Medicine (St Vincent's) - Theses
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ItemThe HBV-STOP study, a prospective study of nucleot(s)ide analogue discontinuation in non-cirrhotic Hepatitis B e-antigen negative chronic hepatitis B patients who have achieved long term virological suppression( 2022)It is estimated that 257 million people have chronic hepatitis B (CHB). HBV infection is endemic throughout Asia, sub-Saharan Africa, Polynesia, as well as in indigenous populations in North America, New Zealand and Australia. Nucleot(s)ide analogues (NA) are standard treatment for HBeAg-negative chronic hepatitis B (CHB). The two first-line NA, entecavir (ETV) and tenofovir disoproxil (TDF), are both potent antiviral agents which effect durable viral suppression, reduce hepatic necro-inflammation, fibrosis progression and reduce risk of cirrhosis, liver failure and hepatocellular carcinoma (HCC). However, HBsAg clearance, or functional cure, is rare, and long-term treatment is recommended. Finite therapy for individuals with HBeAg-negative CHB has been identified as an area of unmet need by expert organisations because of concerns regarding cost, long-term side effects and the risk of the development of drug resistance with indefinite treatment. In the past decade, there has been increasing interest in whether NA therapy can be safely stopped in a subset of patients. In 2012, Hadziyannis and colleagues published a landmark study evaluating clinical outcomes after stopping NA treatment in a small cohort of non-cirrhotic patients with HBeAg-negative CHB who were long-term responders to adefovir monotherapy. All patients experienced early virological relapse. Virological relapse was associated with biochemical relapse in 76% of patients, with antiviral therapy resumed in 15/33 patients. Eighteen patients remained off-treatment through five years of follow-up and all achieved a sustained response, defined by serum HBV DNA level < 2,000 IU/mL and normal serum ALT level. HBsAg loss was observed in 72% (13/18) of patients who maintained a sustained response off treatment by the end of 5 years of follow-up. HBsAg loss was associated with lower HBsAg level at the time adefovir was stopped, and was more common among participants who did not restart treatment. Among those patients who did not restart NA therapy, baseline ALT was higher in those who achieved HBsAg loss, suggesting a role for immune-mediated cytolysis of HBV-infected hepatocytes. Stopping treatment was safe, with no episodes of liver decompensation reported. Since this initial study, there have been a number of reports of clinical outcomes after stopping long-term NA therapy in patients with HBeAg-negative CHB. The studies have been heterogeneous, often retrospective in design, and with considerable variation between protocols for ethnicity of cohort, inclusion / exclusion of people with cirrhosis, duration of follow-up, as well as criteria for re-starting NA therapy. There remain important questions about the rate and outcome of virological and biochemical relapse after stopping NA treatment, the safety of this approach, and the rates of HBsAg loss in prospective follow-up. The answers will inform decisions about patient selection for this strategy in clinical practice. Therefore, as part of my thesis, I have planned to perform a prospective multi-centre study to evaluate clinical outcomes after stopping NA therapy in non-cirrhotic individuals with HBeAg-negative CHB after 96 weeks of follow-up, in addition to a meta-analysis of prior NA cessation studies in HBeAg-negative non-cirrhotic individuals. In addition, NA cessation studies provide a unique opportunity to study the immunology of acute hepatitis flares that occur in the setting of HBV reactivation after stopping NA therapy. ALT flares are preceded by a rise in serum HBV DNA and as HBV is a non-cytopathic virus, it is thought that liver injury is primarily immune-mediated. However, the literature characterizing acute flares of HBV is sparse because flares are difficult to predict and most are asymptomatic. Innate immune pathways may participate in ALT flares either directly or in a bystander fashion. To further investigate the role of innate immunity in the host response to HBV infection in the setting of hepatitis flares, as the final component of my thesis, I have also planned to examine the longitudinal expression and activity of TLRs on peripheral monocytes and markers of peripheral NK cell activity in patients experiencing severe hepatitis flares in the setting of HBV reactivation after NA discontinuation by using samples from patients in our prospective multi-centre study investigating clinical outcomes of stopping NA therapy in non-cirrhotic individuals with HBeAg-negative CHB in order.