长期恩替卡韦经治慢性乙型肝炎患者低病毒血症的相关影响因素

陈贺; 傅涓涓; 李丽; 杨广德; 潘修成

doi:10.3969/j.issn.1001-5256.2021.03.011

长期恩替卡韦经治慢性乙型肝炎患者低病毒血症的相关影响因素

DOI: 10.3969/j.issn.1001-5256.2021.03.011

徐州医科大学附属医院感染性疾病科，江苏徐州 221002

基金项目:

十三五艾滋病和病毒性肝炎等重大传染病防治项目 (2018ZX10302206-001-003)

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，特此声明。

作者贡献声明：陈贺负责课题设计，资料分析，拟定写作思路，撰写论文；傅涓涓、李丽、杨广德参与收集数据；潘修成指导撰写文章并最后定稿。

详细信息

作者简介:
陈贺(1993—)，男，主要从事病毒性肝炎诊治方面的研究

通信作者:
潘修成，xzpxc68@126.com

中图分类号: R512.62
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出版历程
- 收稿日期: 2020-09-12
- 录用日期: 2020-10-06
- 出版日期: 2021-03-20

Influencing factors for low-level viremia in chronic hepatitis B patients treated with long-term entecavir antiviral therapy

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

摘要

摘要: 目的探讨长期接受恩替卡韦治疗的慢性乙型肝炎(CHB)患者仍维持低水平病毒复制的相关影响因素。方法选取2018年11月—2020年6月于徐州医科大学附属医院门诊接受恩替卡韦抗病毒治疗至少1年的CHB患者，根据至观察期结束患者HBV DNA载量分为低病毒血症(LLV)组和持续病毒学应答(SVR)组。观察患者人口学特征参数和实验室检测指标。计量资料两组间比较采用独立样本t检验或Mann-Whitney U检验；计数资料两组间比较采用χ²检验。采用多因素logistic回归分析长期恩替卡韦经治患者出现LLV的影响因素。结果共纳入560例CHB患者，其中LLV组204例，SVR组356例。两组患者比较，年龄(Z=-3.530，P＜0.001)、性别(χ²=4.270，P=0.039)、是否存在肝硬化(χ²=53.879，P＜0.001)、服药依从性(χ²=5.326，P=0.021)、HBeAg阳性率(χ² =90.681，P＜0.001)、治疗前基线HBV DNA载量(Z=-8.337，P＜0.001)、基线HBsAg定量(Z=-10.472，P＜0.001)以及用药类型(χ²=7.558，P=0.006)差异均有统计学意义。多因素logistic回归分析显示，治疗前基线HBeAg状态(OR=3.381，95%CI：1.985~5.756，P＜0.001)、HBV DNA载量(OR=1.223，95%CI：1.050~1.424，P=0.010)和HBsAg定量(OR=2.448，95%CI：1.743~3.438，P＜0.001)是长期恩替卡韦抗病毒治疗出现LLV的危险因素。结论在临床实践中，基线高载量HBV DNA水平、高HBsAg定量和HBeAg阳性的CHB患者即使长期坚持服用恩替卡韦抗病毒治疗，也存在较高的LLV风险。因此，对于此类人群应予以重视，需动态监测HBsAg定量、HBV DNA载量、HBeAg状态。
- 乙型肝炎, 慢性 /
- 低病毒血症 /
- 恩替卡韦 /
- 危险因素
Abstract: Objective To investigate the influencing factors for persistent low-level viremia (LLV) in chronic hepatitis B(CHB) patients receiving long-term entecavir antiviral therapy. Methods The CHB patients who received entecavir antiviral therapy for at least one year in The Affiliated Hospital of Xuzhou Medical University from November 2018 to June 2020 were enrolled as subjects, and according to HBV DNA load at the end of the observation period, the patients were divided into LLV group and sustained virological response (SVR) group. Demographic features and laboratory markers were observed for all patients. The independent samples t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. A multivariate logistic regression analysis was used to investigate the influencing factors for LLV in patients receiving long-term entecavir treatment. Results A total of 560 CHB patients were enrolled, with 204 in the LLV group and 356 in the SVR group. There were significant differences between the two groups in age (Z=-3.530, P < 0.001), sex (χ²=4.270, P=0.039), presence or absence of liver cirrhosis (χ²=53.879, P < 0.001), medication compliance (χ²=5.326, P=0.021), HBeAg positive rate (χ²=90.681, P < 0.001), baseline HBV DNA load before treatment (Z=-8.337, P < 0.001), baseline HBsAg quantification (Z=-10.472, P < 0.001), and medication type (χ²=7.558, P=0.006). The multivariate logistic regression analysis showed that baseline HBeAg status before treatment (odds ratio [OR]=3.381, 95% confidence interval [CI]: 1.985-5.756, P < 0.001), HBV DNA load before treatment (OR=1.223, 95%CI: 1.050-1.424, P=0.010), and HBsAg quantification before treatment (OR=2.448, 95%CI: 1.743-3.438, P < 0.001) were risk factors for LLV in long-term entecavir antiviral therapy. Conclusion In clinical practice, CHB patients with high HBV DNA load, high HBsAg quantification, and positive HBeAg tend to have a high risk of LLV even after long-term entecavir antiviral therapy. Therefore, such population should be taken seriously with the dynamic monitoring of HBsAg quantification, HBV DNA load, and HBeAg status.
- Hepatitis B, Chronic /
- Low-Level Viremia /
- Entecavir /
- Risk Factors

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表 1 纳入CHB患者基线资料

指标	所有患者 (n=560)	SVR组 (n=356)	LLV组 (n=204)	统计值	P值
年龄(岁)	45(36~52)	47(37~53)	42(33~48)	Z=-3.530	＜0.001
男性[例(%)]	399(71.3)	243(68.3)	156(76.5)	χ²=4.270	0.039
BMI(kg/m²)	23.95±3.37	23.87±3.39	24.10±3.35	t=-0.797	0.426
肝硬化[例(%)]	231(41.3)	188(52.8)	43(21.1)	χ²=53.879	＜0.001
家族史[例(%)]	213(38.0)	128(36.0)	85(41.7)	χ²=1.795	0.180
良好服药依从性[例(%)]	507(90.5)	330(92.7)	177(86.8)	χ²=5.326	0.021
糖尿病[例(%)]	28(5.0)	18(5.1)	10(4.9)	χ²=0.006	0.936
HBeAg阳性[例(%)]	350(62.5)	170(47.8)	180(88.2)	χ²=90.681	＜0.001
HBV DNA(log₁₀ IU/ml)	6.17(5.01~7.41)	5.75(4.39~6.97)	7.08(6.00~7.87)	Z=-8.337	＜0.001
HBsAg(log₁₀ IU/ml)	3.47(2.99~3.92)	3.21(2.76~3.69)	3.90(3.37~4.44)	Z=-10.472	＜0.001
AST(U/L)	56.00(36.00~89.75)	56.00(35.00~92.50)	56.00(38.25~88.75)	Z=-0.274	0.784
ALT(U/L)	73.00(45.00~123.75)	68.50(43.00~128.85)	78.00(48.25~117.50)	Z=-0.691	0.489
用药类型[例(%)]				χ²=7.558	0.006
恩替卡韦初治	517(92.3)	337(94.7)	180(88.2)
转换至恩替卡韦	43(7.7)	19(5.3)	24(11.8)

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表 2 恩替卡韦经治CHB患者低病毒血症的多因素logistic回归分析

变量	B值	SE	Wald	OR	95%CI	P值
年龄	-0.001	0.010	0.003	0.999	0.981~1.019	0.957
男性	0.376	0.236	2.527	1.456	0.916~2.314	0.112
肝硬化	-0.469	0.250	3.503	0.626	0.383~1.022	0.061
良好的依从性	-0.504	0.352	2.048	0.604	0.303~1.205	0.152
HBeAg阳性	1.218	0.272	20.122	3.381	1.985~5.756	＜0.001
HBV DNA	0.201	0.078	6.719	1.223	1.050~1.424	0.010
HBsAg	0.895	0.173	26.695	2.448	1.743~3.438	＜0.001
用药类型	0.390	0.379	1.061	1.478	0.703~3.107	0.303

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参考文献(18)

[1]	Chinese Society of Infectious Diseases, Chinese Medical Association; Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the prevention and treatment of chronic hepatitis B (version 2019)[J]. J Clin Hepatol, 2019, 35(12): 2648-2669. (in Chinese) 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
[2]	TERRAULT NA, LOK A, MCMAHON BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance[J]. Hepatology, 2018, 67(4): 1560-1599. DOI: 10.1002/hep.29800
[3]	European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection[J]. J Hepatol, 2017, 67(2): 370-398. DOI: 10.1016/j.jhep.2017.03.021
[4]	OGAWA E, NOMURA H, NAKAMUTA M, et al. Tenofovir alafenamide after switching from entecavir or nucleos(t)ide combination therapy for patients with chronic hepatitis B[J]. Liver Int, 2020, 40(7): 1578-1589. DOI: 10.1111/liv.14482
[5]	KIM JH, SINN DH, KANG W, et al. Low-level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment[J]. Hepatology, 2017, 66(2): 335-343. DOI: 10.1002/hep.28916
[6]	LU JH, YANG L, ZHAO ZX, et al. Comparative study of high-sensitivity and ordinary fluorescence quantitative PCR in monitoring antiviral efficacy of patients with chronic hepatitis B[J]. J Mol Diagn Ther, 2019, 11(5): 361-364. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-YXYQ201905004.htm 卢建华, 杨莉, 赵召霞, 等. 高敏与普通荧光定量PCR技术在慢乙肝患者抗病毒疗效监测中的对比研究[J]. 分子诊断与治疗杂志, 2019, 11(5): 361-364. https://www.cnki.com.cn/Article/CJFDTOTAL-YXYQ201905004.htm
[7]	KIM HJ, CHO YK, JEON WK, et al. Clinical characteristics of patients with chronic hepatitis B who developed genotypic resistance to entecavir: Real-life experience[J]. Clin Mol Hepatol, 2017, 23(4): 323-330. DOI: 10.3350/cmh.2017.0005
[8]	HUANG YJ, YANG SS, YEH HZ, et al. Association of virological breakthrough and clinical outcomes in entecavir-treated HBeAg-positive chronic hepatitis B[J]. PLoS One, 2019, 14(8): e0221958. DOI: 10.1371/journal.pone.0221958
[9]	SUN Y, WU X, ZHOU J, et al. Persistent low level of hepatitis B virus promotes fibrosis progression during therapy[J]. Clin Gastroenterol Hepatol, 2020, 18(11): 2582-2591. DOI: 10.1016/j.cgh.2020.03.001
[10]	SHIN JW, JUNG SW, LEE SB, et al. Medication nonadherence increases hepatocellular carcinoma, cirrhotic complications, and mortality in chronic hepatitis B patients treated with entecavir[J]. Am J Gastroenterol, 2018, 113(7): 998-1008. DOI: 10.1038/s41395-018-0093-9
[11]	LIN L, LIU JY, DENG H, et al. Influencing factors of partial virological response to entecavir monotherapy of patients with chronic hepatitis B[J/CD]. Chin J Liver Dis (Electronic Version), 2019, 11(4): 81-84. (in Chinese) 林丽, 刘俊英, 邓慧, 等. 恩替卡韦单药治疗慢性乙型肝炎患者部分病毒学应答的影响因素[J/CD]. 中国肝脏病杂志(电子版), 2019, 11(4): 81-84.
[12]	GORDON SC, KRASTEV Z, HORBAN A, et al. Efficacy of tenofovir disoproxil fumarate at 240 weeks in patients with chronic hepatitis B with high baseline viral load[J]. Hepatology, 2013, 58(2): 505-513. DOI: 10.1002/hep.26277
[13]	QIU Q, YU HY, PAN J, et al. Antiviral efficacy of entecavir for the treatment of chronic hepatitis B[J]. J Southeast Univ (Med Sci Edi), 2010, 29(6): 685-688. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-NJTD201006025.htm 裘强, 俞海英, 潘剑, 等. 恩替卡韦治疗慢性乙型肝炎疗效观察[J]. 东南大学学报(医学版), 2010, 29(6): 685-688. https://www.cnki.com.cn/Article/CJFDTOTAL-NJTD201006025.htm
[14]	HE LF, LONG YS, ZHANG HY. Correlation study between hepatitis B virus DNA replication level and HBeAg and HBsAg[J]. Clin Med Eng, 2020, 27(1): 65-66. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-YBQJ202001033.htm 何龙芳, 龙云升, 张海业. 乙型肝炎病毒DNA复制水平与HBeAg、HBsAg的相关性研究[J]. 临床医学工程, 2020, 27(1): 65-66. https://www.cnki.com.cn/Article/CJFDTOTAL-YBQJ202001033.htm
[15]	LEE JM, AHN SH, KIM HS, et al. Quantitative hepatitis B surface antigen and hepatitis B e antigen titers in prediction of treatment response to entecavir[J]. Hepatology, 2011, 53(5): 1486-1493. DOI: 10.1002/hep.24221
[16]	CHANG ML, CHIEN RN, YEH CT, et al. Virus and transaminase levels determine the emergence of drug resistance during long-term lamivudine therapy in chronic hepatitis B[J]. J Hepatol, 2005, 43(1): 72-77. DOI: 10.1016/j.jhep.2005.02.021
[17]	ZHANG N. The clinical significance of HBsAg quantitative level in HBeAg-negative patients with chronic HBV infection[D]. Yan'an: Yan'an University, 2020. (in Chinese) 张楠. HBsAg定量水平在HBeAg阴性慢性HBV感染者中的临床意义[D]. 延安: 延安大学, 2020.
[18]	SONG JC, MIN BY, KIM JW, et al. Pretreatment serum HBsAg-to-HBV DNA ratio predicts a virologic response to entecavir in chronic hepatitis B[J]. Korean J Hepatol, 2011, 17(4): 268-273. DOI: 10.3350/kjhep.2011.17.4.268