恩替卡韦对rtA181V/T突变的慢性乙型肝炎患者的抗病毒效果观察

李淑芹; 周静; 高远; 马晓燕; 汪莉萍

doi:10.3969/j.issn.1001-5256.2021.05.016

恩替卡韦对rtA181V/T突变的慢性乙型肝炎患者的抗病毒效果观察

DOI: 10.3969/j.issn.1001-5256.2021.05.016

徐州医科大学附属医院感染性疾病科，江苏徐州 221002

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：李淑芹负责课题设计，资料分析，撰写论文；周静、高远、马晓燕参与收集数据，修改论文；汪莉萍负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

作者简介:
李淑芹(1994—)，女，主要从事病毒性肝炎诊断及治疗方面的研究

通信作者:
汪莉萍，163wangliping@163.com

中图分类号: R512.62
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出版历程
- 收稿日期: 2020-10-14
- 录用日期: 2020-11-20
- 出版日期: 2021-05-20

Antiviral effect of entecavir in chronic hepatitis B patients with rtA181V/T mutation

Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China

摘要

摘要: 目的探讨慢型乙型肝炎(CHB)患者发生rtA181V/T突变时，恩替卡韦(ETV)挽救治疗的临床效果。方法选取2012年1月—2017年1月就诊于徐州医科大学附属医院门诊及住院部，进行逆转录聚合酶区(RT) 基因耐药变异检测的CHB患者174例，其中初治者72例，发生病毒学突破或应答不佳者的经治者102例。比较经治CHB患者既往核苷(酸)类似物(NAs)用药史与变异模式(含有rtA181V/T)的关系。共纳入155例患者，其中无耐药变异患者72例，rtA181V/T变异组45例，rtA181V/T+rtN236T变异组38例。比较3组患者在基线时及ETV挽救治疗24周和48周的病毒学应答、生化学指标。符合正态分布的计量资料2组间比较采用t检验，多组间比较采用单因素方差分析; 非正态分布计量资料多组间比较采用Kruskal-Wallis H检验。计数资料2组间比较采用χ²检验。采用logistic回归分析筛选影响预后不良的相关因素。结果分析所有入组患者的NAs用药史及变异模式，结果提示应用多种NAs用药史的患者，易出现多位点突变和多重耐药(χ²=4.295，P＜0.05)。rtA181V/T变异组和rtA181V/T+rtN236T变异组在发生病毒学突破时其HBV DNA水平较初始服用NAs时低[(6.22±1.48) log₁₀ IU/ml vs (7.08±1.59)log₁₀ IU/ml，t=3.098，P=0.002；(5.94±1.45)log₁₀ IU/ml vs (6.94±1.61)log₁₀ IU/ml，t=2.850，P=0.004]。ETV挽救治疗48周时，3组在HBV DNA阴转率(分别为83.3%、82.2%、81.6%)和HBeAg阴转率(分别为22.2%、17.8%、21.1%)方面差异均无统计学意义(P值均＞0.05)；其ALT复常率(分别为77.1%、85.2%、83.3%)、AST复常率(分别为80.4%、75.9%、76.0%)、TBil复常率(分别为80.8%、79.3%、78.1%)差异亦均无统计学意义(P值均＞0.05)。ETV起始治疗时HBV DNA水平是48周抗病毒治疗效果的影响因素(OR=1.655，95%CI：1.128~2.428，P=0.01)。结论 ETV对发生rtA181位点耐药的经治CHB患者具有良好的抗病毒效果，同时启用ETV治疗时HBV DNA水平可以预测其挽救治疗48周的效果。
- 乙型肝炎, 慢性 /
- 恩替卡韦 /
- 突变 /
- 治疗学
Abstract: Objective To investigate the clinical effect of entecavir (ETV) rescue treatment in chronic hepatitis B (CHB) patients at the onset of rtA181V/T mutation. Methods A total of 174 CHB patients who were treated in the outpatient and inpatient departments of The Affiliated Hospital of Xuzhou Medical University from January 2012 to January 2017 and underwent the detection of drug-resistance mutations of the genes in the reverse transcription (RT) polymerase region were enrolled, among whom there were 72 previously untreated patients and 102 treatment-experienced patients with virological breakthrough or poor response. The association between the previous medication history of nucleos(t)ide analogues and the mutation pattern (including rtA181V/T) was evaluated in the treatment-experienced CHB patients. A total of 155 patients were enrolled, among whom 72 patients had no drug-resistance mutations, 45 had rtA181V/T mutation, and 38 had rtA181V/T+rtN236T mutation. The three groups were compared in terms of virologic response and biochemical parameters at baseline and at weeks 24 and 48 of ETV rescue treatment. The t-test was used for comparison of normally distributed continuous data between two groups, and a one-way analysis of variance was used for comparison between multiple groups; the Kruskal-Wallis H test was used for comparison between multiple groups. The chi-square test was used for comparison of categorical data between two groups. A logistic regression analysis was used to screen out the influencing factors for poor prognosis. Results A analysis of the previous medication history of NAs and the mutation patterns for all patients suggested that the patients with the medication history of multiple NAs tended to have multisite mutations and multi-drug resistance (χ²=4.295, P < 0.05). The level of HBV DNA at the time of virological breakthrough was lower than that at the time of initial administration of NAs in the rtA181V/T mutation group [(6.22±1.48) log₁₀ IU/ml vs (7.08±1.59) log₁₀ IU/ml, t=3.098, P=0.002] and the rtA181V/T+rtN236T mutation group [(5.94±1.45) log₁₀ IU/ml vs (6.94±1.61) log₁₀ IU/ml, t=2.850, P=0.004]. At week 48 of ETV rescue treatment, there were no significant differences between the three groups in HBV DNA negative conversion rate (83.3% vs 82.2% vs 81.6%, P > 0.05) and HBeAg negative conversion rate (22.2% vs 17.8% vs 21.1%, P > 0.05), and there were also no significant differences in alanine aminotransferase normalization rate (77.1% vs 85.2% vs 83.3%, P > 0.05), aspartate aminotransferase normalization rate (80.4% vs 75.9% vs 76.0%, P > 0.05), and total bilirubin normalization rate (80.8% vs 79.3% vs 78.1%, P > 0.05). HBV DNA level at the beginning of ETV treatment was the risk factor for the treatment outcome of 48-week antiviral therapy (odds ratio = 1.655, 95% confidence interval: 1.128-2.428, P=0.01). Conclusion ETV has a good antiviral effect in treatment-experienced CHB patients with rtA181 drug-resistance mutation, and HBV DNA level at the initiation of ETV treatment can predict the outcome of 48-week ETV rescue treatment.
- Hepatitis B, Chronic /
- Entecavir /
- Mutation /
- Therapeutics

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表 1 ETV挽救治疗时3组患者相关基线特征

指标	A组(n=72)	B组(n=45)	C组(n=38)	统计值	P值
男/女(例)	47/25	28/17	20/18	χ²=1.700	0.427
年龄(岁)	47.53±9.80	46.27±9.57	47.42±9.54	F=0.257	0.773
ALT(U/L)	82.00(33.50~193.00)	87.00(33.00~353.50)	135.00(50.00~302.00)	χ²=1.255	0.534
AST(U/L)	79.50(27.25~178.00)	131.00(27.50~184.00)	110.00(29.50~205.50)	χ²=0.293	0.864
TBil(μmol/L)	42.60(18.73~75.73)	33.60(13.10~83.55)	48.25(25.00~86.15)	χ²=1.664	0.435
HBV DNA(log₁₀ IU/ml)	6.23±1.41	6.22±1.48	5.94±1.45	F=0.561	0.572
HBsAg(log₁₀ IU/ml)	3.37±0.81	3.28±0.89	3.33±1.02	F=0.163	0.849
HBeAg(log₁₀ IU/ml)	2.01±0.82	2.06±0.92	1.98±1.09	F=0.097	0.908
初始NAs前HBV DNA(log₁₀ IU/ml)		7.08±1.59	6.94±1.61	t=0.412	0.682

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表 2 102例慢性HBV感染者既往用药情况及耐药变异模式

用药情况	例数	变异模式	例数
LAM单药	3	rtA181T	1
		rtA181T+rtA181V	1
		rtA181T+rtL180M	1
ADV单药	23	rtA181T	6
		rtA181V	5
		rtA181T+rtA181V	3
		rtA181T+rtN236T	3
		rtA181V+rtN236T	4
		rtA181T+rtA181V+rtN236T	2
LAM单药，出现疗效不佳或病毒学突破后	34	rtA181T	6
序贯/联合ADV		rtA181V	3
		rtA181T+rtA181V	4
		rtA181T+rtN236T	4
		rtA181V+rtN236T	6
		rtA181T+rtA181V+rtN236T	3
		rtA181T+rtV173L+rtL180M	1
		rtA181T+rtS202I+rtL180M	1
		rtA181T+rtV207V+rtL180M	1
		rtA181T+rtM204V+rtV173L	1
		rtA181T+rtN236T+rtM204V/I+rtL180M	2
		rtA181T+rtM204V+rtL180M+rtV173L	2
ADV单药，出现疗效不佳或病毒学突破后	30	rtA181T	7
序贯/联合LAM/LdT		rtA181V	2
		rtA181T+rtA181V	2
		rtA181T+rtN236T	7
		rtA181V+rtN236T	2
		rtA181T+rtA181V+rtN236T	3
		rtA181T+rtM204V+rtL180M	1
		rtA181V+rtM204I+rtV173L	1
		rtA181V+rtM204V+rtL180M	1
		rtA181T+rtN236T+rtM204I+rtL180M	1
		rtA181T+rtM204V+rtL180M+rtV173L	3
LAM停药复发，再治疗给予LdT+ADV	6	rtA181T	2
		rtA181T+rtA181V	1
		rtA181V+rtN236T	1
		rtA181T+rtA181V+rtN236T	1
		rtA181T+rtM204V+rtL180M	1
LAM单药耐药后停药，再治疗给予LdT	2	rtA181T+rtM204V/I+rtL180M+rtV173L	1
		rtA181T+rtN236T+rtM204I+rtL180M	1
依次给予LAM、ADV、LdT和LAM+ADV	4	rtA181T	2
		rtA181V+rtN236T	1
		rtA181T+rtN236T	1

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表 3 ETV挽救治疗24周及48周后病毒学反应及生化学反应

组别	例数	HBV DNA阴转率[例(%)]		HBeAg阴转率[例(%)]		ALT复常率[例(%)]		AST复常率[例(%)]		TBil复常率[例(%)]
组别	例数	24周	48周	24周	48周	24周	48周	24周	48周	24周	48周
A组	72	50(69.4)	60(83.3)	3(4.2)	16(22.2)	34(70.8)	37(77.1)	34(73.9)	37(80.4)	37(71.2)	42(80.8)
B组	45	31(68.9)	37(82.2)	1(2.2)	8(17.8)	20(74.1)	23(85.2)	20(69.0)	22(75.9)	21(72.4)	23(79.3)
C组	38	28(73.7)	31(81.6)	2(5.3)	8(21.1)	22(73.3)	25(83.3)	17(68.0)	19(76.0)	24(75.0)	25(78.1)
χ²值		0.277	0.059	0.544	0.339	0.110	0.890	0.357	0.294	0.148	0.088
P值		0.871	0.971	0.762	0.844	0.947	0.641	0.836	0.863	0.929	0.957

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表 4 ETV挽救治疗期间病毒学反应预测的单因素分析

因素	OR	95%CI	P值
性别	1.625	0.662~3.990	0.289
年龄	0.985	0.943~1.028	0.485
ALT	1.002	1.000~1.003	0.138
AST	1.003	0.999~1.007	0.101
TBil	1.007	0.998~1.016	0.123
HBV DNA	1.869	1.318~2.652	＜0.001
HBsAg	1.424	0.881~2.301	0.149
HBeAg	1.708	1.050~2.776	0.031

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参考文献(26)

[1]	OTT JJ, STEVENS GA, GROEGER J, et al. Global epidemiology of hepatitis B virus infection: New estimates of age-specific HBsAg seroprevalence and endemicity[J]. Vaccine, 2012, 30(12): 2212-2219. DOI: 10.1016/j.vaccine.2011.12.116.
[2]	ILOEJE UH, YANG HI, SU J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load[J]. Gastroenterology, 2006, 130(3): 678-686. DOI: 10.1053/j.gastro.2005.11.016.
[3]	KIM GA, LIM YS, HAN S, et al. High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B[J]. Gut, 2018, 67(5): 945-952. DOI: 10.1136/gutjnl-2017-314904.
[4]	WANG H, GUO ZG. Study on HBV pre-C region A1896 gene mutation and clinical drug[J]. J Changchun Univ Chin Med, 2019, 35(1): 144-146. DOI: 10.13463/j.cnki.cczyy.2019.01.042. 王涵, 郭志钢. HBV前C区A1896基因突变的探讨及临床用药研究[J]. 长春中医药大学学报, 2019, 35(1): 144-146. DOI: 10.13463/j.cnki.cczyy.2019.01.042.
[5]	Expert Committee on Hepatitis B Virus Resistance. Expert consensus on hepatitis B virus resistance[J/CD]. Chin J Exp Clin Infect Dis(Electronic Edition), 2008, 2(1): 90-98. DOI: 10.3969/j.issn.1674-1358.2008.01.018. 乙型肝炎病毒耐药专家委员会. 乙型肝炎病毒耐药专家共识[J/CD]. 中华实验和临床感染病杂志(电子版), 2008, 2(1): 90-98. DOI: 10.3969/j.issn.1674-1358.2008.01.018.
[6]	ZOULIM F, LOCARNINI S. Management of treatment failure in chronic hepatitis B[J]. J Hepatol, 2012, 56 Suppl 1: s112-s122. DOI: 10.1016/S0168-8278(12)60012-9.
[7]	YEON JE, YOO W, HONG SP, et al. Resistance to adefovir dipivoxil in lamivudine resistant chronic hepatitis B patients treated with adefovir dipivoxil[J]. Gut, 2006, 55(10): 1488-1495. DOI: 10.1136/gut.2005.077099.
[8]	WARNER N, LOCARNINI S. The antiviral drug selected hepatitis B virus rtA181T/sW172^* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound[J]. Hepatology, 2008, 48(1): 88-98. DOI: 10.1002/hep.22295.
[9]	LIU Y, MILLER MD, KITRINOS KM. HBV clinical isolates expressing adefovir resistance mutations show similar tenofovir susceptibilities across genotypes B, C and D[J]. Liver Int, 2014, 34(7): 1025-1032. DOI: 10.1111/liv.12343.
[10]	European Association For The Study Of The Liver. EASL olinical practice guidelines: Management of chronic hepatitis B[J]. J Hepatol, 2009, 50(2): 227-242. DOI: 10.1016/j.jhep.2008.10.001.
[11]	Chinese Medical Association Infectious Diseases Branch, Chinese Medical Association Hepatology Branch. Guidelines for the prevention and treatment of chronic hepatitis B (version 2019)[J]. J Clin Hepatol, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007. 中华医学会感染病学分会, 中华医学会肝病学分会. 慢性乙型肝炎防治指南(2019年版)[J]. 临床肝胆病杂志, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007.
[12]	Chinese Medical Association Infectious Diseases Branch, Chinese Medical Association Hepatology Branch. Guidelines for the prevention and treatment of chronic hepatitis B (version 2015)[J]. J Clin Hepatol, 2015, 31(12): 1941-1960. DOI: 10.3969/j.issn.1001-5256.2015.12.002. 中华医学会肝病学分会, 中华医学会感染病学分会. 慢性乙型肝炎防治指南(2015年更新版)[J]. 临床肝胆病杂志, 2015, 31(12): 1941-1960. DOI: 10.3969/j.issn.1001-5256.2015.12.002.
[13]	YEH CT, CHIEN RN, CHU CM, et al. Clearance of the original hepatitis B virus YMDD-motif mutants with emergence of distinct lamivudine-resistant mutants during prolonged lamivudine therapy[J]. Hepatology, 2000, 31(6): 1318-1326. DOI: 10.1053/jhep.2000.7296.
[14]	VILLET S, PICHOUD C, BILLIOUD G, et al. Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure[J]. J Hepatol, 2008, 48(5): 747-755. DOI: 10.1016/j.jhep.2008.01.027.
[15]	SUN MS, WANG GQ, ZHANG W, et al. The current status of lamivudine-treated patients with chronic hepatitis B[J]. Chin Prevent Med, 2012, 13(1): 18-22. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-ZGYC201201006.htm 孙秘书, 王贵强, 张伟, 等. 拉米夫定经治慢性乙型肝炎患者治疗现状调查分析[J]. 中国预防医学杂志, 2012, 13(1): 18-22. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGYC201201006.htm
[16]	GAI HP, SUN WX, YUAN DS, et al. The clinical implications of pre-existing drug resistance to nucleo(t)ide analogues-based antiviral therapy[J]. J Clin Hepatol, 2012, 28(11): 841-844. http://lcgdbzz.org/article/id/LCGD201211017 盖洪鹏, 孙伟翔, 袁德胜, 等. 预存耐药对核苷(酸)类似物抗病毒治疗应答和耐药的影响[J]. 临床肝胆病杂志, 2012, 28(11): 841-844. http://lcgdbzz.org/article/id/LCGD201211017
[17]	AHN SH, PARK YK, PARK ES, et al. The impact of the hepatitis B virus polymerase rtA181T mutation on replication and drug resistance is potentially affected by overlapping changes in surface gene[J]. J Virol, 2014, 88(12): 6805-6818. DOI: 10.1128/JVI.00635-14.
[18]	JI FZ, WANG L, YANG BH, et al. Clinical characteristics and effect of secondary individualized therapy in chronic hepatitis B patients infected with rtA181 mutation hepatitis B virus[J]. Chin J Hepatol, 2012, 20(4): 280-284. DOI: 10.3760/cma.j.issn.1007-3418.2012.04.011. 姬粉芝, 王磊, 杨保华, 等. rtA181位点突变乙型肝炎病毒感染患者的临床特点及个体化再治疗效果[J]. 中华肝脏病杂志, 2012, 20(4): 280-284. DOI: 10.3760/cma.j.issn.1007-3418.2012.04.011.
[19]	CHANG TT, LIAW YF, WU SS, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B[J]. Hepatology, 2010, 52(3): 886-893. DOI: 10.1002/hep.23785.
[20]	HAN DG, WU SF. Efficacy comparison of entecavir alone and combined with adefovir dipivoxil in the treatment of patients with rtA181V/T mutation hepatitis B[J]. J Pract Med, 2018, 34(16): 2811-2812, 2815. DOI: 10.3969/j.issn.1006-5725.2018.16.044. 韩登高, 吴韶飞. 恩替卡韦单用与联合阿德福韦酯治疗rtA181V/T突变乙肝患者的疗效对比[J]. 实用医学杂志, 2018, 34(16): 2811-2812, 2815. DOI: 10.3969/j.issn.1006-5725.2018.16.044.
[21]	LUO J, LI X, WU Y, et al. Efficacy of entecavir treatment for up to 5 years in nucleos(t)ide-naïve chronic hepatitis B patients in real life[J]. Int J Med Sci, 2013, 10(4): 427-433. DOI: 10.7150/ijms.5472.
[22]	LU T, LI CZ. Rescue therapy of tenofovir disoproxil fumarate in hepatitis B patients with nucleoside/nucleotide analogue resistant[J]. J Prac Hepatol, 2016, 19(3): 369-372. DOI: 10.3969/j.issn.1672-5069.2016.03.032.
[23]	LIM YS, YOO BC, BYUN KS, et al. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: Results of a randomised trial[J]. Gut, 2016, 65(6): 1042-1051. DOI: 10.1136/gutjnl-2014-308435.
[24]	BERG T, MARCELLIN P, ZOULIM F, et al. Tenofovir is effective alone or with emtricitabine in adefovir-treated patients with chronic-hepatitis B virus infection[J]. Gastroenterology, 2010, 139(4): 1207-1217. DOI: 10.1053/j.gastro.2010.06.053.
[25]	FUNG S, KWAN P, FABRI M, et al. Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B[J]. Gastroenterology, 2014, 146(4): 980-988. DOI: 10.1053/j.gastro.2013.12.028.
[26]	LI P, GENG J, LI W, et al. Antiviral efficacy of entecavir for hepatitis B virus rtA181V/T mutants[J]. Virol J, 2017, 14(1): 68. DOI: 10.1186/s12985-017-0739-z.