Infection with the hepatitis C virus is an important contributor to morbidity and mortality among those with hemophilia and other inherited bleeding disorders in whom such infections are common. Current treatment modalities using pegylated-interferon alfa and ribavirin are suboptimal in terms of response. New small molecules targeted to inhibition of HCV replication offer promise in terms of improved response rates, and shorter durations of therapy, but their use has not been assessed in special populations, including those with hemophilia and related disorders. Furthermore, the optimal regimen which provides high efficacy with low levels of development of viral resistance to the experimental agent has not been established. This pilot study will examine the efficacy and safety of two strategies utilizing telaprevir in combination with pegylated- interferon alfa/ribavirin. Using powerful mathematical modeling techniques we will explore first and second phase kinetic responses to treatment in patients with inherited bleeding disorders who are either treatment na?ve or treatment experienced (interferon-based HCV treatment). Specifically our aims are 1: Development and implementation of a pilot clinical trial designed to assess dynamic kinetic response parameters and safety of telaprevir combined with standard of care therapy in subjects with inherited bleeding disorders, and 2: To evaluate prevalence and rate of emergence of class-specific resistance mutations to protease inhibitors and to identify early predictors of mutational selection. This study will inform development of a large, multicenter trial that would follow completion of the pilot phase proposed herein.
Hepatitis C infection is an important cause of severe disease in patients with hemophilia. Treatment of hepatitis C with interferon-based therapies is the mainstay of current treatment but is inadequate due to relatively poor response rates in terms of viral clearance. Telaprevir is a new direct acting antiviral agent that appears to improve treatment response when combined with interferon and ribavirin, and has not been tested in patients with inherited bleeding disorders.
|Canini, Laetitia; Chatterjee, Anushree; Guedj, Jeremie et al. (2015) A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV. Antivir Ther 20:469-77|
|Graw, Frederik; Balagopal, Ashwin; Kandathil, Abraham J et al. (2014) Inferring viral dynamics in chronically HCV infected patients from the spatial distribution of infected hepatocytes. PLoS Comput Biol 10:e1003934|
|Conway, Jessica M; Perelson, Alan S (2014) A hepatitis C virus infection model with time-varying drug effectiveness: solution and analysis. PLoS Comput Biol 10:e1003769|
|Lin, M V; Charlton, A N; Rouster, S D et al. (2014) Hepatitis C virus NS3 mutations in haemophiliacs. Haemophilia 20:659-65|
|Canini, Laetitia; Perelson, Alan S (2014) Viral kinetic modeling: state of the art. J Pharmacokinet Pharmacodyn 41:431-43|
|Rotman, Yaron; Noureddin, Mazen; Feld, Jordan J et al. (2014) Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C. Gut 63:161-9|
|Chatterjee, Anushree; Smith, Patrick F; Perelson, Alan S (2013) Hepatitis C viral kinetics: the past, present, and future. Clin Liver Dis 17:13-26|
|Guedj, Jeremie; Dahari, Harel; Uprichard, Susan L et al. (2013) The hepatitis C virus NS5A inhibitor daclatasvir has a dual mode of action and leads to a new virus half-life estimate. Expert Rev Gastroenterol Hepatol 7:397-9|
|Rong, Libin; Guedj, Jeremie; Dahari, Harel 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|
|Rong, Libin; Perelson, Alan S (2013) Mathematical analysis of multiscale models for hepatitis C virus dynamics under therapy with direct-acting antiviral agents. Math Biosci 245:22-30|