慢性乙型肝炎病毒感染者阿德福韦酯诱导耐药突变与预存耐药突变的比较分析

Comparative Analysis on Induced Resistance Mutations and Pre-existing Resistance Mutations Related to Adefovir Dipivoxil in Patients with Chronic Hepatitis B Virus Infection

目的:对比分析慢性乙型肝炎病毒(HBV)感染者阿德福韦酯(ADV)诱导耐药突变与预存耐药突变的临床及分子生物学特点。方法:ADV耐药突变的慢性HBV感染者88例,采用基因测序的方法对患者的血清标本进行P区耐药基因测序,同时检测HBV基因型、HBV血清学标志物及HBV-DNA。结果:88例中,发现ADV预存耐药突变9例(10.23%),其中部分患者(4/9,44.44%)曾接受过不规范的抗病毒治疗;诱导耐药组中以rtA181T突变及单个位点突变为主(41/79,51.9%;61/79,77.22%)、完全突变株40例、突变株与野生株共存39例,而预存耐药组以rtN238T突变、多位点突变以及突变株与野生株共存为主;诱导耐药组的HBV-DNA为(5.15±1.23)log10拷贝/mL,预存耐药组为(6.45±0.97)log10拷贝/mL(t=-3.05,P=0.003);诱导耐药组中终末期肝病患者占40.51%(32/79),而预存耐药组均为终末期肝病患者(P=0.001);两组在性别、年龄、E抗原状态及HBV基因型构成方面比较差异无统计学意义(P>0.05)。结论:在未经ADV抗病毒治疗的慢性HBV感染者中可能存在ADV预存耐药突变;诱导耐药的准种变异经过筛选后变得较单一,而预存耐药的准种变异较复杂;终末期肝病患者中可能存在各种抗病毒药物的预存耐药突变;发生ADV诱导突变后的HBV-DNA复制水平常较低;患者应该接受和执行规范的抗病毒治疗和优化治疗,以实现预防耐药,避免挽救治疗。

Objective：To explore the molecular epidemiological and clinical characteristics of induced resistancem utations and pre-existing resistance mutations related to adefovir dipivoxil（ADV） in patients with chronic hepatit is B virus（HBV） infection.Methods：The data of 88 chronic HBV-infected patients with resistance mutationsr elated to ADV from June 2008 to August 2010 were retrospectively analyzed.The gene resistance mutations ofH BV P region were analyzed by gene sequencing,and the HBV genotypes,HBV serum markers,and HBV DNAl evels were also analyzed.Results：There were 9 patients with pre-existing resistance mutations in 88 patients（10.23%） and 4 out of 9（44.44%） had ill-formed usage of antiviral drugs except ADV.Patients in induced mutat ion group mostly had rtA181T mutation and single mutated site（41/79,51.9%;61/79,77.22%）;40 patients had comp lete mutation and 39 had mutation co-existence with wild strain.Patients with pre-existing mutations mostlyh ad rtN238T mutation at multiple sites（5/9,55.56%） and co-existence mutations（8/9,88.89%） .The levels of HBVD NA were 5.15±1.23 log10 copies/ml in the induced mutation group and 6.45±0.97 log10 copies/ml in thep re-existing mutation group（t=-3.05,P=0.003） .There were 32 patients（32/79,40.51%） with end-stage liver dise ases in the induced mutation group compared with all patients（9/9,100%） in the pre-existing mutation group（P=0.001） .No statistically significant differences was noted in constituent ratio of age,sex,HBeAg and HBV genotypesb etween the 2 groups（P0.05） .Conclusion：There may be some patients with pre-existing resistance mutationsr elated to ADV in ADV treatment-naive patients.The HBV quasispecy mutations became unified after selectiono f ADV,whereas they were complex in the pre-existing mutation group.The pre-existing mutations related to nuc leos（t） ide analogues maybe exist in patients with end-stage liver diseases.The levels of HBV DNA are alwaysl ower when patients have induced resistance mutation related to ADV.It is important for patients to accept andt o execute normative usage of antiviral drugs and optimal treatment to reach the aim for preventing resistancea nd avoiding salvage therapy.