Central Nervous System Safety During Brief Analytic Treatment Interruption of Antiretroviral Therapy Within 4 Human Immunodeficiency Virus Remission Trials: An Observational Study in Acutely Treated People Living With Human Immunodeficiency Virus.

BACKGROUND: The central nervous system (CNS) is a likely reservoir of human immunodeficiency virus (HIV), vulnerable to viral rebound, inflammation, and clinical changes upon stopping antiretroviral therapy (ART). It is critical to evaluate the CNS safety of studies using analytic treatment interruption (ATI) to assess HIV remission. METHODS: Thirty participants who started ART during acute HIV infection underwent CNS assessments across 4 ATI remission trials. ART resumption occurred with plasma viral load >1000 copies/mL. CNS measures included paired pre- vs post-ATI measures of mood, cognitive performance, and neurologic examination, with elective cerebrospinal fluid (CSF) sampling, brain diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS). RESULTS: Median participant age was 30 years old and 29/30 were male. Participants' median time on ART before ATI was 3 years, and ATI lasted a median of 35 days. Post-ATI, there were no differences in median mood scores or neurologic findings and cognitive performance improved modestly. During ATI, a low level of CSF HIV-1 RNA was detectable in 6 of 20 participants with plasma viremia, with no group changes in CSF immune activation markers or brain DTI measures. Mild worsening was identified in post-ATI basal ganglia total choline MRS, suggesting an alteration in neuronal membranes. CONCLUSION: No adverse CNS effects were observed with brief, closely monitored ATI in participants with acutely treated HIV, except an MRS alteration in basal ganglia choline. Further studies are needed to assess CNS ATI safety in HIV remission trials, particularly for studies using higher thresholds to restart ART and longer ATI durations.

Resting-state neural signatures of depressive symptoms in acute HIV.

Depressive symptoms are often elevated in acute and chronic HIV. Previous neuroimaging research identifies abnormalities in emotion-related brain regions in depression without HIV, including the anterior cingulate cortex (ACC) and amygdala. However, no studies have examined the neural signatures of depressive symptoms in acute HIV infection (AHI). Seed-based voxelwise resting-state functional connectivity (rsFC) for affective seed regions of interest (pregenual ACC, subgenual ACC [sgACC], bilateral amygdala) was computed for 74 Thai males with AHI and 30 Thai HIV-uninfected controls. Group analyses compared rsFC of ACC and amygdala seed regions between AHI and uninfected control groups. Within the AHI group, voxelwise regression analyses investigated the relationship between depressive symptoms and rsFC for these affective seed regions. Group analyses revealed alterations in rsFC of the amygdala in AHI versus uninfected controls. Depressive symptoms associated with decreased rsFC between ACC regions and posterior cingulate/precuneus, medial temporal, and lateral parietal regions in AHI. Symptoms of depression also correlated to increased rsFC between ACC regions and lateral prefrontal cortex, sgACC, and cerebellum in AHI. Similar to the ACC, depressive symptoms associated with decreased rsFC between amygdala and precuneus. Of blood biomarkers, only HIV RNA inversely correlated with rsFC between posterior sgACC and left uncus. We found that depressive symptoms in AHI associate with altered rsFC of ACC and amygdala regions previously implicated in depression. Longitudinal research in this cohort will be necessary to determine whether these early alterations in rsFC of affective network regions are related to persistent depressive symptoms after combination antiretroviral therapy.

Cerebrovascular Disease Correlates With Longitudinal Brain Atrophy in Virally Suppressed Older People Living With HIV.

BACKGROUND: Mild cognitive difficulties and progressive brain atrophy are observed in older people living with HIV (PLWH) despite persistent viral suppression. Whether cerebrovascular disease (CVD) risk factors and white matter hyperintensity (WMH) volume correspond to the observed progressive brain atrophy is not well understood. METHODS: Longitudinal structural brain atrophy rates and WMH volume were examined among 57 HIV-infected participants and 40 demographically similar HIV-uninfected controls over an average (SD) of 3.4 (1.7) years. We investigated associations between CVD burden (presence of diabetes, hypertension, hyperlipidemia, obesity, smoking history, and atrial fibrillation) and WMH with atrophy over time. RESULTS: The mean (SD) age was 64.8 (4.3) years for PLWH and 66.4 (3.2) years for controls. Participants and controls were similar in age and sex (P > 0.05). PLWH were persistently suppressed (VL <375 copies/mL with 93% <75 copies/mL). The total number of CVD risk factors did not associate with atrophy rates in any regions of interests examined; however, body mass index independently associated with progressive atrophy in the right precentral gyrus (ß = -0.30; P = 0.023), parietal lobe (ß = -0.28; P = 0.030), and frontal lobe atrophy (ß = -0.27; P = 0.026) of the HIV-infected group. No associations were found in the HIV-uninfected group. In both groups, baseline WMH was associated with progressive atrophy rates bilaterally in the parietal gray in the HIV-infected group (ß = -0.30; P = 0.034) and the HIV-uninfected participants (ß = -0.37; P = 0.033). CONCLUSIONS: Body mass index and WMH are associated with atrophy in selective brain regions. However, CVD burden seems to partially contribute to progressive brain atrophy in older individuals regardless of HIV status, with similar effect sizes. Thus, CVD alone is unlikely to explain accelerated atrophy rates observed in virally suppressed PLWH. In older individuals, addressing modifiable CVD risk factors remains important to optimize brain health.

Longitudinal brain atrophy patterns and neuropsychological performance in older adults with HIV-associated neurocognitive disorder compared with early Alzheimer's disease.

Older HIV-infected patients are at risk for both HIV-associated neurocognitive disorder (HAND) and Alzheimer's disease. We investigated neuroimaging and neuropsychological performance of 61 virally suppressed older adults with HAND (mean (SD) age 64.3 (3.9) years), 53 demographically matched individuals with mild cognitive impairment of the Alzheimer's type (MCI-AD; 65.0 [4.8]), and 89 healthy controls (65.0 [4.3]) cross-sectionally and over 20 months. At the baseline, both disease groups exhibited lower volumes in multiple cortical and subcortical regions compared with controls. Hippocampal volume differentiated MCI-AD from HAND. Cognitively, MCI-AD performed worse on memory and language compared with HAND. Adjusted longitudinal models revealed greater diffuse brain atrophy in MCI-AD compared with controls, whereas HAND showed greater atrophy in frontal gray matter and cerebellum compared with controls. Comparing HAND with MCI-AD showed similar atrophy rates in all brain regions explored, with no significant findings. MCI-AD exhibited more pronounced language decline compared with HAND. These findings reveal the need for further work on unique cognitive phenotypes and neuroimaging signatures of HAND compared with early AD, providing preliminary clinical insight for differential diagnosis of age-related brain dysfunction in geriatric neuroHIV.

Structural and functional brain imaging in acute HIV.

Background: HIV RNA is identified in cerebrospinal fluid (CSF) within eight days of estimated viral exposure. Neurological findings and impaired neuropsychological testing performance are documented in a subset of individuals with acute HIV infection (AHI). The purpose of this study was to determine whether microstructural white matter and resting-state functional connectivity (rsFC) are disrupted in AHI. Methods: We examined 49 AHI (100% male; mean age = 30 ±â€¯SD 9.9) and 23 HIV-uninfected Thai participants (78% male; age = 30 ±â€¯5.5) with diffusion tensor imaging (DTI) and rsFC acquired at 3 Tesla, and four neuropsychological tests (summarized as NPZ-4). MRI for the AHI group was performed prior to combination antiretroviral treatment (ART) in 26 participants and on average two days (range:1-5) after ART in 23 participants. Fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivity (RD) were quantified for DTI. Seed-based voxelwise rsFC analyses were completed for the default mode (DMN), fronto-parietal, and salience and 6 subcortical networks. rsFC and DTI analyses were corrected for family-wise error, with voxelwise comparisons completed using t-tests. Group-specific voxelwise regressions were conducted to examine relationships between imaging indices, HIV disease variables, and treatment status. Results: The AHI group had a mean (SD) CD4 count of 421(234) cells/mm3 plasma HIV RNA of 6.07(1.1) log10 copies/mL and estimated duration of infection of 20(5.5) days. Differences between AHI and CO groups did not meet statistical significance for DTI metrics. Within the AHI group, voxelwise analyses revealed associations between brief exposure to ART and higher FA and lower RD and MD bilaterally in the corpus callosum, corona radiata, and superior longitudinal fasciculus (p < 0.05). Diffusion indices were unrelated to clinical variables or NPZ-4. The AHI group had reduced rsFC between left parahippocampal cortex (PHC) of the DMN and left middle frontal gyrus compared to CO (p < 0.002). Within AHI, ART status was unrelated to rsFC. However, higher CD4 cell count associated with increased rsFC for the right lateral parietal and PHC seeds in the DMN. Direct associations were noted between NPZ-4 correspond to higher rsFC of the bilateral caudate seed (p < 0.002). Conclusions: Study findings reveal minimal disruption to structural and functional brain integrity in the earliest stages of HIV. Longitudinal studies are needed to determine if treatment with ART initiated in AHI is sufficient to prevent the evolution of brain dysfunction identified in chronically infected individuals.

Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Patients Older Than 60 Years.

BACKGROUND: Current HIV treatments are successful at suppressing plasma HIV RNA to undetectable levels for most adherent patients. Yet, emerging evidence suggests that viral suppression will inadequately control inflammation and mitigate risk for progressive brain injury. We sought to quantify differences in longitudinal brain atrophy rates among older virally suppressed HIV-infected participants compared with that of healthy aging participants. METHODS: We examined longitudinal structural brain magnetic resonance imaging atrophy rates using region of interest assessments and voxel-wise tensor-based morphometry in HIV-infected participants older than 60 years (n = 38) compared with age-matched HIV-uninfected healthy and cognitively normal controls (n = 24). RESULTS: The mean age of participants was 63 years, the mean estimated duration of infection was 21 years, and the median duration of documented viral suppression was 3.2 years. Average proximal and nadir CD4 counts were 550 and 166, respectively; 15/38 (39%) met criteria for HIV-associated neurocognitive disorder. In models adjusting for age and sex, HIV serostatus was associated with more rapid average annualized rates of atrophy in the cerebellum (0.42% vs. 0.02%, P = 0.016), caudate (0.74% vs. 0.03%, P = 0.012), frontal lobe (0.48% vs. 0.01%, P = 0.034), total cortical gray matter (0.65% vs. 0.16%, P = 0.027), brainstem (0.31% vs. 0.01%, P = 0.026), and pallidum (0.73% vs. 0.39%, P = 0.046). Among those with HIV, atrophy rates did not differ statistically by cognitive status. CONCLUSIONS: Despite persistent control of plasma viremia, these older HIV-infected participants demonstrate more rapid progressive brain atrophy when compared with healthy aging. Either HIV or other factors that differ between older HIV-infected participants and healthy controls could be responsible for these differences.