Mechanism-Based Modeling In Chronic Heptatis B
Gailing Li
Department of Clinical Pharmacology, Janssen China R&D, Beijing, China
Objectives: Chronic hepatitis B virus (HBV) infection contributes to a severe disease burden all around the world. In order to gain a better quantitative understanding of HBV disease progression, a mechanism-based model was built through mathematically integrating data/information from disease natural history, therapeutic experiences of anti-HBV drugs as well as knowledge on molecular virology or immunology of HBV.
Methods: Literature search was through PubMed from 1995 to 2015. The database is composed of clinical data of 12 drugs from 2 classes (immune therapy, and nucleoside analogue i.e. NUC). A modified viral kinetic (VK) model was built using clinical data following NUC treatment only in previously untreated HBV patients (45 studies, 746 observations), including intra- and extra-cellular components such as intrahepatic cccDNA and serum HBsAg.
Results: The typical VK model (Nowak et al. 1996) was modified to account for several intracellular and extracellular components such as serum HBV DNA, serum HBsAg, and intracellular cccDNA. This modified model covers the whole life cycle of a virus. Parameters were either referenced from published in vitro/in vivo/clinical research or estimated by fitting to observed data. A serial sensitivity analysis was performed to identify critical steps/parameters that substantially influence the model outputs. Simulated profiles of viral endpoints were compared with observed data from literature. It showed that HBsAg elimination was estimated at much slower rate than in vitro measurements. Furthermore, some parameter estimates from classic VK model using HBV DNA data only were suggested new values when in our modified VK model using multiple endpoints data. In addition, simulation was performed by interfering in the different steps/pathways in the viral life cycle. It showed inducing immune-mediated elimination of infected cells might be the most effective effort to lead to disease cure. Overlaid with clinical data, simulated virus rebound following cessation of treatment also suggested that immune response might play an important role in sustained virus suppression.
Conclusion: This mechanism-based model incorporated multiple viral endpoints (HBV DNA, cccDNA, and HBsAg) within the context of virus life cycle. The effort in establishing a quantitative framework for HBV disease progression would not only improve our understanding of the disease, but facilitate the advance of discovery and development of new anti-HBV therapies.
References:
[1] Nowak, M.A., Bonhoeffer, S., Hill, A.M., Boehme, R., Thomas, H.C. and McDade, H., 1996. Viral dynamics in hepatitis B virus infection. Proceedings of the National Academy of Sciences, 93(9), pp.4398-4402.c