Changes in functional connectivity in people with HIV switching antiretroviral therapy

Sofia Toniolo,Alan Winston,Borja Mora-Peris,Mark Nelson,Marco Bozzali,Jaime H Vera,Jonathan Underwood,Jasmini Alagaratnam,Mara Cercignani,Marta Boffito

doi:10.1007/s13365-020-00853-0

Abstract

We assessed changes in functional connectivity by fMRI (functional magnetic resonance imaging) and cognitive measures in otherwise neurologically asymptomatic people with HIV (PWH) switching combination antiretroviral therapy (cART). In a prospective study (baseline and follow-up after at least 4 months), virologically suppressed PWH switched non-nuclease reverse-transcriptase inhibitors (NNRTI; tenofovir-DF/emtricitabine with efavirenz to rilpivirine) and integrase-strand-transfer inhibitors (INSTI; tenofovir-DF/emtricitabine with raltegravir to dolutegravir). PWH were assessed by resting-state fMRI and stop-signal reaction time (SSRT) task fMRI as well as with a cognitive battery (CogState™) at baseline and follow-up. Switching from efavirenz to rilpivirine (n = 10) was associated with increased functional connectivity in the dorsal attention network (DAN) and a reduction in SSRTs (p = 0.025) that positively correlated with the time previously on efavirenz (mean = 4.8 years, p = 0.02). Switching from raltegravir to dolutegravir (n = 12) was associated with increased connectivity in the left DAN and bilateral sensory-motor and associative visual networks. In the NNRTI study, significant improvements in the cognitive domains of executive function, working memory and speed of visual processing were observed, whereas no significant changes in cognitive function were observed in the INSTI study. Changes in fMRI are evident in PWH without perceived neuropsychiatric complaints switching cART. fMRI may be a useful tool in assisting to elucidate the underlying pathogenic mechanisms of cART-related neuropsychiatric effects.

Highlights

Earlier treatment initiation and wider access to combination antiretroviral therapy have resulted in a significant decline in the incidence of HIV-associated central nervous system (CNS) diseases (Garvey et al 2011)
What impact antiretroviral drugs might have on brain activity and how it correlates with covert neuropsychiatric symptoms remains poorly described
One MRI scan in the switch arm of the Integrasestrand-transfer inhibitors (INSTI) study at follow-up was corrupted by severe artefacts, so the subject was excluded from the group MRI analysis

Summary

Introduction

Earlier treatment initiation and wider access to combination antiretroviral therapy (cART) have resulted in a significant decline in the incidence of HIV-associated central nervous system (CNS) diseases (Garvey et al 2011). Neuropsychiatric events, such as cognitive deficits, anxiety, depression and insomnia, are frequently reported in people with HIV (PWH) on effective cART (Knights et al 2017). Alongside traditional pathogenic mechanisms such as the legacy effect of HIV in CNS prior to cART initiation and CNS immune activation, antiretroviral toxicity may be a potential pathogenic factor responsible for the occurrence of these neuropsychiatric symptoms (Underwood et al 2014). Efavirenz, a highly efficacious non-nucleoside reverse-transcriptase inhibitor (NNRTI), has been associated with neuropsychiatric symptoms in 20–40% of patients which may persist for several years after treatment initiation (Zhuang et al 2017; Sacktor et al 2006; McCutchan et al 2007). (2020) 26:754–763 increased risk of neuropsychiatric adverse events, with dolutegravir being associated with the highest rate of discontinuation compared with other INSTI (2–6%) (Elzi et al 2017; Hoffmann et al 2017). What impact antiretroviral drugs might have on brain activity and how it correlates with covert neuropsychiatric symptoms remains poorly described

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