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Page 6 of 22 Nevola et al. Hepatoma Res 2018;4:55 I http://dx.doi.org/10.20517/2394-5079.2018.38

[64]
HCV-related cirrhosis and concomitant OBI carrier status than in negative OBI patients . Therefore,
regardless of the etiology, in patients with chronic hepatitis the presence of OBI may represent a significant
co-factor for the development of HCC.

Effect of HBV treatment on development of HCC
It is well known that the long-term suppression of viral replication through the nucleos(t)ide analogues
reduces but does not eliminate the risk of HCC. Several large patient case studies have shown that HCC
incidence rates have significantly decreased in patients undergoing treatment [65,66] . It has recently been
confirmed that the reduced incidence of HCC in patients receiving antiviral treatment is independent of
[67]
age, sex, HBeAg status, cytolysis level and the presence of cirrhosis . Treatment does not appear to have
[67]
a significant clinical impact on patients with low levels of viremia (HBV-DNA < 2000 IU/mL) . A large
retrospective study of non-cirrhotic positive HBV patients showed that the incidence of HCC is significantly
[68]
lower in patients receiving antiviral therapy regardless of the levels of ALT . In addition, the required
number of patients to be treated (NNT) to prevent 1 case of HCC 10 years after initiation of treatment was
found to be similar both in the group of patients with ALT < 2 ULN (NNT = 14) and in those with ALT ≥ 2
[68]
ULN (NNT = 15) . These data appear to confirm that hyper-ALT should not be considered a necessary
[69]
requirement for antiviral treatment in patients with HBV-DNA > 2000 IU/mL .
HCC and HCV chronic infection
Clinical and epidemiological factors affecting development of HCV-related HCC
Chronic HCV infection is the third leading cause of HCC and accounts for about one-third of total
[1]
incidence rates and one-fifth of HCC-related deaths . In recent years, the incidence of HCV- related
[1]
HCC has undergone the greatest increase compared to that associated with other etiologies . The risk of
developing HCC in the course of chronic HCV infection increases in proportion to the degree of hepatic
fibrosis. In fact, most cases of HCV-related HCC occur during an established cirrhosis, suggesting that
[70]
cirrhosis-mediated carcinogenesis may play a primary role in the development of HCC . In patients with
HCV-associated cirrhosis it is estimated that the annual incidence rate of HCC is between 3% and 7% [71,72] .
The incidence of HCC is significantly higher among elderly patients (> 60 years) perhaps also due to the fact
that the progression of fibrosis is related to the duration of the disease [73,74] . Compared to HBV infection
or NAFLD, HCC related to HCV infection shows a tendency to appear in a more advanced phase of liver
[75]
disease . In addition to cirrhosis, other factors such as diabetes mellitus, metabolic syndrome, fatty liver
disease and obesity are associated with a higher risk of developing HCC [76-78] . The presence of HBV or HIV
coinfection, alcohol abuse or iron overload are additional risk factors for hepatocarcinogenesis in HCV-
induced cirrhosis [9,22,79] .

[80]
The role played by serum HCV-RNA levels in the development of HCC is controversial [80-82] . Lee et al. in a
large series reported that elevated serum HCV RNA levels were associated with a significant increase in the
incidence of HCC. Furthermore, they demonstrated that the presence of elevated levels of hepatic cytolysis
[80]
and HCV genotype 1 (12.6% vs. 4.5% for non-genotype 1) were associated with a higher HCC rate . Other
studies have confirmed the oncogenic potential of the HCV genotype 1 [74,83] . A meta-analysis of 57 papers
showed that patients with HCV genotype 1b have twice the risk of developing HCC compared to patients
[83]
with non-1 genotype . Therefore, in patients with HCV infection the presence of high viremia, high levels
of ALT and genotype 1 appear to be risk factors for HCC.

Pathogenic mechanisms of HCV-related HCC
HCV is unable to integrate its genome into host cells and requires a constant replication process to maintain
[84]
chronic infection . Therefore, its oncogenic potential appears to be mostly indirect and mediated by the
development of significant hepatic fibrosis. HCV infection causes a chronic inflammatory state, induces
hepatocyte necrosis, as well as collagen production and accumulation, which will eventually lead to an