Abstract
ObjectiveThe hepatitis B virus (HBV)-polymerase region overlaps pre-S/S genes with high epitope density and plays an essential role in viral replication. We investigated whether genetic variation in the polymerase region determined long-term dynamics of viral load and the risk of hepatitis B progression in a population-based cohort study.MethodsWe sequenced the HBV-polymerase region using baseline plasma from treatment-naïve individuals with HBV-DNA levels≥1000 copies/mL in a longitudinal viral-load study of participants with chronic HBV infection followed-up for 17 years, and obtained sequences from 575 participants (80% with HBV genotype Ba and 17% with Ce).ResultsPatterns of viral sequence diversity across phases (i.e., immune-tolerant, immune-clearance, non/low replicative, and hepatitis B e antigen (HBeAg)-negative hepatitis phases) of HBV-infection, which were associated with viral and clinical features at baseline and during follow-up, were similar between HBV genotypes, despite greater diversity for genotype Ce vs. Ba. Irrespective of genotypes, however, HBeAg-negative participants had 1.5-to-2-fold higher levels of sequence diversity than HBeAg-positive participants (P<0.0001). Furthermore, levels of viral genetic divergence from the population consensus sequence, estimated by numbers of nucleotide substitutions, were inversely associated with long-term viral load even in HBeAg-negative participants. A mixed model developed through analysis of the entire HBV-polymerase region identified 153 viral load-associated single nucleotide polymorphisms in overall and 136 in HBeAg-negative participants, with distinct profiles between HBV genotypes. These polymorphisms were most evident at sites within or flanking T-cell epitopes. Seven polymorphisms revealed associations with both enhanced viral load and a more than 4-fold increased risk of hepatocellular carcinoma and/or liver cirrhosis.ConclusionsThe data highlight a role of viral genetic divergence in the natural course of HBV-infection. Interindividual differences in the long-term dynamics of viral load is not only associated with accumulation of mutations in HBV-polymerase region, but differences in specific viral polymorphisms which differ between genotypes.
Highlights
The natural history of chronic hepatitis B virus (HBV) infection has been divided into four phases: immune-tolerant (IT), immuneclearance (IC), non/low-replicative (LR), and hepatitis B e antigen (HBeAg) negative hepatitis (ENH) phases
The Cohort and Study Design Study subjects were hepatitis B surface antigen (HBsAg)-positive and antibodies to hepatitis C virus-negative, who were selected from a previous longitudinal study on the long-term dynamics of plasma HBV-DNA levels and hepatocellular carcinoma (HCC), which included all incident cases of HCC ascertained by 2005 and a random sample of a subcohort that were chosen according to a case-cohort sampling design (n = 1143)
HBeAg serostatus and serum ALT levels were used as essential criteria to define the phases of HBV-infection, and viral load was used as secondary criterion
Summary
The natural history of chronic hepatitis B virus (HBV) infection has been divided into four phases: immune-tolerant (IT), immuneclearance (IC), non/low-replicative (LR), and hepatitis B e antigen (HBeAg) negative hepatitis (ENH) phases. The durations of these phases are variable among individuals with chronic HBV infection, and a spectrum of clinical severity has been observed [1]. HBV replicates by reverse transcription using an error-prone polymerase lacking proofreading ability [2,3] This error prone replication strategy leads to all possible point mutations within the viral genome during chronic infection [2,3,4]. Viral mutants with higher fitness levels may predominate by competitive replication, influence clinical consequence
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