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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).

Among others, the proteins involved in this process include:

• 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.

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Consequences of the virus

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.²

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)

Fibrosis varies per person and certain factors accelerate its development :

• Sex (M more than F);
• 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);

Hepatic fibrosis may regress if the 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.

A cirrhosis is decompensated when complications related to portal hypertension or liver failure develop (at a rate of 4% to 5% per year). These complicates also include jaundice, ascites, encephalopathy, or gastrointestinal bleeding caused by ruptured esophageal varices. This stage causes a drastic decrease in median survival, dropping from a prognosis of 12 years during the compensated stage to only 2 years as of the decompensated stage.³

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 = 40: 71.3% probability of mortality within three months
• MELD = 30-39: 52.6%
• MELD = 20-29: 19.6%
• MELD = 10-19: 6.0%
• MELD = 9 or less: 1.9%

In cases of liver failure or decompensated cirrhosis, a person may need a liver transplant.

Following alcohol-related liver disease and nonalcoholic steatohepatitis (NASH), hepatitis C is the main cause of cirrhosis, liver transplantation and liver cancer in Canada. HCV is responsible for 7% of deaths of people affected by cirrhosis. A sustained virologic response (SVR) treatment for hepatitis C can have an effect of reducing the accumulation of fibrosis in the liver, possibly incurring a reversal of cirrhosis (from decompensated to compensated), and preventing liver cancer.

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Hepatocellular carcinoma (HCC)

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. For people with cirrhotic livers, the risk of developing HCC can be from 2% to 5% each year. It is important to note that people with fibrosis at stage F3 are also at risk of developing HCC more often than not.

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

HCC contributes to a general decrease in life expectancy, with a mortality rate between 2-6% per year. For 2022, Canada estimated 3500 new diagnoses of HCC and 1650 associated deaths.⁴

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References

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