Role of viral load in Hepatitis B virus evolution in persistently normal ALT chronically infected patients

Area of Science:

• Virology
• Molecular Evolution
• Hepatology

Background:

• Chronic Hepatitis B virus (HBV) infection is a global health concern, often leading to severe liver disease.
• Low replicative carriers represent the largest HBV-infected population, yet longitudinal studies on their molecular evolution are scarce.
• Understanding HBV intra-host dynamics is crucial for managing chronic infection.

Purpose of the Study:

• To investigate the molecular evolution of the whole HBV genome in chronically infected patients with persistently normal ALT levels over a 10-year period.
• To determine the relationship between HBV DNA levels and the rate of nucleotide substitution.
• To identify specific HBV regions influenced by viral load and potential immune pressure.

Main Methods:

• Longitudinal sampling from 10 patients with normal ALT levels over 10 years.
• Sequencing of HBV full-length genomes from baseline, 5-year, and 10-year follow-up samples.
• Grouping patients based on HBV DNA levels (<10^3 IU/ml vs. >10^3 IU/ml) and analyzing substitution rates.

Main Results:

• The rate of nucleotide substitution was inversely related to HBV DNA levels.
• Group A (<10^3 IU/ml) exhibited a significantly higher substitution rate (6.9 × 10^-4) than Group B (>10^3 IU/ml) (2.7 × 10^-4) over 10 years (p < .001).
• Most substitutions occurred in the Core region, particularly in coding and antigenic epitope regions, suggesting immune-driven evolution.

Conclusions:

• Viral load plays a significant role in HBV intra-host dynamics, even in low replicative states.
• The Core region is a key driver of HBV evolutionary differences between patients with varying viral loads.
• Immune pressure likely influences the distinct evolutionary trajectories observed in chronically infected individuals.