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
Nakagawa, M.; Sakamoto, N.; Watanabe, T.; Nishimura-Sakurai, Y.; Onozuka, I.; Azuma, S.; Kakinuma, S.; Nitta, S.; Kiyohashi, K.; Kusano-Kitazume, A.; Murakawa, M.; Yoshino, K.; Itsui, Y.; Tanaka, Y.; Mizokami, M.; Watanabe, M.
Hepatology International 7(1): 153-161
ISSN/ISBN: 1936-0533 PMID: 26201629 DOI: 10.1007/s12072-012-9363-6
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. 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. 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. 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.