title: Association of ITPA gene variation and serum ribavirin concentration with a decline in blood cell concentrations during pegylated interferon-alpha plus ribavirin therapy for chronic hepatitis C.
abstract: BACKGROUND
  Genetic variation leading to inosine triphosphatase (ITPA) deficiency protects chronic hepatitis C patients receiving ribavirin against hemolytic anemia. The relationship between ITPA gene variation and serum ribavirin concentration was analyzed in association with a reduction in blood cells and dose reduction of pegylated interferon (PEG-IFN) or ribavirin.
  
  
  METHODS
  A total of 300 hepatitis C patients treated with PEG-IFN plus ribavirin were analyzed. Genetic polymorphisms were determined in ITPA and the quantitative reduction in blood cells from the baseline was analyzed every 4 weeks for the duration of treatment and after the end of therapy. The decline in hemoglobin (Hb) or platelet (PLT) level at week 4 compared to baseline was also assessed according to ribavirin concentrations.
  
  
  RESULTS
  Patients with the ITPA-CA/AA genotypes showed a lower degree of Hb reduction throughout therapy than those with the ITPA-CC genotype and a marked difference in mean Hb reduction was found at week 4 (CA/AA -1.0 vs. CC -2.8, p < 0.001). The ITPA-CC genotype had significantly less reduction in the mean platelet count than the ITPA-CA/AA genotypes early during treatment (p < 0.001 for weeks 4 and 8). Patients with the ITPA-CA/AA genotypes were less likely to develop anemia, regardless of the concentration of ribavirin. Patients with baseline PLT counts below 130 × 10(3)/μl had a significantly lower tendency to achieve sustained virological response (SVR), especially those with the ITPA-CA/AA genotypes. ITPA gene variation was not extracted by multivariable analysis as an important predictor of SVR.
  
  
  CONCLUSIONS
  Despite the fact that ITPA variants were less likely to develop anemia, patients with low baseline PLT counts were difficult to treat, especially those with the ITPA-CA/AA genotype. These results may give a valuable pharmacogenetic diagnostic tool for the tailoring of dosing to minimize drug-induced adverse events.
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mina
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. nsakamoto.gast@tmd.ac.jp.|Department of Gastroenterology and Hepatology, Graduate School of Medicine Hokkaido University, Sapporo, Japan. nsakamoto.gast@tmd.ac.jp.|Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan. nsakamoto.gast@tmd.ac.jp.
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nishimura-Sakurai
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Onozuka
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Seishin
authors.initials: S
authors.lastname: Azuma
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Kakinuma
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Nitta
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Kiyohashi
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kusano-Kitazume
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Murakawa
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Yoshino
authors.affiliation: Department of Internal Medicine, Soka Municipal Hospital, Saitama, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Itsui
authors.affiliation: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizokami
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
keywords: Hepatitis C virus (HCV); ITPA (inosine triphosphatase); Pegylated interferon plus ribavirin therapy