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Fung et al. Antivirals in hepatitis B hepatocellular carcinoma

sequences can be observed early in the course of HBV B core related antigen and hepatitis B surface antigen
infection, and can be detected in approximately 80% of (HBsAg) [14] .
[5]
HBV-related HCCs .
HBV REPLICATION
Other wildtype/truncated HBV proteins (HBx, HBc,
PreS) may also contribute directly towards the During the initial stage of infection, the HBV enters
development of HCC. HBx is a regulatory protein that the hepatocyte via a host receptor. Once inside the
acts as a transcription activator by interacting with cytoplasm, the relaxed circular DNA (rcDNA) enters
viral and host regulatory elements. HBx can interfere the nucleus to form covalently closed circular DNA
with the hepatocyte DNA repair system, cell cycle (cccDNA) [15] . The cccDNA functions as a template for
[6]
regulation, and apoptosis . Due to the process of DNA mRNA transcription, which is then transported into the
integration into the host genome, the HBx gene can be cytoplasm for translation of viral proteins and genomic
[7]
maintained even in the absence of HBV replication . replication via reverse transcription to form negative-
The preS1/preS2/S region encodes a transcriptional strand DNA. This is followed by formation of positive-
activator, which may promote hepatocyte proliferation strand DNA and rcDNA within the nucleocapsid, which
in the presence of preS mutations. Mutations in can then undergo further assembly and exported as
the HBV surface proteins can also lead to unfolded mature virions, or be recycled back into the nucleus to
proteins accumulating in the cytoplasm and subsequent form cccDNA.
heightened oxidative stress in the endoplasmic
[8]
reticulum, contributing to hepatocarcinogenesis .
The lack of proofreading mechanism by the HBV
polymerase enzyme combined with the high
Similar to other chronic liver diseases, HBV can also replicative rate leads to high genomic variability with
cause HCC indirectly via chronic necro-inflammation, quasi-species containing various mutations. Some
induced apoptosis, and regenerative activity, with of these mutations may be associated with HCC
subsequent accumulation of mutations, which may development. These include mutations in the PreS
be responsible for malignant transformation. During regions as described previously, and drug resistant
repeated episodes of chronic inflammation and mutations as result of antiviral therapy. Other mutations
hepatitic flares, activation and interaction between associated with higher rate of HCC include the basal
different cytokines may promote immune escape core promoter (BCP) mutation (T1762/A1764) [16,17] .
and alter apoptosis. Inflammation-mediated T cell The exact mechanism for hepatocarcinogenesis is
dysfunction may also impair the immune response unclear, although BCP mutations can be associated
[9]
against neoplastic cells .
with disease progression and development of cirrhosis,
thereby conferring a higher risk of HCC.
From the clinical standpoint, older age, male gender,
high viral load, and the presence of cirrhosis are the
commonly associated factors for HCC development in ANTIVIRAL THERAPY FOR CHB
CHB patients [10,11] . Of these factors, only viral load can
be easily modifiable, and emphasizes the importance Presently, the only oral antiviral therapy approved
of antiviral therapy and its ability to induce complete for the treatment of CHB infection are nucleos(t)ide
viral suppression. The REVEAL study demonstrated a analogs (NAs). These are HBV polymerase inhibitors
linear relationship between serum HBV DNA levels and which compete with natural nucleotide substrates
the risk of developing HCC [10] . This is not surprising, that target DNA elongation by acting as chain
as a high viral load may increase the risk of HCC terminators [18] . NAs may also target other synthetic
both directly and indirectly by increasing the chance functions of HBV polymerase, including priming activity,
of oncogenesis with higher rates of HBV integration, reverse transcription, and the synthesis of DNA [19] .
and by increasing inflammatory activity respectively. Although interferon-α2b and peginterferon-α2a are
This highlights the importance of viral suppression in approved for CHB infection, it is not used in the setting
preventing HCC development. As hepatitis B e-antigen of cirrhosis or HCC. The currently approved NAs for
(HBeAg) is a marker of viral replication, its presence CHB are lamivudine (LAM), adefovir (ADV), telbivudine,
has been associated with the development of HCC [12] . entecavir (ETV), tenofovir disoproxil fumarate (TDF),
More recently, HBeAg and its precore precursors and most recently, tenofovir alafenamide (TAF). All NAs
have been shown to interact with NUMB, leading to are formulated as fixed dose tablets to be taken once
reduction of tumor suppressor p53 activity [13] . Other daily. For patients with HCC, the duration of antiviral
HBV serological markers have also been shown to be therapy is usually life-long. Due to the risk of the
associated with HCC development, including hepatitis development of drug-resistant strains, only compounds

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