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中华实验和临床感染病杂志(电子版) ›› 2025, Vol. 19 ›› Issue (06) : 335 -344. doi: 10.3877/cma.j.issn.1674-1358.2025.06.003

论著

人类免疫缺陷病毒感染/获得性免疫缺陷综合征患者接受抗反转录病毒治疗四年后发生免疫重建不全的风险预测模型
张亚琼1, 张雨霖1, 丁科1, 张晓霞1, 胡文佳1, 陈铁龙2, 宋世会1, 熊勇1,()   
  1. 1 430071 武汉市,武汉大学中南医院感染科、武汉大学艾滋病研究中心
    2 430071 武汉市,武汉大学中南医院Ⅰ期临床研究室
  • 收稿日期:2025-04-30 出版日期:2025-12-15
  • 通信作者: 熊勇
  • 基金资助:
    国家重点研发计划(2023YFC2306603); 武汉大学中南医院学科培育项目(ZNXKPY2021025)

Risk prediction model for incomplete immune reconstitution in patients with human immunodeficiency virus infection/acquired immune deficiency syndrome after 4 years of anti-retroviral therapy

Yaqiong Zhang1, Yulin Zhang1, Ke Ding1, Xiaoxia Zhang1, Wenjia Hu1, Tielong Chen2, Shihui Song1, Yong Xiong1,()   

  1. 1 Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, AIDS Research Center of Wuhan University, Wuhan 430071, China
    2 Phase I Clinical Research Laboratory, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
  • Received:2025-04-30 Published:2025-12-15
  • Corresponding author: Yong Xiong
引用本文:

张亚琼, 张雨霖, 丁科, 张晓霞, 胡文佳, 陈铁龙, 宋世会, 熊勇. 人类免疫缺陷病毒感染/获得性免疫缺陷综合征患者接受抗反转录病毒治疗四年后发生免疫重建不全的风险预测模型[J/OL]. 中华实验和临床感染病杂志(电子版), 2025, 19(06): 335-344.

Yaqiong Zhang, Yulin Zhang, Ke Ding, Xiaoxia Zhang, Wenjia Hu, Tielong Chen, Shihui Song, Yong Xiong. Risk prediction model for incomplete immune reconstitution in patients with human immunodeficiency virus infection/acquired immune deficiency syndrome after 4 years of anti-retroviral therapy[J/OL]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2025, 19(06): 335-344.

目的

分析人类免疫缺陷病毒感染/获得性免疫缺陷综合征(HIV/AIDS)患者发生免疫重建不全的危险因素,构建并验证可视化列线图预测模型。

方法

回顾性分析2016年1月1日至2020年11月30日就诊于武汉大学中南医院的302例HIV/AIDS初治患者在抗反转录病毒治疗(ART)启动前的临床资料,根据启动ART后连续4年CD4+ T淋巴细胞计数分为免疫学应答组(IRs组)(202例)和免疫重建不全组(INRs组)(100例);所有参与者按7∶3比例随机分配至训练集(212例)和验证集(90例)。采用随机森林、Lasso回归及多因素Logistic回归分析筛选预测因子并构建列线图预测模型。比较训练集和验证集的受试者工作特征(ROC)曲线、校准曲线和临床决策曲线评估模型的性能。

结果

212例训练集中免疫重建不全HIV/AIDS患者72例,发生率为33.96%;90例验证集中免疫重建不全HIV/AIDS患者28例,发生率为31.11%。训练集中,INRs组患者基线CD4+ T淋巴细胞计数、白细胞(WBC)、血小板(PLT)和血红蛋白(Hb)水平显著低于IRs组(P均<0.05);INRs组乙型肝炎病毒(HBV)合并感染者占比、ART启动年龄、基线HIV载量、丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)水平均显著高于IRs组(P均<0.05);两组感染途径、WHO分期差异有统计学意义(P均<0.05)。而两组患者性别、丙型肝炎病毒(HCV)抗体、ART方案、身体质量指数(BMI)、ART启动延迟、血肌酐(SCr)、甘油三酯(TG)和胆固醇(TC)差异无统计学意义(P均>0.05)。随机森林筛选的免疫重建不全预测因子为基线CD4+ T淋巴细胞计数、ART启动年龄和WBC;Lasso回归筛选的免疫重建不全预测因子为基线CD4+ T淋巴细胞计数、ART启动年龄和HBV合并感染。整合上述因子(基线CD4+ T淋巴细胞计数、ART启动年龄、WBC和HBV合并感染)行多因素Logistic回归分析结果显示,较高的基线CD4+ T淋巴细胞计数(OR=0.986、95%CI:0.982~0.990、P<0.001)为HIV/AIDS患者发生免疫重建不全的保护因素,而ART启动年龄大(OR=1.035、95%CI:1.009~1.061、P=0.008)和HBV合并感染(OR=8.326、95%CI:1.836~37.765、P=0.006)则均为HIV/AIDS患者发生免疫重建不全的独立危险因素。基于上述3个预测因子(基线CD4+ T淋巴细胞计数、ART启动年龄和HBV合并感染)构建免疫重建不全风险预测模型,训练集和验证集ROC曲线下面积(AUC)分别为0.882和0.825,训练集与验证集校准曲线的平均绝对误差分别为0.038和0.030,Brier评分分别为0.135和0.154,临床决策曲线(DCA)分析表明,预测模型在10%~70%阈值概率范围内,于训练集及验证集中均具临床实用价值。

结论

以基线CD4+ T淋巴细胞计数、ART启动年龄和HBV合并感染构建的列线图模型在预测HIV/AIDS患者免疫重建不全方面具有较高性能,有助于临床风险评估及决策。

Objective

To analyze the risk factors for incomplete immune reconstitution in patients with human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS), and to construct and validate a visual nomogram prediction model.

Methods

The clinical data of 302 patients with HIV/AIDS who were treated for the first time at Zhongnan Hospital of Wuhan University from January 1st, 2016 to November 30th, 2020 before the initiation of antiretroviral therapy (ART) were analyzed, retrospectively. The patients were divided into immunological response group (IRs group) (202 cases) and incomplete immune reconstitution group (INRs group) (100 cases) based on the CD4+ T lymphocyte count for four consecutive years after the initiation of ART. All participants were randomly assigned to the training set (212 cases) and the validation set (90 cases) with a ratio of 7∶3. Random forest, Lasso regression and multivariate Logistic regression analysis were used to screen the predictive factors and construct a nomogram prediction model. The performance of the model was evaluated by comparing the receiver operating characteristic (ROC) curves, calibration curves and clinical decision curves of the training set and the validation set.

Results

Among the 212 cases in the training set, 72 cases had incomplete immune reconstitution, with an incidence rate of 33.96%; among the 90 cases in the validation set, 28 cases had incomplete immune reconstitution, with an incidence rate of 31.11%. In the training set, the baseline CD4+ T lymphocyte count, white blood cell (WBC), platelet (PLT), and hemoglobin (Hb) levels of INRs group were significantly lower than those of IRs group (all P<0.05); the proportion of patients with co-infection of hepatitis B virus (HBV), age at ART initiation, baseline HIV load, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels of INRs group were significantly higher than those of the IRs group (all P<0.05); the route of infection and WHO stage between the two groups were with significant differences (both P<0.05). However, there were no statistically significant differences in gender, hepatitis C virus (HCV) antibody, ART regimen, body mass index (BMI), ART initiation delay, serum creatinine (SCr), triglyceride (TG) and cholesterol (TC) between the two groups (all P>0.05). The immune reconstitution incomplete predictors selected by random forest were baseline CD4+ T lymphocyte count, ART initiation age and WBC; the immune reconstitution incomplete predictors selected by Lasso regression were baseline CD4+ T lymphocyte count, ART initiation age and HBV co-infection. The multivariate Logistic regression analysis of the above factors (baseline CD4+ T lymphocyte count, ART initiation age, WBC and HBV co-infection) showed that a higher baseline CD4+ T lymphocyte count (OR=0.986, 95%CI: 0.982-0.990, P<0.001) was a protective factor for incomplete immune reconstitution in patients with HIV/AIDS , while a later ART initiation age (OR=1.035, 95%CI: 1.009-1.061, P=0.008) and HBV co-infection (OR=8.326, 95%CI: 1.836-37.765, P=0.006) were all independent risk factors for incomplete immune reconstitution in HIV/AIDS patients. Based on the above three predictors (baseline CD4+ T lymphocyte count, ART initiation age and HBV co-infection), a risk prediction model for incomplete immune reconstitution was constructed. The area under the ROC curve (AUC) of the training set and validation set were 0.882 and 0.825, respectively. The mean absolute errors of the calibration curves of the training set and validation set were 0.038 and 0.030, respectively; and the Brier scores were 0.135 and 0.154, respectively. The clinical decision curve (DCA) analysis indicated that the prediction model had clinical practical value in both the training set and validation set within the threshold probability range of 10% to 70%.

Conclusions

The nomogram model constructed based on baseline CD4+ T lymphocyte count, age at ART initiation and HBV co-infection has high performance in predicting immune reconstitution failure, and is helpful for clinical risk assessment and clinical decision-making.

图1 本研究参与者筛选与纳入流程图
表1 训练集与验证集HIV/AIDS患者的基线特征
基线特征 训练集(212例) 验证集(90例) 统计量 P
性别 [例(%)] χ2=0.073 0.788a
16(7.55) 6(6.67)
196(92.45) 84(93.33)
HBV合并感染 [例(%)] 16(7.55) 6(6.67) χ2=0.073 0.788a
抗-HCV阳性 [例(%)] 2(0.94) 2(2.22) 0.585b
感染途径 [例(%)] χ2=1.108 0.292a
异性传播 72(33.96) 25(27.78)
同性传播 140(66.04) 65(72.22)
ART方案 [例(%)] χ2=1.057 0.577b
NRTI + NNRTI 166(78.30) 75(83.33)
NRTI + INSTI 41(19.34) 13(14.45)
其他 5(2.36) 2(2.22)
WHO分期 [例(%)] Z=-0.294 0.769
Ⅰ~Ⅱ期 67(31.60) 30(33.33)
Ⅲ~Ⅳ期 145(68.40) 60(66.67)
ART启动年龄 [MP25P75),岁] 31.50(26.00,47.00) 29.50(24.00,43.50) Z=-0.907 0.364
BMI [MP25P75),kg/m2] 21.83(19.60,23.53) 21.42(19.46,23.44) Z=-0.128 0.898
ART启动延迟 [MP25P75),d] 24.00(15.00,56.00) 29.50(17.75,46.25) Z=-0.927 0.354
基线CD4+ T细胞 [MP25P75),个/μl] 207.00(81.75,266.75) 199.00(88.25,271.00) Z=-0.124 0.901
基线HIV载量 [MP25P75),拷贝/ml] 4.71(3.98,5.27) 4.54(3.91,5.02) Z=-1.218 0.223
WBC [MP25P75),×109/L] 4.85(3.81,6.06) 4.73(3.79,6.02) Z=-0.475 0.634
PLT [MP25P75),×109/L] 192.00(161.5,230.75) 185.00(150.00,230.00) Z=-0.970 0.332
Hb [MP25P75),g/L] 141.00(125.00,151.00) 145.00(124.00,154.25) Z=-1.438 0.150
SCr [MP25P75),μmol/L] 71.15(66.00,79.00) 71.85(66.00,79.10) Z=-0.465 0.642
TG [MP25P75),mmol/L] 1.23(0.88,1.73) 1.17(0.83,1.56) Z=-0.963 0.335
TC(
± s,mmol/L)
3.83 ± 0.85 3.85 ± 0.90 t=-0.174 0.862
ALT [MP25P75),U/L] 22.00(15.25,38.00) 23.00(16.75,33.25) Z=-0.144 0.885
AST [MP25P75),U/L] 26.00(21.00,35.75) 26.00(20.00,34.25) Z=-0.766 0.444
表2 训练集中IRs组和INRs组AIDS患者的基线特征
基线特征 IRs组(140例) INRs组(72例) 统计量 P
性别 [例(%)] χ2=1.985 0.159a
8(5.71) 8(11.11)
132(94.29) 64(88.89)
HBV合并感染 [例(%)] 4(2.86) 12(16.67) χ2=12.995 <0.001a
抗-HCV阳性 [例(%)] 2(1.43) 0(0.00) 0.549b
感染途径 [例(%)] χ2=4.020 0.045a
异性传播 41(29.29) 31(43.06)
同性传播 99(70.71) 41(56.94)
ART方案 [例(%)] 0.648b
NRTI + NNRTI 111(79.29) 55(76.39)
NRTI + INSTI 25(17.86) 16(22.22)
其他 4(2.85) 1(1.39)
WHO分期 [例(%)] Z=-3.969 <0.001
Ⅰ~Ⅱ期 57(40.71) 10(13.89)
Ⅲ~Ⅳ期 83(59.29) 62(86.11)
ART启动年龄 [MP25P75),岁] 28.00(23.25,37.75) 38.50(29.00,52.50) Z=-4.508 <0.001
BMI [(MP25P75),kg/m2] 21.97(19.63,23.89) 21.68(19.17,22.93) Z=-1.403 0.161
ART启动延迟 [MP25P75),d] 25.00(15.25,66.00) 23.50(14.00,39.00) Z=-1.459 0.145
基线CD4+ T细胞 [MP25P75),个/μl] 243.00(174.25,302.00) 73.50(13.25,163.00) Z=-8.243 <0.001
基线HIV载量 [MP25P75),拷贝/ml] 4.62(3.87,5.05) 5.00(4.25,5.47) Z=-2.803 0.005
WBC [MP25P75),×109/L] 5.14(4.30,6.34) 4.10(3.10,5.65) Z=-4.072 <0.001
PLT [MP25P75),×109/L] 197.50(174.00,234.00) 172.50(138.25,226.00) Z=-2.721 0.007
Hb [MP25P75),g/L] 145.00(132.00,152.00) 131.00(116.00,147.75) Z=-4.204 <0.001
SCr [MP25P75),μmol/L] 71.35(67.15,78.28) 70.10(64.35,82.65) Z=-0.089 0.929
TG [MP25P75),mmol/L] 1.22(0.84,1.63) 1.35(0.99,1.89) Z=-1.651 0.099
TC(
±s,mmol/L)
3.85±0.79 3.80±0.95 t=0.359 0.720
ALT [MP25P75),U/L] 21.00(15.00,30.75) 25.50(17.00,46.50) Z=-2.485 0.013
AST [MP25P75),U/L] 25.00(21.00,31.00) 30.00(22.25,41.00) Z=-3.229 0.001
图2 基于随机森林免疫重建不全预测变量的筛选 注:A:袋外数据误差随树的数量变化趋势;B:基于平均准确率下降度的特征重要性排序;C:基于平均基尼指数减少量的特征重要性排序。HBV:乙型肝炎病毒、HCV:丙型肝炎病毒、WBC:白细胞、PLT:血小板、Hb:血红蛋白、SCr:血肌酐、TG:甘油三酯、TC:胆固醇、ALT:丙氨酸氨基转移酶、AST:天门冬氨酸氨基转移酶、BMI:身体质量指数
图3 基于Lasso回归筛选免疫重建不全预测变量 注:A:系数路径图;B:交叉验证误差曲线图。Log(λ):正则化参数对数
表3 HIV/AIDS患者发生免疫重建不全的多因素Logistic回归分析
图4 预测HIV/AIDS患者发生免疫重建不全的列线图
图5 训练集与验证集ROC曲线 注:A:训练集;B:验证集
图6 训练集与验证集校准曲线 注:Apparent代表模型的预测概率与实际概率的拟合情况,Bias-corrected代表对模型预测结果的偏差进行校正后的表现,Ideal代表模型的预测概率与实际概率完全一致。A:训练集;B:验证集
图7 训练集与验证集临床决策曲线 注:A:训练集;B:验证集
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