Nakagawa Mina, Sakamoto Naoya, Watanabe Takako, Nishimura-Sakurai Yuki, Onozuka Izumi, Azuma Seishin, Kakinuma Sei, Nitta Sayuri, Kiyohashi Kei, Kusano-Kitazume Akiko, Murakawa Miyako, Yoshino Kohei, Itsui Yasuhiro, Tanaka Yasuhito, Mizokami Masashi, Watanabe Mamoru
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.
Hepatol Int. 2013 Mar;7(1):153-61. doi: 10.1007/s12072-012-9363-6. Epub 2012 Mar 21.
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.
导致肌苷三磷酸酶（ITPA）缺乏的基因变异可保护接受利巴韦林治疗的慢性丙型肝炎患者免受溶血性贫血的影响。结合血细胞减少以及聚乙二醇干扰素（PEG-IFN）或利巴韦林剂量减少的情况，分析了ITPA基因变异与血清利巴韦林浓度之间的关系。
对总共300例接受PEG-IFN加利巴韦林治疗的丙型肝炎患者进行了分析。确定ITPA中的基因多态性，并在治疗期间每4周以及治疗结束后分析血细胞相对于基线的定量减少情况。还根据利巴韦林浓度评估了第4周时血红蛋白（Hb）或血小板（PLT）水平相对于基线的下降情况。
ITPA-CA/AA基因型患者在整个治疗过程中Hb降低程度低于ITPA-CC基因型患者，并且在第4周时发现平均Hb降低存在显著差异（CA/AA为-1.0，CC为-2.8，p<0.001）。在治疗早期，ITPA-CC基因型患者的平均血小板计数降低明显少于ITPA-CA/AA基因型患者（第4周和第8周时p<0.001）。无论利巴韦林浓度如何，ITPA-CA/AA基因型患者发生贫血的可能性较小。基线PLT计数低于130×10(3)/μl的患者实现持续病毒学应答（SVR）的趋势明显较低，尤其是ITPA-CA/AA基因型患者。多变量分析未将ITPA基因变异作为SVR的重要预测指标。
尽管ITPA变异患者发生贫血的可能性较小，但基线PLT计数低的患者难以治疗，尤其是ITPA-CA/AA基因型患者。这些结果可能为调整剂量以尽量减少药物引起的不良事件提供有价值的药物遗传学诊断工具。
