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恩替卡韦经治低病毒血症患者序贯或联合富马酸丙酚替诺福韦的疗效及安全性分析

张伊婧 黄凌鹰 陈博武 朱宛春 李曼 沈杰 高月求

引用本文:
Citation:

恩替卡韦经治低病毒血症患者序贯或联合富马酸丙酚替诺福韦的疗效及安全性分析

DOI: 10.12449/JCH260108
基金项目: 

国家自然科学基金 (82574929);

国家自然科学基金 (82274467);

国家中医药管理局高水平重点学科 (ZYYZDXK-2023060);

上海市卫生健康委员会中医药科研项目 (2024QN006);

上海市科委2023年科技创新行动计划 (23Y21920200)

利益冲突声明:本文不存在任何利益冲突。
作者贡献声明:张伊婧等负责课题设计,资料分析,撰写论文;黄凌鹰、陈博武、朱宛春、李曼、沈杰参与收集数据,修改论文;高月求负责拟定写作思路,指导撰写文章并最后定稿。
详细信息
    通信作者:

    高月求, gaoyueqiu@shutcm.edu.cn (ORCID: 0000-0001-7276-9810)

Efficacy and safety of sequential or combined therapy with tenofovir alafenamide fumarate in entecavir-treated patients with low-level viremia

Research funding: 

National Natural Science Foundation of China (82574929);

National Natural Science Foundation of China (82274467);

High Level Key Disciplines of Medicine of National Administration of Traditional Chinese Medicine (ZYYZDXK-2023060);

Shanghai Municipal Health Commission Traditional Chinese Medicine Research Project (2024QN006);

Shanghai Science and Technology Innovation Action Plan (23Y21920200)

More Information
  • 摘要:   目的  比较序贯富马酸丙酚替诺福韦(TAF)与恩替卡韦(ETV)联合TAF方案,在ETV经治后发生低病毒血症(LLV)的慢性乙型肝炎(CHB)患者中的效果及其对病毒学应答、肝肾功能和血脂水平的影响。  方法  选取2020年5月—2023年12月上海中医药大学附属曙光医院收治的217例ETV治疗后发生LLV的CHB患者,根据治疗方案分为TAF组(序贯TAF治疗,n=180)与联合组(ETV联合TAF治疗,n=37)。采用倾向性评分匹配法按1∶1匹配,最终每组各纳入37例患者以均衡基线混杂因素。比较两组患者的乙型肝炎病毒DNA(HBV DNA)阴转率、乙型肝炎e抗原(HBeAg)阴转率、肝肾功能指标[肝硬度值(LSM)、血小板计数(PLT)、天冬氨酸氨基转氨酶(AST)、丙氨酸氨基转氨酶(ALT)和肌酐(Cr)]、血脂水平[总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)和低密度脂蛋白胆固醇(LDL-C)]及不良反应发生率。符合正态分布的计量资料两组间比较采用成组t检验,组内比较采用配对t检验;计数资料组间比较采用χ2检验。  结果  治疗48周后,联合组的HBV DNA阴转率(86.49% vs 59.46%,χ2=6.852,P=0.009)、HBeAg阴转率(59.46% vs 35.14%,χ2=4.391,P=0.036)均显著高于TAF组。治疗后,联合组的LSM[(7.01±1.50)kPa vs (7.90±1.68)kPa,t=2.404,P=0.019]、AST[(18.02±2.28)U/L vs (21.12±2.85)U/L,t=5.166,P<0.001]、ALT[(19.85±3.86)U/L vs (22.00±3.90)U/L,t=2.383,P=0.020]水平均显著低于TAF组,PLT[(218.35±42.60)×109/L vs (192.82±44.13)×109/L,t=2.532,P=0.014]、Cr[(70.92±6.54)μmoL/L vs (67.60±6.13)μmoL/L,t=2.253,P=0.027]水平均显著高于TAF组。治疗后,TAF组的TC水平[(5.60±0.89)mmol/L vs (5.18±0.85)mmol/L,t=2.076,P=0.041]与联合组的TC水平[(5.45±0.80)mmol/L vs(5.02±0.83)mmol/L,t=2.269,P=0.026]均较本组治疗前轻度升高。TAF组与联合组的不良反应发生率分别为21.62%、18.92%,组间比较差异无统计学意义(χ2=0.084,P=0.772)。  结论  ETV经治发生LLV的CHB患者联合TAF治疗相较于序贯TAF治疗,能够有效提高患者病毒学应答率,减轻肝纤维化程度,改善肝功能,但序贯TAF治疗对肾功能的影响更小。序贯或联合TAF治疗可能轻微升高TC水平,临床须关注其变化。

     

  • 表  1  两组患者PSM匹配前后基线资料比较

    Table  1.   Comparison of baseline data before and after PSM matching between the two groups of patients

    项目 匹配前 匹配后
    TAF组
    n=180)
    联合组
    n=37)
    统计值 P TAF组
    n=37)
    联合组
    n=37)
    统计值 P
    年龄(岁) 53.28±14.12 52.24±12.46 t=0.416 0.678 51.84±14.67 52.24±12.46 t=0.126 0.900
    性别[例(%)] χ2=2.877 0.090 χ2=0.398 0.528
    132(73.33) 32(86.49) 30(81.08) 32(86.49)
    48(26.67) 5(13.51) 7(18.92) 5(13.51)
    BMI(kg/m2 21.96±2.34 22.80±2.17 t=2.012 0.045 22.35±2.12 22.80±2.17 t=0.902 0.370
    饮酒史[例(%)] χ2=0.253 0.615 χ2=0.725 0.394
    14(7.78) 2(5.41) 4(10.81) 2(5.41)
    166(92.22) 35(94.59) 33(89.19) 35(94.59)
    高血脂史[例(%)] χ2=0.769 0.380 χ2=0.158 0.691
    24(13.33) 3(8.11) 4(10.81) 3(8.11)
    156(86.67) 34(91.89) 33(89.19) 34(91.89)
    肝脏基础疾病[例(%)] χ2=2.654 0.103 χ2=3.162 0.075
    152(84.44) 35(94.59) 30(81.08) 35(94.59)
    28(15.56) 2(5.41) 7(18.92) 2(5.41)
    HBV DNA(log10 IU/mL) 5.08±1.03 4.71±0.94 t=2.019 0.045 4.85±0.96 4.71±0.94 t=0.634 0.528
    HBeAg(log10 IU/mL) 2.98±1.12 2.55±1.01 t=2.161 0.032 2.73±1.08 2.55±1.01 t=0.740 0.461
    HBV DNA低于检测下限[例(%)] χ²=2.944 0.086 χ2=0.561 0.454
    36(20.00) 3(8.11) 5(13.51) 3(8.11)
    144(80.00) 34(91.89) 32(86.49) 34(91.89)
    MELD评分(分) 10.80±3.54 9.52±3.25 t=2.030 0.044 9.81±3.42 9.52±3.25 t=0.374 0.710
    高血压史[例(%)] χ2=0.052 0.820 χ2=0.093 0.760
    32(17.78) 6(16.22) 7(18.92) 6(16.22)
    148(82.22) 31(83.78) 30(81.08) 31(83.78)
    冠心病史[例(%)] χ2=0.234 0.628 χ2=1.057 0.304
    8(4.44) 1(2.70) 3(8.11) 1(2.70)
    172(95.56) 36(97.30) 34(91.89) 36(97.30)
    糖尿病史[例(%)] χ2=0.004 0.952 χ2=0.463 0.496
    25(13.89) 5(13.51) 6(16.22) 5(13.51)
    155(86.11) 32(86.49) 31(83.78) 32(86.49)

    注:BMI,体重指数;HBV DNA,乙型肝炎病毒DNA;HBeAg,乙型肝炎e抗原;MELD,终末期肝病模型。

    下载: 导出CSV

    表  2  两组患者HBV DNA、HBeAg阴转情况比较

    Table  2.   Comparison of HBV DNA and HBeAg negative conversion between the two groups of patients

    指标 TAF组
    n=37)
    联合组
    n=37)
    χ2 P
    HBV DNA阴转[例(%)] 22
    (59.46)
    32
    (86.49)
    6.852 0.009
    HBeAg阴转[例(%)] 13
    (35.14)
    22
    (59.46)
    4.391 0.036

    注:TAF,富马酸丙酚替诺福韦;HBV DNA,乙型肝炎病毒DNA;HBeAg,乙型肝炎e抗原。

    下载: 导出CSV

    表  3  两组患者肝肾功能指标比较

    Table  3.   Comparison of liver and kidney function indexes between the two groups of patients

    指标 TAF组
    n=37)
    联合组
    n=37)
    t P

    LSM(kPa)

    治疗前

    治疗后

    8.75±1.90

    7.90±1.681)

    8.49±1.96

    7.01±1.501)

    0.579

    2.404

    0.564

    0.019

    PLT(×109/L)

    治疗前

    治疗后

    171.61±42.50

    192.82±44.131)

    173.80±50.93

    218.35±42.601)

    0.067

    2.532

    0.946

    0.014

    AST(U/L)

    治疗前

    治疗后

    63.82±14.96

    21.12±2.851)

    62.65±14.87

    18.02±2.281)

    0.337

    5.166

    0.737

    <0.001

    ALT(U/L)

    治疗前

    治疗后

    47.56±12.80

    22.00±3.901)

    47.12±12.02

    19.85±3.861)

    0.152

    2.383

    0.879

    0.020

    Cr(μmoL/L)

    治疗前

    治疗后

    63.54±10.16

    67.60±6.131)

    65.31±10.08

    70.92±6.541)

    0.752

    2.253

    0.454

    0.027

    注:与本组治疗前比较,1)P<0.05。TAF,富马酸丙酚替诺福韦;LSM,肝硬度值;PLT,血小板计数;AST,天冬氨酸氨基转移酶;ALT,丙氨酸氨基转氨酶;Cr,肌酐。

    下载: 导出CSV

    表  4  两组患者血脂水平比较

    Table  4.   Comparison of blood lipid levels between the two groups of patients

    指标 TAF组
    n=37)
    联合组
    n=37)
    t P

    TC(mmol/L)

    治疗前

    治疗后

    5.18±0.85

    5.60±0.891)

    5.02±0.83

    5.45±0.801)

    0.819

    0.762

    0.415

    0.448

    TG(mmol/L)

    治疗前

    治疗后

    1.30±0.64

    1.26±0.61

    1.21±0.57

    1.14±0.60

    0.639

    0.853

    0.525

    0.396

    HDL-C(mmol/L)

    治疗前

    治疗后

    1.28±0.36

    1.32±0.37

    1.24±0.30

    1.34±0.38

    0.519

    0.229

    0.605

    0.819

    LDL-C(mmol/L)

    治疗前

    治疗后

    3.37±0.91

    3.30±0.96

    3.31±0.82

    3.25±0.84

    0.298

    0.238

    0.767

    0.812

    注:与本组治疗前比较,1)P<0.05。TAF,富马酸丙酚替诺福韦;TC,总胆固醇;TG,甘油三酯;HDL-C,高密度脂蛋白胆固醇;LDL-C,低密度脂蛋白胆固醇。

    下载: 导出CSV

    表  5  两组患者不良反应发生率比较

    Table  5.   Comparison of the incidence of adverse reactions between the two groups of patients

    不良反应 TAF组(n=37) 联合组(n=37)
    腹泻[例(%)] 1(2.70) 2(5.41)
    肾功能异常[例(%)] 2(5.41) 1(2.70)
    恶心[例(%)] 1(2.70) 1(2.70)
    头痛[例(%)] 4(10.81) 3(8.11)
    合计[例(%)] 8(21.62) 7(18.92)
    下载: 导出CSV
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