Analysis of electronic health record data of hepatitis B virus (HBV) patients in primary care: hepatocellular carcinoma (HCC) risk associated with socioeconomic deprivation and reduced by statins

Background We set out to characterise chronic Hepatitis B (CHB) in the primary care population in England and investigate risk factors for progression to hepatocellular carcinoma (HCC). Methods We identified 8039 individuals with CHB in individuals aged ≥18 years between 1999-2019 in the English primary care database QResearch. HCC risk factors were investigated using Cox proportional hazards modelling. Findings Most of those living with CHB were males (60%) of non-White ethnicity (>70%), and a high proportion were in the most deprived Townsend deprivation quintile (44%). Among 7029 individuals with longitudinal data, 161 HCC cases occurred. Increased HCC hazards significantly associated with male sex (adjusted hazards ratio (aHR) 3.44, 95% Confidence Interval (95CI) 2.07-5.73), older age (for age groups 56-55 and ≥66 years of age, compared to 26-35 years, aHRs 7.52 (95CI 4.14-13.67) and11.89 (95CI 6.26-22.60) respectively), socioeconomic deprivation (aHR for fifth Townsend deprivation quintile 1.69, 95CI 1.01-2.84, compared to third), Caribbean ethnicity (aHR 3.32, 95CI 1.43-7.71, compared to White ethnicity), ascites (aHR 1.85, 95CI 1.02-3.36), cirrhosis (aHR 6.52, 95CI 4.54-9.37) and peptic ulcer disease (aHR 2.20, 95CI 1.39-3.49). Reduced HCC hazards were associated with statin use (aHR 0.47, 95CI 0.22-0.99). Interpretation Targeting resources at vulnerable groups, and addressing modifiable risk factors is essential to improve CHB outcomes, and to support progress towards international goals for the elimination of hepatitis infection as a public health threat. Funding Wellcome (grant ref 110110/Z/15/Z), UCLH NIHR Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, GlaxoSmithKline, NIHR Health Informatics Collaborative, Cancer Research UK. Evidence before this study THE CHB population in England has not been well described. Hepatitis B virus (HBV) reports from the UK Health Security Agency (UHKSA) have not previously reported chronic HBV (CHB) prevalence stratified by relevant subgroups, including ethnicity and socioeconomic status. The burdens of comorbid diseases in this population have also not been characterised. Furthermore, risk factors for the progression of CHB to hepatocellular carcinoma (HCC) have previously been identified largely in homogenous patient samples which may not be widely generalisable. Therefore, risk factors identified in previously published studies require validation in diverse multi-ethnic cohorts. Characterisation of CHB and investigation of novel risk factors for HCC is warranted in a large data source which contains parameters for a large percentage of the population which are collected in a systematic and wide-scale manner in order to improve generalisation of findings. Added value of this study We have characterised the largest cohort of CHB individuals in the UK to date, using the QResearch primary care electronic health record database, and describing the demographics and burdens of comorbid disease in the population. This is novel and has not previously been done in a large socioeconomically and ethnically diverse patient sample. We have also analysed risk factors for HCC in the cohort, both validating previously reported factors and investigating novel factors. Implications of all the available evidence The findings of this study have important implications for CHB prevention, clinical management, and resource planning. Our detailed description of the demographics and disease profile of the CHB population in the UK may facilitate the targeting of health and prevention resources. Findings concerning HCC risk factors have implications for the clinical management of CHB in order to reduce the risk of progression to HCC. ### Competing Interest Statement Funding PCM is funded by Wellcome (grant ref 110110/Z/15/Z), UCLH NIHR Biomedical Research Centre and the Francis Crick Institute. CC's doctoral project is jointly funded by the Nuffield Department of Medicine, University of Oxford and by GlaxoSmithKline. EB is funded by the Oxford NIHR Biomedical Research Centre and is an NIHR Senior Investigator. The views expressed in this article are those of the author and not necessarily those of the NHS or the NIHR. PCM, EB and CC are supported by the DeLIVER program "The Early Detection of Hepatocellular Liver Cancer" project is funded by Cancer Research UK (Early Detection Programme Award, grant reference: C30358/A29725). EB, TW, CC and PCM acknowledge support from the NIHR Health Informatics Collaborative. Conflicts of interest IAG is a full-time GSK employee and holds GSK shares. CC's doctoral project is jointly funded by the Nuffield Department of Medicine, University of Oxford and by GSK. ### Funding Statement PCM is funded by Wellcome (grant ref 110110/Z/15/Z), UCLH NIHR Biomedical Research Centre and the Francis Crick Institute. CC's doctoral project is jointly funded by the Nuffield Department of Medicine, University of Oxford and by GlaxoSmithKline. EB is funded by the Oxford NIHR Biomedical Research Centre and is an NIHR Senior Investigator. The views expressed in this article are those of the author and not necessarily those of the NHS or the NIHR. PCM, EB and CC are supported by the DeLIVER program "The Early Detection of Hepatocellular Liver Cancer" project is funded by Cancer Research UK (Early Detection Programme Award, grant reference: C30358/A29725). EB, TW, CC and PCM acknowledge support from the NIHR Health Informatics Collaborative. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The QResearch database consists of anonymised electronic health records. Ethics approval was granted by the East Midlands Derby Research Ethics Committee (reference 18/EM/0400). The protocol for this study (https://www.qresearch.org/research/approved-research-programs-and-projects/characteristics-of-chronic-hepatitis-b-associated-with-cirrhosis-and-cancer/) was reviewed by the QResearch Scientific Advisory Committee before approval was provided and access to relevant data for this project was accordingly granted, in accordance with ethical approval. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes To guarantee the confidentiality of personal and health information only the authors have had access to the data during the study in accordance with the relevant licence agreements. Access to the QResearch data is according to the information on the QResearch website ( ). * Abbreviation : Definition 95CI : 95% confidence interval aHR : Adjusted Hazards Ration ALT : Alanine aminotransferase AST : Aspartate transaminase BMI : Body mass index CHB : Chronic hepatitis B virus infection EHR : Electronic health record HBsAg : Hepatitis B surface antigen HBV : Hepatitis B virus HCC : Hepatocellular carcinoma HES : Hospital episode statistics HIC : Health Informatics Collaborative ICD : International Classification of Disease IQR : Interquartile range MICE : Multiple imputation by chained equations NA : Nucleoside analogue NCRAS : National Cancer Registration Analysis Service NSAID : Non-steroidal anti-inflammatory drug ONS : Office for National Statistics Plt : Platelet PPI : Proton pump inhibitor SD : Standard deviation SNOMED : Systemised Nomenclature of Medicine T2DM : Type 2 diabetes mellitus UK : United Kingdom VL : Viral load WHO : World Health Organisation