Medicine (St Vincent's) - Theses
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ItemEnhancing the hepatitis B care cascade in Australia: addressing barriers in the Chinese community and general practice, and evaluating cost-effectiveness( 2021)Chronic hepatitis B infection is a significant global public health concern, with untreated chronic hepatitis B leading to cirrhosis, liver failure and liver cancer. In 2015, an estimated 257 million people worldwide were living with chronic hepatitis B, of whom only around 10% were diagnosed, and fewer than 1% received treatment. An estimated 870,000 deaths are attributed to hepatitis B each year. In 2016, the World Health Organization launched the global health sector strategy on eliminating viral hepatitis, which provides guidance and frameworks for country efforts to eliminate viral hepatitis as a major public health threat by 2030. In Australia, despite a high hepatitis B vaccination rate by global standards, there are significant gaps in the coverage of service delivery among people living with chronic hepatitis B. One in three people with chronic hepatitis B are not diagnosed, and 78% are not receiving ongoing clinical care. One of the priority populations of hepatitis B infection are people born in endemic countries, with China being the most common country of birth among overseas-born people living with hepatitis B in Australia. To increase hepatitis B diagnosis, care and treatment (that is, to enhance the hepatitis B care cascade) in Australia, several critical areas for improvement have been identified, including adapting services to the affected population, building health workforce capacity to meet demands, and building the investment case to support models of care that will promote hepatitis B elimination. The overarching aim of the research presented in this thesis was to generate evidence targeting each of these three aspects, with particular emphasis on: 1) engaging the Chinese community in hepatitis B testing and clinical management; 2) engaging general practitioners (GPs) in the provision of hepatitis B-related care; and 3) formulating a robust hepatitis B investment case. To accomplish these objectives, five interlocking studies were conducted. The first two studies focused on an affected community (the Australian Chinese community), the second two on health service providers, and the final study on the cost effectiveness of hepatitis B care. More specifically: Study 1 was a randomised controlled pilot and feasibility study of the impacts of an educational program designed to improve hepatitis B testing uptake in the Australian Chinese community; Study 2 was a qualitative study to explore enablers of hepatitis B clinical management among the Australian Chinese community; Study 3 was a before-and-after evaluation of a self-guided learning package among GPs practising in Victoria; Study 4 was a nationwide survey of knowledge, attitudes, barriers and enablers to the provision of hepatitis B care among GPs in Australia; and Study 5 was a cost-effectiveness study analysing the impacts of enhancing hepatitis B care cascade to reach global and national targets in Australia. The findings of this research indicated that a culturally tailored education program can contribute to improving hepatitis B-related knowledge among the Australian Chinese community. Key messages identified to resonate most strongly among people living with chronic hepatitis B included availability of effective and cheap treatment, and that long-term engagement with clinical management has substantial benefits. A holistic response from community, healthcare providers and the public health sector is required to motivate testing and clinical management among the Australian Chinese community at risk of hepatitis B infection. Additionally, this research showed that concise, clear and practical resources can support GPs to identify who to test for hepatitis B. It also showed that GPs lack of awareness, knowledge, confidence and intention to prescribe treatment for hepatitis B, highlighting the need for interventions to increase their interest and skills in the provision of hepatitis B-related care. Economic evaluation findings suggest that an improvement in the hepatitis B care cascade is required for Australia to reach the global 2030 targets, and that it is cost-effective to spend up to AUD328 million to AUD538 million per year on demand generation activities to reach the national and global targets. Overall, this research provides novel evidence about feasible and effective interventions for improving the hepatitis B care cascade in Australia. It also provides insights into ways to enhance the global hepatitis B care cascade.
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ItemThe B cell response in chronic Hepatitis B: milestones on the road to a cure( 2018)It has been over fifty years since the discovery of the hepatitis B virus (HBV) and yet the disease it causes remains a major public health challenge. Worldwide, over 257 million people have chronic hepatitis B (CHB), with the majority being in the Asia-Pacific region, and there are almost 800,000 deaths each year as a direct consequence of infection. HBV infection is the ninth leading cause of death worldwide, and rates of hepatocellular carcinoma (HCC) as a result of CHB continue to rise. Effective suppressive antiviral therapy has been available for almost two decades. Whilst these agents control viraemia, they are not curative, thereby relegating those with chronic infection to long-term, and often life-long, treatment. Importantly, viral suppression does not reduce the risk of developing HCC to the level of that of the general population. There has been a significant research effort devoted towards understanding the viral life cycle, natural history, and the complex interactions of the virus with the host immune system. This has resulted in a recent explosion in the development of novel therapeutic strategies, each of which aim to promote CHB cure. One of the fundamental difficulties that impedes progress towards a cure is the persistence of the viral genome within host hepatocyte nuclei in the form of a minichromosome, and as viral DNA integrated into host chromosomes. This has hampered progress towards a true sterilising cure. Therefore, the HBV research community has identified the goal of functional cure as an attainable surrogate – the elimination of viral and sub-viral particles from the circulation, with or without evidence of antiviral immunity. To make functional cure a reality for people infected with CHB, however, a deeper understanding of the host immune response is needed, as are biomarkers that stratify patients into response categories to allow for individualised treatment approaches; there is little available data that identifies such categories of patients who are currently being treated with long-term oral antiviral therapy. Additionally, whilst there have been detailed studies into the innate and T cell immune responses to CHB, little is known about the humoral immune response, despite evidence of its key anti-HBV role. Such evidence includes the efficacy of anti-HBV vaccine-generated antibodies in the prevention of infection, as well as the high risk of HBV reactivation in the setting of treatment with B cell-depleting agents. In this context, the aim of this thesis was to address a few of the knowledge gaps that exist as the field moves towards developing a functional cure, including 1) determining a biomarker of HBeAg seroconversion, which is a necessary step towards functional cure, 2) characterising the importance of on-treatment flares of hepatitis in CHB and their association with functional cure, 3) examining in detail antibody responses and B cell phenotype and function across the natural history of CHB infection, and 4) to characterise a murine CHB infection model that could be used to further the study of viral variants, and vaccine- and antibody-based therapeutics against HBV. Various novel techniques were used and developed to explore these questions, and the findings shed further light on the role of humoral immunity in the persistence of CHB, as well as generating new hypotheses and experimental techniques that may form the basis of future work towards HBV cure.
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ItemThe role of Hepatitis B surface antigen in the development of severe liver disease and hepatocellular carcinoma( 2016)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.