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富马酸替诺福韦酯治疗的慢性乙型肝炎患者3年血清HBV DNA和HBsAg的动态变化
DOI: 10.3969/j.issn.1001-5256.2022.10.006
伦理学声明：本研究方案于2020年5月18日经由西安交通大学第二附属医院伦理委员会审批，批号：2020-922。
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：鲁瑞、李梅负责课题设计，资料分析，撰写论文；刘晨瑞、刘怡欣、吴凤萍、鲁瑞、王怡恺参与收集数据，修改论文；党双锁、李梅负责拟定写作思路，指导撰写文章并最后定稿。
Dynamic changes of serum hepatitis B virus DNA and HBsAg in patients with chronic hepatitis B treated with tenofovir disoproxil fumarate for 3 years
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摘要:
目的 观察慢性乙型肝炎(CHB)患者使用富马酸替诺福韦酯(TDF)抗病毒治疗3年HBV DNA和HBsAg的动态变化。 方法 回顾性收集2015年1月—2020年8月就诊于西安交通大学第二附属医院的单用TDF治疗≥3年157例的CHB患者的临床资料，按照基线HBeAg水平分为HBeAg阳性组(n=73)和HBeAg阴性组(n=84)。收集患者在治疗基线、1年、2年、3年时的血清HBV DNA定量、HBsAg定量资料并分析其动态变化。符合正态分布的计量资料两组间比较采用t检验；不符合正态分布的计量资料两组间比较采用Mann-Whitney U检验；不符合正态分布的重复测量资料先进行对数转换，组内或组间比较采用重复测量资料的方差分析；计数资料两组间比较采用χ2检验或Fisher确切概率法。 结果 TDF治疗第1年和2年时HBeAg阳性患者HBV DNA阴转率均显著低于HBeAg阴性患者(第1年：65.8% vs 81.0%，χ2=4.676，P＜0.05；第2年：87.7% vs 98.8%，P＜0.05)，TDF治疗3年两组HBV DNA阴转率差异无统计学意义(97.3% vs 100%，P＞0.05)。HBeAg阳性和HBeAg阴性患者的基线HBsAg水平分别为10 633.6(2 084.8~24 005.7)IU/mL和1 402.8(311.0~2 863.5)IU/mL，经过TDF治疗3年后HBsAg水平分别降至1 534.9(912.7~5 885.9)IU/mL和677.8(119.4~1 974.8)IU/mL，组间差异有统计学意义(F=25.456，P＜0.001)。HBeAg阳性患者第1年中位HBsAg下降值[1 856.5(158.4~12 103.1)IU/mL]显著高于第2年[879.8(130.5~2 382.5)IU/mL]和第3年[479.9(95.0~1 662.4)IU/mL](F=10.972，P＜0.001)，HBeAg阴性患者HBsAg下降速度前后差异无统计学意义(F=0.513，P＞0.05)。此外，TDF治疗3年，59.2%的患者达到HBsAg＜1500 IU/mL，HBsAg转阴率为1.3%。 结论 TDF治疗3年，HBeAg阴性CHB患者HBV DNA定量全部转阴，而HBeAg阳性患者中97.3%实现HBV DNA转阴，仍然有2.7%的患者病毒定量可测及。HBsAg水平随着治疗时间延长均不断下降，且HBeAg阳性患者HBsAg水平下降速度呈现“先快后慢”的趋势特点。单用TDF治疗3年，59.2%的患者达到HBsAg＜1500 IU/mL。 Abstract:Objective To assess the efficacy of tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients receiving antiviral therapy for three years. Methods A total of 157 CHB patients treated with TDF alone for ≥3 years from January 2015 to August 2020 in the Second Affiliated Hospital of Xi'an Jiaotong University were retrospectively studied. The patients were divided into HBeAg-positive and HBeAg-negative groups based on their baseline HBeAg levels. The data of serum HBV DNA and HBsAg levels at baseline, the first, second and third year of treatment were collected to analyze the dynamic changes. The t-test was used to compare continuous variables with normal distributions between two groups, while the Mann-Whitney U test was used to compare continuous variables with non-normal distribution between two groups. Repeated measurement data with non-normal distribution were first transformed into logarithms and the intra- or between-group comparison was performed using repeated measures analysis of variance. The chi-square test or Fisher exact test was used to compare categorical variables between groups. Results HBV DNA clearance rate in HBeAg-positive patients was significantly lower than that in HBeAg-negative patients during the first and second years of TDF treatment (1st year: 65.8% vs 81.0%, χ2=4.676, P < 0.05; 2nd year: 87.7% vs 98.8%, Fisher exact test, P < 0.05). When TDF treatment was given for three years, there was no significant difference in HBV DNA clearance rates (97.3% vs 100%, Fisher exact test, P > 0.05). The baseline HBsAg levels in HBeAg-positive and HBeAg-negative patients were 10 633.6 (2 084.8-24 005.7) IU/mL and 1 402.8 (311.0-2 863.5) IU/mL, respectively, and decreased to 1 534.9 (912.7-5 885.9) IU/mL and 677.8 (119.4-1 974.8) IU/mL after 3 years of TDF treatment, with a significant difference between two groups (F=25.456, P < 0.001). In HBeAg-positive patients, the median decline value of HBsAg level was significantly higher in the first year [1 856.5 (158.4-12 103.1) IU/mL] than in the second year [879.8 (130.5-2 382.5) IU/mL] or the third year [479.9 (95.0-1 662.4) IU/mL] (F=10.972, P < 0.001), while there was no significant difference in HBeAg-negative patients (F=0.513, P > 0.05). In addition, after 3 years of TDF treatment, 59.2% of patients achieved HBsAg < 1500 IU/mL, with a HBsAg negative rate of 1.3%. Conclusion After 3 years of TDF treatment, all HBeAg-negative CHB patients can achieve HBV DNA negative conversion; for HBeAg-positive CHB patients, 97.3% of them achieved HBV DNA negative conversion, while 2.7% of them were still HBV DNA detectable. The HBsAg level declined over treatment time, and the decline rate of HBsAg level in HBeAg positive patients showed a trend of "first fast and then slow". After 3 years of TDF treatment, 59.2% of patients achieved HBsAg < 1500 IU/mL. -
Key words:
- Hepatitis B /
- Chronic /
- Hepatitis B virus /
- Hepatitis B Surface Antigens /
- Tenofovir
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表 1 患者的基线特征
Table 1. Baseline characteristics of the patients
指标 HBeAg阳性组(n=73) HBeAg阴性组(n=84) 统计值 P值 性别[例(%)] χ2=1.004 0.316 男 35(47.9) 47(56.0) 女 38(52.1) 37(44.0) 年龄(岁) 35.2±10.4 42.0±9.7 t=4.189 ＜0.001 ALT(U/L) 56.0(35.0~96.0) 56.0(24.3~77.8) Z=-1.529 0.126 AST(U/L) 48.0(32.0~83.0) 50.5(27.3~69.0) Z=-1.137 0.256 HBsAg(IU/mL) 10 633.6(2 084.8~24 005.7) 1 402.8(311.0~2 863.5) Z=-7.335 ＜0.001 HBV DNA(log10 IU/mL) 5.7±2.3 3.9±1.5 t=-3.021 ＜0.001 
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表 2 各时间点HBeAg阳性和HBeAg阴性患者HBsAg水平
Table 2. HBsAg levels in HBeAg-positive and HBeAg-negative patients at each time point
组别 例数 基线 1年 2年 3年 F值 P值 HBeAg阳性组(IU/mL) 73 10 633.6(2 084.8~24 005.7) 4 200.3(13 59.0~11 003.1) 2 353.8(1 032.2~8 799.4) 1 534.9(912.7~5 885.9) 26.850 ＜0.001 HBeAg阴性组(IU/mL) 84 1 402.8(311.0~2 863.5) 1 020.0(167.3~2 608.8) 703.0(164.2~2 054.0) 677.8(119.4~1 974.8) 8.096 ＜0.001
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表 3 不同基线HBsAg水平的HBeAg阳性患者HBsAg水平的3年动态变化
Table 3. Three-year dynamic changes of HBsAg levels in HBeAg-positive patients with different baseline HBsAg levels
HBsAg水平 例数 基线 1年 2年 3年 F值 P值 ≤3000(IU/mL) 21 1 158.2(935.4~2 072.3) 1 319.1(691.3~1 819.0) 827.0(581.4~1 541.1) 623.2(424.3~1 468.2) 7.202 0.002 3000~10 000(IU/mL) 15 5 873.7(5 231.7~6 906.7) 4 009.9(1 823.9~5 050.2) 2 513.0(1 239.0~4 500.0) 1 985.5(998.2~3 500.2) 11.106 0.001 10 000~20 000(IU/mL) 10 16 228.6(1 094.3~19 252.9) 6 918.4(471.5~9 846.6) 4 015.0(371.4~7 043.0) 2 645.7(290.6~6 731.5) 8.991 0.008 ≥20 000(IU/mL) 27 25 000.0(23 324.1~25 000.0) 12 608.5(6 778.2~22 054.1) 9 669.1(2 353.8~14 158.4) 7 218.1(1 621.0~9 897.2) 77.420 ＜0.001
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表 4 不同基线HBsAg水平的HBeAg阴性患者HBsAg水平的3年动态变化
Table 4. Three-year dynamic changes of HBsAg levels in HBeAg-negative patients with different baseline HBsAg levels
HBsAg水平 例数 基线 1年 2年 3年 F值 P值 ≤3000(IU/mL) 64 684.5(213.8~1 702.9) 518.8(143.5~1 343.4) 387.6(56.4~1 116.5) 356.7(40.0~889.2) 13.427 ＜0.001 3000~10 000(IU/mL) 15 3 979.5(3 250.2~7 315.2) 3 001.2(2 655.5~5 157.0) 2 754.2(2 523.5~5 687.0) 2 498.6(1 821.7~5 301.2) 2.508 0.010 10 000~20 000(IU/mL) 5 10 339.7(10 102.8~11 094.4) 9 846.5(7 249.0~16 127.6) 9 399.2(6 815.4~13 365.4) 8 365.3(6 215.9~12 915.3) 1 571.900 0.001 ≥20 000(IU/mL) 0 - - - - - -
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表 5 各时间点HBeAg阳性和HBeAg阴性不同区段HBsAg的患者分布
Table 5. Distribution of different segments of HBsAg at each time point in HBeAg-positive and HBeAg-negative patients
HBsAg水平 例数 1年 2年 3年 ＜0.05 IU/mL HBeAg阳性[例(%)] 73 0 0 0 HBeAg阴性[例(%)] 84 1(1.2) 1(1.2) 2(2.4) χ2值 0.875 0.875 1.761 P值 0.350 0.350 0.185 ＜100 IU/mL HBeAg阳性[例(%)] 73 1(1.4) 1(1.4) 1(1.4) HBeAg阴性[例(%)] 84 12(14.3) 17(20.2) 21(25.0) χ2值 8.579 13.699 18.100 P值 0.003 ＜0.001 ＜0.001 ＜1000 IU/mL HBeAg阳性[例(%)] 73 10(13.7) 18(24.7) 22(30.1) HBeAg阴性[例(%)] 84 41(48.8) 45(53.6) 49(58.3) χ2值 21.954 13.591 12.535 P值 ＜0.001 ＜0.001 ＜0.001 ＜1500 IU/mL HBeAg阳性[例(%)] 73 19(26.0) 26(35.6) 35(47.9) HBeAg阴性[例(%)] 84 50(59.5) 53(63.1) 58(69.0) χ2值 17.790 11.797 7.203 P值 ＜0.001 0.001 0.009
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