Prolonging survival in adults with chronic hepatitis B virus (HBV) infection through risk-stratified treatment and surveillance

A PhD project for the 2022 doctoral clinical fellows programme with Philippa Matthews (primary supervisor, Crick) and Douglas MacDonald (UCL/Royal Free Hospital/UCLH). 

Project description

Douglas MacDonald

Honorary Associate Professor, UCL Institute for Liver & Digestive Health

There is a huge global burden of hepatitis B virus (HBV) infection, but it is a neglected disease accounting for approaching a million deaths from cirrhosis and hepatocellular carcinoma (HCC) annually [1].

Current treatment guidelines recommend therapy to suppress viral replication, and ultrasound surveillance for HCC in those most at risk [2]. However, the parameters used for assessment (‘liver function tests’, fibrosis and viral load, 6-monthly ultrasound) miss a substantial proportion of patients at risk of complications [3], including early cancers at a potentially curable stage. Further stratification of HCC risk in these cohorts using an expanded dataset of host and viral factors may identify those who would benefit from earlier initiation of preventative treatment and allow development of risk scores, and cost-effective use of enhanced surveillance. 

Working with clinical and research collaborators in the UK (London and Oxford), South Africa and Uganda, we have access to clinical samples and host data representing varied populations. We are currently establishing new partnerships at the Africa Health Research Institute in Durban, South Africa. The Royal Free London (RFL) NHS trust has the largest HBV cohort in England delivered across areas of high HBV prevalence, and offers liver transplantation and systemic therapy trials unavailable elsewhere. 

This PhD project will be linked closely with local NHS services in London, and to international cohorts, to refine approaches to assessing adults with chronic HBV infection to determine the long-term risk of complications. This will include opportunities to refine and apply routine clinical data (demographics, imaging, laboratory, treatment information) together with wet lab techniques, including host and pathogen sequencing [4], application of new and existing biomarkers, imaging data, and analysis of large clinical datasets. Accessing liver tissue from biopsies or explants will provide unique opportunities for exploration of end-organ disease in tissue, for correlation with other biomarkers. The overall aim is optimise approaches to HBV surveillance, for example by incorporating more frequent and sensitive imaging, use of novel laboratory biomarkers (with multiplex approaches to measuring new and existing parameters) and including host and pathogen sequence data. This approach will inform better deployment of treatment and earlier interventions for patients at high risk of liver disease, with a special focus on HCC.

The supervision team will comprise clinician scientists based at the Crick Institute, clinicians working in hepatitis services, and international collaborators. The project will be supported through engagement with state-of-the-art science technology platforms at the Crick, providing expertise and facilities (including sequencing, bioinformatics, flow cytometry and metabolomics). 

Lab members are encouraged to contribute to ideas and planning throughout the course of the PhD. Our aim is to develop and maintain an atmosphere that nurtures scientific creativity and productivity, capitalizing on many opportunities for collaboration. 

We particularly welcome applications from candidates with an interest in infectious diseases and microbiology, hepatology, cancer biology, and/or global health. You will have the opportunity to collaborate in a diverse programme of research with strong translational links, with the aim of developing insights that provide an evidence base for informing clinical practice and policy, and taking steps towards international targets for HBV elimination [5].

The partner institution for this project is UCL.

References

  1. O'Hara, G. A., McNaughton, A. L., Maponga, T., Jooste, P., Ocama, P., Chilengi, R., . . . Matthews, P. C. (2017). Hepatitis B virus infection as a neglected tropical disease. PLoS Negl Trop Dis 11: e0005842. PubMed abstract
  2. European Association for the Study of the Liver. Electronic address, e. e. e. and European Association for the Study of the, L. (2017). EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 67: 370-398. PubMed abstract
  3. McNaughton, A. L., Lemoine, M., van Rensburg, C. and Matthews, P. C. (2021). Extending treatment eligibility for chronic hepatitis B virus infection. Nat Rev Gastroenterol Hepatol 18: 146-147. PubMed abstract
  4. McNaughton, A. L., Roberts, H. E., Bonsall, D., de Cesare, M., Mokaya, J., Lumley, S. F., . . . Matthews, P. C. (2019). Illumina and Nanopore methods for whole genome sequencing of hepatitis B virus (HBV). Sci Rep 9: 7081. PubMed abstract
  5. Ward, J. W., Wiktor, S. Z. and Cooke, G. S. (2020). Launch of the Coalition for Global Hepatitis Elimination: a recommendation of the Lancet Gastroenterology & Hepatology Commission. Lancet Gastroenterol Hepatol 5: 8-10. PubMed abstract