厦门地区乙型肝炎患者HBV RT基因耐药突变模式及临床分析

Drug resistance mutation patterns and clinical analysis of HBV RT regene in patients with hepatitis B in Xiamen area

目的研究厦门地区乙型肝炎(简称乙肝)患者HBVRT基因耐药突变模式的临床特征及与乙肝进程之间的关系。方法收集2015年11月至2018年5月厦门市中医院433例乙肝患者HBV耐药检测数据,以其中167例有完整干扰素与核苷(酸)类似物(NAs)用药信息患者作为观察对象。扩增HBVRT基因经Sanger法测序后分析患者RT基因耐药突变模式、性别、年龄、HBsAg水平、DNA水平、丙氨酸氨基转移酶(ALT)水平及天门冬氨酸氨基转移酶(AST)水平、HBV基因型、HBeAg模式、感染持续时间及与乙肝疾病进程之间的相互关系。结果厦门地区B、C型HBV感染者分别占65.59%和34.41%。C型HBV感染者有较高的HBsAg水平(P=0.026);突变型HBV感染者的年龄、HBsAg、ALT及AST水平均明显高于野生型HBV感染者,差异均有统计学意义(P<0.05);不同临床进程中,肝硬化和肝癌患者的年龄、C型HBV感染比例均高于慢性HBV感染者,差异均有统计学意义(P<0.05),肝癌患者的HBVDNA水平高于慢性HBV感染者,差异有统计学意义(P=0.009)。整体耐药突变率为37.18%(161/433),最常见的3个(rtM204、rtL180和rtA181)耐药突变位点突变率均为C型高于B型。共检出19种突变模式,以单位点突变的rtM204I、rtV173L和rtA181T多见,分别占4.19%、3.59%、1.80%。结论厦门地区HBVRT基因的耐药突变率与基因型有关,B、C基因型在不同耐药位点的突变率存在差异,C型感染者与突变型感染者结局较差。建议HBV感染者使用高耐药屏障的NAs治疗。

Objective To study the clinical features of gene resistance mutation pattern in HBV reverse transcriptase region (RT) of patients with hepatitis B in Xiamen city and the relationship with hepatitis B disease progression. Methods Detection data of HBV drug resistance in a total of 433 patients were collected,of which 167 patients with complete interferon and nucleotide analogs (NAs) medication information were taken as observation group.The HBV RT gene resistance mutation patterns were analyzed after the amplification of HBV RT gene by Sanger method.Then the relationship between the mutation patterns,gender,age,HBsAg,ALT/AST levels,HBV genotype,HBeAg pattern,duration of infection and hepatitis B disease progression were analyzed. Results In Xiamen,65.59% and 34.41% of the patients were infected with HBV B and C,respectively.Patients with genotype C had higher level of HBsAg ( P =0.026).The age,HBsAg level,HBV DNA,ALT and AST levels of patients with mutant HBV were significantly higher than those of wild-type HBV,and the differences were statistically significant ( P < 0.05).In different clinical progress,the age and the proportion of C genotype HBV infection in patients with cirrhosis and hepatocellular carcinoma(HCC) were higher than those in patients with chronic infections,and the differences were statistically significant ( P < 0.05 ).HBV DNA level in patients with HCC was higher than that in patients with chronic HBV infection,and the difference was statistically significant ( P =0.009).The overall drug resistance mutation rate was 37.18 %(161/433),and the mutation rates of the top three resistance mutation sites (rtM204,rtL180 and rtA181) were higher in genotype C than those in genotype B.A total of 19 mutation patterns were detected,the rtM204I,rtV173L and rtA181T mutations with single point mutations were more common (4.19%, 3.59 %,1.80%,respectively). Conclusion The drug resistance mutation rate of HBV RT gene in Xiamen is related to genotype.There is a difference in the mutation rate of B and C genotypes at different drug resistance sites,and the outcomes of patients with genotype C and mutant infections are poor.It is recommended that HBV-infected patients use NAs treatment with high-resistance barriers.