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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
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