title: ITPA Polymorphisms Are Associated with Hematological Side Effects during Antiviral Therapy for Chronic HCV Infection.
abstract: OBJECTIVE
  Genetic polymorphisms in the inosine triphosphatase (ITPA) gene have been associated with the protection from early ribavirin(RBV)-induced hemolytic anemia among patients with chronic hepatitis C virus (HCV) infection. The aim of the present study was to investigate the association between the functional ITPA variants and hematological side effects during antiviral therapy with pegylated interferon (PegIFN) and RBV.
  
  
  METHODS
  This cohort study included all consecutive Caucasian patients treated for chronic HCV infection with PegIFN and RBV between 2000 and 2009 for whom a serum sample was available for genetic testing. The predicted inosine triphosphate pyrophosphatase (ITPase) activity was based on the genotypes of the SNPs rs1127354 and rs7270101. Decline in hemoglobin (Hb) during antiviral therapy, as well as dose reductions, blood transfusions and use of erythropoietin were assessed.
  
  
  RESULTS
  In total, 213 patients were included. The predicted ITPase activity was normal among 152 (71%) patients; 61 (29%) patients had ITPase deficiency. By multivariable linear regression, RBV dose in mg per kilogram (Beta 0.09, 95%CI 0.04-0.13, p<0.001) and normal ITPase activity (Beta 0.89, 95%CI 0.64-1.14, p<0.001) were associated with more Hb decline at week 4 of treatment. Patients with normal ITPase activity underwent more dose adjustments of RBV than patients with ITPase deficiency (19(13%) vs 1(2%),p = 0.014) and received erythropoietin more frequently (12 (8%) vs 0 (0%),p = 0.024).
  
  
  CONCLUSIONS
  Genetic variants in the ITPA gene protected against RBV treatment-induced anemia among Caucasian patients with chronic HCV infection. Patients with normal ITPase activity underwent more dose reductions of RBV and received erythropoietin more frequently.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Raoel
authors.initials: R
authors.lastname: Maan
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Adriaan J
authors.initials: AJ
authors.lastname: van der Meer
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Willem Pieter
authors.initials: WP
authors.lastname: Brouwer
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Elisabeth P C
authors.initials: EP
authors.lastname: Plompen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Milan J
authors.initials: MJ
authors.lastname: Sonneveld
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Roomer
authors.affiliation: Department of Viroscience, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Annemiek A
authors.initials: AA
authors.lastname: van der Eijk
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Zwier M A
authors.initials: ZM
authors.lastname: Groothuismink
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Bettina E
authors.initials: BE
authors.lastname: Hansen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Bart J
authors.initials: BJ
authors.lastname: Veldt
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands; Toronto Centre for Liver Disease, Toronto Western & General Hospital, University Health Network, Toronto, Canada.
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Andre
authors.initials: A
authors.lastname: Boonstra
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: de Knegt
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D006454:Hemoglobins / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D011110:Polymorphism, Genetic / Q000235:genetics*; D011755:Pyrophosphatases / Q000235:genetics*; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D006454:Hemoglobins; D011755:Pyrophosphatases; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase