ribavirin-induced anemia in hepatitis c virus patients undergoing combination therapyribavirin-induced贫血在丙型肝炎病毒接受联合治疗的患者.pdfVIP

Ribavirin-Induced Anemia in Hepatitis C Virus Patients Undergoing Combination Therapy 1 1,2 Sheeja M. Krishnan , Narendra M. Dixit * 1 Department of Chemical Engineering, Indian Institute of Science, Bangalore, India, 2 Bioinformatics Centre, Indian Institute of Science, Bangalore, India Abstract 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