Estimating hepatitis B virus cccDNA persistence in chronic infection

Area of Science:

• Hepatology
• Virology
• Mathematical Biology

Background:

• Hepatitis B virus (HBV) infection affects over 240 million globally, posing risks for liver disease and cancer.
• Current treatments, nucleos(t)ide analogues (NAs), suppress HBV replication but do not eliminate the viral cccDNA reservoir, hindering cures.
• Understanding cccDNA lifespan is crucial for developing effective curative therapies for chronic hepatitis B (CHB).

Purpose of the Study:

• To determine the lifespan of Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in infected hepatocytes.
• To investigate the decline in cccDNA replicative capacity between different phases of HBV infection.
• To evaluate the implications of cccDNA lifespan for the persistence of chronic HBV infection, particularly during NA treatment.

Main Methods:

• Development of a novel mathematical framework to model evolutionary rates during HBV infection.
• Integration of within-host evolutionary rates with the mathematical model to estimate cccDNA lifespan.
• Comparison of estimated cccDNA lifespan during HBe-antigen positive (HBeAg POS) and HBe-antigen negative (HBeAg NEG) infection phases.

Main Results:

• Estimated cccDNA lifespan is 61 days (36-236) during HBeAg POS infection and 26 days (16-81) during HBeAg NEG infection.
• cccDNA replicative capacity decreases significantly, by an order of magnitude, between HBeAg POS and HBeAg NEG phases.
• The estimated cccDNA lifespan is shorter than the duration of chronic infection observed in patients on NA therapy.

Conclusions:

• The short estimated cccDNA lifespan suggests that long-term persistence of HBV during NA treatment may involve long-lived hepatocytes with cccDNA or incomplete viral replication suppression.
• These findings provide critical insights into the HBV cccDNA reservoir dynamics.
• The results can inform the design of novel therapeutic strategies aimed at curing chronic hepatitis B.