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Fung et al. Antivirals in hepatitis B hepatocellular carcinoma

late (beyond 2 years) after resection. Early recurrence function may also increase the likelihood of patients
is usually due to intrahepatic metastasis and is related being able to receive loco-regional bridging therapy. In
more to the characteristics of the primary HCC. In addition, viral inhibition prior to liver transplantation may
contrast, late recurrence is usually as a result of new reduce the likelihood of recurrence of HBV infection
primary HCC from de novo carcinogenesis arising after transplantation. Lifelong antiviral therapy is
from a premalignant liver. Therefore, the latter is more required after transplantation to prevent graft hepatitis
related to the characteristics of the remnant liver, and graft loss. Although liver transplantation is curative
including the presence of cirrhosis, inflammatory for cirrhosis and HCC, it does not eradicate HBV from
activity, and viral load [47,48] . The fibrotic burden and the host, likely due to the existence of extrahepatic
the presence of cirrhosis may increase the chance sites of HBV infection. Prior to the availability of
of recurrence and reduce disease-free and overall effective antiviral prophylaxis, liver transplantation for
survival after resection [49] . Hence, the use of antiviral CHB was a relative contraindication due to the high
therapy after liver resection may also potentially rate of graft hepatitis and subsequent graft loss. The
reduce the risk of HCC recurrence. However, this only availability of hepatitis B immune globulin (HBIG)
applies to new primary HCCs, and antiviral therapy together with LAM was a major milestone in preventing
is unlikely able to prevent intra- or extra- hepatic HBV recurrence [68] . HBIG may bind to HBV surface
disease due to metastasis. To this end, it is likely that protein to prevent uptake of HBV into the hepatocytes
antiviral therapy can help to prevent late rather than by host receptors, and may neutralize viral particles
early HCC recurrences [50,51] . HBV replication and high through the formation of immune complexes [69] . As
viral load has been associated with vascular invasion, a form of passive immunoprophylaxis, HBIG has to
although this has not been consistently shown [52] . be administered parenterally at regular intervals to
Even for patients with low viral load, those with high maintain sufficient levels to be effective. Since then,
levels of HBsAg may be at increased risk of HCC studies have also demonstrated the efficacy of using
recurrence [53,54] . lower doses, and also replacing HBIG with combination
oral antiviral therapy [70,71] . With the introduction of more
In fact, the use of antiviral therapy has been shown to potent NAs with minimal drug resistance, oral antiviral
be independently associated with reduced risk of HCC therapy alone without HBIG has also been shown to
recurrence. As expected, the benefits were mainly be highly effective in preventing graft hepatitis together
seen with late rather than early recurrences [55-59] . with excellent long-term outcome [72-75] .
In a territory-wide study of 2198 CHB patients with
HCC from Hong Kong, NAs reduced the risk of The re-appearance of HBsAg and HBV DNA after
HCC recurrence after surgical resection [60] . A meta- liver transplantation has been associated with HCC
analysis of 7,619 postoperative HBV-HCC patients recurrence [76] . Previous studies have shown a temporal
showed more favorable 1-, 3-, and 5-year recurrence- relationship between the development of post-
free survival with antiviral therapy compared with no transplant HCC recurrence and the re-appearance of
treatment [61] . In another meta-analysis of 12 studies HBsAg and HBV DNA [77] . This suggests an association
involving 8,204 HBV-related HCC patients, NA therapy rather than viral factors being a causative factor for
significantly reduced the risk of recurrence and recurrence. Despite adequate antiviral therapy in this
improved both disease-free and overall survival [62] . For setting, the reappearance of HBsAg and HBV DNA
those with HCC recurrence, a preserved liver function suggests that the source is possibly tumor in origin,
at the time of recurrence via the use of antiviral therapy where the antiviral penetrance may be reduced.
increased the proportion of patients that can receive
curative treatment [63,64] . For patients with repeat ANTIVIRAL THERAPY FOR HCC PATIENTS
hepatectomy for recurrent HCC, antiviral therapy was UNDERGOING LOCOREGIONAL THERAPY
also associated with better long-term prognosis [65] .
For patients ineligible for surgical resection or
ANTIVIRAL THERAPY FOR HCC PATIENTS transplantation, locoregional therapy (LRT) can
UNDERGOING LIVER TRANSPLANTATION be potentially curative, and can offer palliative
control for inoperable tumors. The effect of LRT on
For patients who are eligible for liver transplantation, HBV replication, and the effect of antiviral therapy
antiviral therapy should be commenced at the time of in this setting are not well defined. Transarterial
diagnosis and while they are on the waiting list [66] . The chemoembolization (TACE) is widely used, and can
use of antiviral therapy in this setting can prevent acute be effective in reducing tumor progression, with
flares and chronic inflammation, and thus may prevent improvement in survival [78] . The delivery of highly
liver decompensation [67] . The improvement in liver concentrated chemotherapy using LRT results in a high
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