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核苷(酸)类似物初治的慢性乙型肝炎患者发生低病毒血症的影响因素及其动态变化分析

程齐齐 杨丽霞 蔡天盼 王亮 孙俊 梁佳圆 刘丽萍 甘厦 阮宁杭 葛善飞

引用本文:
Citation:

核苷(酸)类似物初治的慢性乙型肝炎患者发生低病毒血症的影响因素及其动态变化分析

DOI: 10.3969/j.issn.1001-5256.2022.12.008
基金项目: 

江西省自然科学基金面上项目 20192BAB205090

伦理学声明:本研究于2021年8月19日经南昌大学第一附属医院伦理委员会批准实施,批号:(2021)医研伦审第(8-016)号。所有患者均签署知情同意书。
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。
作者贡献声明:程齐齐负责数据采集、数据分析、文章撰写;杨丽霞、蔡天盼、甘厦负责支持指导、修改论文;王亮、孙俊、梁佳圆、刘丽萍、阮宁杭负责数据采集及分析;葛善飞负责研究设计,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:

    葛善飞,geshanfei2010@163.com

Influencing factors for low-level viremia and their dynamic changes in patients with chronic hepatitis B treated with nucleos(t)ide analogues for the first time

Research funding: 

General Program of Jiangxi Natural Science Foundation 20192BAB205090

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  • 摘要:   目的  探讨核苷(酸)类似物(NAs)初治的慢性乙型肝炎(CHB)患者发生低病毒血症(LLV)的影响因素,并进一步分析其动态变化。  方法  选取2020年11月—2022年3月于南昌大学第一附属医院感染科门诊就诊且接受NAs抗病毒治疗至少12个月的CHB患者78例,根据治疗期间的HBV DNA水平,将患者分为持续病毒学应答(SVR)组(n=58)和LLV组(n=20)。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检验或Fisher精确检验;多因素Logistic回归分析CHB患者发生LLV的独立影响因素,并建立预测模型。采用受试者工作特征曲线(ROC曲线)评价模型的预测价值。使用Kaplan-Meier分析HBV DNA累积阴转率,应用Log-rank检验进行比较。采用重复测量方差分析比较两组间或组内0、12、24、36、48周HBV DNA和HBsAg水平及其变化的差异。  结果  LLV组HBeAg阳性率(90.0% vs 48.3%,χ2=10.701,P=0.001)、HBV DNA log值(7.26±1.46 vs 5.65±1.70,t=-4.178,P<0.001)、HBsAg log值(4.53±0.86 vs 3.44±0.93,t=-4.813,P<0.001)高于SVR组,年龄[29(26~34)岁vs 33(30~43)岁,Z=-2.751,P=0.009]、ALT[67.0(54.0~122.0)U/L vs 111.0(47.0~406.0)U/L,Z=-2.203,P=0.028]、AST[43.5(32.8~62.8)U/L vs 77.5(35.0~213.0)U/L,Z=-2.466,P=0.014]、LSM[7.7(6.3~8.5)kPa vs 8.9(7.2~11.4)kPa,Z=-2.022,P=0.043]低于SVR组。多因素Logistic回归分析显示,基线HBV DNA(OR=2.365,95%CI: 1.220~4.587,P=0.011)、HBsAg(OR=4.229,95%CI: 1.098~16.287,P=0.036)和ALT(OR=0.965,95%CI: 0.937~0.994,P=0.018)是CHB患者发生LLV的独立影响因素;由此建立预测模型Logit(MLLV)=-8.668+1.441×lgHBsAg+0.598×lgHBV DNA-0.016×ALT,其ROC曲线下面积为0.931,高于HBV DNA、HBsAg和ALT(ROC曲线下面积分别为0.774、0.856、0.666),最佳截断值为0.44,敏感度、特异度分别为85.00%、93.10%。基线HBV DNA>7.29 lgIU/mL和HBsAg>4.38 lgIU/mL的CHB患者HBV DNA阴转率明显低于HBV DNA≤7.29 lgIU/mL和HBsAg≤4.38 lgIU/mL的患者(χ2值分别为22.52、26.35,P值均<0.001)。CHB患者的HBV DNA和HBsAg的下降速率分别在第12周和第24周最大,LLV组患者HBV DNA和HBsAg水平在0、12、24、36、48周均高于SVR组(HBV DNA:t值分别为-4.084、-4.526、-5.688、-7.123、-6.266,P值均<0.001;HBsAg:t值分别为-4.652、-4.691、-4.952、-4.804、-4.407,P值均<0.001)。  结论  基线高HBV DNA水平、HBsAg定量和低ALT水平的NAs初治CHB患者更易发生LLV,动态监测其变化对LLV的出现有重要意义。

     

  • 图  1  Logistic回归模型的校准度

    Figure  1.  Calibration curve of logistic regression model

    图  2  HBV DNA、HBsAg、ALT和MLLV模型的ROC曲线

    Figure  2.  ROC curve of HBV DNA, HBsAg, ALT and MLLV models

    图  3  不同基线HBV DNA和HBsAg的CHB患者HBV DNA累积转阴率

    注:a,不同HBV DNA水平患者;b,不同HBsAg水平患者。

    Figure  3.  Cumulative negative rate of HBV DNA in CHB patients with different baseline HBV DNA and HBsAg

    图  4  两组患者HBV DNA和HBsAg水平变化

    注:a,期间HBV DNA的比较;b,治疗期间HBsAg的比较。*P<0.05。

    Figure  4.  Dynamic changes of HBV DNA and HBsAg in two groups

    图  5  所有患者HBV DNA和HBsAg下降幅度变化

    注:a,治疗期间HBV DNA下降幅度变化;b,治疗期间HBsAg下降幅度变化。

    Figure  5.  The decrease range changes of HBV DNA and HBsAg

    表  1  CHB患者基线临床特征和实验室指标分析

    Table  1.   Analysis of baseline clinical characteristics and laboratory indexes of CHB patients

    项目 所有患者(n=78) SVR组(n=58) LLV组(n=20) 统计值 P
    年龄(岁) 32(29~39) 33(30~43) 29(26~34) Z=-2.751 0.009
    男性[例(%)] 54(69.2) 40(68.9) 14(70.0) χ2=0.007 0.931
    家族史[例(%)] 22(28.2) 16(27.6) 6(30.0) χ2=0.043 0.836
    BMI(kg/m2) 23.3±3.7 23.7±4.0 22.3±2.5 t=1.359 0.164
    HBeAg阳性[例(%)] 46(59.0) 28(48.3) 18(90.0) χ2=10.701 0.001
    lgHBV DNA(IU/mL) 6.07±1.78 5.65±1.70 7.26±1.46 t=-4.178 <0.001
    lgHBsAg(IU/mL) 3.72±1.02 3.44±0.93 4.53±0.86 t=-4.813 <0.001
    抗-HBc 8.50(7.51~9.83) 8.56(7.65~9.80) 8.46(6.91~9.87) Z=-0.092 0.927
    AST(U/L) 68.0(38.5~125.5) 77.5(35.0~213.0) 43.5(32.8~62.8) Z=-2.466 0.014
    ALT(U/L) 105.0(53.4~218.0) 111.0(47.0~406.0) 67.0(54.0~122.0) Z=-2.203 0.028
    TBil(μmol/L) 15.6(10.2~32.5) 17.0(11.2~36.6) 15.0(9.3~20.7) Z=-1.087 0.277
    Alb(g/L) 44.5(40.2~46.9) 43.6(38.4~46.5) 46.3(42.7~48.5) Z=2.352 0.073
    TG(mmol/L) 1.00(0.63~1.44) 1.03(0.62~1.57) 0.96(0.76~13.20) Z=-0.069 0.945
    Cr(μmol/L) 65.6(56.7~76.4) 62.3(54.9~73.5) 68.2(56.1~71.9) Z=2.432 0.065
    PLT(×109) 181.7±65.9 174.3±67.3 202.7±58.4 t=-1.769 0.067
    LSM(kPa) 8.1(6.8~11.2) 8.9(7.2~11.4) 7.7(6.3~8.5) Z=-2.022 0.043
    肝硬化[例(%)] 25(32.1) 20(34.5) 5(25.0) χ2=0.614 0.433
    抗病毒药物类型[例(%)] χ2=1.345 0.246
      ETV初治 66(84.6) 49(84.5) 17(85.0)
      TDF或TAF初治 12(15.4) 9(15.5) 3(15.0)
    MAFLD[例(%)] 17(21.8) 13(22.4) 4(20.0) χ2=0.051 0.822
    下载: 导出CSV

    表  2  MLLV模型的建立

    Table  2.   Establishment of the MLLV model

    变量 B SE Wald OR 95%CI P
    lgHBV DNA 0.589 0.245 5.932 1.818 1.124~2.942 0.015
    lgHBsAg 1.441 0.586 6.051 4.225 1.340~13.316 0.014
    ALT -0.016 0.007 4.918 0.984 0.969~0.998 0.027
    常数 -8.668 2.355 13.551 0.001 <0.001
    下载: 导出CSV

    表  3  HBV DNA、HBsAg、ALT和MLLV对LLV发生的预测价值

    Table  3.   Predictive value of HBV DNA, HBsAg, ALT and MLLV for the occurrence of LLV

    指标 AUC 95%CI 截断值 敏感度 特异度 P
    HBV DNA 0.774 0.665~0.861 7.29 70.00% 82.76% <0.001
    HBsAg 0.856 0.758~0.925 4.38 85.00% 87.93% <0.001
    ALT 0.666 0.550~0.769 139.80 95.00% 44.83% 0.007
    MLLV 0.931 0.850~0.976 0.44 85.00% 93.10% <0.001
    下载: 导出CSV

    表  4  CHB患者治疗期间HBV DNA和HBsAg动态变化

    Table  4.   Dynamic changes of HBV DNA level and HBsAg level in CHB patients during treatment

    时间 SVR组(n=58) LLV组 (n=20) t P
    HBV DNA(lgIU/mL)
      基线 5.62±1.69 7.35±1.44 -4.084 <0.001
      12周 2.62±1.261) 4.08±1.221) -4.526 <0.001
      24周 1.82±0.731) 2.99±0.861) -5.688 <0.001
      36周 1.43±0.371) 2.73±0.791) -7.123 <0.001
      48周 1.28±0.341) 2.19±0.651) -6.266 <0.001
    HBsAg(lgIU/mL)
      基线 3.44±0.92 4.53±0.86 -4.652 <0.001
      12周 3.23±0.801) 4.22±0.871) -4.691 <0.001
      24周 3.16±0.701) 4.11±0.831) -4.952 <0.001
      36周 3.12±0.661) 3.98±0.771) -4.804 <0.001
      48周 3.00±0.691) 3.81±0.771) -4.407 <0.001
    注:与同组基线比较,1)P<0.05。
    下载: 导出CSV
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