Estimating hepatitis B virus cccDNA persistence in chronic infection

Katrina A Lythgoe; Sheila F Lumley; Lorenzo Pellis; Jane A McKeating; Philippa C Matthews

doi:10.1093/ve/veaa063

Estimating hepatitis B virus cccDNA persistence in chronic infection

Virus Evol. 2020 Aug 25;7(1):veaa063. doi: 10.1093/ve/veaa063. eCollection 2021 Jan.

Authors

Katrina A Lythgoe^{1

2}, Sheila F Lumley^{3

4}, Lorenzo Pellis⁵, Jane A McKeating⁶, Philippa C Matthews^{3

4

7}

Affiliations

¹ Big Data Institute, University of Oxford, Old Road Campus, Oxford OX3 7LF, UK.
² Department of Zoology, University of Oxford, Medawar Building, South Parks Road, Oxford OX1 3SY, UK.
³ Nuffield Department of Medicine, University of Oxford, Medawar Building, South Parks Road, Oxford OX1 3SY, UK.
⁴ Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
⁵ Department of Mathematics, Alan Turing Building, Oxford Rd, Manchester M13 9PL, UK.
⁶ Nuffield Department of Medicine Research Building, University of Oxford, Oxford OX3 7LF, UK.
⁷ NIHR Biomedical Research Centre, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.

Abstract

Hepatitis B virus (HBV) infection is a major global health problem with over 240 million infected individuals at risk of developing progressive liver disease and hepatocellular carcinoma. HBV is an enveloped DNA virus that establishes its genome as an episomal, covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Currently, available standard-of-care treatments for chronic hepatitis B (CHB) include nucleos(t)ide analogues (NAs) that suppress HBV replication but do not target the cccDNA and hence rarely cure infection. There is considerable interest in determining the lifespan of cccDNA molecules to design and evaluate new curative treatments. We took a novel approach to this problem by developing a new mathematical framework to model changes in evolutionary rates during infection which, combined with previously determined within-host evolutionary rates of HBV, we used to determine the lifespan of cccDNA. We estimate that during HBe-antigen positive (HBeAg^POS) infection the cccDNA lifespan is 61 (36-236) days, whereas during the HBeAg^NEG phase of infection it is only 26 (16-81) days. We found that cccDNA replicative capacity declined by an order of magnitude between HBeAg^POS and HBeAg^NEG phases of infection. Our estimated lifespan of cccDNA is too short to explain the long durations of chronic infection observed in patients on NA treatment, suggesting that either a sub-population of long-lived hepatocytes harbouring cccDNA molecules persists during therapy, or that NA therapy does not suppress all viral replication. These results provide a greater understanding of the biology of the cccDNA reservoir and can aid the development of new curative therapeutic strategies for treating CHB.

Keywords: cccDNA; dynamics; evolution; hepatitis B virus; modelling; persistence; reservoir.

Grants and funding

WT_/Wellcome Trust/United Kingdom