Antiretroviral drugs efavirenz, dolutegravir and bictegravir dysregulate blood-brain barrier integrity and function

Chang Huang; Tozammel Hoque; Reina Bendayan

doi:10.3389/fphar.2023.1118580

Antiretroviral drugs efavirenz, dolutegravir and bictegravir dysregulate blood-brain barrier integrity and function

Front Pharmacol. 2023 Mar 8:14:1118580. doi: 10.3389/fphar.2023.1118580. eCollection 2023.

Authors

Chang Huang¹, Tozammel Hoque¹, Reina Bendayan¹

Affiliation

¹ Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.

Abstract

The implementation of combined antiretroviral therapy (cART) significantly reduces the mortality associated with human immunodeficiency virus (HIV) infection. However, complications such as HIV-associated neurocognitive disorders (HAND) remain a major health concern. We hypothesized that the toxicity of antiretroviral drugs (ARVs) may contribute to the pathogenesis of HAND in addition to cerebral viral infection. To address this question, we evaluated the impact of HIV integrase strand transfer inhibitors (dolutegravir and bictegravir), and a non-nucleoside reverse transcriptase inhibitor (efavirenz) on the integrity and permeability of various human and mouse blood-brain barrier (BBB) models, in vitro, ex vivo and in vivo. We observed a significant downregulation of tight junction proteins (TJP1/Tjp1, OCLN/Ocln and CLDN5/Cldn5), upregulation of proinflammatory cytokines (IL6/Il6, IL8/Il8, IL1β/Il1β) and NOS2/Nos2, and alteration of membrane-associated transporters (ABCB1/Abcb1a, ABCG2/Abcg2 and SLC2A1/Slc2a1) mRNA expression, in vitro, in human (hCMEC/D3) and primary cultures of mouse microvascular endothelial cells, and ex vivo in isolated mouse brain capillaries treated with efavirenz, dolutegravir, and/or bictegravir. We also observed a significant increase in BBB permeability in vivo following treatment with the selected ARVs in mice applying NaF permeability assay. Taken together, these results suggest that clinically recommended integrase strand transfer inhibitors such as dolutegravir may exacerbate HIV-associated cerebrovascular pathology, which may contribute to the associated short-term neuropsychiatric side effects and the high incidence of mild forms of HAND reported in the clinical setting.

Keywords: ARV toxicity; HIV-associated neurocognitive disorders; antiretroviral drugs (ARVs); bictegravir; blood-brain barrier; dolutegravir; efavirenz.

Grants and funding

This research was supported by an operating grant from the Canadian Institutes of Health Research (CIHR Grant# 511794) and the Ontario HIV Treatment Network (OHTN Grant# 506657). The funders played no role in the experimental work, data collection, analysis, or interpretation of the data, or drafting of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.