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The anti-HIV drug Efavirenz : a challenge on molecular mechanisms of drug associated neurocognitive disorders
Publication . Grilo, Nádia; Pereira, Sofia Azeredo; Antunes, Alexandra Maria Moita
ABSTRACT: As the list of drugs becoming perceived as neurotoxic is growing, its chronic use has been
raising increased concern. The anti-human immunodeficiency virus (HIV)-infection drug efavirenz (EFV) clearly illustrates these circumstances, being a drug chronically used by both adults and children, for which neurotoxic effects have been consistently recognized. In order to develop preventive/management Strategies, the understanding of the mechanisms underlying EFV-induced neurotoxicity is crucial towards the mechanistic-oriented discovery of suitable biomarkers for their evaluation. Theses biomarkers will be Ethically obtained and ideally will be easily accessed from peripheral biofluids, allowing the evaluation of patient´s risk, the identification of risk factors and the evaluation of the success of toxicity minimization
strategies. A significant number of individuals on the recommended dose of EFV have central nervous
system (CNS) adverse reactions, which represent the main drawback of EFV. These adverse reactions also constitute a major factor for EFV discontinuation, limiting adherence to combined antiretroviral therapy and available therapeutic options. The prevention and management of these neuro-adverse reactions are hampered by their broad-spectrum nature (from sleep disturbances to mood-changes or memory impairment) that might involve distinct underlying mechanisms. Clinical trials have consistently described a high inter-patient variability for type, time to onset, duration and severity of the CNS complaints. Most of
EFV-induced CNS-adverse reactions are reversible and tend to occur during the first weeks of treatment. However, EFV discontinuation continues to occur late in the course of treatment, due to the persistence of CNS toxicity which may negatively impact the health and quality of life of patients on a long-term basis. While short-term effects are usually transient, or if not they are normally a factor for drug switch, the long-term effects are much more difficult to predict and to manage. Patient´s individual metabolic capability is considered a factor on these neuro-adverse reactions, taking into consideration the high inter-patient variability in EFV concentrations and pharmacogenomic data. In particular, strong non-clinical evidence supports that EFV major Phase I metabolite, 8-hydroxy-efavirenz (8-OH-EFV) is a more potent neurotoxin than EFV itself. Nonetheless, the relevance of these findings to a clinically useful neuro-safety evaluation has yet to be demonstrated. Mostly, due to difficulties on the quantification of 8-OH-EFV levels or of its reactive metabolites and/or adducts in brain, given the inaccessibility of the target tissue. Due to these premises, the overall goals of the present translational research project were to study the mechanism underlying EFV-induced long-term CNS adverse reactions and to identify peripheral markers for the risk assessment of EFV-induced neurotoxicity and for the evaluation of strategies for prevention and management of these toxic events.
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Fundação para a Ciência e a Tecnologia
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SFRH
Número da atribuição
SFRH/BD/86791/2012