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development in three meta-analyses, but it appeared to incidence is significantly higher among those who do not
be unchanged in another three. The effect is more evident achieve virologic response than in those who do, with
in Asian than in European studies possibly related to the a significant treatment effect observed in the subgroup
lower incidence of HCC in European patients. [27-32] These of cirrhotic patients. [35-38] This observation provides
controversial results can be explained by extrapolating further evidence that older nucleos(t)ide analogs are
HCC chemoprevention through the retrospective scrutiny not an optimal first-line treatment for chronic hepatitis
of the studies that were originally designed to assess the B, as they are associated with very high rates of drug
antiviral efficacy of IFN therapy. The reanalysis of these resistance during the long-term treatment, especially in
studies was biased by the lack of a separate analysis of the cirrhotic patients. The nucleos(t)ide analogs entecavir and
treatment outcomes between sustained responders and tenofovir, currently recommended as first-line options for
non-responders, who represent a majority of all patients the treatment of chronic hepatitis B, maintain long-term
with CHB receiving IFN. Therefore, proving a direct anti- viral suppression in over 95% of patients and improve liver
[3]
HCC effect of IFN-based therapy with clinical trial data histology. [39-41] Treatment with entecavir and tenofovir
beyond what is currently available will be difficult if not can reduce the risk of HCC. [42-45] The treatment effect
impossible. However, IFN still has a role as an effective was significant in patients with cirrhosis, whereas a
[36]
antiviral for HBV, with finite treatment duration and the significant HCC risk reduction in non-cirrhotic patients
potential for a durable effect. Theoretically, the promotion was noticeable only in some reports. [45,46]
of immune control of viral replication by IFN may have a
more solid rationale in terms of HCC prevention unless Finally, there is an increasing evidence to suggest that
HBV DNA levels have a direct carcinogenic effect, in which antiviral therapy may reduce recurrence and also improve
case nucleos(t)ide analog therapy is likely more effective. [33] survival on post-hepatectomy outcome for hepatitis
B-related HCC. A registry-based study from Taiwan
The role of nucleos(t)ide analog therapies in preventing showed that of 4569 HBV-related HCC patients who
HCC has already been widely investigated. The first received curative liver resections, patients treated with
data date back to the first antiviral agent chronically lamivudine, telbivudine, or entecavir had a significantly
administered to reduce viral load in patients with the lower risk of HCC recurrence as compared to those who
chronic HBV-related liver disease. In 2004, a large RCT received no antiviral therapy (hazard ratio 0.67, 95% CI:
conducted in Asia in patients with chronic hepatitis B, who 0.55-0.81, P < 0.001). Another study by Chan et al.
[47]
[46]
had histologically confirmed cirrhosis or advanced fibrosis, demonstrated that antiviral therapy with lamivudine or
proved that lamivudine was effective in reducing rates of entecavir improves the prognosis of HBV-related HCC: The
progression of disease and hepatic decompensation as 1-, 3-, and 5-year overall survival rates in the treatment
[22]
well as the incidence of HCC. Further studies confirmed group were 88.1%, 79.1%, and 71.2%, respectively; in
[31]
these results. Papatheodoridis et al. showed that long- the control group, 76.5%, 47.5%, and 43.5%, respectively
term therapy with nucleos(t)ide analogs (NUCs) starting (P = 0.005). Huang et al. in a recent RCT showed
[48]
with lamivudine monotherapy did not eliminate the HCC that, in patients with hepatitis B-related HCC treated
risk in HBeAg-negative patients with CHB, especially with adefovir, antiviral therapy leads to a reduction of
those with pre-existing cirrhosis. A recent meta-analysis late HCC recurrence and significantly improves overall
reported that lamivudine treatment significantly reduced survival after hepatic resection when compared with no
the incidence of HCC when compared with no treatment. treatment. IFN treatment as tertiary prevention of HBV-
However, HCC still develops at a rate of 1.3 per 100 HCC-related recurrence remains controversial according
patient years in CHB patients receiving an oral antiviral to the findings in systematic reviews. Furthermore, the
agent. Recent paper on a nationwide study in Greece use of IFN is burdened by several side effects, including
[34]
indicates that the HCC risk remains increased in entecavir- liver decompensation.
treated HBeAg-negative CHB patients with cirrhosis, in
particular, of older age, at least for the first 5 years. The HCV
HCC risk does not seem to be significantly reduced with
entecavir when compared with antiviral therapy starting Increasing incidence of HCC in many countries, especially
with lamivudine. This finding highlights the need for in the United States, is the result of an increase in the
[31]
continued HCC surveillance, particularly in CHB patients prevalence of HCV infection. HCV has been the dominant
with inadequate viral suppression, older age, and cirrhosis. viral cause of HCC in North America, some Western
[49]
countries, and Japan. The incidence of HCC in HCV-
Maintenance of virological remission is also important for infected patients amounts to 1-3% at 30 years after the
the reduction of HCC risk. Among treated patients, HCC infection. [50]

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