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Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants
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 (...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9858383/ https://www.ncbi.nlm.nih.gov/pubmed/36673105 http://dx.doi.org/10.3390/diagnostics13020295 |
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author | 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 |
author_facet | 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 |
author_sort | Cusato, Jessica |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9858383 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-98583832023-01-21 Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants 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 Diagnostics (Basel) Article 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. MDPI 2023-01-12 /pmc/articles/PMC9858383/ /pubmed/36673105 http://dx.doi.org/10.3390/diagnostics13020295 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article 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 Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants |
title | Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants |
title_full | Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants |
title_fullStr | Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants |
title_full_unstemmed | Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants |
title_short | Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants |
title_sort | antiretroviral levels in the cerebrospinal fluid: the effect of inflammation and genetic variants |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9858383/ https://www.ncbi.nlm.nih.gov/pubmed/36673105 http://dx.doi.org/10.3390/diagnostics13020295 |
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