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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 (...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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.
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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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