A Quantitative Systems Pharmacology (QSP) Model of Acute Hepatitis B Virus Infection: Mechanistic Insights and Foundations for Future Extensions

Chronic hepatitis B virus (HBV) infection remains a significant global health challenge. While the dynamic interplay between viral replication and host immune responses determines infection outcomes, the mechanisms driving the resolution of acute infection versus the emergence of chronicity remain incompletely understood. To address this challenge, we developed a detailed quantitative systems pharmacology (QSP) model of acute HBV infection capturing several key host immune and viral mechanisms absent in previous models. The model was parameterized using publicly available data and calibrated against clinical time-course datasets from multiple acute HBV case studies. Perturbation and local sensitivity analyses identified key drivers of biomarker dynamics, particularly hepatitis B virus DNA (HBV DNA), hepatitis B surface antigen (HBsAg), and alanine aminotransferase (ALT). These dynamics were most sensitive to parameters governing viral replication (e.g., HBV entry via the sodium taurocholate cotransporting polypeptide [NTCP] receptor, covalently closed circular DNA [cccDNA] formation, and hepatocyte turnover) and adaptive immune responses (e.g., CD8⁺ T cell activity, dendritic cell-mediated priming, and regulatory T cell [Treg]-driven immunosuppression). These influential parameters were used to generate a virtual population that reproduced the observed heterogeneity in biomarker trajectories. Notably, the magnitude and timing of biomarker peaks captured most of the variability, reflecting interindividual differences in individual immune responses and viral dynamics. While the current model nicely captures processes associated with acute HBV infections, it will be extended to different stages of chronic HBV with the objective of informing the rational design of novel therapies and supporting the development of curative HBV strategies.