title: Inosine triphosphate pyrophosphohydrolase activity: more accurate predictor for ribavirin-induced anemia in hepatitis C infected patients than ITPA genotype.
abstract: BACKGROUND
  ITPA polymorphisms have been associated with protection against ribavirin-induced anemia in chronic hepatitis C (HCV) patients. Here we determined the association of inosine triphosphate pyrophosphohydrolase (inosine triphosphatase or ITPase) enzyme activity with ITPA genotype in predicting ribavirin-induced anemia.
  
  
  METHODS
  In a cohort of 106 HCV patients, hemoglobin (Hb) values were evaluated after 4 weeks (T4) and at the time of lowest Hb value (Tnadir). ITPase activity was measured and ITPA genotype determined. Single-nucleotide polymorphisms (SNPs) tested were c.124+21A>C and c.94C>A. ITPase activity ≥1.11 mU/mol Hb was considered as normal.
  
  
  RESULTS
  After 4 weeks of treatment, 78% of the patients with normal ITPase activity were anemic and 21% of the patients with low ITPase activity (p<0.001). Stratified by genotype, the percentages of anemic patients were: wt/wt 76%, wt/c.124+21A>C 46% (p=0.068), and wt/c.94C>A 29% (p=0.021). At Tnadir, virtually all patients with normal ITPase activity were anemic, compared to only 64% of the patients with low activity (p=0.02). Thirteen patients had wt/c.124+241A>C genotype. Within this group all five patients with normal ITPase activity and only four of eight with decreased activity developed anemia. Presence of HCV RNA did not influence ITPase activity.
  
  
  CONCLUSIONS
  This study is the first to report that ITPase activity predicts the development of anemia during ribavirin treatment. ITPase activity and ITPA genotype have high positive predictive values for development of ribavirin-induced anemia at any time during treatment, but ITPase activity predicts ribavirin-induced anemia more accurately.
authors.forename: Nicole Chantal
authors.initials: NC
authors.lastname: Peltenburg
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Bakker
authors.forename: Wim H M
authors.initials: WH
authors.lastname: Vroemen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: de Knegt
authors.forename: Mathie P G
authors.initials: MP
authors.lastname: Leers
authors.forename: Jörgen
authors.initials: J
authors.lastname: Bierau
authors.forename: Annelies
authors.initials: A
authors.lastname: Verbon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced* / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D015331:Cohort Studies; D004247:DNA / Q000097:blood / Q000235:genetics; D005260:Female; D005838:Genotype; D006526:Hepatitis C / Q000150:complications* / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism*; D012254:Ribavirin / Q000009:adverse effects* / Q000627:therapeutic use; D055815:Young Adult; D000097630:Inosine Triphosphatase
chemical_list: D004247:DNA; D011755:Pyrophosphatases; D012254:Ribavirin; D000097630:Inosine Triphosphatase; C511829:ITPA protein, human