The role of Hepatitis B surface antigen in the development of severe liver disease and hepatocellular carcinoma
AffiliationMedicine (Austin & Northern Health)
Medicine (St Vincent's)
Document TypePhD thesis
Access StatusOpen Access
© 2016 Dr. Lucy Lim
Hepatitis B virus (HBV) infection continues to be a major public health issue worldwide, affecting an estimated 2 billion people globally. In spite of safe vaccination and effective therapy, there is still a large burden of disease due to chronic hepatitis B (CHB), affecting an estimated 240 million people, which may lead to cirrhosis and or the development of hepatocellular carcinoma (HCC). Liver cancer is rapidly emerging as the single greatest challenge in hepatology and liver transplantation and the burden of disease is set to explode in the next 20-30 years. Viral hepatitis is ranked as the seventh leading cause of death worldwide, resulting in at least 1.2 million deaths annually from liver cirrhosis and HCC. HCC is currently the sixth most common cancer and the second leading cause of cancer-related deaths globally. Case-control studies have shown that chronic HBV carriers have more than 100-fold increased risk of HCC compared with non-infected individuals. Approximately 80% of all HCC cases can be attributed to viral hepatitis, more than half of that due to HBV, which is the second most potent carcinogen after tobacco (World Health Organization), and this is despite remarkable improvement in therapy with the advent of nucleos(t)ide analogues (NA). The global reservoir of HBV infection serves as the basis for the generation of HBV variants via recombination and a high frequency of mutation in the HBV genome. Due to the inherent molecular biology of this virus which replicates its DNA genome via a low fidelity viral reverse transcriptase (rt)/polymerase, a population of closely related genetic variants known as a quasispecies is produced. The last two decades have seen a significant increase in the emergence of mutants as the virus responds to selective pressures, such as vaccination and antiviral therapy. Surveillance for clinically significant HBV mutations and an improved understanding of the impact of these emerging variants on the natural history of the disease and its diagnosis, control and management will pose a challenge to global health care in the foreseeable future. This is because these mutants have the potential to alter current diagnostic and treatment algorithms. NA therapy was approved in 1998, which efficiently lowers the HBV DNA viral load in HBV-infected patients. Given that the HCC risk is particularly high in the presence of cirrhosis and/or persistent high HBV DNA replication, NA should be a rational treatment to prevent liver disease progression including liver cancer in such patients. However since the introduction of antiviral therapy, the HCC incidence has continued to rise. Registration for the liver transplant waiting list due to HBV-related HCC in the U.S. has increased in the NA era, which may in part be due to patients no longer dying of liver disease. There is clearly a need for a greater understanding of the role that NA therapy might play in the development of HCC. Numerous risk factors for HBV-related HCC development have been identified. However the relationships are complex. Older patient age, liver cirrhosis, DNA viral load, hepatitis e antigen (HBeAg) status, HBV genotype, gender and family history have all been found to be important risk factors for HCC in most studies. The exact mechanism of HBV-related carcinogenesis is not fully elucidated, however it is likely a multi-factorial process reliant on a combination of mechanisms which include: ongoing inflammation, cycles of damage and regeneration of hepatocytes, increased chromosomal instability through multiple HBV DNA integrations, oxidative stress as a consequence of NA driven alterations to the HBV life cycle, and finally any direct effects of the virus or viral proteins themselves. The aim of this study was to determine the role that the hepatitis B surface antigen (HBsAg) might play in patients with CHB in the development of severe liver disease and HCC in the era of hepatitis B virus (HBV)-specific NA therapy. The hypothesis tested was that the development of HCC may be associated with altered expression of phenotype and abnormal cellular distribution of HBsAg, and that NA-induced drug resistance can influence this process. This is an important question given the rising incidences of HCC. This study will investigate the effects of NA treatment on HBV replication and any subsequent variation in oncogenic potential from common NA resistant variants. This study will also use various novel techniques such as HBV splicing and next generation sequencing to explore new approaches for the molecular pathogenesis of CHB. The findings are important as virological factors may have prognostic importance in patients developing HCC, which may impact existing CHB treatment strategies and professional practice guidelines.
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