Neurotoxicity in the Post-HAART Era: Caution for the Antiretroviral Therapeutics

Abstract

Despite the advent of highly active antiretroviral therapy (HAART), HIV-associated neurological disorders (HAND) remain a major challenge in human immunodeficiency virus (HIV) treatment. The early implementation of HAART in the infected individuals helps suppress the viral replication in the plasma and other compartments. Several studies also report the beneficial effect of drugs that successfully penetrate central nervous system (CNS). However, recent data in both clinical setup and in in vitro studies indicate CNS toxicity of the antiretrovirals (ARVs). Although the evidence is limited, correlation between prolonged use of ARVs and neurotoxicity strongly suggests that it is essential to study the underlying mechanisms responsible for such toxicity. Furthermore, closer attention toward clinical outcomes is required to screen various ARV regimens for their association with HAND and other comorbidities. A growing body of literature also indicates a possible role of accelerated aging in the antiretroviral therapy-associated neurotoxicity. Lastly, owing to high pill burden, multiple drugs in the HIV treatment also invite a possible role of drug–drug interaction via various cytochrome P450 enzymes. The particular emphasis of this review is to highlight the need to identify alternative approaches in reducing the CNS toxicity of the ARV drugs in HIV-infected individuals.

Neuronal Stress and Injury Caused by HIV-1, cART and Drug Abuse: Converging Contributions to HAND

“…In addition, two drugs, ritonavir (RTV) and cobicistat (COBI) are used as pharmacokinetic enhancers [124] (reviewed in [125,126]). The Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents (a working group of the office of AIDS research) [124] keep updating the combination regimens, based on more than 25 antiretroviral drugs approved by the Food and Drug Administration (FDA) in order to guide to the right and best treatment for HIV + individuals.…”

“…However, the occurrence of cognitive impairment milder than HAD persists in HIV patients on cART [9,11,31] and recent studies observed that discontinuation of cART in virologically controlled HIV patients unexpectedly resulted in significant improvement of neurocognitive function [32,33,34,35]. Furthermore, clinical and experimental evidence is accumulating that at least some ARV compounds may themselves have neurotoxic effects [36,37,38,39,40,125,130]. …”

“…The earliest anti-retroviral drug zidovudine (AZT) has also been linked to mitochondrial toxicity, impaired neurogenesis and damage to neuronal dendrites and presynaptic terminals [131,143,144,145]. Overall, CNS neurotoxicity of NRTIs seems limited but also compound- and cell-specific [39,125]. …”

“…NNRTIs: Compounds, such as rilpivirine (TMC278) and delavirdine (DLV) are considered to be non-toxic in the CNS [125]. Etravirine (ETR) recently appeared to be clinically safe but was found to be neurotoxic in vitro [39,146].…”

Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals

“…In addition, the use of the integrase inhibitor raltegravir has been associated with neuropsychiatric symptoms (Harris et al , 2008; Teppler et al , 2011). Several of these ARVs have also been shown to lead to CNS abnormalities in rodent models (Shah et al , 2016). Mitochondrial effects have been examined for a number of these ARVs, as discussed below.…”