins are important because, as will be shown below, they constitute the targets for antiviral treatment.

HCV life cycle

Consequences of the virus

Viral hepatitis can lead to a fibrosis, a cirrhosis or a hepatocellular carcinoma (HCC).

Fibrosis

Following exposure to HCV, for 60-85% of people who develop chronic hepatitis, liver inflammation leads to fibrosis. This involves an accumulation of scar tissue in the extracellular matrix, which replaces damaged liver cells.

Depending on the extent of damage in the liver, fibrosis may be more or less widespread. Five stages of fibrosis can be identified:

  • F0 = healthy liver;
  • F1 = minor fibrosis, some deposition of scar tissue can be observed in portal areas;
  • F2 = moderate fibrosis, some septa (bands of scar tissue bridge together);
  • F3 = severe fibrosis, portal-to-portal septa;
  • F4 = cirrhosis, septa form nodules that surround hepatocytes (regeneration nodules)
Views of different stages of fibrosis (Photos Z. Goodman)

Fibrosis varies from person to person and certain factors accelerate its development:

  • Gender (male exceeds female);
  • Contracting HCV at 40 years or older;
  • Cofactors such as excessive alcohol consumption, type 2 diabetes, excessive weight or obesity, and coinfection with HIV or VHB (which explains how people can develop cirrhosis within 10 years while others remain without fibrosis or at a minimum of F0-F1 for their whole lifetime;
  • Age (the progression of fibrosis is not linear but rather accelerates with aging);
Variable progression of liver fibrosis (Wartelle-Bladou, 2017)

Photo of liver tissue fragment
at fibrosis stage F4

Hepatic fibrosis may regress when HCV is eradicated and no associated cofactors are present. This changes the prognosis.

Cirrhosis

Cirrhosis is denoted by the presence of regeneration nodules (scar tissue surrounding masses of regenerating hepatic cell. At this stage, damaged cells hinder the liver function.

According to estimations, 20% of people living with hepatitis C will develop cirrhosis over a 20 year period. The main complications of cirrhosis are liver failure, portal hypertension and liver cancer.

At first, the cirrhosis is compensated (asymptomatic). It will evolve at a rate of 5% to 7% per year and patients do eventually develop complications.

Cirrhosis is decompensated when complications related to portal hypertension or liver failure develop (at a rate of 4% to 5% per year). These complications include jaundice, ascites, encephalopathy, or gastrointestinal bleeding from ruptured esophageal varices. This stage drastically reduces median survival from a prognosis of 12 years in the compensated stage to only 2 years in the decompensated stage.

The Child-Pugh-Turcotte score is used for calculating the prognosis of a cirrhosis:

  • A : survival for 1 year at 100%
  • B : survival for 1 year at 80%
  • C : survival for 1 year at 45%

The MELD (Model for End-Stage Liver Disease) score is also used to predict survival up to three months:

MELD ScoreObserved mortality at 3 months
40 and over71,3%
30-3952,6%
20-2919,6%
10-196,0%
9 or under1,9%

A person may need a liver transplant if they have liver failure or decompensated cirrhosis.

Hepatitis C is the leading cause of cirrhosis, liver transplantation and liver cancer in Canada, after alcohol-related liver disease and non-alcoholic steatohepatitis (NASH). HCV is responsible for 7% of deaths in people with cirrhosis. Sustained virologic response (SVR) treatment for hepatitis C can reduce the accumulation of fibrosis in the liver, potentially reverse cirrhosis (from decompensated to compensated) and prevent liver cancer.

Hepatocellular carcinoma (HCC)

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. People with cirrhotic livers have a 2% to 5% risk of developing HCC each year. It is important to note that people with stage F3 fibrosis also have an increased risk of developing HCC.

It is recommended to screen people at stage F3 (Fibroscan® score greater than 10 kPa) every six months.

HCC contributes to an overall decrease in life expectancy, with a mortality rate of 2-6% per year. For 2022, Canada estimates 3500 new diagnoses of HCC and 1650 associated deaths.

Evolution of the impact of HCV