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Page 2 of 8 Pazgan-Simon. Hepatoma Res 2020;6:17 I http://dx.doi.org/10.20517/2394-5079.2019.52

organ transplantation. An acute viral infection develops within 14 to 180 days following the exposure. Only
humans and chimpanzees are affected.

To date, seven HCV genotypes with variable prevalence have been identified worldwide. Genotype 1 HCV
has 2 subtypes: 1a predominant in North America and 1b predominant in Europe. Genotype 2 HCV is
fairly rare, occurring in North America. Genotype 3 HCV is the most common among intravenous drug
[3]
users, whilst genotype 4 HCV is the most prevalent in North Africa . The remaining genotypes are very
uncommon. Individuals infected with genotypes 1a and 1b are more likely to develop chronic hepatitis,
whereas those with genotype 3 are more likely to develop fatty liver disease. The highest prevalence of HCV
is noted in Asia, south frontiers of North America and Brazil. The estimated number of people with active
HCV infection worldwide is about 70 million, with over 100 million testing positive for anti-HCV antibodies
(serological evidence of past HCV infection), and another 3-4 million people get infected every year.
Unfortunately, despite ongoing research the HCV vaccine has not been developed to date.

Intravenous drug users, homosexual men, rough sleepers, individuals with HIV co-infection, migrants,
blood and blood product recipients and prisoners are at particular risk of HCV infection.

Whereas HCV infection can be chronic, the virus does not embed in human genome (just as the HBV does),
despite long-term persistence in hepatocytes or liver-resident lymphocytes.

NATURAL COURSE OF HCV INFECTION
After an acute infection, spontaneous virus clearance occurs in up to 30% of infected individuals within
6 months. However, 70% of affected patients develop chronic condition. Up to 80% of infected individuals are
asymptomatic, so the infection may remain undiagnosed in many cases. About 30% of infected individuals
develop cirrhosis. Some of them may present with hepatocellular carcinoma (HCC) in a 30-year follow-up
[4]
study .

Patients with chronic infection often present with extrahepatic manifestations. Their symptoms are usually
caused by cryoglobulins, leading to vasculitis and kidney damage. Osteoarticular, cardiovascular, endocrine
(especially pancreatic and thyroid), central nervous system or skin involvement are also possible. They may
develop lymphomas. Some patients with extrahepatic manifestations may have no identifiable liver disease.

PRIMARY LIVER CANCER AND HCV INFECTION
In patients with HCV-associated cirrhosis, the annual risk of HCC is 2%-8%, whereas the overall risk of
cancer in all HCV-infected patients is 14.4%. HCC recurrence within 5 years following effective treatment
(different therapies) affects 70% of patients. Most HCC cases are found in Japan, Pakistan, Asia, Europe and
the United States.

In HCV-infected patients, HCC development is associated with the progression of fibrosis and cirrhosis.
Structural and non-structural viral proteins virus play the key role in malignant transformation inducing
oxidative stress, aberrant proliferation and apoptosis, chronic inflammation, dysregulated lipid synthesis as
well as excessive and abnormal angiogenesis. Through methylation, HCV core proteins reduce CDKN2A
activity, causing telomerase dysfunction (TERT promoter mutations), the most common genetic aberrations
[5]
seen in HCC .

Furthermore, NS3 and NS5A proteins may disrupt the p53 synthesis pathway, blocking apoptosis and
[6]
nucleocytoplasmic shuttling of p53 .