A review of the potential mechanisms of neuronal toxicity associated with antiretroviral drugs
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REVIEW
A review of the potential mechanisms of neuronal toxicity associated with antiretroviral drugs Ilaria De Benedetto 1
&
Mattia Trunfio 1 & Giulia Guastamacchia 2 & Stefano Bonora 1 & Andrea Calcagno 1
Received: 18 February 2020 / Revised: 25 May 2020 / Accepted: 15 June 2020 # Journal of NeuroVirology, Inc. 2020
Abstract Highly active antiretroviral treatment has led to unprecedented efficacy and tolerability in people living with HIV. This effect was also observed in the central nervous system with the nowadays uncommon observation of dementias; yet in more recent works milder forms are still reported in 20–30% of optimally treated individuals. The idea of a subclinical neuronal toxicity induced by antiretrovirals has been proposed and was somehow supported by the late-emerging effects associated with efavirenz use. In this manuscript we are reviewing all the potential mechanisms by which antiretroviral drugs have been associated with in vitro, ex vivo, or in vivo toxicity to cells pertaining to the central nervous system (neurons, astrocytes, oligodendrocytes, and endothelial cells). These include direct or indirect effects and pathological pathways such as amyloid deposition, damage to small cerebral vessels, and impairment in neurotransmission. The aim of this review is therefore to provide a detailed description of the available literature in order to guide further clinical research for improving patients’ neurocognition and quality of life. Keywords HIV . Neurotoxicity . Antiretroviral . ART . Neuronal . Toxicity
Introduction After the introduction of effectively suppressive antiretroviral therapy (ART), HIV-associated dementia has become a rare observation (Heaton et al. 2010). Nonetheless, even though in more recent works prevalence has been established around 20–30%, overall mild-to-moderate cognitive impairment is estimated to affect approximately 50% of patients under suppressive ART in both high- and low-income countries (Haddow et al. 2018; Heaton et al. 2010; Métral et al. 2019; Schouten et al. 2016; Trunfio et al. 2018; Vassallo et al. 2017). Several factors may be involved in the pathogenesis of neurocognitive impairment including nervous system damage occurred before ART initiation, persisting neuronal damaging caused by ongoing viral replication in nervous system compartment under suppressive ART, immune-activation in the * Ilaria De Benedetto [email protected] 1
Department of Medical Sciences, School of Infectious and Tropical Diseases, University of Torino, c/o Amedeo di Savoia Hospital Corso Svizzera 164, 10169 Torino, Italy
2
Department of Neurology, Maria Vittoria Hospital, Torino, Italy
central nervous system (CNS), comorbidities such as those associated with age (including the highly prevalent vascular disorders), substance misuse, genetic predisposition, malnutrition, co-infections, neurotoxic drugs (antimicrobials, antineoplastic, antiepileptic, others), and, eventually, antiretrovirals’ neurotoxicity (Centner et al. 2013). Since antiretroviral neurotoxicity
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