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慢性乙型肝炎和乙型肝炎肝硬化患者发生低病毒血症的影响因素及其与肝脏炎症、肝纤维化进展的关系
DOI: 10.3969/j.issn.1001-5256.2022.10.011
伦理学声明：本研究方案于2021年3月10日经由青岛大学附属医院伦理委员会审批，批号：QYFY WZLL26423。
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：宣碧碧负责课题设计，资料分析，撰写论文；杜忠彩、刘玉、杨玉玲参与数据收集，修改论文；边城、徐永红负责研究设计，指导撰写文章并最后定稿。
Influencing factors for low-level viremia in patients with chronic hepatitis B or hepatitis B liver cirrhosis and its association with the progression of liver inflammation and liver fibrosis
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摘要:
目的 研究接受抗病毒治疗的慢性乙型肝炎(CHB)和乙型肝炎肝硬化患者发生低病毒血症(LLV)的影响因素以及LLV与肝脏炎症、纤维化进展的关系。 方法 选取2020年7月1日—2021年11月30日就诊于青岛大学附属医院肝病门诊口服核苷(酸)类(NUC)药物抗病毒治疗疗程≥1年，且HBV DNA＜2000 IU/mL的CHB和乙型肝炎肝硬化患者417例，根据HBV DNA水平将患者分为LLV组(10 IU/mL≤HBV DNA＜2000 IU/mL)和完全病毒学应答(CVR)组(HBV DNA＜10 IU/mL)，比较两组患者抗病毒治疗前后一般资料、病毒学、生化学及肝纤维化指标等方面的差异，分析发生LLV的影响因素。此外，比较两组患者抗病毒治疗前、后肝脏炎症和纤维化指标变化程度，分析LLV与肝脏炎症、纤维化进展的关系。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。相关性检验采用Kendall’s tau-b分析。采用Logistic多因素回归分析LLV发生的影响因素。 结果 417例CHB和肝硬化患者中有173例发生LLV，LLV构成比为41.5%，且以10 IU/mL≤HBV DNA＜1000 IU/mL为主，占比达94.8%。Logistic回归分析结果显示，抗病毒治疗前患者HBeAg阳性(OR=3.009，95%CI：1.346~6.729，P=0.007)、有肝硬化或HCC家族史(OR=2.929，95%CI：1.344~6.383，P=0.007)及HBV DNA水平＞1.0×108 IU/mL(OR=10.790，95%CI：1.265~92.007，P=0.030)是LLV发生的危险因素，而AST＞40 U/L(OR=0.355，95%CI：0.171~0.737，P=0.005)是LLV发生的保护因素。抗病毒治疗后HBeAg阳性(OR=4.394，95%CI：1.962~9.841，P＜0.001)仍是LLV发生的危险因素；2年≤抗病毒治疗疗程＜3年(OR=0.175，95%CI：0.046~0.674，P=0.010)和抗病毒治疗疗程≥3年(OR=0.170，95%CI：0.048~0.600，P=0.006)是LLV发生的保护因素。CVR组患者抗病毒治疗后AST、AFP、APRI、FIB-4变化程度(ΔAST、ΔAFP、ΔAPRI、ΔFIB-4)均较LLV组明显(P值均＜0.05)。相关分析结果显示，ΔAST(τ=-0.192，P＜0.001)、ΔAFP(τ=-0.192，P＜0.001)、ΔAPRI(τ=-0.210，P=0.002)、ΔFIB-4(τ=-0.202，P=0.003)与LLV均呈负相关。 结论 高灵敏的HBV DNA检测方法有助于LLV的早期诊断。对于存在肝硬化或肝癌家族史、高水平HBV DNA、HBeAg阳性、低水平AST的患者应进行强效的抗病毒药物治疗，并监测HBV DNA、AST及HBeAg情况，尽早发现LLV。 Abstract:Objective To investigate the influencing factors for low-level viremia (LLV) in patients with chronic hepatitis B (CHB) or hepatitis B liver cirrhosis (LC) receiving antiviral therapy and the association of LLV with the progression of liver inflammation and liver fibrosis. Methods A total of 417 patients with CHB or LC who attended the outpatient service of liver diseases in The Affiliated Hospital of Qingdao University from July 1, 2020 to November 30, 2021 were enrolled, and all patients received oral administration of nucleos(t)ide analogues as antiviral therapy for ≥1 year and had an HBV DNA level of < 2000 IU/mL. According to the HBV DNA level, the patients were divided into LLV group (10 IU/mL ≤HBV DNA < 2000 IU/mL) and complete virologic response (CVR) group (HBV DNA < 10 IU/mL). The two groups were compared in terms of general data, virology, biochemistry, and liver fibrosis markers before and after antiviral therapy to investigate the influencing factors for LLV. Meanwhile, the degree of changes in liver inflammation and liver fibrosis markers after antiviral therapy was compared between the two groups to analyze the association of LLV with the progression of liver inflammation and liver fibrosis. The independent samples t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. The Kendall's tau-b method was used for correlation analysis, and a multivariate logistic regression analysis was used to investigate the influencing factors for LLV. Results Among the 417 patients with CHB or LC, 173 developed LLV, and the constituent ratio of LLV was 41.5%; the patients with 10 IU/mL≤HBV DNA < 1000 IU/mL accounted for 94.8%. The logistic regression analysis showed that positive HBeAg (odds ratio [OR]=3.009, 95%CI: 1.346-6.729, P=0.007), a family history of LC or HCC (OR=2.929, 95%CI: 1.344-6.383, P=0.007), and HBV DNA > 1.0×108 IU/mL (OR=10.790, 95%CI: 1.265-92.007, P=0.030) before antiviral therapy were risk factors for the development of LLV, while aspartate aminotransferase (AST) > 40 U/L (OR=0.355, 95%CI: 0.171-0.737, P=0.005) was a protective factor against LLV; positive HBeAg after antiviral therapy (OR=4.394, 95%CI: 1.962-9.841, P < 0.001) was still a risk factor for LLV, and course of antiviral therapy ≥2 years and < 3 years (OR=0.175, 95%CI: 0.046-0.674, P=0.010) and course of antiviral therapy ≥3 years (OR=0.170, 95%CI: 0.048-0.600, P=0.006) were protective factors against LLV. Compared with the LLV group, the CVR group had significantly greater changes in AST, alpha-fetoprotein (AFP), aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis-4 (FIB-4) (ΔAST, ΔAFP, ΔAPRI, and ΔFIB-4, respectively) (all P < 0.05). Correlation analysis showed that ΔAST (τ=-0.192, P= < 0.001), ΔAFP (τ=-0.192, P < 0.001), ΔAPRI (τ=-0.210, P=0.002), and ΔFIB-4 (τ=-0.202, P=0.003) were all negatively correlated with LLV. Conclusion A highly sensitive HBV DNA detection method helps with the early diagnosis of LLV. Strong antiviral therapy should be given to patients with a family history of LC or HCC, a high HBV DNA level, positive HBeAg, or a low AST level, and HBV DNA, AST, and HBeAg should be closely monitored to identify LLV as early as possible. -
Key words:
- Hepatitis B, Chronic /
- Liver Cirrhosis /
- Low-Level Viremia /
- Root Cause Analysis
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表 1 抗病毒治疗前LLV组和CVR组患者一般资料比较
Table 1. Comparison of general data of patients before antiviral therapy between LLV group and CVR group
指标 LLV组(n=115) CVR组(n=179) 统计值 P值 性别[例(%)] χ2=1.207 0.272 男 81(70.4) 115(64.2) 女 34(29.6) 64(35.8) 年龄(岁) 39.8±9.8 40.3±10.8 t=0.799 0.496 有肝硬化或HCC家族史[例(%)] 30(26.1) 25(14.0) χ2=6.764 0.009 临床诊断[例(%)] χ2=4.094 0.043 CHB 65(56.5) 122(68.2) 肝硬化 50(43.5) 57(31.8) 
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表 2 抗病毒治疗前LLV组和CVR组患者HBV DNA、HBV血清标志物比较
Table 2. Comparison of HBV DNA and HBV serum markers before antiviral therapy in patients between LLV group and CVR group
指标 LLV组(n=90) CVR组(n=150) 统计值 P值 HBV DNA[例(%)] χ2=7.111 0.008 ≤1.0×108 IU/mL 75(83.3) 141(94.0) ＞1.0×108 IU/mL 15(16.7) 9 (6.0) HBeAg阳性[例(%)] 75(83.3) 92(61.3) χ2=12.863 ＜0.001 抗-HBc定量(PEIU/mL) 9.70(3.20~1 920.30) 10.20(0.08~1 765.37) Z=-1.644 0.100
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表 3 抗病毒治疗前LLV组和CVR组患者生化学、PLT及纤维化指数比较
Table 3. Comparison of biochemical, PLT and fibrosis index data of patients before antiviral therapy between LLV group and CVR group
指标 LLV组(n=78) CVR组(n=150) 统计值 P值 ALT(U/L) 58.3(10.4~805.8) 75.3(9.0~1 558.8) Z=-1.223 0.218 AST(U/L) 39.0(12.6~298.0) 49.4(13.0~744.6) Z=-2.439 0.015 GGT(U/L) 30.8(5.9~364.9) 37.6(5.0~451.0) Z=-1.115 0.248 AFP(μg/L) 3.7(0.9~161.0) 4.2(0.8~195.2) Z=-2.469 0.014 PLT(×109/L) 173.4±57.6 149.2±51.7 t=-3.002 0.003 APRI 0.663(0.204~10.234) 1.033(0.144~12.295) Z=-3.669 ＜0.001 FIB-4 1.083(0.282~8.719) 1.792(0.142~13.912) Z=-3.609 ＜0.001 GPR 0.430(0.084~5.666) 0.668(0.061~7.625) Z=-1.894 0.058
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表 4 抗病毒治疗后LLV组和CVR组患者一般资料比较
Table 4. Comparison of general data of patients after antiviral therapy between LLV group and CVR group
指标 LLV组(n=173) CVR组(n=244) 统计值 P值 性别[例(%)] χ2=0.753 0.386 男 130(75.1) 174(71.3) 女 43(24.9) 70(28.7) 年龄(岁) 42.4±9.9 42.1±10.9 t=1.427 0.154 肝硬化或HCC家族史[例(%)] 44(25.4) 34(13.9) χ2=8.802 0.003 临床诊断 χ2=0.099 0.745 CHB 123(71.1) 170(69.7) 肝硬化 50(28.9) 74(30.3) 治疗疗程[例(%)] χ2=18.182 ＜0.001 1年≤疗程＜2年 49(28.3) 31(12.7) 2年≤疗程＜3年 46(26.6) 62(25.4) 疗程≥3年 78(45.1) 151(61.9)
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表 5 抗病毒治疗后LLV组和CVR组患者HBV血清学标志物比较
Table 5. Comparison of HBV serum markers after antiviral therapy in patients between LLV group and CVR group
指标 LLV组(n=100) CVR组(n=157) 统计值 P值 HBsAg定量(IU/mL) 3 141.9(19.6~34 499.9) 2 313.8(0.1~44 191.8) Z=-2.139 0.032 HBeAg阳性[例(%)] 69(69.0) 63(40.1) χ2=20.385 ＜0.001 抗-HBc定量(PEIU/mL) 1.5(0.1~53.1) 0.9(0.1~30.9) Z=-3.619 ＜0.001
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表 6 抗病毒治疗后LLV组和CVR组患者生化学指标比较
Table 6. Comparison of biochemical of patients after antiviral therapy between LLV group and CVR group
指标 LLV组(n=166) CVR组(n=234) Z值 P值 ALT(U/L) 25.9(6.0~119.0) 21.0(7.0~84.0) -3.682 ＜0.001 AST(U/L) 21.1(12.1~65.0) 20.0(12.0~173.0) -1.274 0.203 GGT(U/L) 17.9(7.0~116.5) 18.0(6.0~220.0) -0.367 0.713 AFP(μg/L) 2.7(0.9~15.8) 2.3(0.7~14.5) -3.705 ＜0.001
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表 7 抗病毒治疗后LLV组和CVR组患者PLT、APRI、FIB-4、GPR指数比较
Table 7. Comparison of PLT, APRI、FIB-4、GPR index after antiviral therapy in patients between LLV group and CVR group
指标 LLV组(n=115) CVR组(n=181) 统计值 P值 PLT(×109/L) 186.7±7.1 182.3±4.5 t=-1.165 0.245 APRI 0.308(0.125~4.422) 0.324(0.134~1.568) Z=-0.275 0.783 FIB-4 0.245(0.050~1.960) 0.264(0.080~2.810) Z=-2.174 0.145 GPR 0.246(0.052~1.964) 0.264(0.085~2.728) Z=-0.718 0.473
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表 8 抗病毒治疗后LLV组和CVR组患者肝纤维化五项及CD4+绝对计数比较
Table 8. Comparison of liver fibrosis indicators and absolute CD4+ count after antiviral therapy in patients between LLV group and CVR group
指标 LLV组(n=46) CVR组(n=97) Z值 P值 透明质酸(mg/L) 53.5(0.7~120.4) 53.6(0.6~168.9) -0.311 0.756 层粘连蛋白(μg/mL) 19.9(6.3~36.7) 22.8(2.0~81.7) -1.316 0.188 Ⅲ型前胶原N端肽(μg/L) 25.1(13.9~61.5) 23.4(12.6~137.9) -1.197 0.231 Ⅳ型胶原(μg/L) 16.0(12.3~48.9) 16.4(10.2~44.4) -0.612 0.541 甘胆酸(mg/L) 1.2(0.1~93.5) 0.9(0.1~76.1) -1.192 0.233 CD4+绝对计数(/mm3) 609(153~1209) 556(166~1247) -1.412 0.156
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表 9 LLV组和CVR组患者抗病毒治疗前后ΔALT、ΔAST及ΔAFP比较
Table 9. Comparison of ΔALT, ΔAST and ΔAFP before and after antiviral therapy in patients between LLV group and CVR group
指标 LLV组(n=178) CVR组(n=111) Z值 P值 ΔALT(U/L) 22.8(-91.1~550.2) 36.9(-79.2~1 542.2) -1.402 0.161 ΔAST(U/L) 16.3(-8.1~391.0) 29.5(-22.0~646.8) -2.373 0.018 ΔAFP(μg/L) 0.5(-13.3~156.7) 1.7(-2.3~194.0) -3.984 ＜0.001
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表 10 LLV组和CVR组患者抗病毒治疗前后肝纤维化指数比较
Table 10. Comparison of liver fibrosis index before and after antiviral therapy between LLV group and CVR group
指标 LLV组(n=48) CVR组(n=101) Z值 P值 ΔPLT(×109/L) 16(-82~127) 24(-76~173) -0.434 0.664 ΔAPRI 0.294(-0.471~5.573) 0.633(-0.674~11.477) -3.124 0.002 ΔFIB-4 0.145(-1.723~4.026) 0.532(-3.813~10.859) -2.994 0.003 ΔGRP 0.244(-0.526~5.552) 0.448(-0.605~6.645) -1.796 0.073
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