伏立康唑治疗侵袭性真菌感染致肝损伤影响因素及CYP2C19基因多态性

Influencing factors for invasive fungal infection-induced liver injury in patients treated with voriconazole and CYP2C19 gene polymorphisms

目的探究伏立康唑治疗侵袭性真菌感染致肝损伤影响因素及CYP2C19基因多态性。方法选取2017年1月-2019年12月海南医学院第一附属医院采用伏立康唑治疗的IFI患者135例为样本进行前瞻性研究,均在治疗原发疾病基础上采用伏立康唑静脉注射进行抗真菌感染治疗,监测血药浓度并观察治疗效果和药物不良反应,同时检测CYP2C19基因多态性,比较各组伏立康唑药物谷浓度(Cmin)、治疗效果和不良反应,分析影响患者肝损伤的因素。结果135例IFI患者CYP2C19*1/*1、CYP2C19*1/*2、CYP2C19*1/*3、CYP2C19*2/*2、CYP2C19*2/*3和CYP2C19*3/*3基因型占比分别为45.19%、21.48%、12.59%、5.93%、9.63%和5.19%;根据CYP2C19基因多态性将患者分为快代谢型(EM)61例、中等代谢型(IM)46例和慢代谢型(PM)28例共三组;不同代谢类型IFI患者伏立康唑Cmin比较差异有统计学意义(P<0.05),治疗效果比较,无统计学差异,PM组不良反应发生率高于EM和IM组,且肝损伤发生率比较差异有统计学意义(P<0.05);年龄、用药前合并肝损伤和PM代谢类型为伏立康唑治疗IFI导致肝损害的独立危险因素(P<0.05)。结论我国IFI患者CYP2C19*2和CYP2C19*3突变较为常见,对伏立康唑代谢速度造成明显影响,同时可能导致肝损伤发生风险增加,因此对PM代谢型患者用药过程中应加强肝功能监测。

OBJECTIVE To explore the influencing factors for invasive fungal infection(IFI)-induced liver injury in patients who were treated with voriconazole and observe the CYP2 C19 gene polymorphisms.METHODS A prospective study was conducted for 135 patients with IFI who were treated in the First Affiliated Hospital of Hainan Medical University from Jan 2017 to Dec 2019.All of the patients were given with voriconazole injection for treatment of fungal infection on basis of treatment of primary diseases.The blood concentrations were monitored,curative effects and drug-induced adverse reactions were observed,the CYP2 C19 gene polymorphisms were detected,the concentration min(Cmin),curative effects and adverse reactions of voriconazole were compared among the groups,and the influencing factors for the liver injury were analyzed.RESULTS Among the 135 patients with IFI,45.19%had genotype CYP2 C19*1/*1,21.48%had genotype CYP2 C19*1/*2,12.59%had genotype CYP2 C19*1/*3,5.93%had genotype CYP2 C19*2/*2,9.63%had genotype CYP2 C19*2/*3,and 5.19%had CYP2 C19*3/*3 genotype.The patients were divided into the fast metabolism(EM)group with 61 cases,the moderate metabolism(IM)group with 46 cases and the slow metabolism(PM)group with 28 cases according to the CYP2 C19 gene polymorphism.There was significant difference in the Cmin of voriconazole among the IFI patients with the three types of metabolisms(P<0.05),there was no significant difference in the curative effect;the incidence of adverse reactions of the PM group was significantly higher than that of the EM group and the IM group(P<0.05).Complication with liver injury before medication,age and PM were the independent risk factors for the liver injury caused by voriconazole(P<0.05).CONCLUSION The mutations of CYP2 C19*2 and CYP2 C19*3 are very common among the IFI patients in China,have remarkable effect on the metabolism of voriconazole and result in the increase of risk of liver injury,therefore,it is necessary to strengthen the surveillance of liver function of the PM patients during the medication.