Cerebral Vascular Toxicity of Antiretroviral Therapy

Abstract

HIV infection is associated with comorbidities that are likely to be driven not only by HIV itself, but also by the toxicity of longterm use of antiretroviral therapy (ART). Indeed, increasing evidence demonstrates that the antiretroviral drugs used for HIV treatment have toxic effects resulting in various cellular and tissue pathologies. The blood-brain barrier (BBB) is a modulated anatomophysiological interface which separates and controls substance exchange between the blood and the brain parenchyma; therefore, it is particularly exposed to ART-induced toxicity. Balancing the health risks and gains of ART has to be considered in order to maximize the positive effects of therapy. The current review discusses the cerebrovascular toxicity of ART, with the focus on mitochondrial dysfunction.

Dual antiretroviral therapies are effective and safe regimens in the central nervous system of neurologically symptomatic people living with HIV

“…For instance, we found that patients on TT have BBB alterations four times more commonly than those on DT. Despite the difference was not statistically significant, the finding requires further studies since evidence exists on BBB injury caused by some ARVs, primarily EFV [37,39], which is not included in any current DT.…”

“…The absence of any difference in CSF biomarkers of intrathecal humoral response, inflammation, monocyte/macrophages activation, BBB integrity, astrocytosis, neuronal injury and amyloid plaques deposition, already variably associated with viral replication, CVE and with the presence and severity of HAND [26,[32][33][34][35], once again confirms the equality in safety and effectiveness of DT and TT in our clinical setting. Interestingly, some of the pathways linked to the CSF biomarkers used here have also been associated to cART-related neurotoxicity [36][37][38]. The lack of any difference in CSF biomarkers in an era where one of the main driver to DT simplification is the proactive prevention of cART-related toxicity could be disappointing.…”

Spatial Distribution Profiles of Emtricitabine, Tenofovir, Efavirenz, and Rilpivirine in Murine Tissues Following In Vivo Dosing Correlate with Their Safety Profiles in Humans

“…Efflux transporters present in the BBB including P-glycoprotein may decrease the drug penetration into the brain. 46 Interestingly, it has been reported that EFV disrupts the integrity of the BBB resulting in an increase in permeability. 47 Although varying degrees of antiretroviral penetration into the brain have been reported, our MALDI MSI drug distribution data add to these existing findings by providing the spatial distributions of TFV, FTC, EFV, and RPV across brain tissue slices.…”

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

“…Nevertheless, a vascular pathology in the PP model is supported by a two-fold reduction of Claudin 5, Cldn5, a key regulator of BBB permeability. The rise in proin ammatory cytokines causes disruption of BBB's tight junction and endothelial proteins like Cldn5 and vascular angiogenic factors like Angptl4 which has been largely identi ed in various neuroin ammatory and neuroinfectious diseases caused by RNA viruses (Bertrand, Velichkovska, and Toborek 2019;Salimi and Klein 2019;Liu et al 2019;Leda et al 2019). While the number of human samples analyzed is small, the translational validation of the PolyI:C data clearly demonstrates that this mouse model can reproduce some of the characteristic features of reactive central in ammation (Hampel et al 2020) and vascular pathology encountered in neurodegenerative dementia.…”