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Fung et al. Antivirals in hepatitis B hepatocellular carcinoma

with high potency and high barriers to resistance, ANTIVIRAL THERAPY FOR HCC PATIENTS
such as ETV, TDF, and TAF, should be used [20-22] . UNDERGOING SURGICAL RESECTION
A high barrier to resistance ensures that long-term
use of these drugs is associated with minimal risk of For patients with preserved liver synthetic function,
developing drug resistance. The development of drug absence of significant portal hypertension, and
resistance leads to virological rebound and subsequent resectable tumors, surgical resection remains the best
hepatitic flares, leading to higher viral load and increase curative option [32] . Compared to HCV, HBV may be
in inflammatory activity respectively, resulting in higher associated with less risk of recurrence after resection,
rates of disease progression [23] . As a result, the risk of although the reason for this is unclear [33] . However,
developing HCC may be increased. In a meta-analysis another study has shown a worse prognosis after
of 14 observational studies with 1,284 patients, the resection for HBV-related HCCs compared to non-
one year overall survival and HCC recurrence were HBV disease [34] . There is evidence to suggest that
significantly reduced and increased respectively patients with high viral load at the time of resection
with LAM use when compared with ETV [24] . Several are associated with post-resection liver failure and
studies have also demonstrated a link between the recurrence of HCC [35-37] . Active HBV replication may
presence of de novo drug resistance mutation and also be associated with an increased risk of vascular
the development of HCC, although the mechanism of invasion [38] . Given that sufficient remnant liver function
tumor development remains unclear [25,26] . is a prerequisite for survival after partial hepatectomy,
it would be important to preserve or improve liver
Long-term oral antiviral therapy has been shown to be function by inhibiting HBV, and to prevent ongoing
effective in preventing and even reversing cirrhosis [27,28] . inflammation or damage which may worsen liver
However, the evidence for preventing HCC is less function. For these reasons, all CHB patients with HCC
robust. Although it is likely that antiviral therapy can and planning for resection should receive antiviral
reduce the incidence of HCC, complete elimination of therapy prior to surgery.
the risk is not possible [23,29-31] . The paradoxical effect of
survival of CHB patients to an older age may increase After resection, patients should remain on long-term
the risk of development of HCC by allowing time for antiviral therapy. Surgery itself may predispose patients
detrimental effects caused by HBV carriage and HBV to HBV reactivation after resection, and is a significant
DNA integration. The risk is likely highest for those cause of hepatitis and liver failure [39,40] . Although
with established cirrhosis, whereby the liver is already the exact mechanism for reactivation is unclear, the
at a carcinogenic stage. This may also explain in part stress of partial hepatectomy itself may represent
why antiviral therapy is unable to fully prevent the a physiological immunosuppressed state, thereby
development of HCC. To this end, CHB patients are at increasing the risk of reactivation [41] . Factors that may
a lifelong risk of HCC, and should receive appropriate increase this risk include general anesthesia, the use
surveillance to enable earlier diagnosis. of blood transfusion, and intraoperative ischemic injury.
Studies in animal models have also documented that
For CHB patients who develop HCC, the role of duck HBV (DHBV) reactivation occurs following partial
antiviral therapy is even less well defined. Despite hepatectomy in ducks [42] . It is possible in this case
this, most patients will receive antiviral therapy, even that hepatocytes remaining in the liver after partial
though the evidence for its use may not be apparent hepatectomy will divide to increase the mass of the
to the prescriber. Given that antiviral therapy is unable liver to preoperative levels and these newly divided
to fully prevent HCC occurrence, a proportion of hepatocytes provide targets for high levels of DHBV
patients will already be on antiviral therapy at the infection and replication, which may be detected as
time of tumor diagnosis. For these patients, it is likely postoperative reactivation.
that antiviral therapy will be continued irrespective of
the therapeutic approach adopted for management The highest risk for reactivation is likely observed in
of HCC. For patients not on treatment at the time of patients who are not on antiviral therapy [43] . Even for
HCC diagnosis, most will be commenced on antiviral patients with low HBV DNA levels, there is still a risk of
therapy. However this will often be dependent on the postoperative reactivation [44,45] . HBV reactivation may
stage and treatability of the HCC. Although the clinical worsen liver function, but has also been associated
scenario may differ depending upon the stage of HCC with recurrence of HCC for those with low viral load at
and the treatment offered, the general indications of baseline [46] .
antiviral therapy include preserving liver function and
prevention of de novo or recurrent HCCs. Recurrence of HCC can occur early (within 2 years) or

286 Hepatoma Research ¦ Volume 3 ¦ November 27, 2017