Page 66 - Read Online

Page 2 of 8 Lee et al. Hepatoma Res 2020;6:21 I http://dx.doi.org/10.20517/2394-5079.2019.44

The sharply increased incidence of HCC in the last several decades in the United States and worldwide has
[2]
partly resulted from an increase in hepatitis C virus (HCV) infection . In the United States, chronic hepatitis
[2,3]
C accounts for approximately 20%-31% of HCC deaths .

HCV AND HCC
HCV carcinogenesis is speculated to be indirectly related to multiple steps from chronic inflammation
to fibrosis, advanced fibrosis and cirrhosis with somatic genetic/epigenetic alterations, and malignant
[4,5]
transformation of hepatocytes over 20 or more years . Patients with HCV cirrhosis had a three-fold higher
adjusted risk of HCC than those with cirrhosis from other etiologies, implying direct carcinogenic effects of
[10]
[6-9]
the virus . HCC may develop in non-cirrhotic HCV patients, suggesting a direct HCV oncogenic effect .
Additionally, HCV core protein was shown to have oncogenic potential by using transgenic mouse models,
[11]
indicating its direct involvement in carcinogenesis .
HCV-infected patients with advanced fibrosis or cirrhosis and older age are well-established risk for HCC
development [4,12-14] . The prevalence of HCC is especially high in cirrhotic HCV patients with an estimated
[14]
annual risk of 2%-4% .

HCV ERADICATION BY INTERFERON-BASED THERAPY AND HCC RISKS
Long-term eradication of HCV reduced HCC risk, which was initially demonstrated in patients who
achieved SVR by interferon (IFN)-based therapies [14-18] . An analysis from 12 observational studies
demonstrated that IFN-induced SVR led to nearly four-fold HCC risk reduction irrespective of liver disease
[19]
stage .
[20]
Van der Meer et al. found that the 10-year cumulative HCC incidence with SVR was 5.1%, vs. 21.8% in
those without SVR (P < 0.001).

Although IFN has potential anti-inflammatory and/or immunomodulatory effects for the prevention
[22]
of HCC, HCV eradication does not eliminate the risk of HCC [21,22] . El-Serag et al. reported an overall
incidence rate of 0.33% in new HCC development, which could occur more than 10 years after HCV
eradication by IFN-based therapy.

HCV ERADICATION BY DAAS AND HCC RISKS
DAAs for HCV infection directly targeting viral protease, polymerase, or non-structural proteins have
replaced IFN-based therapy over the past few years. They have changed the management of hepatitis C virus
infection significantly, as the treatment is easy to administer, well-tolerated, safe, and highly effective with an
SVR rate exceeding 90% [23-25] .

DAAs can be used in HCV infection with advanced and complicated liver disease [25-31] . Multiple large cohort
[33]
studies have shown that DAA-induced SVR is associated with a reduced risk of HCC [14,32-35] . Kanwal et al.
reported a significantly reduced risk of HCC (0.9 vs. 3.45 HCC/100 person-years) in 22,500 hepatitis C
patients treated by DAAs with SVR compared to those without.

[35]
Piñero et al. showed an overall 73% relative risk reduction for de novo HCC in DAAs-treated HCV patients
with SVR, but the risk remained high in patients with advanced fibrosis and cirrhosis. Furthermore, reduced
[34]
HCC risk by DAAs with SVR was demonstrated in patients with or without cirrhosis by Ioannou et al. .

HCC RISK IN CHRONIC HEPATITIS C TREATED BY DAA COMPARED TO THAT OF IFN
THERAPY
IFN, an immune modulator, inhibits proliferation and may prevent the development of HCC. IFN-based
HCV antiviral therapy due to its potential side effects was used mostly on patients without cirrhosis.