治疗基线乙型肝炎病毒BCP区和PC区变异对拉米夫定耐药预测的探讨

Hepatitis B virus basal core promoter and precore mutations and lamivudine resistance in the treatment of chronic hepatitis B

目的探讨慢性乙型肝炎患者治疗基线乙型肝炎病毒(HBV)BCP区和PC区基因变异对拉米夫定耐药的影响。方法收集接受拉米夫定(100mg/片)初治2年内耐药的26例(耐药组)和2年内无耐药的16例(对照组)慢性乙型肝炎患者治疗基线的血清标本,采用型特异性多引物对巢式PCR法检测HBV基因型,用PCR产物直接测序技术检测治疗基线HBV的BCP区、PC区和P区变异位点,对发生频率较高的两组位点变异进行统计学分析。结果两组病人无1例发生P区rt204/180变异;在HBV BCP/PC区突变中,耐药组与对照组在点突变A1762T(38.48%vs 68.75%,P>0.05)、G1764A(26.92%vs50.00%,P>0.05)和G1896A(19.23%vs 18.75%,P>0.05)差异无统计学意义;对照组在点突变C1799G(43.75%vs 0,P<0.05)、T1802C(18.75%vs 0,P<0.05)、G1838A(25.00%vs 0,P<0.05)、A1846C(37.50%vs 0,P<0.05)、C1856T(31.25%vs 0,P<0.05)、G1888A(25.00%vs 0,P<0.05)明显高于耐药组。结论治疗基线HBV BCP区的A1762T/G1764A变异和PC区的G1896A变异对拉米夫定的2年疗效影响不大;治疗基线HBV BCP区的C1799G、T1802C、G1838A、A1846C的变异和PC区的C1856T、G1888A的变异可能是接受拉米夫定初始治疗获得长期维持应答的预测因素之一。

Objective To study the relationship of basal core promoter（BCP） and precore mutations of hepatitis B virus（HBV）and the lamivudine resistance during the baseline treatment of chronic hepatitis B（CHB）.Methods Twenty-six CHB cases resistant to lamivudine（resistant group） and 16 cases without resistance（sensitive group） were included.HBV genotypes were determined by nested PCR using multi-pair primers.Mutations in polymerase,basal core promoter and precore were analyzed by direct sequencing of PCR products.Results No rt204/180 mutation was detected in all samples.Frequent point mutations of the HBV BCP/Pre-C regions were found in the sensitive group at positions C1799G（43.75%）,T1802C（18.75%）,G1838A（25.00%）,A1846C（37.50%）,C1856T（31.25%） and G1888A（25.00%） while there were no mutations at these points in the resistant group（P0.05）.Although there were no significant differences（P0.05）,the following point mutations were higher in the resistant group than in the sensitive group：A1762T-（38.48% vs 68.75%）,G1764A（26.92% vs 50.00%） and G1896A（19.23% vs 18.75%）.ConclusionsPoint mutations of the HBV BCP/Pre-C regions at positions C1799G,T1802C,G1838A,A1846C,C1856T and G1888A may serve as predictors for long-term lamivudine treatment.