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聚乙二醇干扰素α治疗非活动性HBsAg携带者血清肿瘤坏死因子α水平的变化趋势及其与HBsAg清除的关系
DOI: 10.12449/JCH250714
伦理学声明：本研究方案于2018年1月14日经由西安交通大学第二附属医院伦理委员会审批，批号：2018033，所纳入患者均签署了书面知情同意书。
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作者贡献声明：吴凤萍负责课题设计，资料收集、分析，撰写论文；何玲、王文浩参与收集临床资料；刘晨瑞参与收集血液标本、修改论文；李茹参与收集血液标本及临床资料；党双锁负责拟定写作思路，指导撰写文章并最后定稿。
Changing trend of serum tumor necrosis factor-alpha level during pegylated interferon-alpha treatment in inactive HBsAg carriers and its association with HBsAg clearance
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摘要:
目的 观察聚乙二醇干扰素α（PEG-IFN-α）治疗非活动性乙型肝炎表面抗原（HBsAg）携带者（IHC）过程中血清肿瘤坏死因子α（TNF-α）水平的变化，探索其动态变化与HBsAg清除之间的关系，并评估TNF-α作为预测PEG-IFN-α疗效的潜在生物标志物的价值。 方法 前瞻性纳入2018年1月—2023年3月就诊于西安交通大学第二附属医院的IHC患者455例，分为治疗组210例，自愿接受PEG-IFNα-2b治疗48周并随访24周；IHC对照组245例，仅随访观察72周。分别于研究的0、12、24、48、72周时检测血清TNF-α水平，并在72周时将治疗组分为HBsAg清除组与未清除组。比较各组不同时间点TNF-α水平差异。采用Logistic回归分析评估TNF-α对HBsAg清除的预测价值。正态分布的计量资料两组间比较采用t检验，多组间比较采用单因素方差分析；正态分布的重复测量资料的组内和组间比较采用重复测量数据的方差分析；计数资料组间比较采用χ²检验或Fisher确切概率法。使用单因素和多因素Logistic回归分析HBsAg清除的预测因素，使用受试者操作特征曲线（ROC曲线）确定TNF-α预测HBsAg清除的cut-off值。 结果 72周时治疗组的HBsAg清除率（46.2%）和血清学转换率（34.8%）均显著高于IHC对照组（HBsAg清除率为1.2%；HBsAg血清学转换率为0.8%）（χ2值分别为133.333、94.650，P值均<0.001）。HBsAg清除组和未清除组在治疗期间血清TNF-α水平较基线均显著升高，在停药后逐渐恢复至基线水平（F值分别为351.733、76.434，P值均<0.001）。组间比较显示，在12、24及48周时血清TNF-α水平HBsAg清除组>HBsAg未清除组>IHC对照组（P值均<0.001）。多因素Logistic回归分析显示，基线HBsAg水平（OR=0.329，95%CI：0.189～0.571，P<0.001）、基线HBV DNA<20 IU/mL（OR=1.414，95%CI：1.057～1.787，P=0.045）、12周时ALT≥2倍的正常值上限（OR=1.127，95%CI：1.028～1.722，P=0.043）、12周时TNF-α水平（OR=1.336，95%CI：1.018～1.754，P=0.037）和24周时TNF-α水平（OR=1.879，95%CI：1.477～2.391，P<0.001）是HBsAg清除的独立预测因素。ROC曲线分析显示，12周时血清TNF-α水平预测72周时HBsAg清除的ROC曲线下面积（AUC）为0.846（95%CI：0.814～0.889），敏感度和特异度分别为76.3%、81.0%；24周时AUC为0.912（95%CI：0.758～0.972），敏感度和特异度分别为81.4%、96.2%。 结论 PEG-IFN-α治疗可导致IHC血清TNF-α水平升高，且治疗12周和24周时血清TNF-α水平可有效预测PEG-IFN-α诱导的HBsAg清除。 Abstract:Objective To observe the changes in the serum level of tumor necrosis factor-α （TNF-α） during pegylated interferon-alpha （PEG-IFN-α） treatment in inactive HBsAg carriers （IHCs）， to investigate the association between the dynamic changes of TNF-α and HBsAg clearance， and to assess the value of TNF-α as a potential biomarker for predicting the therapeutic efficacy of PEG-IFN-α. Methods A prospective study was conducted among 455 IHCs who attended our hospital from January 2018 to March 2023， and they were divided into treatment group and IHC control group. The 210 IHCs in the treatment group voluntarily received PEG-IFNα-2b treatment for 48 weeks， followed by follow-up for 24 weeks， and the 245 IHCs in the IHC control group were followed up for 72 weeks without treatment. The serum level of TNF-α was measured at baseline （week 0） and at weeks 12， 24，48， and 72， and at week 72， the treatment group was further divided into HBsAg clearance group and non-clearance group. The serum level of TNF-α at different time points was compared between groups. The logistic regression analysis was used to assess the value of TNF-α in predicting HBsAg clearance. The t-test was used for comparison of normally distributed continuous data between two groups， and a one-way analysis of variance used for comparison between multiple groups； the repeated measures analysis of variance was used for comparison of normally distributed repeated measurement data within each group and between groups； the chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups. Univariate and multivariate logistic regression analyses were used to investigate the predictive factors for HBsAg clearance， and the receiver operating characteristic （ROC） curve was used to determine the cut-off value of TNF-α in predicting HBsAg clearance. Results At week 72， compared with the IHC control group， the treatment group had significantly higher HBsAg clearance rate （46.2% vs 1.2%， χ2=133.333，P<0.001） and seroconversion rate （34.8% vs 0.8%， χ2=94.650，P<0.001）. The HBsAg clearance group and the non-clearance group had a significant increase in the serum level of TNF-α during treatment， which gradually returned to the baseline level after drug withdrawal （F=351.733 and 76.434， both P<0.001）. Comparisons between groups showed that the HBsAg clearance group had the highest serum level of TNF-α at weeks 12， 24， and 48， followed by the non-clearance group and the IHC control group （all P<0.001）. The multivariate logistic regression analysis showed that baseline HBsAg level （odds ratio ［OR］=0.329，95% confidence interval ［CI］：0.189 — 0.571，P<0.001）， baseline HBV DNA <20 IU/mL （OR=1.414，95%CI：1.057 — 1.787，P=0.045）， ALT≥2×upper limit of normal at week 12 （OR=1.127，95%CI：1.028 — 1.722，P=0.043）， TNF-α level at week 12 （OR=1.336，95%CI：1.018 — 1.754，P=0.037）， and TNF-α level at week 24 （OR=1.879，95%CI：1.477 — 2.391，P<0.001） were independent predictive factors for HBsAg clearance. The ROC analysis showed that TNF-α level at week 12 had an area under the ROC curve （AUC） of 0.846 （95%CI：0.814 — 0.889） in predicting HBsAg clearance at week 72， with a sensitivity of 76.3% and a specificity of 81.0%， while TNF-α level at week 24 had an AUC of 0.912 （95%CI：0.758 — 0.972）， with a sensitivity of 81.4% and a specificity of 96.2%. Conclusion PEG-IFN-α can increase the serum level of TNF-α in IHCs， and the serum level of TNF-α at weeks 12 and 24 can effectively predict HBsAg clearance induced by PEG-IFN-α. -
图 1 治疗组和IHC对照组的HBsAg清除率及血清学转换率比较
Figure 1. Comparison of HBsAg clearance rate and HBsAg seroconversion rate between the treatment and IHC control groups
图 2 HBsAg清除组、未清除组、IHC对照组和健康对照组基线TNF-α水平比较
Figure 2. Comparison of baseline TNF-α levels between the HBsAg clearance， non-clearance， IHC control， and healthy control groups
图 3 血清TNF-α预测72周时PEG-IFN-α诱导的HBsAg清除的ROC曲线
Figure 3. ROC curve of serum TNF-α for predicting HBsAg clearance induced by PEG-IFN-α at week 72
表 1 HBsAg清除组、未清除组、IHC对照组和健康对照组的基线资料
Table 1. Baseline characteristics of HBsAg clearance， non-clearance， IHC control， and healthy control groups
指标 HBsAg清除组
（n=97）HBsAg未清除组
（n=113）IHC对照组
（n=245）健康对照组
（n=47）统计值 P值 男/女（例） 59/38 85/28 155/90 30/17 χ2=6.266 0.100 年龄（岁） 36.5±9.4 38.8±10.5 37.2±10.7 37.5±9.8 F=0.962 0.411 ALT（U/L） 30.1±10.4 32.5±8.7 31.5±9.7 29.0±10.2 F=0.979 0.402 AST（U/L） 26.8±11.0 29.5±12.2 27.9±9.5 28.6±10.0 F=1.134 0.335 FibroScan值（kPa） 6.6±2.9 8.9±1.81） 9.3±2.61） F=19.024 0.043 HBsAg（log10 IU/mL） 1.5±1.1 2.5±0.81） 2.4±0.61） F=31.837 <0.001 HBV DNA（阳/阴，例） 31/66 66/471） 149/961） χ2=24.442 <0.001 注：与HBsAg清除组比较，1）P<0.05。
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表 2 HBsAg清除组、未清除组及IHC对照组血清TNF-α水平随时间的动态变化
Table 2. Dynamic changes in serum TNF-α levels in the HBsAg clearance， non-clearance， and IHC control groups
时间 HBsAg清除组 HBsAg未清除组 IHC对照组 F值 P值 0周 6.1±2.4 6.1±2.1 6.2±2.2 0.406 0.666 12周 12.5±2.8a 9.4±2.31） a 6.2±2.01） 2） 307.758 <0.001 24周 14.9±2.9ab 10.1±1.71） a 6.3±2.11） 2） 505.691 <0.001 48周 12.5±4.6ac 9.6±2.71） a 6.3±1.91） 2） 192.945 <0.001 72周 5.8±1.7bcd 6.0±1.7 bcd 5.9±2.1 0.063 0.939 F值 351.733 76.434 1.486 P值 <0.001 <0.001 0.206 整体性检验 组别（F值，P值） 424.894，<0.001 时间（F值，P值） 318.051，<0.001 组别×时间（F值，P值） 246.128，<0.001 注：组间比较：与HBsAg清除组比较，1）P<0.001；与HBsAg未清除组比较，2）P<0.001。组内比较：与0周比较，a，P<0.001；与12周比较，b，P<0.001；与24周比较，c，P<0.001；与48周比较，d，P<0.001。
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表 3 早期预测72周时PEG-IFN-α诱导的HBsAg清除的因素分析
Table 3. Factors analysis for early prediction of HBsAg clearance induced by PEG-IFN-α at week 72
预测因素 单因素分析 多因素分析 OR 95%CI P值 OR 95%CI P值 男性 0.712 0.535～0.946 0.025 1.504 0.434～5.217 0.520 基线LSM（kPa） 0.784 0.558～0.981 0.043 0.814 0.628～1.202 0.869 年龄（岁） 0.977 0.950～1.004 0.100 基线HBsAg水平（log10 IU/mL） 0.356 0.251～0.505 <0.001 0.329 0.189～0.571 <0.001 基线HBV DNA<20 IU/mL 1.828 1.315～2.541 <0.001 1.414 1.057～1.787 0.045 基线ALT水平（U/L） 0.997 0.987～1.007 0.536 12周ALT≥2×ULN（U/L） 1.357 1.037～1.844 0.036 1.127 1.028～1.722 0.043 24周ALT≥2×ULN（U/L） 0.995 0.988～1.033 0.223 基线TNF-α水平（pg/mL） 1.017 0.901～1.148 0.785 12周时TNF-α水平（pg/mL） 1.713 1.456～2.016 <0.001 1.336 1.018～1.754 0.037 24周时TNF-α水平（pg/mL） 2.173 1.774～2.661 <0.001 1.879 1.477～2.391 <0.001
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表 4 血清TNF-α预测72周时PEG-IFN-α诱导的HBsAg清除的ROC曲线分析
Table 4. ROC analysis of serum TNF-α for predicting HBsAg clearance induced by PEG-IFN-α at week 72
影响因素 AUC 最佳cut-off值 敏感度 特异度 HBsAg清除率 基线HBsAg 0.770 <2.0 63.9% 79.6% 72.1%（62/86） 12周TNF-α水平 0.846 >10.0 76.3% 81.0% 74.3%（78/105） 24周TNF-α水平 0.912 >13.0 81.4% 96.2% 90.4%（75/83）
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[1] YAO KF, LIU JC, WANG J, et al. Distribution and clinical characteristics of patients with chronic hepatitis B virus infection in the grey zone[J]. J Viral Hepat, 2021, 28( 7): 1025- 1033. DOI: 10.1111/jvh.13511. [2] INVERNIZZI F, VIGANÒ M, GROSSI G, et al. The prognosis and management of inactive HBV carriers[J]. Liver Int, 2016, 36( S1): 100- 104. DOI: 10.1111/liv.13006. [3] YOU H, WANG FS, LI TS, et al. Guidelines for the prevention and treatment of chronic hepatitis B(version 2022)[J]. J Clin Transl Hepatol, 2023, 11( 6): 1425- 1442. DOI: 10.14218/JCTH.2023.00320. [4] WU FP, LU R, LIU YX, et al. Efficacy and safety of peginterferon alpha monotherapy in Chinese inactive chronic hepatitis B virus carriers[J]. Liver Int, 2021, 41( 9): 2032- 2045. DOI: 10.1111/liv.14897. [5] WONG GLH, GANE E, LOK ASF. How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development?[J]. J Hepatol, 2022, 76( 6): 1249- 1262. DOI: 10.1016/j.jhep.2021.11.024. [6] HE XJ, LONG YZ, ZHOU J, et al. Monitoring serum hepatitis B virus RNA to assess the efficacy of pegylated interferon therapy in nucleos(t)ide analog-experienced chronic hepatitis B patients with low viral load[J]. Clin J Med Offic, 2023, 51( 10): 1091- 1095. DOI: 10.16680/j.1671-3826.2023.10.27.贺潇瑾, 龙云铸, 周娟, 等. 血清乙型肝炎病毒RNA监测聚乙二醇干扰素治疗核苷(酸)类似物经治低病毒载量慢性乙型肝炎患者疗效[J]. 临床军医杂志, 2023, 51( 10): 1091- 1095. DOI: 10.16680/j.1671-3826.2023.10.27. [7] XIAO LX, TANG K, FU T, et al. Cytokine profiles and virological markers highlight distinctive immune statuses, and effectivenesses and limitations of NAs across different courses of chronic HBV infection[J]. Cytokine, 2024, 173: 156442. DOI: 10.1016/j.cyto.2023.156442. [8] Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association. The guideline of prevention and treatment for chronic hepatitis B: a 2015 update[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. [9] CAO ZH, LIU YL, MA LN, et al. A potent hepatitis B surface antigen response in subjects with inactive hepatitis B surface antigen carrier treated with pegylated-interferon alpha[J]. Hepatology, 2017, 66( 4): 1058- 1066. DOI: 10.1002/hep.29213. [10] ZENG QL, YU ZJ, SHANG J, et al. Short-term peginterferon-induced high functional cure rate in inactive chronic hepatitis B virus carriers with low surface antigen levels[J]. Open Forum Infect Dis, 2020, 7( 6): ofaa208. DOI: 10.1093/ofid/ofaa208. [11] WU FP, WANG YK, CUI D, et al. Short-term peg-IFN alpha-2b re-treatment induced a high functional cure rate in patients with HBsAg recurrence after stopping PEG-IFN alpha-based regimens[J]. J Clin Med, 2023, 12( 1): 361. DOI: 10.3390/jcm12010361. [12] BEKCIBASI M, DEVECI O, OGUZ A, et al. Serum TNF-alpha, IL-1beta, and IL-6 levels in chronic HBV-infected patients[J]. Int J Clin Pract, 2021, 75( 8): e14292. DOI: 10.1111/ijcp.14292. [13] LE BERT N, GILL US, HONG M, et al. Effects of hepatitis B surface antigen on virus-specific and global T cells in patients with chronic hepatitis B virus infection[J]. Gastroenterology, 2020, 159( 2): 652- 664. DOI: 10.1053/j.gastro.2020.04.019. [14] WU FP, YANG Y, LI M, et al. Add-on pegylated interferon augments hepatitis B surface antigen clearance vs continuous nucleos(t)ide analog monotherapy in Chinese patients with chronic hepatitis B and hepatitis B surface antigen≤1 500 IU/mL: An observational study[J]. World J Gastroenterol, 2020, 26( 13): 1525- 1539. DOI: 10.3748/wjg.v26.i13.1525. -
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