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Background: The pathogenesis of HIV-associated neurocognitive (NC) impairment is multifactorial, and antiretroviral (ARV) neurotoxicity may contribute. However, interventional pharmacological studies are limited., Methods: Single-blind, randomized (1:1), controlled trial to assess the change of NC performance (Global Deficit Score, GDS, and domain scores) in PLWH with NC impairment randomized to continue their standard of care treatment or to switch to a less neurotoxic ARV regimen: darunavir/cobicistat, maraviroc, emtricitabine (MARAND-X). Participants had plasma and cerebrospinal fluid HIV RNA< 50 copies/mL, R5-tropic HIV, and were on ARV regimens that did not include efavirenz and darunavir. The change of resting-state electroencephalography was also evaluated. The outcomes were assessed at week 24 of the intervention through tests for longitudinal paired data and mixed-effect models., Results: Thirty-eight participants were enrolled and 28 completed the follow-up. Global Deficit Score improved over time but with no difference between arms in longitudinal adjusted models. Perceptual functions improved in the MARAND-X, while long-term memory improved only in participants within the MARAND-X for whom the central nervous system penetration-effectiveness (CNS penetration effectiveness) score increased by ≥3. No significant changes in resting-state electroencephalography were observed., Conclusions: In this small but well-controlled study, the use of less neurotoxic ARV showed no major beneficial effect over an unchanged regimen. The beneficial effects on the memory domain of increasing CNS penetration effectiveness score suggest that ARV neuropenetration may have a role in cognitive function., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Parietal resting-state electroencephalographic (rsEEG) alpha (8-10 Hz) source connectivity is abnormal in HIV-positive persons. Here we tested whether this abnormality may be associated with subcortical white matter vascular lesions in the cerebral hemispheres., Methods: Clinical, rsEEG, and magnetic resonance imaging (MRI) datasets in 38 HIV-positive persons and clinical and rsEEG datasets in 13 healthy controls were analyzed. Radiologists visually evaluated the subcortical white matter hyperintensities from T2-weighted FLAIR MRIs (i.e., Fazekas scale). In parallel, neurophysiologists estimated the eLORETA rsEEG source lagged linear connectivity from parietal cortical regions of interest., Results: Compared to the HIV participants with no/negligible subcortical white matter hyperintensities, the HIV participants with mild/moderate subcortical white matter hyperintensities showed lower parietal interhemispheric rsEEG alpha lagged linear connectivity. This effect was also observed in HIV-positive persons with unimpaired cognition. This rsEEG marker allowed good discrimination (area under the receiver operating characteristic curve > 0.80) between the HIV-positive individuals with different amounts of subcortical white matter hyperintensities., Conclusions: The parietal rsEEG alpha source connectivity is associated with subcortical white matter vascular lesions in HIV-positive persons, even without neurocognitive disorders., Significance: Those MRI-rsEEG markers may be used to screen HIV-positive persons at risk of neurocognitive disorders., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

HIV-associated neurocognitive disorders (HAND) are highly prevalent in people living with HIV (PLWH) despite successful treatment with combination antiretroviral therapy (cART). HAND pathogenesis is complex and definitive surrogate biomarkers are not clearly defined. Brain function has been assessed through the evaluation of cortical source rhythms with delta waves associated with neurological impairment. The aim of this study was to assess the correlation between EEG cortical sources, cerebrospinal fluid (CSF) biomarkers, and neurocognitive tests in PLWH with HAND. PLWH with HAND without significant comorbidities were enrolled. Baseline rsEEG-LORETA waves, CSF biomarkers (t-tau, p-tau, β-amiloid 42 , neopterin, S100β), and neurocognitive tests were correlated and compared through non-parametric tests (Spearman's rho and Mann-Whitney); data are presented as medians (interquartile ranges). Fifty-four patients were enrolled. Median time of suppressed HIV-RNA and CD4 + T-lymphocyte were 10 years (5.5-15) and 691/uL (477-929). Thirty-nine participants (72%) underwent CSF collection: abnormal biomarkers were found in a small percentage. Only neopterin showed a statistically significant correlation with delta activity [parietal (rho 0.579; p < 0.001), occipital (rho 0.493; p = 0.007), and global sources (rho 0.464 p = 0.011)]. Seven patients (12.9%) showed an abnormal neopterin level (> 1.5 ng/mL) with significantly higher delta source activity compared to the ones with in-range concentrations. We observed a statistically significant correlation between working memory test Trail Making B with both CSF neopterin levels and delta waves (p values < 0.05). In a small sample of PLWH with HAND, we observed that higher CSF neopterin levels were associated with higher EEG delta waves and worse working memory tests., (© 2022. Journal of NeuroVirology, Inc.)

Previous evidence showed abnormal parietal sources of resting-state electroencephalographic (EEG) delta (< 4 Hz) and alpha (8-12 Hz) rhythms in treatment-Naïve HIV (Naïve HIV) subjects, as cortical neural synchronization markers in quiet wakefulness. Here, we tested the hypothesis that these local abnormalities may be related to functional cortical dysconnectivity as an oscillatory brain network disorder. The present EEG database regarded 128 Naïve HIV and 60 Healthy subjects. The eLORETA freeware estimated lagged linear EEG source connectivity (LLC). The area under receiver operating characteristic (AUROC) curve indexed the accuracy in the classification between Healthy and HIV individuals. Parietal intrahemispheric LLC solutions in alpha sources were abnormally lower in the Naïve HIV than in the control group. Furthermore, those abnormalities were greater in the Naïve HIV subgroup with executive and visuospatial deficits than the Naïve HIV subgroup with normal cognition. AUROC curves of those LLC solutions exhibited moderate/good accuracies (0.75-0.88) in the discrimination between the Naïve HIV individuals with executive and visuospatial deficits vs. Naïve HIV individuals with normal cognition and control individuals. In quiet wakefulness, Naïve HIV subjects showed clinically relevant abnormalities in parietal alpha source connectivity. HIV may alter a parietal "hub" oscillating at the alpha frequency in quiet wakefulness as a brain network disorder., (Copyright © 2022. Published by Elsevier Inc.)

Objective: Here we evaluated the hypothesis that resting state electroencephalographic (EEG) cortical sources correlated with cognitive functions and discriminated asymptomatic treatment-naïve HIV subjects (no AIDS)., Methods: EEG, clinical, and neuropsychological data were collected in 103 treatment-naïve HIV subjects (88 males; mean age 39.8 years ± 1.1 standard error of the mean, SE). An age-matched group of 70 cognitively normal and HIV-negative (Healthy; 56 males; 39.0 years ± 2.0 SE) subjects, selected from a local university archive, was used for control purposes. LORETA freeware was used for EEG source estimation in fronto-central, temporal, and parieto-occipital regions of interest., Results: Widespread sources of delta (<4 Hz) and alpha (8-12 Hz) rhythms were abnormal in the treatment-naïve HIV group. Fronto-central delta source activity showed a slight but significant (p < 0.05, corrected) negative correlation with verbal and semantic test scores. So did parieto-occipital delta/alpha source ratio with memory and composite cognitive scores. These sources allowed a moderate classification accuracy between HIV and control individuals (area under the ROC curves of 70-75%)., Conclusions: Regional EEG abnormalities in quiet wakefulness characterized treatment-naïve HIV subjects at the individual level., Significance: This EEG approach may contribute to the management of treatment-naïve HIV subjects at risk of cognitive deficits., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Cortical sources of electroencephalographic (EEG) rhythms were investigated in two sub-populations of naïve HIV subjects, grouped based on clinical criteria to receive different combination anti-retroviral therapies (cARTs). These EEG sources were hypothesized to reflect beneficial effects of both regimes., Methods: Eyes-closed resting state EEG data were collected in 19 (Group A) and 39 (Group B) naïve HIV subjects at baseline (i.e. pre-treatment; T0) and after 5months of cART (T5). Compared with the Group A, the Group B was characterized by slightly worse serological parameters and higher cardiovascular risk. At T0, mean viral load (VL) and CD4 count were 87,694copies/ml and 435cells/μl in the Group A and 187,370copies/ml and 331cells/μl in the Group B. The EEG data were also collected in 50 matched control HIV-negative subjects. Cortical EEG sources were assessed by LORETA software., Results: Compared to the Control Group, the HIV Groups showed lower alpha (8-12Hz) source activity at T0 while the Group B also exhibited higher delta source activity. The treatment partially normalized alpha and delta source activity in the Group A and B, respectively, in association with improved VL, CD4, and cognitive functions., Conclusions: Different cART regimens induced diverse beneficial effects in delta or alpha source activity in the two naïve HIV Groups., Significance: These sources might unveil different neurophysiological effects of diverse cART on brain function in naïve HIV Groups as a function of clinical status and/or therapeutic compounds., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: Here we tested the effect of combined antiretroviral therapy (cART) on deviant electroencephalographic (EEG) source activity in treatment-naïve HIV individuals., Methods: Resting state eyes-closed EEG data were recorded before and after 5 months of cART in 48 male HIV subjects, who were naïve at the study start. The EEG data were also recorded in 59 age- and sex-matched healthy subjects as a control group. Frequency bands of interest included delta, theta, alpha1, alpha2 and alpha3, based on alpha frequency peak specific to each individual. They also included beta1 (13-20 Hz) and beta2 (20-30 Hz). Low-resolution brain electromagnetic tomography (LORETA) estimated EEG cortical source activity in frontal, central, temporal, parietal, and occipital regions., Results: Before the therapy, the HIV group showed greater parietal delta source activity and lower spatially diffuse alpha source activity compared to the control group. Thus, the ratio of parietal delta and alpha3 source activity served as an EEG marker. The z-score showed a statistically deviant EEG marker (EEG +) in 50% of the HIV individuals before therapy (p < 0.05). After 5 months of cART, delta source activity decreased, and alpha3 source activity increased in the HIV subjects with EEG + (about 50% of them showed a normalized EEG marker)., Conclusions: This procedure detected a deviant EEG marker before therapy and its post-therapy normalization in naïve HIV single individuals., Significance: The parietal delta/alpha3 EEG marker may be used to monitor cART effects on brain function in such individuals.

Objective: This study tested a simple statistical procedure to recognize single treatment-naïve HIV individuals having abnormal cortical sources of resting state delta (<4 Hz) and alpha (8-13 Hz) electroencephalographic (EEG) rhythms with reference to a control group of sex-, age-, and education-matched healthy individuals. Compared to the HIV individuals with a statistically normal EEG marker, those with abnormal values were expected to show worse cognitive status., Methods: Resting state eyes-closed EEG data were recorded in 82 treatment-naïve HIV (39.8 ys.±1.2 standard error mean, SE) and 59 age-matched cognitively healthy subjects (39 ys.±2.2 SE). Low-resolution brain electromagnetic tomography (LORETA) estimated delta and alpha sources in frontal, central, temporal, parietal, and occipital cortical regions., Results: Ratio of the activity of parietal delta and high-frequency alpha sources (EEG marker) showed the maximum difference between the healthy and the treatment-naïve HIV group. Z-score of the EEG marker was statistically abnormal in 47.6% of treatment-naïve HIV individuals with reference to the healthy group (p<0.05). Compared to the HIV individuals with a statistically normal EEG marker, those with abnormal values exhibited lower mini mental state evaluation (MMSE) score, higher CD4 count, and lower viral load (p<0.05)., Conclusions: This statistical procedure permitted for the first time to identify single treatment-naïve HIV individuals having abnormal EEG activity., Significance: This procedure might enrich the detection and monitoring of effects of HIV on brain function in single treatment-naïve HIV individuals., (Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: We tested the hypothesis that 5months of combined anti-retroviral therapy (cART) affect cortical sources of resting state cortical electroencephalographic (EEG) rhythms in naïve HIV subjects., Methods: Eyes-closed resting state EEG data were recorded at baseline (i.e. pre-treatment; T0), T1 (after 4weeks of cART), T2 (after 8weeks of cART), and T5 (after 5months of cART) in 38 naïve HIV subjects. EEG data were also recorded in 40 age-matched cognitively normal subjects for control purposes. EEG rhythms of interest were delta (2-4Hz), theta (4-8Hz), alpha 1 (8-10.5Hz), alpha 2 (10.5-13Hz), beta 1 (13-20Hz), and beta 2 (20-30Hz). Cortical EEG sources were estimated by LORETA software., Results: Compared to the control group, the HIV group at T0 showed greater delta sources and lower widespread alpha sources. cART induced a global improvement of biological (viral load, CD4 count) and EEG (delta, alpha) markers, remarkable even after 4weeks. Compared to HIV Responders (>100cells/μl at 5-month follow up), the HIV Mild Responders (<100cells/μl) showed greater parietal delta sources at baseline and lower occipital alpha sources at 5-month follow up., Conclusions: In naïve HIV subjects, 5months of successful cART affect brain synchronization mechanisms at the basis of the generation of delta and alpha rhythms., Significance: The present EEG markers may be useful secondary neurophysiological end points for pharmacological clinical trials in naïve HIV subjects., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: Treatment-naïve patients with human immunodeficiency virus (HIV) are characterized by diffuse abnormalities of resting-state cortical electroencephalographic (EEG) rhythms (Babiloni et al., 2012a). Here, we tested the hypothesis that these EEG rhythms vary as a function of the systemic immune activity and antiretroviral therapy (ART) in HIV patients., Methods: Resting-state eyes-closed EEG data were recorded in 68 ART-HIV patients (mini mental state evaluation (MMSE) of 27.5 ± 0.3 SEM), in 60 treatment-naïve HIV subjects (MMSE of 27.5 ± 0.4 SEM) and in 75 age-matched cognitively normal subjects (MMSE of 29.3 ± 0.1 SEM). Based on the CD4 lymphocytes' count, we divided ART-HIV subjects into two subgroups: those with CD4>500 cells/μl (ART-HIV+) and those with CD4<500 cells/μl (ART-HIV-). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-12 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). Cortical EEG sources were estimated by LORETA software., Results: Widespread theta, alpha, and beta sources were lower in ART-HIV subjects than in control subjects. Furthermore, occipital and temporal alpha 1 sources were lower in treatment-naïve HIV than in ART-HIV subjects. Moreover, the opposite was true for widespread pathological delta sources. Finally, parietal, occipital, and temporal alpha 1 sources were lower in ART-HIV- than in ART-HIV+ subjects., Conclusions: In ART-HIV subjects, cortical sources of resting-state alpha rhythms are related to systemic immune activity and cART., Significance: This EEG procedure may produce biomarkers of treatment response in patients' brain compartments for longitudinal clinical studies., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)