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目的1例拉米夫定耐药患者在接受恩替卡韦治疗过程中出现恩替卡韦耐药相关性变异,继续治疗后恩替卡韦耐药株自动消失,并发生HBeAg血清学转换,对该例患者HBV耐药株的动态变化进行了动态观察。方法收集该患者的系列血清标本及血清HBV DNA、转氨酶等系列临床数据,采用血清HBV DNA的PCR扩增与直接测序,限制性片段长度多态性(PCR-RFLP)分析,RT序列的克隆与测序等方法,检测HBV耐药株的比例及动态变化。结果该患者在应用恩替卡韦治疗前就已经存在拉米夫定耐药株(rtL180M+rtM204V),在恩替卡韦治疗后拉米夫定耐药株一度被抑制,随着治疗时间的延长,拉米夫定耐药株的比例又占主导地位。在此基础上,于恩替卡韦治疗第128周,选择出恩替卡韦耐药株(rtL180M+rtM204V+rtT184L),临床上伴随有ALT和HBV DNA水平的反弹。该例患者在发生恩替卡韦耐药后继续接受恩替卡韦治疗,恩替卡韦耐药株自行消失,HBV DNA转阴(套式PCR方法),ALT复常,并出现HBeAg血清学转换。结论恩替卡韦可有效地治疗拉米夫定耐药慢性乙型肝炎患者,但长期单药治疗可出现恩替卡韦耐药;在出现恩替卡韦耐药后,继续应用恩替卡韦仍然有效,甚至可发生HBeAg血清学转换和HBV DNA的清除。在恩替卡韦治疗过程中,在出现恩替卡韦变异株之前,可能需要先出现拉米夫定耐药株,在此基础上再选择出恩替卡韦耐药株。
Objective One case of lamivudine-resistant patients experienced entecavir resistance-related mutations during entecavir treatment. Entecavir resistant isolates disappeared automatically and HBeAg seroconversion occurred after continued treatment. The HBV-resistant strains of this patient Dynamic changes were observed dynamically. Methods Serum HBV DNA, aminotransferase and other clinical data were collected and analyzed by PCR amplification, direct sequencing, restriction fragment length polymorphism (PCR-RFLP) and RT-PCR Sequencing and other methods to detect the proportion of HBV resistant strains and dynamic changes. Results The patient had already had lamivudine resistant strain (rtL180M + rtM204V) before entecavir treatment. Lamivudine resistant strain was inhibited once after entecavir treatment. With the prolongation of treatment time, lamivudine The proportion of resistant strains also dominates. On this basis, entecavir resistant strains (rtL180M + rtM204V + rtT184L) were selected for the 128th week of entecavir treatment and were clinically associated with a rebound of ALT and HBV DNA levels. The patient continued entecavir therapy after entecavir resistance, entecavir resistant isolates disappeared, HBV DNA negative (nested PCR method), ALT normal, and HBeAg seroconversion. Conclusions Entecavir is effective in treating patients with lamivudine-resistant chronic hepatitis B, but entecavir is resistant to long-term monotherapy; continued entecavir therapy remains effective after entecavir resistance and even HBeAg seroconversion Elimination of HBV DNA. During the treatment of entecavir, lamivudine-resistant strains may need to be present prior to the emergence of entecavir mutants, on the basis of which entecavir resistant strains will be selected.