Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants.
Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants.
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DOI：
10.3390/diagnostics13020295
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发表时间：
2023-01-12
期刊：
影响因子：
3.6
通讯作者：
Calcagno, Andrea
中科院分区：
文献类型：
--
作者：
Cusato, Jessica;Avataneo, Valeria;Antonucci, Miriam;Trunfio, Mattia;Marinaro, Letizia;Palermiti, Alice;Manca, Alessandra;Di Perri, Giovanni;Mula, Jacopo;Bonora, Stefano;D'Avolio, Antonio;Calcagno, Andrea
神经认知障碍在艾滋病毒感染者中很常见。某些疾病，如慢性炎症、星形胶质细胞感染和血脑屏障（BBBi）受损，沿着宿主转运蛋白基因的遗传变异，可能会影响脑脊液（CSF）中的抗逆转录病毒（ARV）暴露。本研究的目的是根据隔室炎症、血脑屏障通透性和药物转运蛋白编码基因的单核苷酸多态性（SNP）来评估ARV CSF渗透性。测量CSF新蝶呤（ELISA）、血浆和CSF ARV浓度（HPLC）以及ABCC 2、HNF 4 α、SLCO 1A 2和SLC 22 A6中的宿主遗传变异（实时PCR）。对单个抗逆转录病毒药物和类别进行双变量和多变量分析。我们纳入了259名参与者，提供了405份配对的血浆和CSF样本。CSF/血浆比值（CPR）显示NRTI和奈韦拉平增加，大多数ARV的渗透性较低。在双变量分析中，提出了几种相关性，包括BBBi（恩曲他滨、雷特格韦）、年龄（齐多夫定和达芦那韦）和高CSF新蝶呤（NRTI和PI的边界线）的影响。发现遗传变异与整合酶链转移（ABCC 2和HNF 4 α）、非核苷逆转录酶抑制剂（SLCO 1A 2）和蛋白酶抑制剂（SLC 22 A6）之间存在关联。在多变量分析中，年龄、性别、BMI和BBB改变是脑脊液核苷逆转录酶浓度的独立预测因素;年龄（蛋白酶抑制剂）、体重指数和BBB改变（整合酶链转移抑制剂）也与ARV CSF暴露相关。我们描述了与CSF浓度相关的因素，表明人口统计学、BBB完整性和部分遗传因素可能是中枢神经系统药物通过的预测因子。
Neurocognitive impairments are common in people living with HIV. Some conditions, such as chronic inflammation, astrocyte infection and an impaired blood–brain barrier (BBBi), along with host genetic variants in transporter genes, may affect antiretroviral (ARV) exposure in the cerebrospinal fluid (CSF). The aim of this study was to evaluate ARV CSF penetration according to compartmental inflammation, BBB permeability and single-nucleotide polymorphisms (SNPs) in drug transporter encoding genes. CSF neopterin (ELISA), plasma and CSF ARV concentrations (HPLC) and host genetic variants in ABCC2, HNF4α, SLCO1A2 and SLC22A6 (real-time PCR) were measured. Bi- and multivariate analyses were performed for single ARV and classes. We included 259 participants providing 405 paired plasma and CSF samples. CSF/plasma ratios (CPR) showed an increase for NRTIs and nevirapine with low penetrations for the majority of ARVs. At bi-variate analysis, several associations, including the effect of BBBi (emtricitabine, raltegravir), age (zidovudine and darunavir), and high CSF neopterin (NRTIs and border-line for PIs) were suggested. An association was found between genetic variants and integrase strand transfer (ABCC2 and HNF4α), non-nucleoside reverse transcriptase inhibitors (SLCO1A2), and protease inhibitors (SLC22A6). At multivariate analysis age, gender, BMI, and altered BBB were independent predictors of nucleoside reverse transcriptase CSF concentrations; age (for protease inhibitors) and body mass index and altered BBB (integrase strand transfer inhibitors) were also associated with ARV CSF exposure. We describe factors associated with CSF concentrations, showing that demographic, BBB integrity and, partially, genetic factors may be predictors of drug passage in the central nervous system.
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DOI：
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发表时间：
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期刊：
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影响因子：
--
作者：
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发表时间：
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影响因子：
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