TORNA ALL’ELENCO

Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants in Diagnostics

2023
ASL Città di Torino

Tipo pubblicazione

Article

Autori/Collaboratori (12)Vedi tutti...

Palermiti A
Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
Manca A
Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
Di Perri G
Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy

et alii...

Abstract

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, HNF4?, 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 HNF4?), 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.

DOI : 10.3390/diagnostics13020295

Keywords

virus load; tandem mass spectrometry; single nucleotide polymorphism; real time polymerase chain reaction; pharmacogenetics; male; major clinical study; limit of detection; inflammation; human tissue; human; high performance liquid chromatography; genotype; genetic variability; gender; female; enzyme linked immunosorbent assay; drug cerebrospinal fluid level; drug blood level; controlled study; cerebrospinal fluid-to-plasma ratio; CD4 lymphocyte count; body mass; blood brain barrier; article; antiretroviral therapy; adult; zidovudine; virus RNA; tenofovir; solute carrier organic anion transporter 1A2; ritonavir; rilpivirine; raltegravir; organic anion transporter 1; nevirapine; neopterin; multidrug resistance associated protein 2; maraviroc; lopinavir; lamivudine; integrase; hepatocyte nuclear factor 4; genomic DNA; etravirine; emtricitabine; elvitegravir; dolutegravir; darunavir; cobicistat; breast cancer resistance protein; anti human immunodeficiency virus agent; amprenavir; abacavir;