External evaluation of a Hepatitis C viral kinetic model which links viral dynamics to sustained virologic response (SVR)
Annabelle Lemenuel-Diot (1), Eric Snoeck (2), Barbara Brennan (1), James Thommes (1) and Nicolas Frey (1)
(1) F. Hoffmann-La Roche Ltd., (2) Exprimo NV.
Objectives: A Hepatitis C viral (HCV) kinetic model has been developed based on a large clinical database (1773 Chronic Hepatitis C (CHC) patients) treated with peginterferon α-2a ▒ ribavirin for either 24 or 48 weeks1,2. This model characterizes the complexity and diversity of clinically observed HCV kinetics and links it to sustained virologic response (SVR, the primary clinical endpoint of HCV treatment defined as an undetectable viral load at 24 weeks after treatment completion). The objective of this analysis was to conduct an external evaluation of this model by simulating the outcomes of clinical trials involving treatment strategies or populations different from those entering into the model.
Methods: Two trials have been used to perform this external evaluation. One trial, know as CHARIOT3, was designed to examine the benefits of using a fixed-dose induction (360 μg) of peginterferon α-2a in combination with ribavirin for the first 12 weeks of therapy in patients infected with genotype 1 HCV. The second trial, known as PROGRESS4, was designed to examine the benefits of using the same fixed-dose induction (360 μg) of peginterferon α-2a for the first 12 weeks of therapy in combination with different doses of ribavirin in difficult-to-cure genotype 1 HCV patients. The viral kinetic model has been implemented into a simulation software (Trial Simulator«). The individual model parameters have been sampled from a subset of the individual post-hoc parameters generated by the final model. This subset was defined based on the main inclusion criteria specific to each trial: treatment-naive genotype 1 patients for CHARIOT, and treatment-naive genotype 1 patients with high baseline viral load and high body weight for PROGRESS. Visual and posterior predictive checks were performed by simulating each study design 300 times.
Results/Conclusions: The time course of the viral load and the SVR rate from the CHARIOT and PROGRESS studies were adequately predicted by the model, confirming that a 12-week induction period of peginterferon α-2a does not lead to a further increase in the SVR rate. The successful external evaluation of our viral kinetic model supports the further use of this model to perform simulations investigating new treatment strategies in Hepatitis C patients.
 Snoeck E, Lavielle M, Chanu P, Jorga K and Frey N. The challenge of modelling hepatitis C virus dynamics after long term treatment: Application of MONOLIX. PAGE 17 (2008) Abstr 1348 [www.page-meeting.org/?abstract=1348]
 Snoeck E, Chanu P, Lavielle M, Jacqmin P, Jonsson NJ, Jorga K, Goggin T, Grippo J, Jumbe NL and Frey N. A comprÚhensive Hepatitis C viral kinetic model explaining cure. Submitted to Clin. Pharm Ther.
 Crawford DHG, Roberts S, Weltman M, et al. Baseline factors associated with rapid and early virological responses in HCV genotype 1 patients treated with induction dosing of pegylated interferon: the CHARIOT study. 43rd Annual Meeting of the European Association for the Study of the Liver; 2008 Apr 23-27; Milan
 Roche Pharmaceuticals. Roche driving PROGRESS in treat ment of difficult-to-cure Hepatitis C patients with new PEGASYS« (peginterferon alfa-2a (40 kD)) and COPEGUS« (ribavirin) trial [media release: online]. Available from URL: http://www.prnewswire.co.uk [Accessed 2007 Mar 27]