Title: Optimising the management of chronic hepatitis B (CHB) in children and young people: A cohort study to evaluate the use of quantitative Hepatitis B surface Antigen as a marker to risk stratify patients.
Funder: Department of Health and Social Care

Abstract: One in four children infected with Hepatitis B virus (HBV) at birth or in the first few years of life will develop liver cirrhosis or hepatocellular carcinoma (HCC). The prevalence of Chronic Hepatitis B (CHB) is increasing in the UK, particularly in London and Birmingham, owing to recent migration patterns to the major UK cities Historically, CHB was believed to run a benign course in children and young people (CYP) and based on this assumption national and international guidelines overlooked treatment in this cohort. Despite this, there is a recognition that immune tolerant CHB, synonymous with disease in young people, is poorly understood (EASL 2012). Our recent work further challenged this concept of tolerance in young people. We could demonstrate that CYP exhibited an immune response that was less compromised than that observed in adult patients with CHB. CYP did not display a suppressive or tolerant cytokine profile, they had increased expression of PD1; a marker of exhaustion; and a HBV-specific response which was more robust than that seen in their adult counterparts (Kennedy et al., Gastroenterology 2012). These data have highlighted the limitations of currently used clinical parameters to define CHB; namely serum ALT and HBV DNA. Furthermore, we have recently put forward an alternative interpretation of the immunological events which evolve with disease progression from childhood to adulthood (Bertoletti & Kennedy., Cell Mol Immunol. 2014). The aim of this study is to demonstrate that an additional biomarker, an available commercial assay; quantitative Hepatitis B surface antigen (qHBsAg); can be used in conjunction with the current clinical parameters to more accurately define disease phase and risk-stratify patients. We propose that the addition of qHBsAg to the diagnostic algorithm will enhance the clinical definition of immune tolerance by accurately defining those with minimal disease and low-risk of disease progression. Conversely, changes in qHBsAg may herald a more dynamic disease phase where disease progression is likely and antiviral therapy is indicated. In addition, in line with recently published data, we propose that low levels of qHBsAg can be used in CYP to distinguish a low-risk inactive carrier state in eAg negative disease from those where progressive disease is more likely and therapy is indicated. The addition of qHBsAg to currently used clinical parameters will improve clinical care and provide more cost effective management by reducing hospital monitoring and enhancing patient selection for antiviral therapy. Our preliminary data (generated at The Royal London) has demonstrated that qHBsAg can significantly enhance disease categorisation and risk stratification. We have shown that high levels of qHBsAg in eAg+ patients are associated with minimal liver damage or fibrosis and a low-risk of disease progression. Similarly in eAg- disease, we believe we can determine a threshold level for qHBsAg in CYP to identify a low-risk inactive carrier disease state. We will utilise qHBsAg to develop a clinical predictor model, based on data that we will collect from the retrospective cohort. This model will then be validated in a prospective study to determine its accuracy in real-time patient monitoring to identify low-risk disease states, the frequency of hospital monitoring and its ability to enhance the decision to treat process. In addition, we will evaluate how qHBsAg performs against other non-invasive serum markers of fibrosis and transient elastography; potentially obviating the need for liver biopsy in CYP. A more robust assessment of CHB with the inclusion of qHBsAg will improve patient care by accurately defining disease phase, the indications for treatment and the frequency of hospital follow-up. This simple blood test will reduce NHS costs by providing diagnostic accuracy, thus reducing morbidity and mortality associated with CHB.

Lay abstract: Chronic Hepatitis B (CHB) affects >300 million people worldwide and is complicated by the development of liver failure and liver cancer. In the UK, CHB is a disease of the major cities, particularly London and Birmingham, reflecting recent migration patterns. The majority of those who develop CHB contract the virus at birth or in early childhood. Despite this, CHB is poorly understood and poorly managed in children and young people (CYP). CHB is a dynamic disease which progresses through distinct phases. Accurately defining disease phase in CYP is challenging; disease can be mild with minimal or no progression; conversely disease may lead to the development of liver scarring which ultimately leads to liver failure or liver cancer. Currently used clinical parameters lack accuracy in defining disease phase and our recent work has demonstrated the limitations of these clinical categorisations in CHB. Thus, the current premise on which management decisions are made in CYP is unsound. The aim of this work is to demonstrate that the addition of quantitative Hepatitis B surface antigen (qHBsAg); to currently used laboratory parameters; can more accurately define disease phase and risk-stratify patients in line with our preliminary data. We will use qHBsAg as part of a predictor model to identify patients with minimal disease, where therapy is not indicated, thus reducing the frequency of hospital monitoring. Conversely, qHBsAg levels can also identify those at risk of more progressive disease; our model will be used in the real-life setting to determine if we are able to accurately define disease phase and inform management decisions. We have considered the opinions of patients/parents when planning this research and their desire for safe but less frequent monitoring. The utility of qHBsAg as part of our predictor model will improve patient management and simultaneously reduce NHS costs.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION