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Ribavirin-Induced Anemia in Hepatitis C Virus Patients Undergoing Combination Therapy

The current standard of care for hepatitis C virus (HCV) infection – combination therapy with pegylated interferon and ribavirin – elicits sustained responses in only ∼50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin sub...

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Autores principales: Krishnan, Sheeja M., Dixit, Narendra M.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033369/
https://www.ncbi.nlm.nih.gov/pubmed/21304937
http://dx.doi.org/10.1371/journal.pcbi.1001072
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author Krishnan, Sheeja M.
Dixit, Narendra M.
author_facet Krishnan, Sheeja M.
Dixit, Narendra M.
author_sort Krishnan, Sheeja M.
collection PubMed
description The current standard of care for hepatitis C virus (HCV) infection – combination therapy with pegylated interferon and ribavirin – elicits sustained responses in only ∼50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in conjunction with models of viral kinetics, the rational identification of treatment protocols that maximize treatment response while curtailing side effects.
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spelling pubmed-30333692011-02-08 Ribavirin-Induced Anemia in Hepatitis C Virus Patients Undergoing Combination Therapy Krishnan, Sheeja M. Dixit, Narendra M. PLoS Comput Biol Research Article The current standard of care for hepatitis C virus (HCV) infection – combination therapy with pegylated interferon and ribavirin – elicits sustained responses in only ∼50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in conjunction with models of viral kinetics, the rational identification of treatment protocols that maximize treatment response while curtailing side effects. Public Library of Science 2011-02-03 /pmc/articles/PMC3033369/ /pubmed/21304937 http://dx.doi.org/10.1371/journal.pcbi.1001072 Text en Krishnan, Dixit. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Krishnan, Sheeja M.
Dixit, Narendra M.
Ribavirin-Induced Anemia in Hepatitis C Virus Patients Undergoing Combination Therapy
title Ribavirin-Induced Anemia in Hepatitis C Virus Patients Undergoing Combination Therapy
title_full Ribavirin-Induced Anemia in Hepatitis C Virus Patients Undergoing Combination Therapy
title_fullStr Ribavirin-Induced Anemia in Hepatitis C Virus Patients Undergoing Combination Therapy
title_full_unstemmed Ribavirin-Induced Anemia in Hepatitis C Virus Patients Undergoing Combination Therapy
title_short Ribavirin-Induced Anemia in Hepatitis C Virus Patients Undergoing Combination Therapy
title_sort ribavirin-induced anemia in hepatitis c virus patients undergoing combination therapy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033369/
https://www.ncbi.nlm.nih.gov/pubmed/21304937
http://dx.doi.org/10.1371/journal.pcbi.1001072
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