Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants
Jessica Cusato,
Valeria Avataneo,
Miriam Antonucci,
Mattia Trunfio,
Letizia Marinaro,
Alice Palermiti,
Alessandra Manca,
Giovanni Di Perri,
Jacopo Mula,
Stefano Bonora,
Antonio D’Avolio,
Andrea Calcagno
Affiliations
Jessica Cusato
Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy
Valeria Avataneo
Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy
Miriam Antonucci
SCDU Infectious Diseases, Amedeo di Savoia Hospital, ASL Città di Torino, 10149 Turin, Italy
Mattia Trunfio
Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy
Letizia Marinaro
SCDU Infectious Diseases, Amedeo di Savoia Hospital, ASL Città di Torino, 10149 Turin, Italy
Alice Palermiti
Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy
Alessandra Manca
Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy
Giovanni Di Perri
Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy
Jacopo Mula
Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy
Stefano Bonora
Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy
Antonio D’Avolio
Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy
Andrea Calcagno
Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy
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.
