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. 2013 Mar;7(1):153-61.
doi: 10.1007/s12072-012-9363-6. Epub 2012 Mar 21.

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

Mina Nakagawa  1   2 , Naoya Sakamoto  3   4   5 , Takako Watanabe  1 , Yuki Nishimura-Sakurai  1 , Izumi Onozuka  1 , Seishin Azuma  1 , Sei Kakinuma  1   2 , Sayuri Nitta  1 , Kei Kiyohashi  1 , Akiko Kusano-Kitazume  1 , Miyako Murakawa  1 , Kohei Yoshino  1 , Yasuhiro Itsui  6 , Yasuhito Tanaka  7 , Masashi Mizokami  8 , Mamoru Watanabe  1 ; Ochanomizu-Liver Conference Study Group
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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

Mina Nakagawa et al. Hepatol Int. 2013 Mar.

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.

Keywords: Hepatitis C virus (HCV); ITPA (inosine triphosphatase); Pegylated interferon plus ribavirin therapy.

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