Speaker
Description
Hepatitis B infections become chronic in approximately 5% of adult infections and 80-90% of childhood infections. Once HBV has become chronic, no cure exists yet. Current clinical research aims to reach a functional cure, defined as the sustained loss of HBV surface antigens (HBsAg). Lately, the GLP-26, a capsid assembly modulator leading to the release of uninfectious empty particles, has shown a decrease in HBV DNA, HBsAg, and covalently closed circular DNA (cccDNA) in humanised mice. Based on two cohorts (comprising 27 mice in total), we have HBV DNA and HBsAg dynamics for durations ranging from 18 to 24 weeks. We propose using non-linear mixed effect mechanistic models to reproduce the observed data and quantify the treatment effectiveness and the intensity of the immune-induced cytotoxic response. Using virtual mouse cohorts generated with the mechanistic model, we explore alternative treatment strategies and explain the mechanisms leading to clearance in our simulations. Our model can reproduce the observed HBV DNA and HBsAg dynamics, suggesting the underlying mechanisms are well captured. GLP-26 inhibits the HBV replication cycle and reduces the production of HBsAg. Our results suggest that an increase in treatment duration would also increase the proportion of mice controlling their infections. While not reaching a 100% response, a key emergent property is that the treated mice that controlled the infection present a strong adaptive immune response. A possible explanation is that GLP-26 could act as a facilitator by decreasing circulating HBsAg, allowing the immune system to neutralise infected hepatocytes. This work consist as a proof of concept on the methodology to use to build a mechanistic virtual mice cohort.
