DataSheet_1_Impact of Early Versus Late Antiretroviral Treatment Initiation on Naive T Lymphocytes in HIV-1-Infected Children and Adolescents – The-ANRS-EP59-CLEAC Study.docx

BackgroundThe early initiation of antiretroviral therapy (ART) in HIV-1-infected infants reduces mortality and prevents early CD4 T-cell loss. However, the impact of early ART on the immune system has not been thoroughly investigated in children over five years of age or adolescents. Here, we describe the levels of naive CD4 and CD8 T lymphocytes (CD4/CD8TN), reflecting the quality of immune reconstitution, as a function of the timing of ART initiation (early (<6 months) versus late (≥24 months of age)).
MethodsThe ANRS-EP59-CLEAC study enrolled 27 children (5-12 years of age) and nine adolescents (13-17 years of age) in the early-treatment group, and 19 children (L-Ch) and 21 adolescents (L-Ado) in the late-treatment group. T lymphocytes were analyzed by flow cytometry and plasma markers were analyzed by ELISA. Linear regression analysis was performed with univariate and multivariate models.
ResultsAt the time of evaluation, all patients were on ART and had a good immunovirological status: 83% had HIV RNA loads below 50 copies/mL and the median CD4 T-cell count was 856 cells/µL (interquartile range: 685-1236 cells/µL). In children, early ART was associated with higher CD8TN percentages (medians: 48.7% vs. 31.0%, P = 0.001), and a marginally higher CD4TN (61.2% vs. 53.1%, P = 0.33). In adolescents, early ART was associated with low CD4TN percentages and less differentiated memory CD8 T cells. CD4TN and CD8TN levels were inversely related to cellular activation and gut permeability.
ConclusionIn children and adolescents, the benefits of early ART for CD8TN were clear after long-term ART. The impact of early ART on CD4TN appears to be modest, because pediatric patients treated late respond to HIV-driven CD4 T-lymphocyte loss by the de novo production of TN cells in the thymus. Our data also suggest that current immune activation and/or gut permeability has a negative impact on TN levels.
Clinical Trial RegistrationClinicalTrials.gov, identifier NCT02674867.

背景：对HIV-1感染婴儿尽早启动抗反转录病毒治疗（antiretroviral therapy, ART）可降低死亡率，并预防早期CD4 T细胞丢失。然而，早期ART对免疫系统的影响尚未在5岁以上儿童及青少年群体中得到充分研究。本研究旨在探讨反映免疫重建质量的初始型CD4和CD8 T淋巴细胞（naive CD4 and CD8 T lymphocytes, CD4TN/CD8TN）水平与ART启动时机的关联，其中启动时机分为早期（<6月龄）与晚期（≥24月龄）。
方法：本研究的ANRS-EP59-CLEAC队列共纳入早期治疗组的27名儿童（5~12岁）与9名青少年（13~17岁），以及晚期治疗组的19名儿童（L-Ch）与21名青少年（L-Ado）。采用流式细胞术分析T淋巴细胞，通过酶联免疫吸附试验（enzyme-linked immunosorbent assay, ELISA）检测血浆标志物。采用单变量与多变量模型进行线性回归分析。
结果：评估时所有受试者均接受ART治疗，且具备良好的免疫病毒学状态：83%的受试者HIV RNA载量低于50拷贝/毫升，CD4 T细胞计数中位数为856细胞/微升（四分位间距：685~1236细胞/微升）。在儿童群体中，早期ART与更高的CD8TN百分比相关（中位数：48.7% vs. 31.0%，P=0.001），同时CD4TN水平也略有升高（61.2% vs. 53.1%，P=0.33）。在青少年群体中，早期ART与较低的CD4TN百分比及分化程度更低的记忆性CD8 T细胞相关。CD4TN与CD8TN水平与细胞活化及肠道通透性呈负相关。
结论：在儿童与青少年群体中，长期ART治疗后，早期ART对CD8TN的获益十分明确。早期ART对CD4TN的影响相对有限，这是因为晚期接受治疗的儿科患者可通过胸腺从头生成初始型T细胞，以代偿HIV驱动的CD4 T细胞丢失。本研究数据还提示，当前的细胞活化状态和/或肠道通透性对初始型T细胞水平存在负面影响。
临床试验注册：临床试验注册平台（ClinicalTrials.gov），编号NCT02674867。