Neuronal toxicity of efavirenz: a systematic review

Decloedt, Eric H.; Maartens, Gary

doi:10.1517/14740338.2013.823396

Cited by 91 publications

(77 citation statements)

References 52 publications

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“…As surprising as that could be, patients in our study had in general very high plasma concentrations of EFV. Opposite to several authors who have found association between EFV plasma concentration and presence of neuropsychic AE [1,5,[25][26][27][28], we did not highlighted such an association in our study. This could be related to the transverse nature of our study involving under-notification.…”

Section: Plasma Concentrations and Adverse Effectscontrasting

confidence: 99%

Over Exposure to Efavirenz Plasma Concentrations among Beninese HIV Patients Treated by A 600 mg Daily Dose

Constant¹,

Mikal²,

Marcel³

et al. 2017

JPP

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Therapeutic plasma concentrations of EFV (efavirenz) are between 1,000 ng/mL and 4,000 ng/mL. Concentrations below 1000 ng/mL are associated with higher risk of treatment failure, and concentrations above 4,000 ng/mL are associated with toxicity. The aim of the study was to appreciate EFV plasmas concentrations profile and the association between plasma levels and various characteristics in Beninese patients treated by a 600 mg standard daily-dose. Blood samples were collected and EFV plasma levels were measured by liquid chromatography coupled with mass spectrometry detection in HIV-infected patients receiving EFV in combination with other antiretroviral drugs for at least 14 days. Adverse effects occurring during treatment were collected through a questionnaire. An over-exposure to EFV among Beninese HIV patients were observed, with 46.4% of patients presenting EFV concentration above 4,000 ng/mL, although adverse effects were tolerated indicating that antiretroviral treatment is safe. The measurement of plasma concentration at the steady-state could contribute to early detection of treatment failure and adapt treatment in subjects presenting serious adverse effects within context of therapeutic drug monitoring.

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Section: Plasma Concentrations and Adverse Effectscontrasting

confidence: 99%

Over Exposure to Efavirenz Plasma Concentrations among Beninese HIV Patients Treated by A 600 mg Daily Dose

Constant¹,

Mikal²,

Marcel³

et al. 2017

JPP

View full text Add to dashboard Cite

show abstract

“…Understanding the etiology of acute CNS neuropsychiatric adverse effects is vital due to the wide use of EFV in cART (Decloedt and Maartens, 2013). Here, we investigated the acute effects of EFV on mitochondrial ATP production, mitochondrial morphology, and autophagy in SH-SY5Y cells and neurons.…”

Section: Discussionmentioning

confidence: 99%

Efavirenz Induces Neuronal Autophagy and Mitochondrial Alterations

Purnell

Fox

2014

J Pharmacol Exp Ther

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Efavirenz (EFV) is a non-nucleoside reverse-transcriptase inhibitor in wide use for the treatment of human immunodeficiency virus infection. Although EFV is generally well tolerated, neuropsychiatric toxicity has been well documented. The toxic effects of EFV in hepatocytes and keratinocytes have been linked to mitochondrial perturbations and changes in autophagy. Here, we studied the effect of EFV on mitochondria and autophagy in neuronal cell lines and primary neurons. In SH-SY5Y cells, EFV induced a drop in ATP production, which coincided with increased autophagy, mitochondrial fragmentation, and mitochondrial depolarization. EFV-induced mitophagy was also detected by colocalization of mitochondria and autophagosomes and use of an outer mitochondrial membrane tandem fluorescent vector. Pharmacologic inhibition of autophagy with 3-methyladenine increased the cytotoxic effect of EFV, suggesting that autophagy promotes cell survival. EFV also reduces ATP production in primary neurons, induces autophagy, and changes mitochondrial morphology. Overall, EFV is able to acutely induce autophagy and mitochondrial changes in neurons. These changes may be involved in the mechanism leading to central nervous system toxicity observed in clinical EFV use.

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“…Several reports also demonstrated hepatotoxicity and the blockage of proteasome activity by HIV protease inhibitors (Liang et al, 2001;Carr, 2003). In addition, secretion of proinflammatory cytokines (Diaz-Delfin et al, 2011) and neurotoxicity has been associated with the use of NNRTI, namely, efavirenz and nevirapine (Decloedt and Maartens, 2013). The neurotoxic impact of these drugs may be mediated, at least in part, by inhibition of creatine kinase and cytochrome C complex IV activity in the brain (Streck et al, 2008(Streck et al, , 2011, mitochondria dysfunction (Purnell and Fox, 2014), or iNOS upregulation (Apostolova et al, 2014).…”

Section: Dysregulation Of Er Stress and Autophagy By Efavirenzmentioning

confidence: 99%

Dysregulation of Endoplasmic Reticulum Stress and Autophagic Responses by the Antiretroviral Drug Efavirenz

Bertrand

Toborek

2015

Mol Pharmacol

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Increasing evidence demonstrates that the antiretroviral drugs (ARVds) used for human immunodeficiency virus (HIV) treatment have toxic effects that result in various cellular and tissue pathologies; however, their impact on the cells composing the blood-brain barrier is poorly understood. The current study focused on ARVds, used either in combination or alone, on the induction of endoplasmic reticulum (ER) stress responses in human brain endothelial cells. Among studied drugs (efavirenz, tenofovir, emtricitabine, lamivudine, and indinavir), only efavirenz increased ER stress via upregulation and activation of protein kinase-like ER kinase PERK and inositol requiring kinase 1a (IRE1a). At the same time, efavirenz diminished autophagic activity, a surprising result because typically the induction of ER stress is linked to enhanced autophagy. These results were confirmed in microvessels of HIV transgenic mice chronically administered with efavirenz. In a series of further experiments, we identified that efavirenz dysregulated ER stress and autophagy by blocking the activity of the Beclin-1/ Atg14/PI3KIII complex in regard to synthesis of phosphatidylinositol 3-phosphate, a process that is linked to the formation of autophagosomes. Because autophagy is a protective mechanism involved in the removal of dysfunctional proteins and organelles, its inhibition can contribute to the toxicity of efavirenz or the development of neurodegenerative disease in HIV patients treated with this drug.

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Neuronal toxicity of efavirenz: a systematic review

Cited by 91 publications

References 52 publications

Over Exposure to Efavirenz Plasma Concentrations among Beninese HIV Patients Treated by A 600 mg Daily Dose

Over Exposure to Efavirenz Plasma Concentrations among Beninese HIV Patients Treated by A 600 mg Daily Dose

Efavirenz Induces Neuronal Autophagy and Mitochondrial Alterations

Dysregulation of Endoplasmic Reticulum Stress and Autophagic Responses by the Antiretroviral Drug Efavirenz

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