title: Inosine triphosphatase polymorphisms and ribavirin pharmacokinetics as determinants of ribavirin-associate anemia in patients receiving standard anti-HCV treatment.
abstract: BACKGROUND
  Functional variants of inosine triphosphatase (ITPA) were recently found to protect against ribavirin (RBV)-induced hemolytic anemia. However, no definitive data are yet available on the role of plasma RBV concentrations on hemoglobin (Hb) decrement. Moreover, no data have been published on the possible interplay between these 2 factors.
  
  
  METHODS
  A retrospective analysis included 167 patients. The ITPA variants rs7270101 and rs1127354 were genotyped and tested using the χ test for association with Hb reduction at week 4. We also investigated, using multivariate logistic regression, the impact of RBV plasma exposure on Hb concentrations.
  
  
  RESULTS
  Both single nucleotide polymorphisms were associated with Hb decrease. The carrier of at least 1 variant allele in the functional ITPA single nucleotide polymorphisms was associated with a lower decrement of Hb (-1.1 g/dL), as compared with patients without a variant allele (-2.75 g/dL; P = 4.09 × 10). RBV concentrations were not influenced by ITPA genotypes. A cut-off of 2.3 μg/mL of RBV was found to be associated with anemia (area-under-receiver operating characteristic = 0.630, sensitivity = 50.0%, and specificity = 69.5%, P = 0.008). In multivariate logistic regression analyses, the carrier of a variant allele (P = 0.005) and plasma RBV concentrations <2.3 μg/mL (P = 0.016) were independently associated with protection against clinically significant anemia at week 4.
  
  
  CONCLUSIONS
  Although no direct relationship was found between ITPA polymorphisms and plasma RBV concentrations, both factors were shown to be significantly associated with anemia. A multivariate regression model based on ITPA genetic polymorphisms and RBV trough concentration was developed for predicting the risk of anemia. By relying upon these 2 variables, an individualized management of anemia seems to be feasible in recipients of pegylated interferon-RBV therapy.
authors.affiliation: Department of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, Italy. antonio.davolio@unito.it
authors.forename: Antonio
authors.initials: A
authors.lastname: DʼAvolio
authors.forename: Alessia
authors.initials: A
authors.lastname: Ciancio
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
authors.forename: Antonina
authors.initials: A
authors.lastname: Smedile
authors.forename: Lorena
authors.initials: L
authors.lastname: Baietto
authors.forename: Marco
authors.initials: M
authors.lastname: Simiele
authors.forename: Diego Aguilar
authors.initials: DA
authors.lastname: Marucco
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cariti
authors.forename: Andrea
authors.initials: A
authors.lastname: Calcagno
authors.forename: Daniel Gonzalez
authors.initials: DG
authors.lastname: de Requena
authors.forename: Mauro
authors.initials: M
authors.lastname: Sciandra
authors.forename: Jessica
authors.initials: J
authors.lastname: Cusato
authors.forename: Giulia
authors.initials: G
authors.lastname: Troshina
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
authors.forename: Mario
authors.initials: M
authors.lastname: Rizzetto
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
mesh_terms: D000328:Adult; D000483:Alleles; D000743:Anemia, Hemolytic / Q000139:chemically induced; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005240:Feasibility Studies; D005260:Female; D005838:Genotype; D006454:Hemoglobins / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012189:Retrospective Studies; D012254:Ribavirin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; 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; D000097630:Inosine Triphosphatase; C417083:peginterferon alfa-2b