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
Efficacy and safety of sequential or combined therapy with tenofovir alafenamide fumarate in entecavir-treated patients with low-level viremia
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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。 Abstract:Objective To investigate the efficacy of sequential tenofovir alafenamide fumarate (TAF) therapy versus the regimen of entecavir (ETV) combined with TAF in chronic hepatitis B (CHB) patients experiencing low-level viremia (LLV) after ETV therapy, as well as their impact on virologic response, liver and renal function, and blood lipid levels. Methods A total of 217 CHB patients with LLV after ETV treatment who were admitted to Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from May 2020 to December 2023 were enrolled, and according to the treatment regimen, they were divided into TAF group (180 patients receiving sequential TAF therapy) and combined group (37 patients receiving ETV+TAF therapy). The propensity score matching (PSM) method was used to match the patients at a ratio of 1∶1, and finally 37 patients were included in each group to balance the baseline confounding factors. The two groups were compared in terms of hepatitis B virus DNA (HBV DNA) clearance rate, hepatitis B envelope antigen (HBeAg) clearance rate, liver and renal function parameters (liver stiffness measurement [LSM], platelet count [PLT], aspartate aminotransferase [AST], alanine aminotransferase [ALT], and creatinine [Cr]), blood lipid levels (total cholesterol [TC], triglyceride [TG], high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol [LDL-C]), and the incidence rate of adverse reactions. The independent samples t-test was used for comparison of normally distributed continuous data between two groups, and the paired t-test was used for comparison within each group; the chi-square test was used for comparison of categorical data between groups. Results After 48 weeks of treatment, compared with the TAF group, the combined group had significantly higher HBV DNA clearance rate (86.49% vs 59.46%, χ²=6.852, P=0.009) and HBeAg clearance rate (59.46% vs 35.14%, χ²=4.391, P=0.036). After treatment, compared with the TAF group, the combined group had significantly lower levels of 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), and ALT (19.85±3.86 U/L vs 22.00±3.90 U/L, t=2.383, P=0.020) and significantly higher levels of PLT [(218.35±42.60)×109/L vs (192.82±44.13)×109/L, t=2.532, P=0.014] and Cr (70.92±6.54 μmoL/L vs 67.60±6.13 μmoL/L, t=2.253, P=0.027). After treatment, there was a slight increase in the level of TC in both the TAF group (5.60±0.89 mmol/L vs 5.18±0.85 mmol/L, t=2.076, P=0.041) and the combined group (5.45±0.80 mmol/L vs 5.02±0.83 mmol/L, t=2.269, P=0.026). There was no significant difference in the incidence rate of adverse reactions between the TAF group and the combined group (21.62% vs 18.92%, χ²=0.084, P=0.772). Conclusion For ETV-treated CHB patients experiencing LLV, compared with sequential TAF therapy, the ETV+TAF combined therapy can effectively increase virologic response rate, alleviate liver fibrosis, and improve liver function, whereas sequential TAF therapy has less impact on renal function. Sequential or combined therapy with TAF may induce a slight increase in the level of TC, which should be taken seriously in clinical practice. -
Key words:
- Chronic Hepatitis B /
- Entecavir /
- Tenofovir Alafenamide /
- Low-Level Viremia
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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值 TAF组
(n=37)联合组
(n=37)统计值 P值 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 男 132(73.33) 32(86.49) 30(81.08) 32(86.49) 女 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 有 14(7.78) 2(5.41) 4(10.81) 2(5.41) 无 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 有 24(13.33) 3(8.11) 4(10.81) 3(8.11) 无 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 有 152(84.44) 35(94.59) 30(81.08) 35(94.59) 无 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 是 36(20.00) 3(8.11) 5(13.51) 3(8.11) 否 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 有 32(17.78) 6(16.22) 7(18.92) 6(16.22) 无 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 有 8(4.44) 1(2.70) 3(8.11) 1(2.70) 无 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 有 25(13.89) 5(13.51) 6(16.22) 5(13.51) 无 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。
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值 P值 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。
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值 P值 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。
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值 P值 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。
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) -
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