恩替卡韦单药治疗慢性乙型肝炎患者5年HBsAg与HBV DNA的动态变化

吴凤萍; 李妙羡; 王怡恺; 鲁瑞; 刘怡欣; 党双锁

doi:10.3969/j.issn.1001-5256.2021.05.015

恩替卡韦单药治疗慢性乙型肝炎患者5年HBsAg与HBV DNA的动态变化

DOI: 10.3969/j.issn.1001-5256.2021.05.015

a.
西安交通大学第二附属医院感染科，西安 710004
b.
西安交通大学第二附属医院检验科，西安 710004

基金项目:

陕西省重点研发计划项目 (2020SF-297)

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

作者贡献声明：吴风萍负责课题设计，资料收集、分析，撰写论文；李妙羡参与收集资料；王怡恺、鲁瑞、刘怡欣参与收集数据，修改论文；党双锁负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

作者简介:
吴凤萍(1989—)，女，主要从事聚乙二醇干扰素α治疗慢性乙型肝炎方面的研究

通信作者:
党双锁，dang212@126.com

中图分类号: R512.62
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出版历程
- 收稿日期: 2020-10-20
- 录用日期: 2021-01-27
- 出版日期: 2021-05-20

Dynamic changes of HBsAg and hepatitis B virus DNA in chronic hepatitis B patients with entecavir monotherapy for 5 years

a.
Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
b.
Department of Clinical Laboratory, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China

摘要

摘要: 目的分析慢性乙型肝炎(CHB)患者单用恩替卡韦(ETV)治疗5年血清HBsAg和HBV DNA的动态变化。方法回顾性收集2012年1月—2020年8月就诊于西安交通大学第二附属医院的单用ETV治疗≥5年的CHB患者918例，其中初始治疗时HBeAg阳性患者556例，HBeAg阴性患者362例。收集患者在治疗基线、1年、2年、3年、4年、5年时的血清HBsAg水平和HBV DNA载量并分析其动态变化。符合正态分布的计量资料2组间比较采用t检验，不符合正态分布的计量资料2组间比较采用Mann-Whitney U检验；不符合正态分布的重复测量资料先进行log₁₀对数转换，组内或组间比较采用重复测量资料的方差分析；计数资料2组间比较采用χ²检验。结果 HBeAg阳性和HBeAg阴性患者随着ETV治疗时间的延长，HBsAg水平均呈逐渐下降趋势，组内比较差异有统计学意义(F值分别为174.168、49.845，P值均＜0.001)。HBeAg阳性患者基线HBsAg水平为18 043.1(7868.9~26 342.4)IU/ml，ETV治疗5年后降至1397.6 (626.4~3419.4) IU/ml，差异具有统计学意义(P＜0.001)；HBeAg阳性患者基线HBV DNA载量为(6.7±1.7) log₁₀ IU/ml, ETV治疗5年后HBV DNA阴转率为100%。HBeAg阴性患者的基线HBsAg水平为2420.0(662.6~5621.2)IU/ml，ETV治疗5年后降至407.2 (56.7~1104.7) IU/ml，差异具有统计学意义(P＜0.001)；HBeAg阴性患者基线HBV DNA载量为(4.9±1.4)log₁₀ IU/ml，ETV治疗5年后HBV DNA阴转率亦为100%。HBeAg阳性患者的中位HBsAg水平在各时间点上均高于HBeAg阴性患者(P值均＜0.001)。HBeAg阳性和阴性患者的HBsAg下降均呈现出“先快后慢”的趋势，ETV治疗前两年的HBsAg年均下降速率显著大于后3年(HBeAg阳性: Z=-13.605，P＜0.001; HBeAg阴性：Z=-5.950，P＜0.001)。HBeAg阳性患者除ETV治疗1年时HBV DNA阴转率显著低于HBeAg阴性患者外(χ²=71.013, P＜0.001)，其余时间点上两组患者的HBV DNA阴转率均为100%。此外，ETV治疗5年，累计HBsAg转阴、＜200 IU/ml、＜1000 IU/ml、＜1500 IU/ml的患者的比例分别为3.6%、23.9%、57.0%、67.3%。结论 ETV治疗CHB、HBsAg和HBV DNA水平逐渐下降，并且HBsAg水平的下降呈“先快后慢”的趋势。单用ETV治疗5年，67.3%的患者可以达到HBsAg＜1500 IU/ml。
- 乙型肝炎，慢性 /
- 乙型肝炎表面抗原 /
- 病毒载量 /
- 恩替卡韦
Abstract: Objective To investigate the dynamic changes of serum HBsAg and hepatitis B virus (HBV) DNA in chronic hepatitis B patients (CHB) with entecavir (ETV) monotherapy for 5 years. Methods A retrospective analysis was performed for the clinical data of 918 CHB patients who attended the Second Affiliated Hospital of Xi'an Jiaotong University from January 2012 to August 2020 and received ETV monotherapy for ≥5 years, among whom 556 had positive HBeAg and 362 had negative HBeAg at initial treatment. Serum HBsAg level and HBV DNA load at baseline and at 1, 2, 3, 4, and 5 years of treatment were collected to analyze their dynamic changes. The t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; log₁₀ logarithmic transformation was performed for non-normally distributed repeated measurement data, and then a repeated-measures analysis of variance was used for comparison between groups or within each group; the chi-square test was used for comparison of categorical data between two groups. Results Both HBeAg-positive and HBeAg-negative patients had a significant reduction in HBsAg level over the time of ETV treatment (F=174.168 and 49.845, both P < 0.001). The HBeAg-positive patients had a baseline HBsAg level of 18 043.1 (7868.9-26 342.4) IU/ml, which significantly decreased to 1397.6 (626.4-3419.4) IU/ml after 5 years of ETV treatment (P < 0.001); the HBeAg-positive patients had a baseline HBV DNA load of (6.7±1.7) log₁₀ IU/ml and achieved an HBV DNA clearance rate of 100% after 5 years of ETV treatment. The HBeAg-negative patients had a baseline HBsAg level of 2420.0 (662.6-5621.2) IU/ml, which significantly decreased to 407.2 (56.7-1104.7) IU/ml after 5 years of ETV treatment (P < 0.001); the HBeAg-negative patients had a baseline HBV DNA load of 4.9±1.4 log₁₀ IU/ml and achieved an HBV DNA clearance rate of 100% after 5 years of ETV treatment. The HBeAg-positive patients had a significantly higher median HBsAg level than the HBeAg-negative patients at each time point (all P < 0.001). Both HBeAg-positive and HBeAg-negative patients showed a changing trend of rapid reduction followed by slow reduction in HBsAg, and the mean annual rate of reduction in HBsAg in the first 2 years of ETV treatment was significantly higher than that in the last 3 years of ETV treatment (HBeAg-positive: Z=-13.605, P < 0.001; HBeAg-negative: Z=-5.950, P < 0.001). The HBeAg-positive patients had a significantly lower HBV DNA clearance rate than the HBeAg-negative patients at 1 year of ETV treatment (χ²=71.013, P < 0.001), and both HBeAg-positive and HBeAg-negative patients achieved an HBV DNA clearance rate of 100% at 2, 3, 4, and 5 years of treatment. After 5 years of ETV treatment, the cumulative proportions of patients with HBsAg clearance, HBsAg < 200 IU/ml, HBsAg < 1000 IU/ml, and HBsAg < 1500 IU/ml were 3.6%, 23.9%, 57.0%, and 67.3%, respectively. Conclusion During the EVT treatment of CHB, the levels of HBsAg and HBV DNA gradually decrease, and the level of HBsAg shows a trend of rapid reduction followed by slow reduction. After 5 years of ETV monotherapy, 67.3% of the patients can achieve an HBsAg level of < 1500 IU/ml.
- Hepatitis B, Chronic /
- Hepatitis B Surface Antigens /
- Viral Load /
- Entecavir

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图 1 HBsAg不同区段累计百分比随治疗时间的变化

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图 2 各时间点上的HBV DNA阴转率

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表 1 患者的基线特征

指标	HBeAg阳性(n=556)	HBeAg阴性(n=362)	统计值	P值
性别[例(%)]			χ²=3.330	0.073
男	384 (69.1)	229(63.5)
女	172 (30.9)	133(36.7)
年龄(岁)	38.8±11.6	42.8±10.9	t=1.302	0.308
ALT(U/L)	169.9±67.3	153.7±48.7	t=1.312	0.194
AST(U/L)	121.3±13.3	112.4±26.9	t=0.702	0.399
HBsAg(U/ml)	18 043.1(7868.9~26 342.4)	2420.0(662.6~5621.2)	Z=-12.665	＜0.001
HBV DNA定量(log₁₀ IU/ml)	6.7±1.7	4.9±1.4	t=17.583	＜0.001
治疗时间(月)	78.8(69.5~83.6)	75.5(66.3~82.7)	Z=3.665	0.032

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表 2 HBeAg阳性和阴性CHB患者ETV治疗5年血清HBsAg水平动态变化

组别	例数	基线	1年	2年	3年	4年	5年	F值	P值
HBeAg阳性	556	18 043.1 (7868.9~26 342.4)	5893.1 (2742.5~13 265.4)	3868.8 (1904.8~8377.8)	2620.6 (1387.0~6022.1)	1824.9 (923.3~4479.5)	1397.6 (626.4~3419.4)	174.168	＜0.001
HBeAg阴性	362	2420.0 (662.6~5621.2)	1244.4 (303.9~2562.5)	1038.7 (195.0~2041.9)	826.2 (122.9~1674.9)	615.7 (88.3~1420.5)	407.2 (56.7~1104.7)	49.845	＜0.001
注：各时间点组间比较，P＜0.001；组内各时间点两两比较，P＜0.001。

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表 3 不同水平基线HBsAg的HBeAg阳性患者HBsAg水平的5年动态变化

HBsAg水平	例数	基线	1年	2年	3年	4年	5年	F值	P值
＜3000 IU/ml	62	1262.1 (692.0~2251.9)	899.7 (377.7~2190.0)	708.5 (295.4~2046.3)	619.1 (190.5~1639.4)	435.9 (104.3~1290.4)	320.8 (80.3~826.4)	22.201	＜0.001
3000~10 000 IU/ml	122	6982.6 (5282.5~8385.2)	2968.2 (1890.3~3758.7)	2116.8 (1576.3~2814.3)	1787.7 (908.7~2442.9)	1410.2 (759.9~1835.6)	1025.9 (560.1~1613.8)	37.877	＜0.001
10 000~20 000 IU/ml	108	15 317.0 (12 412.7~16 385.5)	6 027.47 (3596.4~7740.7)	3947.0 (2091.0~5577.7)	2610.0 (1083.7~4371.8)	1633.3 (787.5~3917.5)	1491.7 (618.2~3081.9)	51.770	＜0.001
≥20 000 IU/ml	264	26 691.1 (25 000.0~38 816.0)	13 290.5 (7383.8~18 600.0)	8304.3 (4258.5~14 090.0)	5672.0 (2649.1~9325.9)	3929.3 (1623.4~7272.5)	2682.0 (1065.0~5402.4)	136.124	＜0.001

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表 4 不同水平基线HBsAg的HBeAg阴性患者HBsAg水平的5年动态变化

HBsAg水平	例数	基线	1年	2年	3年	4年	5年	F值	P值
＜3000 IU/ml	166	749.3 (222.4~1913.5)	363.8 (80.5~1014.1)	300.5 (49.0~955.9)	233.9 (37.0~808.7)	149.8 (29.3~632.1)	79.6 (14.3~420.5)	22.866	＜0.001
3000~10 000 IU/ml	128	5552.4 (3709.9~7075.3)	2400.0 (1690.5~3835.6)	1928.9 (1273.2~2846.1)	1483.0 (868.5~2422.4)	1126.3 (629.9~1924.7)	928.1 (411.9~1666.9)	33.684	＜0.001
10 000~20 000 IU/ml	35	13 142.5 (11 578.7~15 600.7)	6937.0 (5495.0~11 289.5)	4980.7 (4219.5~9006.2)	4410.1 (2447.4~6832.0)	3775.1 (1985.5~5372.1)	2731.9 (1682.2~4097.9)	21.129	＜0.001
≥20 000 IU/ml	33	22 190.4 (21 004.2~29 850.9)	11 390.3 (5283.5~14 280.2)	6536.4 (2933.2~9240.4)	4694.0 (2622.7~8037.3)	4236.3 (2304.2~6944.9)	2902.3 (1429.5~6030.2)	16.562	＜0.001

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表 5 不同时间点HBeAg阳性和HBeAg阴性CHB患者的HBsAg分布

HBsAg水平	1年	2年	3年	4年	5年
＜0.05 IU/ml
HBeAg阳性	1(0.2)	6(1.1)	9(1.6)	14(2.5)	19(3.4)
HBeAg阴性	0	2(0.6)	5(1.4)	8(2.2)	14(3.9)
χ²值	0	0.226	0.082	0.089	0.128
P值	1.000	0.490	0.794	0.829	0.856
＜200 IU/ml
HBeAg阳性	24(4.3)	43(7.8)	51(9.2)	71(12.8)	85(15.3)
HBeAg阴性	30(8.3)	43(11.9)	63 (17.4)	86(23.8)	134(37.1)
χ²值	6.244	4.436	13.656	18.669	56.987
P值	0.015	0.037	＜0.001	＜0.001	＜0.001
＜1000 IU/ml
HBeAg阳性	76(13.7)	102(18.3)	138(24.8)	177(31.8)	258(46.4)
HBeAg阴性	92(25.4)	143(39.5)	184(50.8)	238(65.7)	265(73.2)
χ²值	20.229	50.162	65.126	101.789	64.246
P值	＜0.001	＜0.001	＜0.001	＜0.001	＜0.001
＜1500 IU/ml
HBeAg阳性	98(17.6)	135(24.3)	196(35.3)	243(43.7)	341(61.3)
HBeAg阴性	106(29.3)	176(48.6)	233(64.4)	254(70.2)	277(76.5)
χ²值	17.234	57.977	74.650	61.829	22.990
P值	＜0.001	＜0.001	＜0.001	＜0.001	＜0.001

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