病毒学应答状态对代偿期乙型肝炎肝硬化患者疾病进展的影响
DOI: 10.3969/j.issn.1001-5256.2021.08.014
Influence of virologic response on disease progression in patients with compensated hepatitis B cirrhosis
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摘要:
目的 研究是否获得持续性病毒学应答对接受核苷(酸)类似物(NAs)抗病毒治疗的代偿期乙型肝炎肝硬化患者疾病进展、肝癌发生的影响。 方法 纳入2013年1月1日—12月31日就诊于上海中医药大学附属曙光医院,随访5年以上、接受抗病毒治疗的代偿期乙型肝炎肝硬化患者542例,依据随访期间病毒学应答状态分为持续病毒学应答队列(n=496)和非持续病毒学应答队列(n=46),以患者疾病进展为终点事件,收集、整理患者5年随访期间一般资料及检验检查资料。符合正态分布的计量资料两组间比较采用t检验;不服从正态分布的计量资料两组间比较采用Mann-Whitney U检验。计数资料两组间比较采用χ2检验。多元分析采用logistic回归分析。用危险度测量因素与肝硬化疾病进展的相关程度,用风险比(HR)及95%CI表示。应用寿命表法计算患者1、3、5年疾病无进展生存率,Kaplan-Meier法绘制生存曲线;采用log-rank检验进行单因素分析,Cox模型进行多因素回归分析。 结果 542例患者的平均疾病无进展生存时间为62.50(95%CI:61.01~63.92)个月,1、3、5年疾病无进展生存率分别为94%、82%、71%。持续病毒学应答队列患者平均疾病无进展生存时间为63.10(95%CI:61.65~64.55)个月,较非持续病毒学应答队列[55.95(95%CI :50.19~61.71)个月]延长,两组5年疾病无进展生存率差异有统计学意义(χ2=12.058,P=0.001)。持续病毒学应答队列患者5年累积肝癌发生率低,两组差异有统计学意义(20.6% vs 34.8%,χ2=5.759,P=0.016);持续病毒学应答队列患者5年累积肝硬化失代偿发生率低,两组差异有统计学意义(5.0% vs 15.2%,χ2=8.239,P=0.004)。病毒学应答是影响疾病进展的独立危险因素[HR(95%CI)=2.32(1.45~3.72)]。 结论 持续病毒学应答可降低代偿期乙型肝炎肝硬化患者并发症及肝癌发生率,改善长期预后、延长生存时间。 Abstract:Objective To investigate the effect of sustained virologic response on disease progression and the development of hepatocellular carcinoma (HCC) in patients with compensated hepatitis B cirrhosis receiving antiviral therapy with nucleos(t)ide analogues (NAs). Methods A total of 542 patients with compensated hepatitis B cirrhosis who attended Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from January 1 to December 31, 2013, received antiviral therapy, and were followed up for more than 5 years were enrolled, and according to the status of virologic response during follow-up, they were divided into a sustained virologic response cohort with 496 cases and a non-sustained virologic response cohort with 46 cases. With disease progression as the outcome event, general information and examination data were collected during the 5-year follow-up period. The t-test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. A multivariate logistic regression analysis was performed; relative risk and 95% confidence interval (CI) were used to investigate the degree of correlation of factors measured with the progression of liver cirrhosis. The life-table method was used to calculate the 1-, 3-, and 5-year progression-free survival rates, and the Kaplan-Meier method was used to plot survival curves; the log-rank test was used for univariate analysis, and the Cox regression model was used for multivariate regression analysis. Results For the 542 patients, the mean progression-free survival time was 62.50 months (95% CI: 61.01-63.92), and the 1-, 3-, and 5-year progression-free survival rates were 94%, 82%, and 71%, respectively. The sustained virologic response cohort had a significantly longer mean progression-free survival time than the non-sustained virologic response cohort [63.10 months (95% CI: 61.65-64.55) vs 55.95 months (95% CI: 50.19-61.71), χ2=12.058, P=0.001]. Compared with the non-sustained virologic response cohort, the sustained virologic response cohort had significantly lower 5-year cumulative incidence rate of HCC than (20.6% vs 34.8%, χ2=5.759, P=0.016) and 5-year cumulative incidence rate of decompensated cirrhosis (5.0% vs 15.2%, χ2=8.239, P=0.004). Virologic response was an independent risk factor for disease progression (hazard ratio=2.32, 95% CI: 1.45-3.72). Conclusion Sustained virologic response can reduce the incidence rates of complications and HCC, improve long-term prognosis, and prolong survival time in patients with compensated hepatitis B cirrhosis. -
Key words:
- Hepatitis B /
- Liver Cirrhosis /
- Sustained Virologic Response
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表 1 持续病毒学应答队列与非持续病毒学应答队列患者基线资料比较
指标 所有患者(n=542) 持续病毒学应答队列(n=496) 非持续病毒学应答队列(n=46) 统计值 P值 男/女(例) 376/166 341/155 35/11 χ2=1.067 0.302 年龄(岁) 51.90±10.39 52.10±10.38 50.20±10.37 t=1.155 0.249 饮酒史[例(%)] 30(5.5) 26(5.2) 4(8.7) χ2=0.960 0.327 肝病家族史[例(%)] 221(40.8) 203(40.9) 18(39.1) χ2=0.056 0.812 糖尿病史[例(%)] 47(8.7) 40(8.1) 7(15.2) χ2=2.720 0.099 HBeAg阳性[例(%)] 134(24.7) 118(23.8) 16(34.8) χ2=2.733 0.098 ALT(U/L) 31.30±18.82 30.10±14.91 44.10±40.38 t=-4.926 <0.001 TBil(μmol/L) 21.60±11.53 21.60±11.62 21.40±10.62 t= 0.072 0.943 Alb(g/L) 43.30±5.59 43.30±5.46 42.20±6.88 t=1.403 0.161 SCr(μmol/L) 68.00±14.27 68.00±14.44 67.20±12.33 t=0.388 0.698 PLT(×109/L) 111.50±60.12 112.60±61.13 99.90±46.85 t=1.367 0.172 INR 1.12±0.17 1.10±0.17 1.10±0.10 t=0.492 0.623 AFP(ng/ml) 51(9.4) 43(8.7) 8(17.4) χ2=3.757 0.053 MPV(mm) 12.00±1.37 12.00±1.38 12.00±1.33 t=0.086 0.932 MELD评分 5.30±3.33 5.40±3.35 5.10±3.13 t=0.463 0.644 APRI≥2[例(%)] 70(12.9) 61(12.3) 9(19.6) χ2=1.976 0.160 FIB-4≥3.25[例(%)] 242(44.6) 221(44.6) 21(45.7) χ2=0.020 0.886 注:MPV, 门静脉宽度。 表 2 病毒学应答对患者疾病无进展生存时间影响
组别 例数 疾病无进展[例(%)] 疾病无进展生存时间 平均时间(月) 标准误 95%CI 持续病毒学应答队列 496 379(76.4) 63.10 0.740 61.65~64.55 非持续病毒学应答队列 46 25(54.3) 55.95 2.939 50.19~61.71 合计 542 404(74.5) 62.50 0.726 61.07~63.92 表 3 病毒学应答对患者未发生肝癌生存时间影响
组别 例数 未发生肝癌[例(%)] 未发生肝癌生存时间 平均时间(月) 标准误 95%CI 持续病毒学应答队列 496 394(79.4) 64.12 0.704 62.74~65.50 非持续病毒学应答队列 46 30(65.2) 58.51 2.888 52.84~64.17 合计 542 424(78.2) 63.65 0.693 62.29~65.00 表 4 病毒学应答对患者未发生失代偿生存时间影响
组别 例数 未发生失代偿[例(%)] 未发生失代偿生存时间 平均时间(月) 标准误 95%CI 持续病毒学应答队列 496 471(95.0) 69.67 0.297 69.09~70.26 非持续病毒学应答队列 46 39(84.8) 67.34 1.432 64.54~70.15 合计 542 510(94.1) 63.65 0.693 68.89~70.06 表 5 542例患者疾病进展Cox多因素分析
影响因素 回归系数 标准误 Wald P值 HR 95%CI 性别 -0.481 0.202 5.697 0.017 0.62 0.42~0.92 年龄 0.040 0.009 17.677 <0.001 1.04 1.02~1.06 肝病家族史 0.363 0.179 4.118 0.042 1.44 1.01~2.04 Alb 0.913 0.200 20.749 <0.001 2.49 1.68~3.69 PLT 0.492 0.189 6.752 0.009 1.64 1.13~2.37 AFP 1.047 0.228 21.061 <0.001 2.85 1.82~4.45 病毒学应答 0.841 0.241 12.184 <0.001 2.32 1.45~3.72 表 6 496例持续病毒学应答患者疾病进展Cox多因素分析
影响因素 回归系数 标准误 Wald P值 HR 95%CI 性别 -0.445 0.202 4.861 0.037 0.64 0.43~0.95 年龄 0.669 0.191 12.240 <0.001 1.95 1.34~2.84 肝病家族史 0.337 0.177 3.629 0.057 1.40 0.99~1.98 Alb 0.933 0.199 22.027 <0.001 2.54 1.72~3.75 PLT 0.547 0.190 8.293 0.004 1.73 1.19~2.51 AFP 1.118 0.222 25.254 <0.001 3.06 1.98~4.73 -
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