早期血清前S1抗原(PreS1)对干扰素α治疗的HBeAg阳性慢性乙型肝炎儿童HBsAg阴转的预测价值

樊佩瑶; 王福川; 高银杰; 徐志强; 董漪; 闫建国; 曹丽丽; 冯丹妮; 钟彦伟; 张敏

doi:10.3969/j.issn.1001-5256.2023.08.010

早期血清前S1抗原(PreS1)对干扰素α治疗的HBeAg阳性慢性乙型肝炎儿童HBsAg阴转的预测价值

DOI: 10.3969/j.issn.1001-5256.2023.08.010

樊佩瑶^{1, 2},
王福川²,
高银杰²,
徐志强²,
董漪²,
闫建国²,
曹丽丽²,
冯丹妮²,
钟彦伟²,
张敏^{1, 2, , ,}

1.
北京大学三〇二临床医学院，北京 100191
2.
解放军总医院第五医学中心肝病学部，北京 100039

基金项目:

国家科技重大专项 (2018ZX10301404);

北京市科技计划项目 (Z201100005520048);

首都临床诊疗技术研究及转化应用项目 (Z201100005520048)

伦理学声明：本研究方案于2020年4月经由解放军总医院第五医学中心伦理委员会审批，批号：2020048D，患者监护人均签署知情同意书。

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：王福川、高银杰、徐志强、董漪、闫建国、曹丽丽和冯丹妮负责收集数据和初步统计分析；樊佩瑶负责数据统计分析和撰写初稿；张敏、钟彦伟负责课题设计，拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
张敏，gcmw2001@163.com (ORCID：0000-0003-2497-6748)

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出版历程
- 收稿日期: 2022-12-07
- 录用日期: 2023-01-16
- 出版日期: 2023-08-20

Value of serum PreS1 in early prediction of HBsAg clearance after IFN-α treatment in children with HBeAg-positive chronic hepatitis B

1.
Peking University 302 Clinical Medical School, Beijing 100191, China
2.
Department of Liver Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China

Research funding:

the National Science and Technology Major Project of the Infectious Diseases (2018ZX10301404);

Beijing Science and Technology Program (Z201100005520048);

the Capital Clinical Diagnosis and Treatment Technology Research and Translational Application Program (Z201100005520048)

More Information

Corresponding author: ZHANG Min, gcmw2001@163.com (ORCID: 0000-0003-2497-6748)

摘要

摘要: 目的探讨血清前S1抗原(PreS1)水平作为预测干扰素α(IFN-α)治疗48周的HBeAg阳性慢性乙型肝炎(CHB)儿童HBsAg转阴指标的价值。方法纳入2016年6月—2020年1月接受IFN-α治疗48周的88例1~16岁HBeAg阳性CHB患儿，每3个月评估患儿的HBsAg定量(qHBsAg)、HBV DNA定量、ALT等，并采用磁微粒化学发光免疫分析法(双抗体夹心法)检测PreS1水平。根据IFN-α治疗48周终点时HBsAg是否转阴分为转阴组(n=17)和未转阴组(n=71)。计量资料的两组间比较采用Mann-Whitney U检验，计数资料的两组间比较采用χ²检验或Fisher精确检验。用Spearman秩相关检验评估PreS1水平和其他生物标志物之间的关系。用受试者工作特征曲线下面积(AUC)评估不同标志物对IFN-α治疗48周终点HBsAg转阴的预测价值。结果 PreS1水平与血清qHBsAg、HBV DNA水平呈正相关(r值分别为0.912、0.535，P值均＜0.05)。基线时，PreS1/qHBsAg比值(AUC=0.694)较PreS1水平(AUC=0.530)和qHBsAg水平(AUC=0.514)具有较好的48周HBsAg转阴预测价值。治疗12周的PreS1水平(AUC=0.867，P＜0.001)和PreS1/qHBsAg比值下降量(AUC=0.800，P=0.002)均对48周终点时HBsAg转阴有很好的预测作用。治疗24周的PreS1水平、qHBsAg水平和HBV DNA均可有效预测第48周的HBsAg转阴，AUC分别为0.917、0.949和0.762(P值均＜0.001)。结论治疗12周时血清PreS1水平和PreS1/qHBsAg比值下降量是预测IFN-α治疗期间CHB患儿HBsAg转阴的候选标志物。
- PreS1 /
- 生物标记 /
- 乙型肝炎, 慢性 /
- 儿童 /
- 干扰素α
Abstract: Objective To investigate the value of PreS1 level in predicting HBsAg clearance in children with HBeAg-positive chronic hepatitis B (CHB) after 48 weeks of IFN-α treatment. Methods A total of 88 children with HBeAg-positive CHB, aged 1-16 years, who received 48 weeks of IFN-α treatment from June 2016 to January 2020 were enrolled. HBsAg quantification (qHBsAg), HBV DNA quantification, and alanine aminotransferase were measured every three months, and magnetic particle chemiluminescence immunoassay (double-antibody sandwich) was used to measure the level of PreS1. According to whether HBsAg clearance was achieved at the end of IFN-α treatment for 48 weeks, the 88 children were divided into HBsAg clearance group with 17 children and non-HBsAg clearance group with 71 children. The Mann-Whitney U test was used for comparison of quantitative data between the two groups, and the chi-square test or the Fisher's exact test was used for comparison of qualitative data between the two groups. The Spearman rank correlation test was used to evaluate the correlation of PreS1 level with other biomarkers, and the area under the ROC curve (AUC) was used to investigate the value of different markers in predicting HBsAg clearance at the end of 48-week IFN-α treatment. Results PreS1 level was positively correlated with the serum levels of qHBsAg and HBV DNA (r=0.912 and 0.535, both P < 0.05), and baseline PreS1/qHBsAg ratio (AUC=0.694) had a better value than PreS1 level (AUC=0.530) and qHBsAg level (AUC=0.514) in predicting HBsAg clearance at week 48. PreS1 level (AUC=0.867, P < 0.001) and the reduction in PreS1/qHBsAg ratio (AUC=0.800, P=0.002) at week 12 of treatment had a good value in predicting HBsAg clearance at week 48. PreS1 level, qHBsAg level, and HBV DNA at week 24 of treatment could effectively predict HBsAg clearance at week 48, with AUCs of 0.917, 0.949, and 0.762, respectively (all P < 0.001). Conclusion Serum PreS1 level and the reduction in PreS1/qHBsAg ratio at week 12 of treatment can be used as candidate markers for predicting HBsAg clearance in children with CHB during IFN-α treatment.
- PreS1 /
- Biomarkers /
- Hepatitis B, Chronic /
- Child /
- Interferon-alpha

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图 1 血清PreS1与qHBsAg、HBV DNA、年龄和ALT之间的相关性分析

Figure 1. Correlation between serum PreS1 levels and qHBsAg, HBV DNA, age and ALT

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图 2 基线血清PreS1水平、qHBsAg水平、PreS1/qHBsAg比值在预测48周IFN-α治疗方案后HBsAg转阴的ROC曲线

Figure 2. The ROC curve of the serum PreS1 level, the qHBsAg level and the PreS1/qHBsAg ratio at baseline for predicting HBsAg loss after the 48-week IFN-α therapy protocol

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图 3 治疗12周血清PreS1水平、PreS1/qHBsAg比值下降量在预测48周IFN-α治疗方案后HBsAg转阴的ROC曲线

Figure 3. The ROC curve of the serum PreS1 level and the decrease in PreS1/qHBsAg ratio at week 12 for predicting HBsAg loss after the 48-week IFN-α therapy protocol

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表 1 HBeAg阳性CHB患儿的基线特征

Table 1. Baseline characteristics of the pediatric patients with HBeAg-positive CHB

指标	总体(n=88)	转阴组(n=17)	未转阴组(n=71)	统计值	P值
年龄(岁)	4.62(3.13~6.56)	3.42(2.67~3.75)	5.42(3.38~8.16)	Z=-2.759	0.006
PreS1(log₁₀ ng/mL)	3.35(2.78~3.76)	3.38(2.83~3.84)	3.34(2.77~3.64)	Z=-0.386	0.700
qHBsAg(log₁₀ IU/mL)	4.19(3.73~4.52)	4.19(3.78~4.53)	4.19(3.72~4.51)	Z=-0.185	0.849
HBV DNA(log₁₀ IU/mL)	7.37(6.98~7.75)	7.53(6.68~7.81)	7.36 (7.02~7.72)	Z=-0.011	0.992
ALT(U/L)	103.50(75.25~178.75)	100.00(71.00~124.00)	111.00(76.00~199.00)	Z=-1.020	0.308
性别[例(%)]				χ²=0.547	0.459
男	56(63.6)	9(52.9)	47(66.2)
女	32(36.4)	8(47.1)	24(33.8)
HBV基因型[例(%)]				χ²=1.610	0.447
B	14(15.9)	2(11.8)	12(16.9)
C	69(78.4)	13(76.4)	56(78.9)
未检测	5(5.7)	2(11.8)	3(4.2)
炎症活动度[例(%)]					0.081
G1	20(23.5)	7(41.2)	13(19.1)
G2	57(67.1)	10(58.8)	47(69.1)
G3	8(9.4)	0	8(11.8)
纤维化程度[例(%)]				χ²=0.926	0.629
S1	48(56.4)	8(47.0)	40(58.8)
S2	27(31.8)	7(41.2)	20(29.4)
S3	10(11.8)	2(11.8)	8(11.8)

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