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The molecular mechanism of a malignant transformation reduced by 20%. [63-65] In the group of patients with chronic
[51]
of hepatocyte induced by HCV infection is still unclear. hepatitis treated with IFN ± ribavirin, the incidence rate
The pathogenesis of HCC is generally accepted as of HCC is markedly reduced, while in the group of cirrhotic
chronic inflammation and injury, which leads to fibrosis patients data are not sufficient to support the efficacy of
with eventual progression to cirrhosis and subsequent therapy to preventing cancer. [64-66] A meta-analysis in 2010
[52]
development of HCC. In this setting, the prevention of compared 20 studies with 4,700 patients overall; the risk
HCC could be achieved by preventing cirrhosis and chronic in treatment group of HCC was reduced (RR: 0.43, 95%
[67]
[58]
liver inflammation and injury. The most effective approach CI: 0.33-0.56). Pinzoni et al. showed that the risk of
to prevent HCC is averting HCV infection by vaccination. developing HCC after achieving SVR persisted in patients
Unfortunately, despite researcher’s efforts, HCV vaccine is with HCV-related cirrhosis: among 598 patients with CHC
[53]
not yet available. When infection is acquired the only who underwent a complete course of treatment with Peg-
way to preventing cancer and progression of liver disease IFN and ribavirin, 221 (37%) patients obtained a SVR and
depends on antiviral therapy. throughout the 10-year post-treatment follow-up, 5.8%
of these 221 patients developed HCC. Authors conclude
Not all patients with chronic hepatitis C (CHC) progress to that these patients should continue to undergo long-term
cirrhosis and not all patients with HCV-related cirrhosis surveillance for HCC, to ensure the early detection and
develop HCC, and the risk factors involved are still treatment. Standard therapy can decrease the risk of HCC,
unknown. Furthermore, the progression from chronic but the patients with this benefit are those who achieve
hepatitis to cirrhosis occurs over several decades thus SVR and who have not yet progressed to cirrhosis or
implying that for RCTs to assess efficacy of antiviral advanced fibrosis.
therapy to preventing HCC as a primary endpoint, need to
enroll large sample size of patients and long-term follow- The risk of HCC is reduced but not eliminated also in
up. These limitations ensure that evidence to support the patients with SVR: these patients are older, thus reflecting
role of antiviral therapy to prevent cancer is based mainly a long duration of infection or increased prevalence
on cohort follow-up, retrospective analysis, and meta- of cirrhosis and other risk factors for HCC in aged
analysis. population. [68,69] In addition, non-viral carcinogenic factors
such as diabetes, obesity, and alcohol abuse may explain
In the 2000s, the standard therapy of HCV was Peg-IFN and the failure of HCC prevention in SVR patients. Although
[70]
ribavirin; many reports in this period showed a benefit of this calls for a reassessment of current strategies of patient
treatment, even though only a few of these were RCTs, prioritization to antiviral therapies, which are mostly
and most of these studies were retrospective or cohort dictated by cost-utility criteria and, therefore, target the
studies. [54-57] The protective effect of antiviral therapy was most in need patients with advanced liver disease, we
seen in most studies when patients achieved sustained became progressively aware that uncertainty regarding
virological response (SVR). [58,59] These data have recently rates and the pattern of HCC chemoprevention by antiviral
been confirmed by Moon et al. in a retrospective regimens is mainly the consequence of methodological
[60]
analysis including 494 CHC patients: Among the group of flaws generated by the retrospective scrutiny of the
patients who did not achieve SVR, the incidence of HCC literature. Because of its chemopreventive and antifibrotic
was significantly higher (5.5%) vs. the group of patients effects, IFN monotherapy has been adopted as a long-term
with SVR (1%, P = 0.005). In this study, the clinical factors maintenance therapy to prevent HCC development.
associated with SVR were non-cirrhosis, age younger than
40 years, HCV genotype 2 or 3, low HCV RNA level, and Three large RCTs of long-term (3-4 years), low-dose Peg-
low body weight, as reported in the previous studies. This IFN in patients with advanced fibrosis or cirrhosis showed
suggests that the main chemoprotective effect is achieved no benefit of treatment on overall clinical outcomes or
for younger patients without cirrhosis and non-advanced HCC. [71-73] A subsequent report of the HALT-C Trial focusing
liver disease. on HCC development with a slightly longer duration of
follow-up also showed no difference in the incidence
The strength of these data are enforced by three meta- of HCC between the patients that were randomized
analyses suggesting that IFN therapy reduces the incidence to the maintenance IFN or no treatment. The same
[74]
of HCC in patients with CHC with an RR among treated results were observed even when the duration of follow-
patients of 0.43 (95% CI: 0.33-0.56, P < 0.00001). [58,61,62] up in these studies was more prolonged. Even after
[75]
Some studies report that the risk of HCC is reduced in radical treatment, tumor recurrence of de novo second
these patients independent of fibrosis stage, while among primary HCC was extremely frequent (70% after 5 years
cirrhotic patients that achieve SVR incidence of HCC is of surgical resection) and treatment options available,

Hepatoma Research | Volume 2 | Issue 1 | January 15, 2016 13