拉米夫定治疗前后乙型肝炎病毒YMDD变异的相关因素分析  

Identification of factors associated with YMDD mutation in patients with chronic hepatitis B receiving lamivudine treatment

作　　者：曹新鲜[1] 李佳[1] 邱隆敏[1] 罗亚文[1] 陈应华[1] 冉燕[1] 

机构地区：[1]遵义医学院附属医院感染科,563003

出　　处：《中华肝脏病杂志》2009年第9期641-644,共4页Chinese Journal of Hepatology

基　　金：贵州省卫生厅2005年度科研计划（黔卫发[2005]138号）

摘　　要：目的了解遵义地区HBV基因型以及拉米夫定治疗前后发生YMDD变异的相关因素，及早进行拉米夫定疗效及耐药的预测。方法53例慢性乙型肝炎患者分别在口服拉米夫定前及治疗后3、6、12、18、24个月进行血清HBV DNA定量、乙型肝炎标志物、ALT、AST、总胆红素、白蛋白的检测。同时在接受拉米夫定治疗前采用基因测序法检测HBV基因型及YMDD变异株，治疗后HBV DNA定量下降又反弹升高，且血清HBV DNA〉1×10^4拷贝／ml时，再次进行YMDD变异株检测。率的比较用卡方检验及确切概率法，两组均数之间比较采用独立样本t检验，有序变量之间的比较采用秩和检验。结果遵义地区的HBV基因型由B、C及B＋C基因型构成。拉米夫定治疗后18例检出YMDD变异株，用药1年和2年的变异率分别为15．1％和34．0％。HBV突变类型有rtL180M／M204V、rtL180M／M204I、rtM204I和rtL180M四种，其中C区rtM204V全部合并rtL180M突变（100％），C基因型中rtL180M／M204V联合突变及rtL180M／M204I联合突变明显高于B基因型（77．8％比25．0％及22．2％比12．5％）；C基因型中未见点突变，而rtM204I、rtL180M的点突变仅见于B基因型。YMDD变异与未变异组性别、民族、乙型肝炎家族史及HBeAg情况差异无统计学意义（P〉0．05），病程≥2年组和年龄〈35岁组变异率明显升高（x^2值分别为4．707和5．853，P值均〈0．05）。不同HBV DNA滴度患者YMDD变异率差异无统计学意义（x^2=0．801，P〉0．05），但HBV DNA〈10^5拷贝／ml者未发现YMDD变异。结论拉米夫定治疗后YMDD变异可能与HBV基因型及P基因突变类型有关，并随治疗时间的延长而增加。为了减少YMDD变异的发生，应选用病程短、HBV DNA水平较低、肝损害较重的患者进行拉米夫定治疗，有条件的应检测HBV基因型。Objective To identify factors associated with YMDD mutation in patients with chronic hepatitis B before and after lamivudine treatment in Zunyi region. Methods 53 patients with chronic hepatitis B were enrolled in this study, HBV DNA,HBV markers, ALT, AST, TBil, albumin in the serum were examined at 0, 3, 6, 12, 18 and 24 months after lamivudine treatment. HBV genotype and YMDD mutation were determined by sequencing before lamivudine treatment. YMDD mutation was checked again if serum HBV DNA rebound to more than 1 × 10^4 copies/ml after the initial decrease. Results HBV genotype in Zunyi region is constitute of B, C and B＋C genotype. YMDD mutation occurred in 18 cases after laraivudine treatment, the rate of YMDD mutation was 15.1 %, and 34.0% after 1 year and 2 years treatment. There are four types of mutation： rtL180M/M204V, rtL180M/M204I, rtM204I, rtL180M, rtM204V mutation in C gene was always acompanied by rtL180M mutation （100%）. The rate of rtL180M/M204V mutation in genotype C group was significantly higher than that in genotype B group （77.8% to 25.0%）, the same was true for the rtL180M/M204I mutation （22.2% to 12.5%）. There was no point mutation in genotype C group. The point mutation of rtM204I and rtL180M appeared only in genotype B group. Gender, nation, family history of hepatitis B and HBeAg were not associated with YMDD mutation （P 〉 0.05）, while the mutation rate was associated with the disease course and severity of disease. YMDD mutation did not occure in patients with low HBV DNA level （〈 105 copies/ml）. Conclusion YMDD mutation after lamivudine therapy is associated with HBV genotype and P gene mutation type, and prolonged treatment increases the the mutation rate. In order to reduce the incidence of YMDD mutation, patients with shorter disease course, lower HBV DNA level, more serious liver damage should be treated with lamivudine.

关 键 词：肝炎病毒 乙型 拉米夫定 基因型 YMDD变异 

分 类 号：R51[医药卫生—内科学]