Validation of a Quantitative Systems Pharmacology model for Chronic Hepatitis B

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Authors: Galina Lebedeva (1), Alexander Stepanov (1), Veronika Musatova (2), Oleg Demin (1), Loveleena Bansal (3), Cibele V. Falkenberg (3), Valeriu Damian (3)

Affiliation: (1) InSysBio UK, Edinburgh, UK; (2) InSysBio CY, Paphos, Cyprus; (3) GSK, Collegeville, PA, US

Background: Chronic hepatitis B (CHB) is a complex disease caused by Hepatitis B virus (HBV) that has no specific treatment. We aimed to build a comprehensive quantitative systems pharmacology (QSP) model of chronic hepatitis B (CHB platform) that captures key CHB processes and the effects of standard (Nucleoside analogs (NUC) and pegylated interferon (PegIFNa)) therapies. We apply the model to analyze the mechanisms of HBV persistence and the therapy impact on clinical outcomes.

Methods:CHB platform is an ODE-based model that links HBV infection and dysregulation of cellular and biomolecular processes in relevant tissue compartments (liver, blood plasma, lymph node). The model includes the following modules:

1. Infected Hepatocyte life cycle: production/distribution of HBV-related products and their regulation by effector molecules.
2. Effector cells: Natural killer and CD8 T cell life cycles and their effector function on infected hepatocytes
3. B cells: B cell life cycle, production and distribution of antibodies, and their interaction with antigens
4. Auxiliary cell types: CD4 and Treg cell life cycles, Kupffer, endothelial, stellate and dendritic cells, acting as cytokine producers and antigen presenting cells.
5. Bioactive products: production, distribution and degradation of cytokines and chemokines;
6. Standard therapies: NUCs and PegIFNa effects on cell dynamics and biosynthetic processes.

The CHB platform was parameterized, calibrated and validated on the wide range of in vitro and in vivo data from the public domain.

Results: The CHB platform successfully described the baseline levels of selected CHB biomarkers (HBV DNA, pgRNA, and HBsAg) in patients with high and low viral loads, as well as their response to standard treatments (Entecavir, PegIFNa).

Conclusion: The CHB platform provides insight into cellular and molecular mechanisms of CHB infection, allows for prediction of the efficacy of standard treatments in patients with different viral loads. In order to facilitate evaluation of novel CHB therapies and cover the broad range of patient phenotypes and responses (including non-responders and achievers of functional cure), comprehensive virtual population must be pursued. Depending on the pathways impacted by new therapies addition or simplification of pathways may be necessary.