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

doi:10.3969/j.issn.1672-5069.2016.01.010

摘要/Abstract

摘要： 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。

关键词: 慢性乙型肝炎, 替诺福韦, 病毒耐药, 挽救治疗

Abstract: Objective To evaluate the efficacy and safety of tenofovir disoproxil fummte （TDF） monotherapy or in combination with entecavir（ETV） for relapsed chronic hepatitis B patients with nucleos（t）ide resistance. Methods Eleven 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. Results All 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 or other adverse events observed during treatment. Conclusion TDF 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

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[J]. 实用肝脏病杂志, 2016, 19(1): 37-40.

Zhu Dongmei, Ye Chunyan, Qian Meiyun, Xu Tianmin, LiuLonggen. Efficacy of 48-week tenofovir rescue therapy for relapsed chronic hepatitis B patients with nucleos(t)ide resistance[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2016, 19(1): 37-40.

参考文献

[1] 参加慢性乙型肝炎长期治疗讨论会专家. 核苷和核苷酸类药物治疗慢性乙型肝炎的长期性. 实用肝脏病杂志,2015,18（1）：1-7.
[2] Deng L,Tang H. Hepatitis B virus drug resistance to current nucleos（t）ide analogs:Mechanisms and mutation sites. Hepatol Res,2011,41（11）:1017-1024.
[3] 常静霞,汪茂荣. 乙型肝炎病毒基因耐药变异研究进展. 实用肝脏病杂志,2013,16（5）：467-470.
[4] 中华医学会肝病学分会和感染病学分会.慢性乙型肝炎防治指南（2010年版）. 实用肝脏病杂志,2011,14（2）：81-89.
[5] Lee CI,Kwon SY,Kim JH,et al. Efficacy and safety of tenofovir-based rescue therapy for chronic hepatitis B patients with previous nucleo（s/t）ide treatment failure. Gut Liver,2014,8（1）:64-69.
[6] Kim YJ,Sinn DH,Gwak GY,et al. Tenofovir rescue therapy for chronic hepatitis B patients after multiple treatment failures.World J Gastroenterol,2012,18（47）:6996-7002.
[7] Lim YS,Byun KS,Yoo BC,et al. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure:results of a randomised trial.Gut,2015,Epub ahead of print.
[8] 黄明星,李新华,吴元凯,等. 替诺福韦单独与联合其他核苷类似物治疗慢性乙型肝炎患者72周疗效比较.中山大学学报,2014,35（4）：250-254.
[9] Liu Y,Zhang Y,Yuan J,et al. Efficacy of tenofovir disoproxil fumarate therapy in Chinese chronic hepatitis B patients after multiple antiviral failures. Hepatol Res,2014,Epub ahead of print.
[10] van Bmmel F,de Man RA,Wedemeyer H,et al. Long-term efficacy of tenofovir monotherapy for hepatitis B virus-monoinfected patients after failure of nucleoside/nucleotide analogues.Hepatology,2010,51（1）:73-80.
[11] Patterson SJ,George J,Strasser SI,et al. Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B.Gut,2011, 60（2）:247-254.
[12] 庄辉,翁心华. 核苷和核苷酸类药物治疗慢性乙型肝炎的耐药及其管理. 中华肝脏病杂志,2013,21（1）:15-22.
[13] Duarte-Rojo A,Heathcote EJ. Efficacy and safety of tenofovir disoproxil fumarate in patients with chronic hepatitis B. Therap Adv Gastroenterol,2010,3（2）:107-119.
[14] 杨丹红,赵年丰,潘红英,等. 替诺福韦酯挽救治疗核苷（酸）类药物多重耐药慢性乙型肝炎. 中华肝脏病杂志,2015,23（1）：75-76.
[15] Yip B,Chaung K,Wong CR,et al. Tenofovir monotherapy and tenofovir plus entecavir combination as rescue therapy for entecavir partial responders. Dig Dis Sci,2012,57（11）:3011-3016.
[16] Qi X,Xiong S,Yang H,et al. In vitro susceptibility of adefovir-associated hepatitis B virus polymerase mutations to other antiviral agents. Antivir Ther,2007,12（3）:355-362.
[17] Jafari A,Khalili H,Dashti-Khavidaki S. Tenofovir-induced nephrotoxicity:incidence,mechanism,risk factors,prognosis and proposed agents for prevention. Eur J Clin Pharmacol,2014,70（9）:1029-1040.
[18] Hall AM. Update on tenofovir toxicity in the kidney.Pediatr Nephrol,2013,28（7）:1011-1123.