title: Genetic variants at the ITPA locus protect against ribavirin-induced hemolytic anemia and dose reduction in an HCV G2/G3 cohort.
abstract: OBJECTIVE
  Two functional genetic variants in the inosine triphosphatase (ITPA) gene have been shown to be strongly associated with protection from ribavirin (RBV)-induced hemolysis. We aimed at evaluating this finding in a chronic hepatitis C genotype 2/3 cohort with a predominance of genotype 3 patients where available data are scarce. A second objective was to determine whether a protective association translated into the need for RBV reduction and hence a possible impact on treatment response.
  
  
  METHODS
  Overall, 457 patients were recruited from two trials of genotype 2/3 patients treated with pegylated interferon α-2b and weight-based RBV. rs1127354 and rs7270101 were genotyped and a composite ITPAase deficiency variable was graded according to the two single nucleotide polymorphisms. The primary endpoints were hemoglobin (Hb) decline from baseline and Hb decline of more than 3 g/dl at week 4.
  
  
  RESULTS
  Both single nucleotide polymorphisms and the composite ITPAase deficiency variable were strongly and independently associated with protection from a decline in Hb at week 4 in multivariate linear regression models (Prs1127354=7.0×10, Prs7270101=0.0036, PITPase deficiency variable =6.3×10). Patients with any degree of reduced ITPAase activity were less likely to have their RBV dose reduced (odds ratio 0.39, 95% confidence interval 0.16-0.96, P=0.040), although this did not translate into increased rapid viral response or sustained viral response (Prvr=0.93, Psvr=0.22).
  
  
  CONCLUSIONS
  We have confirmed a strong association between functional ITPA variants and RBV-induced hemolysis and showed protection from RBV dose reduction, although this did not translate into increased rapid viral response or sustained viral response.
authors.affiliation: Department of Infectious Diseases, Medical Division, Akershus University Hospital, Lørenskog, Norway. arne.eskesen@ahus.no
authors.forename: Arne Nørgaard
authors.initials: AN
authors.lastname: Eskesen
authors.forename: Espen
authors.initials: E
authors.lastname: Melum
authors.forename: Amir
authors.initials: A
authors.lastname: Moghaddam
authors.forename: Kristian
authors.initials: K
authors.lastname: Bjøro
authors.forename: Hans
authors.initials: H
authors.lastname: Verbaan
authors.forename: Helmer
authors.initials: H
authors.lastname: Ring-Larsen
authors.forename: Olav
authors.initials: O
authors.lastname: Dalgard
mesh_terms: D000328:Adult; D000743:Anemia, Hemolytic / Q000139:chemically induced / Q000517:prevention & control*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006454:Hemoglobins / Q000032:analysis; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics*; D011994:Recombinant Proteins / Q000008:administration & dosage; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects*; D012537:Scandinavian and Nordic Countries; D016896:Treatment Outcome; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D006454:Hemoglobins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011755:Pyrophosphatases; D011994:Recombinant Proteins; D012254:Ribavirin; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase; C417083:peginterferon alfa-2b