朱冬梅，叶春艳，钱梅云，徐天敏，柳龙根

替诺福韦挽救治疗耐药复发的慢性乙型肝炎患者48周疗效初探

朱冬梅，叶春艳，钱梅云，徐天敏，柳龙根

目的观察替诺福韦（TDF）单药或联合恩替卡韦（ETV）挽救治疗耐药复发的慢性乙型肝炎患者的疗效及安全性。方法回顾性分析11例耐药复发的慢性乙型肝炎患者的挽救治疗，其中6例患者单用TDF，5例患者采用TDF联合ETV。采用时间分辨免疫荧光法检测血清乙型肝炎病毒标志物，采用脱氧核糖核酸测序法检测与耐药相关的HBV P区169、173、180、181、184、202、204、233、236、250位耐药变异，采用PCR-荧光探针法检测血清HBV DNA载量，采用苦味酸法检测血清肌酐（Cr）水平。应用Kaplan-Meier分析血清HBV DNA累积不可检出率。结果挽救治疗前，1例患者检测到ADV基因型耐药，7例患者检测到LAM/ETV基因型耐药，3例患者检测到LAM/ETV/ADA基因型耐药；HBV DNA基线水平为（4.82±1.29）lg IU/ml，挽救治疗第4周降至（3.57±0.55）lg IU/ml，第12周降至（2.91±0.37）lg IU/ml，随访至第48周，仅1例患者可检测出HBV DNA。挽救治疗4、12、24和36周，血清HBV DNA累积不可检出率分别为36.4%（4/11）、63.6%（7/11）、81.8%（9/11）和90.9%（10/11）；随访结束时，血清ALT水平由（64.36±34.55）U/L降至（37.7±24.49）U/L；治疗期间未发生肾功能异常或其他不良事件。结论TDF单药或联合ETV挽救治疗耐药复发的慢性乙型肝炎患者仍能较快速地抑制病毒复制，具有良好的疗效和安全性。

慢性乙型肝炎；替诺福韦；病毒耐药；挽救治疗

【Abstract】ObjectiveToevaluatetheefficacyandsafetyoftenofovirdisoproxilfummte（TDF）monotherapy or in combination with entecavir（ETV）for relapsed chronic hepatitis B patients with nucleos（t）ide resistance.MethodsEleven chronic hepatitis B patients with nucleos（t）ide resistance were treated with TDF. Out of them，six patients were treated with TDF monotherapy and five patients were treated with TDF in combination with ETV.The serum HBV DNA，ALT and serum creatinine（Cr）levels were detected at weeks 4，12，24，36 and 48 since the rescue treatment started.Cumulative probability of serum HBV DNA undetectable rate during the treatment period was calculated by using the Kaplan-Meier method.ResultsAll patients at presentation had nucleos（t）ide resistance mutations，including one patient with ADV-related mutations，seven patients with LAM/ETV-resistant mutations，and three patients with LAM/ETV/ADA-resistant mutations;After rescue therapy，serum HBV DNA level decreased from（4.82±1.29）lg IU/mL at onset to（3.57±0.55）lg IU/mL and to（2.91±0.37）lg IU/mL at 4 and 12 weeks，respectively；At 48 weeks of rescue treatment，serum HBV DNA was detectable in only one of 11 patients；Serum HBV DNA became undetectable in 36.4%（4/11），63.6%（7/11），81.8%（9/11）and 90.9%（10/11）of patients at 4，12，24 and 36 weeks of rescue treatment，respectively；Serum ALT levels decreased from（64.36±34.55）U/L at onset to（37.7±24.49）U/L at the end of follow-up；There were no renal dysfunction orotheradverse eventsobserved during treatment.ConclusionTDF monotherapy or in combination with ETV is effective in reducing serum HBV DNA levels and is safe for CHB patients with nucleos（t）ide resistance.

【Key words】Chronic hepatitis B；Nucleos（t）ide resistance；Tenofovir；Rescue therapy

有研究认为，替诺福韦酯（Tenofovir disoproxil fumarate，TDF）对既往一种或多种核苷（酸）类（NAs）抗病毒治疗不应答者仍有较好的疗效[1~7]，但应用其治疗耐药复发患者的研究仍较少。我们回顾性分析了我院11例因出现耐药复发而应用TDF或TDF联合恩替卡韦（ETV）挽救治疗的慢性乙型肝炎患者，现将结果报告如下。……