【摘要】 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。更多还原

【Abstract】 Objective Backgrounds & Aims:Entecavir-resistant strains were selected in a lamivudine-resistant hepatitis B patient during entecavir monotherapy.The entecavir-resistant strains afterward disappeared spontaneously and HBeAg seroconversion occurred while entecavir therapy continued.The evolution of the viral quasispecies of the patient was analyzed.Methods A series of blood samples and clinical data of the patient were collected.PCR-Restriction Fragment Length Polymorphism(RFLP)、clonal analysis and DNA sequencing methods were used to examine the evolution of HBV populations in serum samples.Results The patient had pre-existing lamivudine-resistant mutants(rtL180M+rtM204V)before starting entecavir therapy,and these mutants were once inhibited after entecavir therapy.Lamivudine-resistant mutants became predominant HBV population again during extended entecavir therapy over time.The entecavir-resistant strain(rtL180M+rtM204V+rtT184L)was selected 128 weeks with entecavir monotherapy,accompanied by ALT flares and virological rebounds.However,when the patient continued to receive entecavir monotherapy,the entecavir-resistant strains disappeared,with undetectable levels of HBV-DNA by nested PCR 、 ALT normalization and HBeAg seroconversion.Conclusion Entecavir is effective for the treatment of lamivudine-resistant chronic HBV patients,but increased risk of entecavir-resistance is associated with long-term entecavir monotherapy.However,continued entecavir therapy after the selection of entecavir-resistant strain may remain effective,and even HBeAg seroconversion and clearance of HBV DNA may occur.If is possible that pre-existing lamivudine-resistant mutants before the selection of entecavir-resistant strain is prerequisite for the clearance of hepatitis B virus.更多还原