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Fung et al. Antivirals in hepatitis B hepatocellular carcinoma

Those already on antiviral therapy should remain size, number, differentiation, and the presence of
on treatment, as there may still be chance of severe lymphovascular permeation. In a large study of 3,855
flare with cessation of therapy. For those not on HBV-related HCC patients, antiviral therapy did not
antiviral therapies with advanced HCC for palliation, reduce the risk of progressive disease or mortality after
commencing antiviral therapy at this juncture will be adjusting for the tumor status [109] .
futile for the overwhelming majority. Even in the setting
of high viral load and elevated transaminases, it may be For those undergoing liver transplantation, recurrence
difficult to confirm that it is due to HBV-related hepatitis of HCC after transplantation is likely related to pre-
rather than locally advanced infiltrative disease. The transplant tumor factors, rather than from HBV-related
decision for antiviral therapy in this setting should be factors. Despite this, antiviral therapy is essential for
made on a case-by-case basis, taking into account the CHB patients to prevent graft loss from reactivation of
tumor stage and life expectancy of the patient. hepatitis B.

SUMMARY The role of antiviral therapy for those undergoing
palliation is less clear, and is likely determined by the
Although direct evidence is sparse, there is a general stage of HCC and the life expectancy of the patient.
consensus that antiviral therapy can reduce the risk of It will be prudent to ensure that all HBV-related HCC
HCC in CHB patients. To date, only one randomized patients be considered for antiviral therapy, especially
placebo-controlled study has been published, showing with current NAs being extremely safe with minimal
a reduction in HCC and cirrhosis for advanced CHB side effects and risks. For those with extensive disease
patients treated with lamivudine [23] . It is unlikely that and limited life expectancy, where quality of life and
future placebo-controlled studies will be performed survival is determined by HCC rather than HBV
due to ethical reasons. However, there is increasing infection, the use of NAs is unlikely to be of benefit.
circumstantial evidence to suggest that long term For those with less advanced disease and reasonable
antiviral therapy will reduce or delay HCC [100,101] . The short-term survival, NAs may preserve underlying liver
key to antiviral therapy therefore is starting early, as the function and prevent hepatitis flares.
presence of advanced fibrosis and cirrhosis at the time
of starting therapy is already associated with higher Currently, there are numerous novel agents undergoing
risk of HCC [102,103] . development in clinical trials for both HCC and HBV
infection. It is likely that NAs will continue to have
Once HCC occurs, antiviral therapy is likely still an important role with viral inhibition. Newer agents
beneficial. The goals of therapy in this instance include will target different sites of the HBV replication
HBV DNA inhibition, preservation of liver function, cycle, including viral entry, the formation of cccDNA,
prevention of further disease progression, reduction transcription, viral packaging and assembly, and the
in the risk of flares, reduction in the risk of HCC release of mature virions [110] . These novel therapies may
recurrence, and hopefully improvement in survival [104] . increase the chance of HBsAg and cccDNA clearance,
The choice of antiviral therapy will be dependent on thereby reducing the production of oncogenic proteins,
the availability, but in general, a highly potent agent and potentially reducing the risk of developing HCC.
with high barriers to resistance should be used. For
HBV-related HCC, ETV has been shown to have better DECLARATIONS
overall survival, decompensation-free survival, and
recurrence-free survival compared to LAM [105] . Authors’ contributions
Concept, literature search, manuscript preparation,
A meta-analysis of 15 studies totaling 8,060 patients manuscript editing, manuscript review: J. Fung
with HBV-related HCC after curative therapy showed Concept, manuscript preparation, manuscript editing,
a better 1-, 3-, and 5-year overall and disease-free manuscript review: K.S.H. Chok
survival for those that received NAs [106] . In another
meta-analysis of 21 studies including 8,072 similar Financial support and sponsorship
patients, NA therapy significantly improved recurrence- None.
free and overall survival [58] . Other systematic reviews
of HBV-related HCC patients also demonstrated Conflicts of interest
improve survival and reduced early recurrence after There are no conflicts of interest.
curative treatment [107,108] . However, the most important
determinant factors for short-term recurrence are likely Patient consent
those related to the tumor. These include the tumor Not applicable.

Hepatoma Research ¦ Volume 3 ¦ November 27, 2017 289