Associations Between HIV and Severe Mpox in an Atlanta Cohort.

BACKGROUND: In the Southeastern United States, the 2022 mpox outbreak disproportionately impacted people who are black and people with HIV (PWH). METHODS: We analyzed a cohort of 395 individuals diagnosed with mpox across 3 health care systems in Atlanta, Georgia between 1 June 2022 and 7 October 2022. We present demographic and clinical characteristics and use multivariable logistic regression analyses to evaluate the association between HIV status and severe mpox (per the US Centers for Disease Control and Prevention definition) and, among PWH, the associations between CD4+ T-cell count and HIV load with severe mpox. RESULTS: Of 395 people diagnosed with mpox, 384 (97.2%) were cisgender men, 335 (84.8%) identified as black, and 324 (82.0%) were PWH. Of 257 PWH with a known HIV load, 90 (35.0%) had > 200 copies/mL. Severe mpox occurred in 77 (19.5%) individuals and there was 1 (0.3%) death. Tecovirimat was prescribed to 112 (28.4%) people, including 56 (72.7%) people with severe mpox. In the multivariable analysis of the total population, PWH had 2.52 times higher odds of severe mpox (95% confidence interval [CI], 1.01-6.27) compared with people without HIV. In the multivariable analysis of PWH, individuals with HIV load > 200 copies/mL had 2.10 (95% CI, 1.00-4.39) times higher odds of severe mpox than PWH who were virologically suppressed. Lower CD4+ T-cell count showed a significant univariate association with severe mpox but was not found to be significantly associated with severe mpox in multivariable analysis. CONCLUSIONS: PWH with nonsuppressed HIV loads had more mpox complications, hospitalizations, and protracted disease courses than people without HIV or PWH with suppressed viral loads. PWH with nonsuppressed HIV loads who are diagnosed with mpox warrant particularly aggressive monitoring and treatment.

Multisite Mpox Infection and Viral Dynamics Among Persons With HIV in Metro Atlanta.

The 2022 mpox outbreak primarily involved sexual transmission among men who have sex with men and disproportionately affected persons with human immunodeficiency virus (HIV). We examined viral dynamics and clinical features in a cohort evaluated for mpox infection at a comprehensive HIV clinic in Atlanta, Georgia. Viral DNA was found in 8 oropharyngeal and 5 anorectal specimens among 10 mpox cases confirmed by lesion swab polymerase chain reaction. Within-participant anatomic site of lowest cycle threshold (Ct) value varied, and lower Ct values were found in oropharyngeal and anorectal swabs when corresponding symptoms were present. This provides insight into mpox infection across multiple anatomic sites among people with HIV.

Cerebrospinal fluid levels of 5-HIAA and dopamine in people with HIV and depression.

Depression is a common illness in people with HIV (PWH) and is associated with substantial morbidity and mortality. The mechanisms that underpin depression in PWH remain incompletely elucidated, and more research is therefore needed to develop effective treatments. One hypothesis is that neurotransmitter levels may be altered. These levels could be influenced by the chronic inflammation and viral persistence that occurs in PWH. We examined a panel of cerebrospinal fluid (CSF) neurotransmitters in PWH on suppressive antiretroviral therapy (ART), many of whom had a current depression diagnosis. CSF monoamine neurotransmitters and their metabolites were measured from participants in studies at the Emory Center for AIDS Research (CFAR). Only participants on stable ART with suppressed HIV RNA from both plasma and CSF were analyzed. Neurotransmitter levels were measured with high-performance liquid chromatography (HPLC). Neurotransmitters and their metabolites included dopamine (DA), homovanillic acid (HVA, a major metabolite of dopamine), serotonin (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA, a major metabolite of serotonin), and 4-hydroxy-3-methoxyphenylglycol (MHPG, a major metabolite of norepinephrine). Multivariable logistic regression was used to evaluate factors associated with depression. There were 79 PWH with plasma and CSF HIV RNA levels < 200 copies/mL at the time of the visit, and 25 (31.6%) carried a current diagnosis of depression. Participants with depression were significantly older (median age 53 years versus 47 years, P = 0.014) and were significantly less likely to be African American (48.0% versus 77.8%, P = 0.008). Participants with depression had significantly lower dopamine levels (median 0.49 ng/mL versus 0.62 ng/mL, P = 0.03) and significantly lower 5-HIAA levels (median 12.57 ng/mL versus 15.41 ng/mL, P = 0.015). Dopamine and 5-HIAA were highly correlated. In the multivariable logistic regression models, lower 5-HIAA was significantly associated with the depression diagnosis when accounting for other significant demographic factors. The associations between lower 5-HIAA, lower dopamine, and depression in PWH suggest that altered neurotransmission may contribute to these comorbid conditions. However, the effects of antidepressants on neurotransmitters cannot be ruled out as a factor in the 5-HIAA results.

Mild Cognitive Impairment, But Not HIV Status, is Related to Reduced Awareness of Level of Cognitive Performance Among Older Adults.

OBJECTIVE: Self-assessment of cognitive abilities can be an important predictor of clinical outcomes. This study examined impairments in self-assessments of cognitive performance, assessed with traditional neuropsychological assessments and novel virtual reality tests among older persons with and without human immunodeficiency virus (HIV) and mild cognitive impairment (MCI). METHODS: One hundred twenty-two participants (82 persons with HIV; 79 MCI+) completed a traditional neuropsychological battery, DETECT virtual reality cognitive battery, and self-reported their general cognitive complaints, depressive symptoms, and perceptions of DETECT performance. Relationships between DETECT performance and self-assessments of performance were examined as were the correlations between general cognitive complaints and performance. These relations were evaluated across HIV and MCI status, considering the associations of depressive symptoms, performance, and self-assessment. RESULTS: We found no effect of HIV status on objective performance or self-assessment of DETECT performance. However, MCI+ participants performed worse on DETECT and traditional cognitive tests, while also showing a directional bias towards overestimation of their performance. MCI- participants showed a bias toward underestimation. Cognitive complaints were reduced compared to objective performance in MCI+ participants. Correlations between self-reported depressive symptoms and cognitive performance or self-assessment of performance were nonsignificant. CONCLUSIONS: MCI+ participants underperformed on neuropsychological testing, while overestimating performance. Interestingly, MCI- participants underestimated performance to approximately the same extent as MCI+ participants overestimated. Practical implications include providing support for persons with MCI regarding awareness of limitations and consideration that self-assessments of cognitive performance may be overestimated. Similarly, supporting older persons without MCI to realistically appraise their abilities may have clinical importance.

A comprehensive data-driven analysis framework for detecting impairments in brain function networks with resting state fMRI in HIV-infected individuals on cART.

Central nervous system (CNS) sequelae continue to be common in HIV-infected individuals despite combination antiretroviral therapy (cART). These sequelae include HIV-associated neurocognitive disorder (HAND) and virologic persistence in the CNS. Resting state functional magnetic resonance imaging (rsfMRI) is a widely used tool to examine the integrity of brain function and pathology. In this study, we examined 16 HIV-positive (HIV+) subjects and 12 age, sex, and race matched HIV seronegative controls (HIV-) whole-brain high-resolution rsfMRI along with a battery of neurocognitive tests. A comprehensive data-driven analysis of rsfMRI revealed impaired functional connectivity, with very large effect sizes in executive function, language, and multisensory processing networks in HIV+ subjects. These results indicate the potential of high-resolution rsfMRI in combination with advanced data analysis techniques to yield biomarkers of neural impairment in HIV.

Soluble Biomarkers of Cognition and Depression in Adults with HIV Infection in the Combination Therapy Era.

PURPOSE OF REVIEW: Cognitive impairment and depression continue to be common among people with HIV (PWH) in the combination antiretroviral therapy (ART) era. A better understanding of the biological mechanisms that may underpin these disorders is needed. The purpose of this review is to describe published findings on soluble biomarkers from blood and cerebrospinal fluid (CSF) that have been associated with either cognition or depression among PWH in the setting of ART. RECENT FINDINGS: Several biomarkers, including those that reflect viral persistence, monocyte/macrophage activation, and other processes, are associated with cognition and depressive symptoms. Some but not all results have been consistent across multiple studies. More research has been published on biomarkers of cognition relative to biomarkers of depression (particularly from CSF). More studies are needed that investigate multiple biomarkers to understand the role of distinct but additive pathways in these disorders and to guide the development of new therapies.

Measurement of Human Immunodeficiency Virus p24 Antigen in Human Cerebrospinal Fluid With Digital Enzyme-Linked Immunosorbent Assay and Association With Decreased Neuropsychological Performance.

New tools are needed to understand human immunodeficiency virus central nervous system involvement. Testing 15 cerebrospinal fluid (CSF) samples for p24 antigen, using a high-sensitivity assay, we found a strong correlation trend between CSF p24 concentration and worse neuropsychological performance.

Neurofilament light chain in blood is negatively associated with neuropsychological performance in HIV-infected adults and declines with initiation of antiretroviral therapy.

HIV-associated neurocognitive disorder (HAND) persists in the combination antiretroviral therapy (cART) era and is associated with diminished quality of life. The disorder remains challenging to diagnose given the requirement for comprehensive neuropsychological testing. Blood biomarkers are needed to facilitate the diagnosis of HAND and to gauge neurological response to antiretroviral therapy. We performed a study of plasma neurofilament light chain (NFL) that included 37 HIV-infected and 54 HIV-negative adults. In the univariate mixed-effect model involving HIV-infected participants, there was a statistically significant linear relationship between composite neuropsychological score (NPT-11) and plasma NFL (slope = - 9.9, standard error = 3.0 with 95% confidence interval - 3.2 to - 16.6 and p = 0.008 when testing slope = 0). Similarly, in the multivariate mixed-effect model, higher plasma NFL was significantly associated with worse NPT-11 (slope = - 11.5, standard error = 3.3 with 95% confidence interval - 3.7 to - 19.0 and p = 0.01 when testing slope = 0). The association between NPT-11 and NFL appeared to be driven by the group of individuals off cART. In a subset of participants who had visits before and after 24 weeks on cART (n = 11), plasma NFL declined over time (median = 22.7 versus 13.4 pg/ml, p = 0.02). In contrast, plasma NFL tended to increase over time among HIV-negative participants (median 10.3 versus 12.6 pg/ml, p = 0.065, n = 54). Plasma NFL therefore shows promise as a marker of neuropsychological performance during HIV. Larger studies are needed to determine if NFL could serve as a diagnostic tool for HAND during suppressive cART.

Prevalence and Correlates of Persistent HIV-1 RNA in Cerebrospinal Fluid During Antiretroviral Therapy.

BACKGROUND: Neurocognitive disorders remain common among human immunodeficiency virus (HIV)-positive adults, perhaps owing to persistent HIV-1 RNA in cerebrospinal fluid (CSF) during antiretroviral therapy (ART). METHODS: Using a single-copy assay, we measured HIV-1 RNA levels in CSF and plasma specimens from 220 HIV-positive adults who were taking suppressive ART. Fifty-five participants were tested twice. RESULTS: HIV-1 RNA was detected in 42.3% of CSF and 65.2% of plasma samples. Correlates of higher CSF HIV-1 RNA levels included higher nadir and current CD4+ T-cell counts, a plasma HIV-1 RNA level of ≥ 1 copy/mL, and a lower central nervous system penetration-effectiveness score (model P < .001). Worse neurocognitive performance was associated with discordance in HIV-1 RNA detection between plasma and CSF, lower overall CSF HIV-1 RNA level, and longer ART duration, among others (model P < .001). In the longitudinal subgroup, CSF HIV-1 RNA persisted in most participants (69%) over 7 months. CONCLUSIONS: Low-level HIV-1 RNA in CSF is common during suppressive ART and is associated with low-level HIV-1 RNA in blood, better immune status, and lower ART drug distribution into CSF. The association between HIV-1 RNA discordance and HIV-associated neurocognitive disorder (HAND) may reflect compartmentalization. The relationship between HAND, lower HIV-1 RNA levels in CSF, and lower CD4+ T-cell counts may reflect disturbances in the immune response to HIV-1 in the CNS.

Cerebrospinal fluid interferon alpha levels correlate with neurocognitive impairment in ambulatory HIV-Infected individuals.

HIV-associated neurocognitive disorders (HANDs) continue to be common and are associated with increased morbidity and mortality. However, the underlying mechanisms in the combination antiretroviral therapy (cART) era are not fully understood. Interferon alpha (IFNα) is an antiviral cytokine found to be elevated in the cerebrospinal fluid (CSF) of individuals with advanced HIV-associated dementia in the pre-cART era. In this cross-sectional study, we investigated the association between IFNα and neurocognitive performance in ambulatory HIV-infected individuals with milder impairment. An eight-test neuropsychological battery representing six cognitive domains was administered. Individual scores were adjusted for demographic characteristics, and a composite neuropsychological score (NPT-8) was calculated. IFNα and CSF neurofilament light chain (NFL) levels were measured using enzyme-linked immunosorbent assay (ELISA). There were 15 chronically infected participants with a history of significant immunocompromise (median nadir CD4+ of 49 cells/µl). Most participants were neurocognitively impaired (mean global deficit score of 0.86). CSF IFNα negatively correlated with three individual tests (Trailmaking A, Trailmaking B, and Stroop Color-Word) as well as the composite NPT-8 score (r = -0.67, p = 0.006). These negative correlations persisted in multivariable analyses adjusting for chronic hepatitis B and C. Additionally, CSF IFNα correlated strongly with CSF NFL, a marker of neuronal damage (rho = 0.748, p = 0.0013). These results extend findings from individuals with severe HIV-associated dementia in the pre-cART era and suggest that IFNα may continue to play a role in HAND pathogenesis during the cART era. Further investigation into the role of IFNα is indicated.

Preliminary study of a novel cognitive assessment device for the evaluation of HIV-associated neurocognitive impairment.

Given the high prevalence of HIV-associated neurocognitive disorders (HAND), we examined the performance of a novel computerized cognitive assessment device (NCAD) for the evaluation of neurocognitive impairment in the setting of HIV. In addition to a standard 8-test neuropsychological battery, each participant underwent testing with the NCAD, which requires approximately 20 min and has been shown to accurately measure neurocognition in elderly individuals. The NCAD yields seven subtest scores in addition to an overall predictive score that is calculated based on subtest results. Thirty-nine HIV-infected participants were included in this study; the majority of which (71.8 %) had undetectable plasma HIV RNA levels and a history of significant immunocompromise (median nadir CD4+ count 34 cells/µl). The mean composite neuropsychological score (NPT-8) was 46.07, and mean global deficit score (GDS) was 0.59. NCAD total subtest accuracy correlated significantly with NPT-8 (Pearson correlation r = 0.59, p < 0.0001) as well as GDS (Spearman's rho = -0.36, p = 0.02). NCAD predictive score also correlated significantly with NPT-8 (Spearman's rho = -0.5601, p = 0.0016) and GDS (Spearman's rho = 0.45, p = 0.0144). When using the most recent nosology of HAND criteria for neurocognitive impairment, the area under the curve (AUC) for NCAD total subtest accuracy was 0.7562 (p = 0.012), while the AUC for the HIV dementia scale was 0.508 (p = 0.930). While not as comprehensive as a full neuropsychological battery, the NCAD shows promise as a rapid screening tool for HIV-infected individuals, and additional research of this device is indicated.

CSF biomarkers of monocyte activation and chemotaxis correlate with magnetic resonance spectroscopy metabolites during chronic HIV disease.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) persist despite combination antiretroviral therapy (cART), supporting the need to better understand HIV neuropathogenesis. Magnetic resonance spectroscopy (MRS) of the brain has demonstrated abnormalities in HIV-infected individuals despite cART. We examined the associations between MRS metabolites and selected cerebrospinal fluid (CSF) biomarkers reflecting monocyte/macrophage activation and chemotaxis. A multicenter cross-sectional study involving five sites in the USA was conducted. The following CSF biomarkers were measured: soluble CD14 (sCD14), monocyte chemotactic protein-1 (MCP-1), interferon inducible protein 10 (IP-10), and stromal cell-derived growth factor 1 alpha (SDF-1α). The following MRS metabolites were measured from basal ganglia (BG), frontal white matter (FWM), and frontal gray matter (FGM): N-acetylaspartate (NAA), myo-inositol (MI), choline (Cho), and creatine (Cr). CSF biomarkers were compared to absolute MRS metabolites as well as metabolite/Cr ratios using linear regression. Eighty-three HIV-infected individuals were included, 78 % on cART and 37 % with HAND. The most robust positive correlations were between MCP-1 and Cho in BG (R (2) 0.179, p < 0.001) as well as MCP-1 and MI in FWM (R (2) 0.137, p = 0.002). Higher Cr levels in FWM were associated with MCP-1 (R (2) 0. 075, p = 0.01) and IP-10 (R (2) 0.106, p = 0.003). Comparing biomarkers to MRS metabolite/Cr ratios impacted some relationships, e.g., higher sCD14 levels were associated with lower Cho/Cr ratios in FGM (R (2) 0.224, p < 0.001), although higher MCP-1 levels remained associated with Cho/Cr in BG. These findings provide evidence that monocyte activation and chemotaxis continue to contribute to HIV-associated brain abnormalities in cART-treated individuals.

Changes in neurocognition and adherence over six months in HIV-infected individuals with cocaine or heroin dependence.

We sought to examine the course of adherence and cognition in HIV-infected individuals with either cocaine or heroin dependence and investigate independent predictors of cognition change. A prospective study over six months was undertaken in which adherence was measured by monthly electronic pill cap monitoring (Medication Event Monitoring System), while a comprehensive neuropsychological battery resulting in a composite score (NPZ8) was performed at baseline and six months. Multivariable regression models were performed in order to determine independent associations with change in cognition. There were 101 subjects at baseline, of whom 62% were male and 83% were non-Hispanic black. 46.6% of subjects at baseline had completed high school, 36.6% reported active cocaine use during the course of the study, and 0% reported active heroin use during the course of the study. 66 subjects completed the final cognitive assessment at six months. Subjects had markedly impaired cognitive function at baseline (NPZ8 -1.49) which persisted at six months (NPZ8 -1.47) in the group of study completers. There was an average monthly decrease in adherence of -2.91% overall (p = 0.008). In the multivariable model, each of the following variables: baseline cognition (R(2) change = 0.121, p = 0.006), cocaine use during the study (R(2) change = 0.059, p = 0.046), and monthly adherence change (R(2) change = 0.078, p = 0.018) independently contributed to NPZ8 change with an overall R(2) change = 0.219 (p = 0.001). This study shows an overall decrease in adherence over time in this population of subjects with a history of drug dependence. Active cocaine use, baseline cognition, and temporal adherence changes independently contributed to changes in cognition. Further study on enhancing adherence, cognition, and limiting drug abuse are warranted in this subgroup of HIV-infected individuals.

The identification of intact HIV proviral DNA from human cerebrospinal fluid.

We evaluated the HIV-1 DNA reservoir in peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid (CSF) in people with HIV (PWH) and associations to cognitive dysfunction. Using the intact proviral DNA assay (IPDA), an emerging technique to identify provirus that may be the source of viral rebound, we assessed HIV DNA in CSF and PBMC in PWH regardless of antiretroviral therapy (ART). CSF was used as a sampling surrogate for the central nervous system (CNS) as opposed to tissue. IDPA results (3' defective, 5' defective, and intact HIV DNA) were analyzed by compartment (Wilcoxon signed rank; matched and unmatched pairs). Cognitive performance, measured via a battery of nine neuropsychological (NP) tests, were analyzed for correlation to HIV DNA (Spearman's rho). 11 CSF and 8 PBMC samples from PWH were evaluated both unmatched and matched. Total CSF HIV DNA was detectable in all participants and was significantly higher than in matched PBMCs (p â€‹= â€‹0.0039). Intact CSF HIV DNA was detected in 7/11 participants and correlated closely with those in PBMCs but tended to be higher in CSF than in PBMC. CSF HIV DNA did not correlate with global NP performance, but higher values did correlate with worse executive function (p â€‹= â€‹0.0440). Intact HIV DNA is frequently present in the CSF of PWH regardless of ART. This further supports the presence of an HIV CNS reservoir and provides a method to study CNS reservoirs during HIV cure studies. Larger studies are needed to evaluate relationships with CNS clinical outcomes.

CROI 2023: Neuropsychiatric Complications in People With HIV.

The 2023 Conference on Retroviruses and Opportunistic Infections (CROI) featured new and impactful findings about neuropsychiatric complications in people with HIV and other infections. Reports included new evidence of (a) the importance of myeloid cells in the pathogenesis of HIV disease in the central nervous system, including as an HIV reservoir; (b) eukaryotic and prokaryotic viruses in cerebrospinal fluid during suppressive antiretroviral therapy; (c) the influence of sex on pathogenesis, including in novel neuropsychiatric biotypes identified by machine learning and other methods;(d) premature aging in people with HIV, including the brain-age gap observed on magnetic resonance imaging; (e) cellular and soluble biomarkers of neuropsychiatric complications in people with HIV; and (f) the neurotoxicity of certain antiretroviral drugs. This review summarizes these and other new findings and highlights new research directions for the neuro-HIV field.

Auditory and cognitive function in older adults living with and without HIV.

OBJECTIVES: To evaluate the peripheral hearing sensitivity and central auditory processing in persons with HIV (PWH) and persons without HIV (PWoH); and the association between cognitive function and central auditory processing in PWH and PWoH. DESIGN: Cross-sectional, observational study. METHODS: Participants included 67 PWH {70.2% men; mean age = 66.6 years [standard deviation (SD) = 4.7 years]} and 35 PWoH [51.4% men; mean age = 72.9 years (SD = 7.0 years)]. Participants completed a hearing assessment and a central auditory processing assessment that included dichotic digits testing (DDT). Pure-tone air-conduction thresholds were obtained at octave frequencies from 0.25 through 8 kHz. A pure-tone average (PTA) was calculated from 0.5, 1, 2, and 4 kHz thresholds for each ear. Participants also completed a neuropsychological battery assessing cognition in seven domains. RESULTS: PWH had slightly lower (i.e. better) PTAs compared with PWoH, but this was not statistically significant. Conversely, PWH and PWoH had similar DDT results for both ears. Poorer verbal fluency, learning, and working memory performance was significantly related to lower DDT scores, and those defined as having verbal fluency, learning, and working memory impairment had significantly poorer DDT scores (8-18% lower) in both ears. CONCLUSION: Hearing and DDT results were similar in PWH and PWoH. The relationship between verbal fluency, learning, and working memory impairment and poorer DDT results did not differ by HIV serostatus. Clinicians, particularly audiologists, should be mindful of cognitive functioning abilities when evaluating central auditory processing.

The comorbidity of depression and neurocognitive disorder in persons with HIV infection: call for investigation and treatment.

Depression and neurocognitive disorder continue to be the major neuropsychiatric disorders affecting persons with HIV (PWH). The prevalence of major depressive disorder is two to fourfold higher among PWH than the general population (∼6.7%). Prevalence estimates of neurocognitive disorder among PWH range from 25 to over 47% - depending upon the definition used (which is currently evolving), the size of the test battery employed, and the demographic and HIV disease characteristics of the participants included, such as age range and sex distribution. Both major depressive disorder and neurocognitive disorder also result in substantial morbidity and premature mortality. However, though anticipated to be relatively common, the comorbidity of these two disorders in PWH has not been formally studied. This is partly due to the clinical overlap of the neurocognitive symptoms of these two disorders. Both also share neurobehavioral aspects - particularly apathy - as well as an increased risk for non-adherence to antiretroviral therapy. Shared pathophysiological mechanisms potentially explain these intersecting phenotypes, including neuroinflammatory, vascular, and microbiomic, as well as neuroendocrine/neurotransmitter dynamic mechanisms. Treatment of either disorder affects the other with respect to symptom reduction as well as medication toxicity. We present a unified model for the comorbidity based upon deficits in dopaminergic transmission that occur in both major depressive disorder and HIV-associated neurocognitive disorder. Specific treatments for the comorbidity that decrease neuroinflammation and/or restore associated deficits in dopaminergic transmission may be indicated and merit study.

Elevated Plasma Protein Carbonyl Concentration Is Associated with More Abnormal White Matter in People with HIV.

Structural brain abnormalities, including those in white matter (WM), remain common in people with HIV (PWH). Their pathogenesis is uncertain and may reflect multiple etiologies. Oxidative stress is associated with inflammation, HIV, and its comorbidities. The post-translational carbonylation of proteins results from oxidative stress, and circulating protein carbonyls may reflect this. In this cross-sectional analysis, we evaluated the associations between protein carbonyls and a panel of soluble biomarkers of neuronal injury and inflammation in plasma (N = 45) and cerebrospinal fluid (CSF, n = 32) with structural brain MRI. The volume of abnormal WM was normalized for the total WM volume (nAWM). In this multisite project, all regression models were adjusted for the scanner. The candidate covariates included demographics, HIV disease characteristics, and comorbidities. Participants were PWH on virally suppressive antiretroviral therapy (ART) and were mostly white (64.4%) men (88.9%), with a mean age of 56.8 years. In unadjusted analyses, more nAWM was associated with higher plasma protein carbonyls (p = 0.002) and higher CCL2 (p = 0.045). In the adjusted regression models for nAWM, the association with plasma protein carbonyls remained significant (FDR p = 0.018). Protein carbonyls in plasma may be a valuable biomarker of oxidative stress and its associated adverse health effects, including within the central nervous system. If confirmed, these findings would support the hypothesis that reducing oxidative stress could treat or prevent WM injury in PWH.

An Automated Virtual Reality Program Accurately Diagnoses HIV-Associated Neurocognitive Disorders in Older People With HIV.

Background: HIV-associated neurocognitive disorders (HANDs) remain prevalent despite antiretroviral therapy, particularly among older people with HIV (PWH). However, the diagnosis of HAND is labor intensive and requires expertise to administer neuropsychological tests. Our prior pilot work established the feasibility and accuracy of a computerized self-administered virtual reality program (DETECT; Display Enhanced Testing for Cognitive Impairment and Traumatic Brain Injury) to measure cognition in younger PWH. The present study expands this to a larger sample of older PWH. Methods: We enrolled PWH who were ≥60 years old, were undergoing antiretroviral therapy, had undetectable plasma viral loads, and were without significant neuropsychological confounds. HAND status was determined via Frascati criteria. Regression models that controlled for demographic differences (age, sex, education, race/ethnicity) examined the association between DETECT's cognition module and both HAND status and Global Deficit Score (GDS) derived via traditional neuropsychological tests. Results: Seventy-nine PWH (mean age, 66 years; 28% women) completed a comprehensive neuropsychological battery and DETECT's cognition module. Twenty-five (32%) had HAND based on the comprehensive battery. A significant correlation was found between the DETECT cognition module and the neuropsychological battery (r = 0.45, P < .001). Furthermore, in two separate regression models, HAND status (b = -0.79, P < .001) and GDS impairment status (b = -0.83, P < .001) significantly predicted DETECT performance. Areas under the curve for DETECT were 0.78 for differentiating participants by HAND status (HAND vs no HAND) and 0.85 for detecting GDS impairment. Conclusions: The DETECT cognition module provides a novel means to identify cognitive impairment in older PWH. As DETECT is fully immersive and self-administered, this virtual reality tool holds promise as a scalable cognitive screening battery.

CROI 2022: neurologic complications of HIV-1, SARS-CoV-2, and other pathogens.

The 2022 Conference on Retroviruses and Opportunistic Infections featured new and important findings about the neurologic complications of HIV-1, COVID-19, and other infections. Long-term analyses identified that cognitive decline over time, phenotypic aging, and stroke are associated with various comorbidities in people with HIV. Neuroimaging studies showed greater neuroinflammation, white matter damage, demyelination, and overall brain aging in people with chronic HIV infection. Childhood trauma and exposure to environmental pollutants contribute to these neuroimaging findings. Studies of blood and cerebrospinal fluid biomarkers showed that systemic inflammation, neurodegeneration, endothelial activation, oxidative stress, and iron dysregulation are associated with worse cognition in people with HIV. Some animal studies focused on myeloid cells of the central nervous system, but other animal and human studies showed that lymphoid cells also contribute to HIV neuropathogenesis. The deleterious central nervous system effects of polypharmacy and anticholinergic drugs in people with HIV were demonstrated. In contrast, a large randomized controlled trial showed that integrase strand transfer inhibitor therapy was not associated with neurotoxicity. Studies of cryptococcal meningitis demonstrated he cost-effectiveness of single high-dose liposomal amphotericin and the prognostic value of the cryptococcal antigen lateral flow assay. People hospitalized with COVID-19 had more anxiety over time after discharge. The SARS-CoV-2 nucleocapsid antigen is present in cerebrospinal fluid in the absence of viral RNA. Systemic inflammation, astrocyte activation, and tryptophan metabolism pathways are associated with post-COVID-19 neurologic syndromes. Whether these processes are independent or intertwined during HIV-1 and COVID-19 infections requires further study.