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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
DOI: 10.3969/j.issn.1001-5256.2022.12.008
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。
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
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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。 Abstract:Objective To investigate the influencing factors for low-level viremia (LLV) and their dynamic changes in chronic hepatitis B (CHB) patients treated with nucleos(t)ide analogues (NAs) for the first time. Methods A retrospective analysis was performed for 78 CHB patients who attended Department of Infectious Diseases, The First Affiliated Hospital of Nanchang University, from November 2020 to March 2022 and received antiviral therapy with NAs for at least 12 months, and according to HBV DNA level during treatment, they were divided into sustained virologic response (SVR) group with 58 patients and LLV group with 20 patients. 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 or the Fisher's exact test was used for comparison of categorical data between two groups. The multivariate Logistic regression analysis was used to investigate the independent influencing factors for LLV and establish a predictive model, and the receiver operating characteristic (ROC) curve was used to evaluate the predictive value of this model. The Kaplan-Meier method was used to analyze cumulative HBV DNA negative conversion rate, and the Log-rank test was used for comparison. The analysis of variance with repeated measures was used to analyze the differences in HBV DNA and HBsAg between the two groups or within each group at weeks 0, 12, 24, 36, and 48. Results Compare with the SVR group, the LLV group had significantly higher HBeAg positive rate (90.0% vs 48.3%, χ2=10.701, P=0.001), log(HBV DNA) value (7.26±1.46 vs 5.65±1.70, t=-4.178, P < 0.001), and log(HBsAg) value (4.53±0.86 vs 3.44±0.93, t=-4.813, P < 0.001) and significantly lower age [29 (26-34) vs 33 (30-43), Z=-2.751, P=0.009], alanine aminotransferase (ALT) [67.0 (54.0-122.0)U/L vs 111.0 (47.0-406.0)U/L, Z=-2.203, P=0.028], aspartate aminotransferase [43.5 (32.8-62.8) U/L vs 77.5 (35.0-213.0)U/L, Z=-2.466, P=0.014], and liver stiffness measurement [7.7 (6.3-8.5)kPa vs 8.9 (7.2-11.4)kPa, Z=-2.022, P=0.043]. The multivariate logistic regression analysis showed that baseline HBV DNA (odds ratio [OR]=2.365, 95% confidence interval [CI]: 1.220-4.587, P=0.011), HBsAg (OR=4.229, 95% CI: 1.098-16.287, P=0.036), and ALT (OR=0.965, 95% CI: 0.937-0.994, P=0.018) were independent influencing factors for LLV in CHB patients, and the predictive model of Logit(MLLV)=-8.668+1.441×lgHBsAg+0.598×lgHBV DNA-0.016×ALT was established based on these factors, which had a larger area under the ROC curve than HBV DNA, HBsAg, and ALT (0.931 vs 0.774/0.856/0.666), with a sensitivity of 85.00% and a specificity of 93.10% at the optimal cut-off value of 0.44. The CHB patients with baseline HBV DNA > 7.29 lgIU/mL or HBsAg > 4.38 lgIU/mL had a significantly lower DNA negative conversion rate than those with DNA ≤7.29 lgIU/mL or HBsAg ≤4.38 lgIU/mL (χ2=22.52 and 26.35, both P < 0.001). In the CHB patients, the highest reduction rates of HBV DNA and HBsAg were observed at weeks 12 and 24, respectively, and the LLV group had significantly higher levels of HBV DNA and HBsAg than the SVR group at weeks 0, 12, 24, 36, and 48 (HBV DNA: t=-4.084, -4.526, -5.688, -7.123, and -6.266, all P < 0.001; HBsAg: t=-4.652, -4.691, -4.952, -4.804, and -4.407, all P < 0.001). Conclusion For the CHB patients treated with NAs for the first time, those with high HBV DNA load, high HBsAg quantification, and low ALT level at baseline are more likely to develop LLV, and dynamic monitoring of these indices is of great significance to observe the onset of LLV. -
Key words:
- Hepatitis B, Chronic /
- Low-level Viremia /
- Forecasting
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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
注：a，不同HBV DNA水平患者；b，不同HBsAg水平患者。
图 3 不同基线HBV DNA和HBsAg的CHB患者HBV DNA累积转阴率
Figure 3. Cumulative negative rate of HBV DNA in CHB patients with different baseline HBV DNA and HBsAg
注：a，期间HBV DNA的比较；b，治疗期间HBsAg的比较。*P＜0.05。
图 4 两组患者HBV DNA和HBsAg水平变化
Figure 4. Dynamic changes of HBV DNA and HBsAg in two groups
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。
图 5 所有患者HBV DNA和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值 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 
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表 2 MLLV模型的建立
Table 2. Establishment of the MLLV model
变量 B值 SE Wald OR 95%CI P值 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
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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值 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
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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值 P值 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。
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