Estimating hepatitis B virus cccDNA persistence in chronic infection

Abstract

AbstractHepatitis 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 (NA) 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 (HBeAgPOS) infection the cccDNA lifespan is 61 (36-236) days, whereas during the HBeAgNEG phase of infection it is only 26 (16-81) days. We found that cccDNA replicative capacity declined by an order of magnitude between HBeAgPOS and HBeAgNEG 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.Author SummaryNearly one million people die each year due to hepatitis B virus (HBV) related diseases. Although antiviral treatments for HBV exist, cure is rare and treatment is typically life-long, reflecting the persistence of episomal copies of the viral DNA (cccDNA) in the liver. Our knowledge of the cccDNA reservoir in chronic hepatitis B (CHB) is limited. HBV has a high mutation rate and the key determinants of cccDNA dynamics can be inferred by examining the rate of viral evolution. Combining a mathematical model and known rates of HBV evolution we estimate the cccDNA lifespan during different phases of CHB. Our results provide important insights into the dynamics of the HBV reservoir that will inform the design of future treatment interventions.