基线HBV血清标志物联合评分对核苷(酸)类似物抗病毒治疗慢性乙型肝炎患者HBeAg血清学转换的预测价值

王扬; 廖昊; 邓中平; 赵景; 卞丹丹; 任艳; 蒋莹莹; 刘霜; 陈煜; 鲁凤民; 段钟平; 郑素军

doi:10.3969/j.issn.1001-5256.2023.05.011

基线HBV血清标志物联合评分对核苷(酸)类似物抗病毒治疗慢性乙型肝炎患者HBeAg血清学转换的预测价值

DOI: 10.3969/j.issn.1001-5256.2023.05.011

王扬¹,
廖昊²,
邓中平^{3, 4},
赵景¹,
卞丹丹⁵,
任艳¹,
蒋莹莹¹,
刘霜¹,
陈煜¹,
鲁凤民⁶,
段钟平¹,
郑素军^1, , ,

1.
首都医科大学附属北京佑安医院肝病中心，北京 100069
2.
国家感染性疾病临床研究中心，南方科技大学第二附属医院(深圳市第三人民医院) 检验医学部，广州深圳 518112
3.
北京大学前沿交叉学科研究院，北京 100871
4.
基因诊断技术湖南省重点实验室，长沙 410205
5.
首都医科大学电力教学医院感染性疾病科，北京 100073
6.
北京大学基础医学院病原生物学系暨感染病中心，北京 100191

基金项目:

国家科技重大专项“艾滋病和病毒性肝炎等重大传染病防治” (2017ZX10302201-004);

国家科技重大专项“艾滋病和病毒性肝炎等重大传染病防治” (2017ZX10202203-006);

国家科技重大专项“艾滋病和病毒性肝炎等重大传染病防治” (2017ZX10201201);

国家科技重大专项“艾滋病和病毒性肝炎等重大传染病防治” (2017ZX10203201-005)

伦理学声明：本研究方案于2019年5月20日经由首都医科大学附属北京佑安医院伦理委员会审批，批号：LL2018-003K。

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：王扬负责整理、统计数据并撰写稿件；廖昊、邓中平给予试验平台及负责试验操作；赵景、卞丹丹、任艳、蒋莹莹负责临床数据及血清样本的收集和整理；刘霜、陈煜负责管理项目实施；鲁凤民、段钟平、郑素军负责课题设计，严格审阅及修订稿件并最后定稿。

详细信息

通信作者:
郑素军，zhengsujun@ccmu.edu.cn (ORCID: 0000-0002-6367-5764)

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出版历程
- 收稿日期: 2022-09-23
- 录用日期: 2022-12-22
- 出版日期: 2023-05-20

Value of combined baseline serum HBV markers in predicting HBeAg seroconversion in chronic hepatitis B patients treated by nucleos(t)ide analogues

1.
Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
2.
Department of Clinical Laboratory, Shenzhen Third People's Hospital & The Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, Guangdong 518112, China
3.
Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
4.
Hunan Key Laboratory of Gene Diagnostic Technology, Changsha 410205, China
5.
Department of Infectious Diseases, Electric Power Teaching Hospital, Capital Medical University, Beijing 100073, China
6.
Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China

Research funding:

National Science and Technology Key Project on "Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Prevention and Treatment" (2017ZX10302201-004);

National Science and Technology Key Project on "Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Prevention and Treatment" (2017ZX10202203-006);

National Science and Technology Key Project on "Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Prevention and Treatment" (2017ZX10201201);

National Science and Technology Key Project on "Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Prevention and Treatment" (2017ZX10203201-005)

More Information

Corresponding author: ZHENG Sujun, zhengsujun@ccmu.edu.cn (ORCID: 0000-0002-6367-5764)

摘要

摘要: 目的评估基线血清指标HBV DNA、HBV RNA、HBsAg和HBcrAg联合对HBeAg阳性慢性乙型肝炎患者(CHB)核苷(酸)类似物治疗过程中HBeAg血清学转换的预测能力。方法以2007年6月—2008年7月首都医科大学附属北京佑安医院疑难肝病及人工肝中心组建的CHB前瞻性随访队列中83例HBeAg阳性患者为研究对象，回顾性分析基线血清HBV DNA、HBV RNA、HBsAg和HBcrAg水平。计量资料两组间比较采用成组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Spearman法进行相关性分析。构建Cox回归模型并计算HBeAg转换预测评分，时间依赖性受试者工作特征曲线评估病毒学标志物联合对HBeAg血清学转换的预测能力。不同组别累积转换率的计算使用Kaplan-Meier分析，差异比较采用Log-rank检验。结果 83例HBeAg阳性患者中位随访108个月，其中44.58%(37/83)的患者发生HBeAg血清学转换。HBeAg转换组患者基线血清HBV DNA[6.23(1.99~9.28) log₁₀IU/mL vs 7.69(2.05~8.96) log₁₀IU/mL，Z=-2.345，P=0.019]和HBV RNA[4.81(1.40~7.53) log₁₀拷贝/mL vs 6.22(2.00~8.49) log₁₀拷贝/mL，Z=-1.702，P=0.010]水平显著低于未转换组；HBsAg和HBcrAg水平两组间比较，差异均无统计意义(P值均＞0.05)。基于以上血清标志物构建Cox回归方程，计算联合预测HBeAg血清学转换评分中位数为0.95(范围0.37~3.45)。在总体患者中，联合评分与HBsAg、HBV DNA、HBV RNA和HBcrAg呈负相关，相关系数分别为-0.697、-0.787、-0.990和-0.819(P值均＜0.001)。基于联合预测评分中位值，将患者分为高HBeAg转换组和低HBeAg转换组，预测36个月、60个月及84个月时HBeAg血清学转换率，高HBeAg转换组分别为43.90%、51.20%和63.10%，低HBeAg转换组分别为9.60%、17.00%和19.80%，两组间差异有统计学意义(χ²=11.6，P＜0.001)。结论基于基线血清HBV标志物构建的联合预测评分可以预测CHB患者核苷(酸)类似物治疗过程中HBeAg的血清学转换。
- 乙型肝炎, 慢性 /
- 核苷类 /
- 核苷酸类 /
- 生物标记 /
- 乙型肝炎e抗原 /
- 血清转换
Abstract: Objective To investigate the ability of combined baseline serum markers, i.e., HBV DNA, HBV RNA, HBsAg, and HBcrAg, to predict HBeAg seroconversion in patients with HBeAg-positive chronic hepatitis B (CHB) treated by nucleos(t)ide analogues. Methods A retrospective analysis was performed for 83 HBeAg-positive patients selected as subjects from the prospective CHB follow-up cohort established by Difficult & Complicated Liver Diseases and Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, from June 2007 to July 2008, and the baseline serum levels of HBV DNA, HBV RNA, HBsAg, and HBcrAg were analyzed. The 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. The Spearman method was used for correlation analysis. A Cox regression model was established to calculate HBeAg seroconversion prediction score, and the time-dependent receiver operating characteristic curve was used to evaluate the ability of combined markers in predicting HBeAg seroconversion. The Kaplan-Meier method was used to calculate cumulative seroconversion rate in each group, and the Log-rank test was used for comparison between groups. Results For the 83 HBeAg-positive patients, the median follow-up time was 108 months, and 44.58%(37/83) of these patients achieved HBeAg seroconversion. Compared with the non-seroconversion group, the HBeAg seroconversion group had significantly lower baseline serum levels of HBV DNA [6.23(1.99-9.28) log₁₀IU/mL vs 7.69(2.05-8.96) log₁₀IU/mL, Z=-2.345, P=0.019] and HBV RNA [4.81(1.40-7.53) log₁₀copies/mL vs 6.22(2.00-8.49) log₁₀copies/mL, Z=-1.702, P=0.010], and there were no significant differences in the levels of HBsAg and HBcrAg between the two groups (P > 0.05). The Cox regression equation constructed based on the above serum markers showed a median score of 0.95(range 0.37-3.45) for predicting HBeAg seroconversion. In the total population, the combined score was negatively correlated with HBsAg, HBV DNA, HBV RNA, and HBcrAg (r=-0.697, -0.787, -0.990, and -0.819, all P < 0.001). Based on the median prediction score, the patients were divided into high HBeAg seroconversion group and low HBeAg seroconversion group; as for the prediction of HBeAg seroconversion rate at 36, 60, and 84 months, the high HBeAg seroconversion group had a seroconversion rate of 43.90%, 51.20%, and 63.10%, respectively, while the low HBeAg seroconversion group had a seroconversion rate of 9.60%, 17.00%, and 19.8%, respectively, and there was a significant difference between the two groups (χ²=11.6, P < 0.001). Conclusion The combined prediction score based on baseline serum HBV markers can predict HBeAg seroconversion in CHB patients treated by nucleos(t)ide analogues.
- Hepatitis B, Chronic /
- Nucleosides /
- Nucleotides /
- Biomarkers /
- Hepatitis B e Antigens /
- Seroconversion

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表 1 患者基线临床特征

Table 1. The baseline characteristics of patients

指标	总数(n=83)	HBeAg转换组(n=37)	HBeAg未转换组(n=46)	统计值	P值
年龄(岁)	36.42±9.78	37.84±10.51	35.28±9.12	t=-1.186	0.239
男性[例(%)]	68(81.93)	28(75.68)	40(86.96)	χ²=1.762	0.184
ETV/ADV治疗(例)	46/37	18/19	28/18	χ²=1.240	0.266
初治/LAM经治(例)	36/47	16/21	20/26	χ²＜0.001	0.983
BMI(kg/m²)	23.89±3.71	24.24±3.18	23.61±4.10	t=-0.765	0.446
ALT(U/L)	68.50(12.60~681.90)	69.50(14.90~681.90)	68.00(112.60~520.10)	Z=-0.050	0.960
AST(U/L)	44.00(10.90~358.80)	46.00(10.90~358.80)	41.55(12.90~249.30)	Z=-0.366	0.714
AST/ALT	0.66(0.25~2.32)	0.78(0.25~1.48)	0.74(0.26~2.32)	Z=-0.788	0.431
TBil(μmol/L)	15.00(6.70~59.40)	15.90(6.70~36.40)	14.70(7.90~59.40)	Z=-0.316	0.752
ALP(U/L)	88.15(45.00~412.20)	87.45(46.90~252.90)	88.50(45.00~412.20)	Z=-0.229	0.819
HBsAg(log₁₀IU/mL)	3.77(-0.07~4.95)	3.48(2.15~4.74)	4.00(-0.07~4.95)	Z=-1.162	0.098
HBV DNA(log₁₀IU/mL)	6.79(1.99~9.28)	6.23(1.99~9.28)	7.69(2.05~8.96)	Z=-2.345	0.019
HBV RNA(log₁₀拷贝/mL)	5.45(1.40~8.49)	4.81(1.40~7.53)	6.22(2.00~8.49)	Z=-1.702	0.010
HBcrAg(log₁₀U/mL)	7.15±1.12	6.75±1.25	7.71±0.96	t=1.981	0.054
注：ETV，恩替卡韦；ADV，阿德福韦酯；LAM，拉米夫定。

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表 2 基线病毒学标志物联合预测36、60和84个月HBeAg血清学转换的时间依赖性AUC分析

Table 2. The time-dependent area under the curve analysis of combined indicator for HBeAg seroconversion at month 36, 60 and 84

时间点	AUC(95%CI)	cut-off值	敏感度	特异度	阳性预测值	阴性预测值
36个月	0.86(0.74~0.99)	1.17	0.86	0.70	0.40	0.95
60个月	0.79(0.64~0.94)	1.09	0.82	0.71	0.52	0.91
84个月	0.84(0.70~0.98)	0.82	0.93	0.63	0.59	0.94

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