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目的探讨慢性乙型肝炎患者发生拉米夫定耐药常见的模式及耐药后体内免疫环境的改变。方法应用PCR及基因测序方法回顾性分析72例发生拉米夫定耐药患者血清HBVDNA多聚酶区基因变异模式,比较72例患者拉米夫定抗病毒6个月时及耐药后血清INF-γ、IL-2、IL-4因子水平与对照组细胞因子的水平差异。结果拉米夫定耐药4种主要的突变模式分别为:单位点rtM204I突变,占34.7%(25/72);rtL180M+rtM204V,占30.56%(22/72);rtL180M+rtM204I,占16.67%(12/72);rtV173L+rtV180M+rtM204V,占12.5%(9/72);抗病毒6个月时,未变异组与对照组IL-2(P=0.20)、IFN-γ(P=0.14)、IL-4(P=0.119)水平差异无统计学意义。耐药组HBVDNA发生病毒变异后,IL-2、IFN-γ水平显著低于对照组(P<0.01),而IL-4水平则高于对照组(P<0.01),差异有统计学意义。结论慢性乙型肝炎应用拉米夫定抗病毒治疗耐药模式主要是rtM204I突变及rtL180M、rtV173L、rtM204V、rtM204I联合变异,发生耐药后慢性乙型肝炎患者体内免疫环境将从Th1优势应答转换为Th2优势应答。
Objective To investigate the common patterns of lamivudine resistance in patients with chronic hepatitis B and the changes of immune environment in vivo after drug resistance. Methods 72 cases of lamivudine-resistant patients were retrospectively analyzed by polymerase chain reaction and gene sequencing methods. The 72-h lamivudine-resistant virus was detected at 6 months and the serum INF-γ , IL-2, IL-4 and cytokines levels in control group. Results The four major mutation patterns of lamivudine resistance were as follows: single point rtM204I mutation, accounting for 34.7% (25/72); rtL180M + rtM204V, accounting for 30.56% (22/72); rtL180M + rtM204I, accounting for 16.67% (P = 0.14), IFN-γ (P = 0.14) in the non-mutation group and the control group (P = 0.14) ), IL-4 (P = 0.119) no significant difference between the levels. The level of IL-2 and IFN-γ in HBVDNA group was significantly lower than that in control group (P <0.01), while the level of IL-4 was higher in control group (P <0.01). The difference was statistically significant. Conclusion The drug resistance of chronic hepatitis B patients treated with lamivudine is mainly rtM204I mutation and rtL180M, rtV173L, rtM204V and rtM204I combined mutation. The immune environment in chronic hepatitis B patients will change from Th1 predominant response to Th2 dominant response.