Multiscale modelling for hepatitis C treatment
Dimitra Bon, Eva Herrmann
Goethe University Frankfurt
Objectives: In parallel to the beginning of a new era of HCV treatment with direct-acting antivirals (DAAs), new models where developed in order to describe the viral kinetics. Clinical data with such new drugs showed a triphasic decay with a rapid first phase, a moderate second phase decay and a relatively slow third phase decay during the first few weeks. Therefore, classical biphasic models may not been suitable. Some recently proposed models take into account the dynamics of intracellular replication, which is the main target of the DAAs.
Methods: Here we describe a new variant of a multiscale model that describes both, intracellular and cellular dynamics, with an ordinary differential equation system. We compare our model with two multiscale models, the ICCI model [1] and the age-structured multiscale model [2,4]. We evaluate all three models with the design of the SYNERGY study [3]. In some cases, patients showed a three phase viral decline and we analysed if such a decline could be modelled with biologically reasonable parameters.
Results: Only the new multiscale model and the age-structured multiscale model could reasonably describe this three phase viral decline. The rapid first phase is associated with viral clearance, the intermediate second phase is only visible if the effect of blocking vRNA packaging is close to 1 and the third phase reflects infected cell clearance. In contrast to the other two models, the age-structured multiscale model is relatively complicated to analyse. There exist easy approximations but those cannot be easily adapted for modelling full PK-PD.
Conclusions: The new variant of a multiscale model proposed here is able to describe the viral kinetics of HCV under these new treatments without a computational effort.
References:
[1] Guedj J, Neumann AU (2010) Understanding hepatitis c viral dynamics with direct-acting antiviral agents due to the interplay between intracellular replication and cellular infection dynamics. JTheor Biol 267: 330-340.
[2] Guedj J, Dahari H, Rong L, Sansone ND, Nettles RE, et al. (2013) Modeling shows that the ns5a inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis c virus half-life. Proc Natl Acad Sci U S A 110: 3991-3996.
[3] Kohli A, Osinusi A, Sims ZS, Nelson A, Meissner EG, et al. (2015) Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. The Lancet (In Press)
[4] Rong L, Guedj J, Dahari H, Coffield DJ Jr, Levi M, et al. (2013) Analysis of hepatitis c virus decline during treatment with the protease inhibitor danoprevir using a multiscale model. PLoS Comput Biol 9: e1002959.