Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity

Abstract

The introduction of antiretroviral drugs (ARVd) changed the prognosis of HIV infection from a deadly disease to a chronic disease. However, even with undetectable viral loads, patients still develop a wide range of pathologies, including cerebrovascular complications and stroke. It is hypothesized that toxic side effects of ARVd may contribute to these effects. To address this notion, we evaluated the impact of several non-nucleoside reverse transcriptase inhibitors (NNRTI; Efavirenz, Etravirine, Rilpivirine and Nevirapine) on the integrity of the blood-brain barrier, and their impact on severity of stroke. Among studied drugs, Efavirenz, but not other NNRTIs, altered claudin-5 expression, increased endothelial permeability, and disrupted the blood-brain barrier integrity. Importantly, Efavirenz exposure increased the severity of stroke in a model of middle cerebral artery occlusion in mice. Taken together, these results indicate that selected ARVd can exacerbate HIV-associated cerebrovascular pathology. Therefore, careful consideration should be taken when choosing an anti-retroviral therapy regimen.

Brain Magnetic Resonance Imaging Findings Associated With Cognitive Impairment in Children and Adolescents With Human Immunodeficiency Virus in Zambia

“…47 These disease states include infections including varicella zoster virus, 42 cryptococcus, 48,49 neurocysticercosis, 50 hepatitis B, 51 syphilis, 52 and tuberculosis, 53 as well as neoplastic and prothrombotic states. 47 Immune reconstitution syndrome 54 and ART may also contribute to cerebrovascular disease, with evidence for both protease inhibitors 55 and efavirenz 56 potentially contributing to cerebrovascular disease. The current study was not powered to evaluate MRI differences based on specific antiretroviral drug regimens and was not designed to investigate the etiology of cerebrovascular disease.…”

HIV Alters Gap Junction-Mediated Intercellular Communication in Human Brain Pericytes

“…Male C57BL/6 mice (12-week-old, Jackson Laboratories, Bar Harbor, ME, USA) were acclimatized to the animal facility for 1 week with free access to food and water. Animals were then infused with EcoHIV/NDK (1 μg of p24) through the internal carotid artery using a method previously described (Bertrand et al, 2016 ; Leda et al, 2017 ), while control animals received saline. Mice were sacrificed at day 7 post-infection.…”

Cerebral Vascular Toxicity of Antiretroviral Therapy

“…Exposure of endothelial cells to Efavirenz can severely impact BBB integrity by decreasing levels of tight junction proteins claudins-1/5, occludin, ZO-1, and JAM-1. This results in an increase in permeability, a phenomenon which has been shown both in vivo and in vitro (Bertrand and Toborek 2015;Bertrand et al 2016b;Faltz et al 2017). Furthermore, it can affect cellular stress response by disrupting ER stress and autophagic responses.…”

“…More recently, a study has found evidence that Emtricitabine can be linked to the development of CSVD in forebrain white matter (Soontornniyomkij et al 2018). Experimental studies also demonstrated that Efavirenz can have deleterious effects on ischemic stroke, leading to increased tissue damage and BBB deterioration (Bertrand et al 2016b). On the other hand, administration of low toxicity ART is beneficial for the outcome of stroke when compared to the untreated HIVinfected group (Bertrand et al 2019b).…”