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目的探讨阿德福韦酯(ADV)治疗失败慢性乙型肝炎(CHB)患者的基因型耐药情况。方法收集ADV治疗失败CHB患者的血清样本及临床资料,将患者分为病毒学突破组与应答不佳组,应用PCR产物直接测序法联合焦磷酸测序法进行基因型耐药检测;比较两组患者耐药发生情况,并分析耐药发生与患者抗病毒治疗的关系。结果共210例ADV治疗失败的CHB患者纳入研究,其中病毒学突破组106例,应答不佳组104例。两组共检出耐药变异67例(31.9%),其中rt A181V/T位点变异38例(18.1%),rt N236T变异7例(3.3%),rt A181V/T+rt N236T联合变异22例(10.5%)。病毒学突破组耐药检出率显著高于应答不佳组(42.5%vs.21.2%;掊2=10.961,P=0.0009)。病毒学突破组rt A181T变异患者比例低于应答不佳组(28.9%vs.59.1%;掊2=5.676,P=0.017)。病毒学突破组拉米夫定(LAM)经治换用ADV患者的ADV耐药基因变异检出率显著高于ADV初治患者(56.5%vs.31.7%;P=0.010)。应答不佳组LAM经治换用ADV的耐药基因变异检出率亦显著高于ADV初治患者(31.3%vs.12.5%,P=0.020)。结论 ADV治疗失败患者ADV基因型耐药检出率为31.9%,对于ADV治疗≥48周应答不佳者,即使未出现病毒学突破,也应酌情考虑进行耐药检测。
Objective To investigate the genotypes of drug resistant patients with chronic hepatitis B (CHB) treated with adefovir dipivoxil (ADV). Methods Serum samples and clinical data of CHB patients with ADV failure were collected. The patients were divided into virological breakthrough group and poor response group. PCR products direct sequencing and pyrosequencing were used to detect the genotypes of drug resistance. The incidence of drug resistance, and analyze the relationship between drug resistance and anti-virus therapy in patients. Results A total of 210 cases of CHB patients with ADV failure were included in the study, of which 106 cases were virological breakthrough group and 104 cases poor response group. There were 67 cases (31.9%) of resistance mutations in the two groups, including 38 cases (18.1%) of rt A181V / T mutation, 7 cases of rt N236T mutation (3.3%), rt A181V / T + Example (10.5%). The detection rate of drug resistance in virological breakthrough group was significantly higher than that in poor response group (42.5% vs.21.2%; 掊2 = 10.961, P = 0.0009). The proportion of rt A181T mutation in the virologic breakthrough group was lower than that in the poor response group (28.9% vs.59.1%; 掊 2 = 5.676, P = 0.017). Virulence breakthrough group lamivudine (LAM) ADV with ADV treatment of patients with ADV mutation resistance was significantly higher than the newly diagnosed patients (56.5% vs.31.7%; P = 0.010). In the poor response group, the mutation rate of resistant gene in LAM treated with ADV was also significantly higher than that in patients with untreated ADV (31.3% vs. 12.5%, P = 0.020). Conclusions ADV genotype resistance was detected in 31.9% of patients with ADV failure. For those with poor response of ≥48 weeks in ADV treatment, drug resistance testing should be considered as appropriate even if no virological breakthrough occurred.