阿德福韦酯联合拉米夫定治疗慢性乙型肝炎病毒耐药分析

Drug resistance analysis of chronic hepatitis B patients after adefovir dipivoxil combined lamivudine treatment

目的通过研究乙型肝炎患者乙型肝炎病毒(HBV)基因型的分布特点及耐药位点的分布,了解拉米夫定联合阿德福韦酯治疗慢性HBV耐药情况的发生,以探讨其临床意义。方法选取在我院门诊和住院部就诊的曾经单用过拉米夫定或阿德福韦酯治疗失败的患者,再次使用拉米夫定联合阿德福韦酯治疗2年以上的慢性乙型肝炎患者73例,应用实时荧光聚合酶链式反应(PCR)方法检测HBV DNA分型情况,用连接酶检测反应(LDR)方法检测位点变异情况。结果 73例中14例未能检测出基因型,基因型检出率80.8%(59/73);其余59例标本检测到了基因型,其中B型11例(18.6%)、C型43例(72.9%)、非B非C型5例(8.5%)。治疗1年的59例标本中有9例患者检测到了耐药位点,耐药发生率为15.3%,其中B基因型中检出2例(18.2%),C基因型中检出7例(16.3%),非B非C型基因型中未检出;各基因型中变异位点的检出率差异无统计学意义(χ2=1.286,P>0.05)。治疗2年的59例患者中有24例患者检测到了耐药位点,耐药发生率40.7%,其中B基因型中检出4例(36.4%),C基因型中检出18例(41.9%),非B非C型基因型中检出2例(3.3%);各基因型中变异位点的检出率差异亦无统计学意义(χ2=6.578,P>0.05)。治疗2年后在24例耐药患者中发生相关阿德福韦酯耐药率33.3%(8/24),发生相关拉米夫定耐药率58.3%(14/24),发生联合耐药率8.3%(2/24)。结论兰州地区HBV基因型主要以C基因型分布为主,其次是B型,还有其他基因型存在;不同基因型耐药发生概率相近,突变概率与基因型无关。对单用拉米夫定或阿德福韦酯治疗失败后的患者再次使用两者联合治疗,亦有较高的耐药风险。

Objective To investigate the distribution of hepatitis B virus genotypes and its drug resistance sites, and explore the occurrence of drug resistance after lamivudine combined with adefovir dipivoxil treatment for chronic hepatitis B and its clinical significance. Methods 73 cases of hepatitis B patients in our hospital outpatient and inpatient department who failed in lamivudine or adefovir dipivoxil treatment alone,were recruited and then they were treated by lamivudine combined with adefovir dipivoxil for more than two years. HBV genotypes were detected by real-time quantitative PCR,and mutation sites were detected by ligase detection reaction（LDR）. Results 14 cases of 73 patients genotypes were failed to detect, the classification rate was 80.8% （59/73）; in the other 59 cases, genotypes were detected. Genotype B 11 cases（18.6%）,genotype C 43 cases（72.9%）,no B no C genotype 5 cases（8.5%）. 9 of 59 cases were detected the mutation sites after one year＇s treatment. The mutation ratio was 15.3 %, genotype B 2 cases （18.2%） ,genotype C 7 cases （16.3%）,no eases were found in no B no C genotype,the difference had no statistical significance（x^2 = 1. 286, P 〉0.05）. 24 cases were detected the mutation sites after two years＇ treatment,the mutation ratio was 40.7% ,genotype B were 4 eases （36.4%） ,genotype C were 18 cases （41.9%） ,genotype no B no C were 2 eases （3.3%）,the difference also had no statistical significance （x^2 =6. 578, P 〉0.05）. 24 cases were found drug resistance after two years＇ treatment, adefovir dipivoxil resistance drug resistance ratio was 33.3 % （8/24）, lamivudine resistance ratio was 58.3% （14/24）, adefovir dipivoxil combined lamivudine resistance ratio was 8.3% （2/24）. Conclusion The most frequent HBV genotype distribution in Lanzhou area is type C,genotype 13 is followed,the other genotypes are rare. The drug resistent ratios in different genotypes were nearly, the mutation ratio is not associated with genotypes. The treatment lamivudine combined with adefovir dipivoxil for those failure for lamivudine or adefovir dipivoxil alone patients also have high risk in drug resistance.