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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
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