title: Several factors including ITPA polymorphism influence ribavirin-induced anemia in chronic hepatitis C.
abstract: OBJECTIVE
  To construct formulae for predicting the likelihood of ribavirin-induced anemia in pegylated interferon α plus ribavirin for chronic hepatitis C.
  
  
  METHODS
  Five hundred and sixty-one Japanese patients with hepatitis C virus genotype 1b who had received combination treatment were enrolled and assigned randomly to the derivation and confirmatory groups. Single nucleotide polymorphisms at or nearby ITPA were genotyped by real-time detection polymerase chain reaction. Factors influencing significant anemia (hemoglobin concentration < 10.0 g/dL at week 4 of treatment) and significant hemoglobin decline (declining concentrations > 3.0 g/dL at week 4) were analyzed using multiple regression analyses. Prediction formulae were constructed by significantly independent factors.
  
  
  RESULTS
  Multivariate analysis for the derivation group identified four independent factors associated with significant hemoglobin decline: hemoglobin decline at week 2 [P = 3.29 × 10(-17), odds ratio (OR) = 7.54 (g/dL)], estimated glomerular filtration rate [P = 2.16 × 10(-4), OR = 0.962 (mL/min/1.73 m(2))], rs1127354 (P = 5.75 × 10(-4), OR = 10.94) and baseline hemoglobin [P = 7.86 × 10(-4), OR = 1.50 (g/dL)]. Using the model constructed by these factors, positive and negative predictive values and predictive accuracy were 79.8%, 88.8% and 86.2%, respectively. For the confirmatory group, they were 83.3%, 91.0% and 88.3%. These factors were closely correlated with significant anemia. However, the model could not be constructed, because no patients with rs1127354 minor genotype CA/AA had significant anemia.
  
  
  CONCLUSIONS
  Reliable formulae for predicting the likelihood of ribavirin-induced anemia were constructed. Such modeling may be useful in developing individual tailoring and optimization of ribavirin dosage.
authors.affiliation: Institute of Clinical Medicine and Research, The Jikei University School of Medicine, 163-1 Kashiwa-shita, Kashiwa, Chiba 277-8567, Japan. atsubo@jikei.ac.jp
authors.forename: Akihito
authors.initials: A
authors.lastname: Tsubota
authors.forename: Noritomo
authors.initials: N
authors.lastname: Shimada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Abe
authors.forename: Kai
authors.initials: K
authors.lastname: Yoshizawa
authors.forename: Rie
authors.initials: R
authors.lastname: Agata
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yumoto
authors.forename: Makiko
authors.initials: M
authors.lastname: Ika
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Namiki
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagatsuma
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsudaira
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Fujise
authors.forename: Norio
authors.initials: N
authors.lastname: Tada
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Aizawa
mesh_terms: D000368:Aged; D000740:Anemia / Q000097:blood / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics*; D000998:Antiviral Agents / Q000009:adverse effects*; D015415:Biomarkers / Q000097:blood; D016009:Chi-Square Distribution; D004359:Drug Therapy, Combination; D005260:Female; D020022:Genetic Predisposition to Disease; D006454:Hemoglobins / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D007564:Japan; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D010641:Phenotype; D011092:Polyethylene Glycols / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000009:adverse effects*; D018570:Risk Assessment; D012307:Risk Factors; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; 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; C100416:peginterferon alfa-2a
keywords: Chronic hepatitis C virus infection; Hemolytic anemia; Pegylated interferon α; Prediction model; Ribavirin; Single nucleotide polymorphism