Mina Nakagawa1,2, Naoya Sakamoto3,4,5, Takako Watanabe1, Yuki Nishimura-Sakurai1, Izumi Onozuka1, Seishin Azuma1, Sei Kakinuma1,2, Sayuri Nitta1, Kei Kiyohashi1, Akiko Kusano-Kitazume1, Miyako Murakawa1, Kohei Yoshino1, Yasuhiro Itsui6, Yasuhito Tanaka7, Masashi Mizokami8, Mamoru Watanabe1. 1. Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. 2. Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan. 3. 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. 4. Department of Gastroenterology and Hepatology, Graduate School of Medicine Hokkaido University, Sapporo, Japan. nsakamoto.gast@tmd.ac.jp. 5. Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan. nsakamoto.gast@tmd.ac.jp. 6. Department of Internal Medicine, Soka Municipal Hospital, Saitama, Japan. 7. Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. 8. Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
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. PATIENTS AND 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.
BACKGROUND: Genetic variation leading to inosine triphosphatase (ITPA) deficiency protects chronic hepatitis Cpatients 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. PATIENTS AND 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.
Entities:
Keywords:
Hepatitis C virus (HCV); ITPA (inosine triphosphatase); Pegylated interferon plus ribavirin therapy
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