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bioRxiv · 10.1101/2024.07.16.603658

A multiscale model of the action of a capsid assembly modulator for the treatment of chronic hepatitis B

Iyaniwura, S.·Cassidy, T.·Ribeiro, R. M.·Perelson, A. S.
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Abstract

Chronic hepatitis B virus (HBV) infection is strongly associated with increased risk of liver cancer and cirrhosis. While existing treatments effectively inhibit the HBV life cycle, viral rebound occurs rapidly following treatment interruption. Consequently, functional cure rates of chronic HBV infection remain low and there is increased interest in a novel treatment modality, capsid assembly modulators (CAMs). Here, we develop a multiscale mathematical model of CAM treatment in chronic HBV infection. By fitting the model to participant data from a phase I trial of the first-generation CAM vebicorvir, we estimate the drugs dose-dependent effectiveness and identify the physiological mechanisms that drive the observed biphasic decline in HBV DNA and RNA, and mechanistic differences between HBeAg-positive and negative infection. Finally, we demonstrate analytically and numerically that HBV RNA is more sensitive than HBV DNA to increases in CAM effectiveness. Author summaryCapsid assembly modulators (CAMs) are a novel class of anti-hepatitis B virus (HBV) treatments in clinical trials. These CAMs have a distinct mechanism of action from nucleos(t)ide analogues and thus represent an attractive option for the treatment of chronic HBV infection. We developed a multiscale model of the intracellular HBV lifecycle and extracellular dynamics using a time-since-infection structured partial differential equation. We fit the model to participant data from a recent phase I trial, performed a detailed parameter sensitivity analysis, identified key mechanisms driving viral response to first-generation CAM treatment, and demonstrated that HBV RNA is more sensitive than HBV DNA to changes in CAM efficacy, highlighting the potential role of HBV RNA as a biomarker for CAM effectiveness.

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Iyaniwura, S., Cassidy, T., Ribeiro, R. M., Perelson, A. S.. 2024-07-16. A multiscale model of the action of a capsid assembly modulator for the treatment of chronic hepatitis B. https://doi.org/10.1101/2024.07.16.603658

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