HIV-1 Integrase Strand Transfer Inhibitors and Neurodevelopment

Abstract

Children born to mothers, with or at risk, of human immunodeficiency virus type-1 (HIV-1) infection are on the rise due to affordable access of antiretroviral therapy (ART) to pregnant women or those of childbearing age. Each year, up to 1.3 million HIV-1-infected women on ART have given birth with recorded mother-to-child HIV-1 transmission rates of less than 1%. Despite this benefit, the outcomes of children exposed to antiretroviral drugs during pregnancy, especially pre- and post- natal neurodevelopment remain incompletely understood. This is due, in part, to the fact that pregnant women are underrepresented in clinical trials. This is underscored by any potential risks of neural tube defects (NTDs) linked, in measure, to periconceptional usage of dolutegravir (DTG). A potential association between DTG and NTDs was first described in Botswana in 2018. Incidence studies of neurodevelopmental outcomes associated with DTG, and other integrase strand transfer inhibitors (INSTIs) are limited as widespread use of INSTIs has begun only recently in pregnant women. Therefore, any associations between INSTI use during pregnancy, and neurodevelopmental abnormalities remain to be explored. Herein, United States Food and Drug Administration approved ARVs and their use during pregnancy are discussed. We provide updates on INSTI pharmacokinetics and adverse events during pregnancy together with underlying mechanisms which could affect fetal neurodevelopment. Overall, this review seeks to educate both clinical and basic scientists on potential consequences of INSTIs on fetal outcomes as a foundation for future scientific investigations.

Human iPSC-derived neurons reveal NMDAR-independent dysfunction following HIV-associated insults

“…One of the gene subsets most commonly downregulated across INSTIs were those associated with extracellular matrix interactions and cell motility, including ADAM metallopeptidases, laminins and collagens, and C3 and CXCL12 , classic pro-inflammatory genes with known roles in neural structure and development ( Figures 6A–C, E ). These observations are consistent with a recent report relating integrase inhibitors’ ability to impair matrix metalloproteinase function with the frequent–yet inconclusive–clinical reports of structural defects in the developing CNS when exposed to INSTIs in utero ( Xu et al, 2017 ; Bade et al, 2021 ; Foster et al, 2022 , 2023 ; Zizioli et al, 2023 ). The majority of the significant differentially expressed genes altered by EVG were shared with RAL ( Figure 6D ), and several of the unique RAL genes also involved morphogenesis and TGF-β signaling.…”

Perinatal exposure to atazanavir-based antiretroviral regimens in a mouse model leads to differential long-term motor and cognitive deficits dependent on the NRTI backbone

“…Increased neurodegeneration, including shrinkage of cytoplasm and pyknotic nuclei in CA1 and dentate gyrus, has been reported in Wistar rats exposed to TDF/3TC and efavirenz (Akang, 2019). Multiple in vitro studies report oxidative and mitochondrial stress, neurotoxicity and astrocyte senescence in cultured neurons and astrocytes exposed to monotherapy or combined antiretroviral therapy (Ellis et al, 2007;Liner et al, 2010;Robertson et al, 2012;Akay et al, 2014;Blas-García et al, 2014;Shah et al, 2016;Cohen et al, 2017;Nooka and Ghorpade, 2017;Sanchez and Kaul, 2017;De Benedetto et al, 2020;Bertrand et al, 2021;Lanman et al, 2021;Foster et al, 2022;Rudd and Toborek, 2022). While these studies investigated the direct neurotoxic effects of ARVs, our mice were only exposed to ARVs in utero.…”

Association of combination antiretroviral therapy with risk of neurological diseases in patients with HIV/AIDS in Taiwan: a nested case-control study

“…Studies have explored the association between various categories of ART drugs, such as NRTIs, NNRTIs, PIs, and INSTIs, and neurotoxicity ( Blanche et al, 1999 ; Cepeda and Wilks, 2000 ; Streck et al, 2008 ; Streck et al, 2011 ; Abers et al, 2014 ; Underwood et al, 2015 ; Hoffmann and Llibre, 2019 ; Zash et al, 2019 ; Foster et al, 2022 ); however, their relationship remains to be elucidated. In this study, we investigated which classes of ART drugs are associated with the risk of neurological diseases in patients with HIV/AIDS in Taiwan and observed that low cumulative DDDs or poor adherence to ART drugs increase the risk of neurological diseases across various classes of drugs, including NRTIs, PIs, NNRTIs, INSTIs, and multi-drug tablets.…”

“…ART drugs are classified based on their distinct molecular mechanisms and pharmacological characteristics, such as nucleoside reverse-transcriptase inhibitors (NRTIs), protease inhibitors (PIs), non-nucleoside reverse-transcriptase inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs), fusion inhibitors, and co-receptor antagonists ( Arts and Hazuda, 2012 ; Nastri et al, 2023 ). Neurotoxicity is linked to different classes of antiretroviral drugs, including NRTIs, NNRTIs, PIs, and INSTIs ( Abers et al, 2014 ; Xu et al, 2014 ; Underwood et al, 2015 ; Hoffmann and Llibre, 2019 ; Zash et al, 2019 ; Foster et al, 2022 ). Furthermore, studies have reported that NRTI administration is associated with an increased risk of neurotoxicity in both the CNS and peripheral nervous system ( Blanche et al, 1999 ; Cepeda and Wilks, 2000 ).…”

“…Other studies have reported that NNRTIs are associated with CNS neurotoxicity ( Streck et al, 2008 ; Streck et al, 2011 ). Other studies have reported that INSTIs are associated with neuropsychiatric adverse events ( Hoffmann and Llibre, 2019 ) and fetal neurodevelopmental abnormalities in pregnant women ( Zash et al, 2019 ; Foster et al, 2022 ).…”