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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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