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Fung et al. Antivirals in hepatitis B hepatocellular carcinoma

intra-tumor concentration of cytotoxic drugs. Although longer-term benefits of antiviral therapy are more
systemic chemotherapy can be associated with HBV difficult to assess, given that a significant proportion
reactivation, it is likely that chemotherapy delivered by will succumb to their underling malignancy independent
TACE poses a far less risk. The lipiodol that is widely of the HBV status. However, viral suppression may
used to deliver the drug to the tumor allows for the drug potentially improve long-term survival by reducing HBV
to remain concentrated in the tumor for longer periods, reactivation and HCC recurrence [92] . In a systematic
thereby reducing the systemic effect. In addition, the review of 994 patients with unresectable HCC
risk of HBV reactivation is dependent on the type of receiving LRT, there were significant improvements for
chemotherapeutic agent used. Although doxorubicin progression-free and overall survival in the NA treated
can cause HBV reactivation, the risk is likely relatively group compared with the control group [93] .
lower than chemotherapy regimens that contain
rituximab and high dose steroid [79] . ANTIVIRAL THERAPY FOR HCC
PATIENTS AFTER CHEMOTHERAPY/
Several risk factors have been identified for HBV
reactivation. These include HBeAg status, viral IMMUNOTHERAPY
load, baseline liver function, age, gender, and the
intensity of LRT and the use of anthracyclines [80] . Unlike other solid organ tumors, chemotherapeutic
However, the data for HBV reactivation following TACE options for HCC remain limited. Sorafenib was
remains somewhat inconclusive, with some studies approved for the treatment of advanced HCC in 2007.
suggesting increase risk, whereas other studies have In contrast to the traditional chemotherapy agents,
demonstrated no changes, or even decline in HBV which are associated with immunosuppression,
DNA after chemoembolization [81,82] . The mechanism sorafenib may have immunomodulatory function
underlying the decline in viral load remains unclear, through its effect on T cells, thereby augmenting the
and may be due to the natural fluctuation that is immune system [94] . Therefore one would anticipate a
independent of the TACE, or possibly from a reduction low risk for HBV reactivation, although there is currently
in tumor load, which may support HBV replication limited data regarding HBV reactivation with the use of
or impair the host immunity. On the other hand, sorafenib. A high baseline viral load has been shown
patients with low viral load are still at risk of HBV to be an adverse prognostic factor for HBV reactivation
reactivation after TACE [83] . For patients receiving and survival in patients with advanced HCC receiving
TACE, prophylactic oral antiviral therapy significantly sorafenib [95,96] . In this setting, antiviral therapy may
decreased virological events and hepatitis flares due to be associated with improve survival, and is a cost-
reactivation [39,84,85] . Achieving undetectable HBV DNA effective approach [95,97,98] . However, in a recent meta-
with antiviral therapy has been shown to significantly analysis of 3,256 patients receiving sorafenib for
improve the progression-free survival in patients advanced HCC, improvement in survival was only
receiving TACE [86] . observed in HCV patients and not those with HBV .
[99]
Whether these patients were on antiviral therapy,
For LRT that does not involve chemotherapy, the data and its effect on survival, was not studied. In 2017,
is even sparser. HBV reactivation for CHB patients regorafenib, a multikinase inhibitor, was approved for
receiving radiofrequency ablation (RFA) is significantly HCC previously treated by sorafenib. The effect of
lower than those undergoing surgical resection, regorafenib on HBV replication is unknown, although
although it still can occur [87] . The pre-RFA viral load it is likely to be similar to sorafenib. It is likely that the
has been shown to be associated with HCC recurrence long-term outcome for patients with advanced HCC
after RFA [88] , and the use of antiviral therapy after and receiving palliative chemotherapy/immunotherapy
curative RFA was associated with better outcomes will be unchanged by antiviral therapy, as the survival
regarding HCC recurrence and overall survival [89] . In a is limited by the advanced nature of the tumor.
case control study of 399 post-RFA patients, antiviral
therapy was shown to be an independent factor ANTIVIRAL THERAPY FOR PATIENTS
associated with a decreased risk of HCC recurrence [90] .
WITH UNTREATABLE HCC
Therefore, antiviral therapy should be recommended
for those receiving LRT with HBV-related HCC. The For patients with advanced HCC not amenable to
likely benefits of antiviral therapy are most likely those treatment, the role of antiviral therapy is limited.
that can be observed in the short term. These include Patients will succumb to disease progression arising
improving and preserving liver function, suppressing from the tumor rather than from HBV infection.
viral load, prevention of reactivation, and subsequently Therefore, the life expectancy and quality of life
decrease the risk of hepatic failure after LRT . The is unlikely to be improved with antiviral therapy.
[91]
288 Hepatoma Research ¦ Volume 3 ¦ November 27, 2017