Longitudinal analysis of CSF HIV RNA in untreated people with HIV: Identification of CSF controllers.

Interindividual variation of human immunodeficiency virus (HIV) RNA setpoint in cerebrospinal fluid (CSF) and its determinants are poorly understood, but relevant for HIV neuropathology, brain reservoirs, viral escape, and reseeding after antiretroviral interruptions. Longitudinal multicentric study on demographic, clinical, and laboratory correlates of CSF HIV RNA in 2000 follow-up visits from 597 people with HIV (PWH) off antiretroviral therapy (ART) and with plasma HIV RNA > the lower limit of quantification (LLQ). Factors associated with CSF control (CSFC; CSF HIV RNA < LLQ while plasma HIV RNA > LLQ) and with CSF/plasma discordance (CSF > plasma HIV RNA > LLQ) were also assessed through mixed-effects models. Posthoc and sensitivity analyses were performed for persistent CSFC and ART-naïve participants, respectively. Over a median follow-up of 2.1 years, CSF HIV RNA was associated with CD4+ and CD8+ T cells, CSF leukocytes, blood-brain barrier (BBB) integrity, biomarkers of iron and lipid metabolism, serum globulins, past exposure to lamivudine, and plasma HIV RNA (model p < 0.0001). CSFC (persistent in 7.7% over 3 years) and CSF/plasma discordance (persistent in <0.01% over 1 year) were variably associated with the same parameters (model p < 0.001). Sensitivity analyses confirmed most of the previous associations in participants never exposed to ART. Persistent CSFC was associated with higher CD4+ T-cell count nadir (p < 0.001), lower serum globulins (p = 0.003), and lower CSF leukocytes (p < 0.001). Without ART, one in 13 PWH had persistently undetectable CSF HIV RNA, while persistent CSF/plasma discordance was extremely rare over years. Immune responses, inflammation, BBB permeability, and iron and lipid metabolism were all associated with HIV replication in CSF.

Effects of Opioid Withdrawal on Psychobiology in People Living with HIV.

OBJECTIVE: Many persons with opioid use disorders (OUDs) have HIV disease and experience clinically significant stress after they enroll in abstinence-based treatment and undergo medically assisted withdrawal. We examined whether opioid withdrawal affects virologic control, inflammatory markers, cognition, and mood in persons with an OUD and HIV, and explored whether measures of withdrawal stress, such as activation of the HPA axis, contribute to alterations in immune function, cognition, and mood. METHOD AND PARTICIPANTS: Study participants were 53 persons with HIV who were admitted for OUD treatment at the City Addiction Hospital in Saint Petersburg, Russian Federation. Participants were examined at admission, at the anticipated peak of withdrawal 3 to 7 days after the last day of a clonidine-based withdrawal process lasting 7 to 14 days, and 3 to 4 weeks after completing withdrawal. At these times, participants received medical exams and were evaluated for symptoms of withdrawal, as well as cognition and mood. Viral load, plasma cortisol, DHEA sulfate ester (DHEA-S), interleukin-6 (IL-6), and soluble CD14 (sCD14) were determined. Multivariable models examined the relationships between markers of HPA activation and the other parameters over time. RESULTS: HPA activation as indexed by cortisol/DHEA-S ratio increased during withdrawal, as did markers of immune activation, IL-6 and sCD14. There were no significant associations between viral load and indicators of HPA activation. In longitudinal analyses, higher cortisol/DHEA sulfate was related to worse cognition overall, and more mood disturbance. Increase in IL-6 was associated with worse cognitive performance on a learning task. There were no significant associations with sCD14. CONCLUSIONS: Worsening of cognition and measures of mood disturbance during withdrawal were associated with activation of the HPA axis and some measures of inflammation. Whether repeated episodes of opioid withdrawal have a cumulative impact on long-term HIV outcomes and neurocognition is a topic for further investigation.

Identifying and distinguishing cognitive profiles among virally suppressed people with HIV.

OBJECTIVE: Cognitive deficits are common among people with HIV (PWH), even when virally suppressed. We identified cognitive profiles among virally suppressed PWH and determined how sociodemographic, clinical/behavioral, and HIV disease characteristics distinguish profile membership. METHOD: Participants included 704 virally suppressed PWH (Mage = 43.9 [SD = 10.2], 88% male, 58.9% non-Hispanic White) from the HIV Neurobehavioral Research Program. Demographically adjusted T scores were derived from a neuropsychological evaluation comprised of 13 tests. We implemented a pipeline involving dimension reduction and clustering to identify profiles of cognitive performance. Random forest models on a 70/30 training/testing set with internal cross-validation were used to identify sociodemographic, clinical/behavioral, and HIV disease correlates of profile membership. RESULTS: Six cognitive profiles were identified: (a) "unimpaired" (19.9%); (b) weakness in verbal learning and memory (15.5%); (c) weakness in executive function and learning (25.8%); (d) weakness in motor, processing speed, and executive function (8.1%); (e) impaired learning and recall with weak-to-impaired motor, processing speed, and executive function (13.1%); (f) global deficits (17.6%). The most discriminative sociodemographic, clinical/behavioral, and HIV disease characteristics varied by profile with self-reported mood symptoms and cognitive/functional difficulties (e.g., language/communication, memory, and overall everyday function complaints) most consistently associated with profile membership. CONCLUSIONS: Cognitive profiles and their associated factors among PWH are heterogeneous, but learning/memory deficits were most common and self-reported mood, and cognitive/functional difficulties were most consistently related to profile membership. This heterogeneity in cognitive profiles and their correlates in PWH suggests that differing mechanisms contribute to cognitive deficits and, thus, underscores the need for personalized risk reduction and therapeutic strategies among PWH. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Cannabis use may attenuate neurocognitive performance deficits resulting from methamphetamine use disorder.

OBJECTIVE: Methamphetamine and cannabis are two widely used, and frequently co-used, substances with possibly opposing effects on the central nervous system. Evidence of neurocognitive deficits related to use is robust for methamphetamine and mixed for cannabis. Findings regarding their combined use are inconclusive. We aimed to compare neurocognitive performance in people with lifetime cannabis or methamphetamine use disorder diagnoses, or both, relative to people without substance use disorders. METHOD: 423 (71.9% male, aged 44.6 ± 14.2 years) participants, stratified by presence or absence of lifetime methamphetamine (M-/M+) and/or cannabis (C-/C+) DSM-IV abuse/dependence, completed a comprehensive neuropsychological, substance use, and psychiatric assessment. Neurocognitive domain T-scores and impairment rates were examined using multiple linear and binomial regression, respectively, controlling for covariates that may impact cognition. RESULTS: Globally, M+C+ performed worse than M-C- but better than M+C-. M+C+ outperformed M+C- on measures of verbal fluency, information processing speed, learning, memory, and working memory. M-C+ did not display lower performance than M-C- globally or on any domain measures, and M-C+ even performed better than M-C- on measures of learning, memory, and working memory. CONCLUSIONS: Our findings are consistent with prior work showing that methamphetamine use confers risk for worse neurocognitive outcomes, and that cannabis use does not appear to exacerbate and may even reduce this risk. People with a history of cannabis use disorders performed similarly to our nonsubstance using comparison group and outperformed them in some domains. These findings warrant further investigation as to whether cannabis use may ameliorate methamphetamine neurotoxicity.

Distinct effects of SSRIs and SNRIs on Soluble Biomarkers in Blood and Cerebrospinal Fluid of people with HIV.

BACKGROUND: Persistent inflammation affects people with HIV (PWH) despite antiretroviral therapy (ART). Selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs, SNRIs), HMG-CoA reductase-inhibitors (statins), and angiotensin-converting enzyme inhibitors (ACEIs) have immuno-modulant properties. We evaluated the potential impact of these drugs on inflammation and neurodegeneration in PWH. METHODS: Cross-sectional single-center (U.S.) analysis in 184 PWH on ART with plasma HIV RNA < 200 cp/mL. All participants had 10 biomarkers measured in blood and cerebrospinal fluid (CSF). To reduce dimensionality, hierarchical clustering and principal components (PCs) analysis were employed. The analyses were adjusted for duration of the drugs and and clinical conditions. RESULTS: Participants were mostly middle-aged men, with median CD4+ T-cells of 620/µL. In adjusted models, SSRI use was associated with three PCs: higher CSF and plasma Aß42 and CSF CCL2 (aß=0.14, p = 0.040); lower CSF 8-oxo-dG, total tau, and sCD14 (aß=-0.12, p = 0.042); higher plasma sCD14 with lower sCD40L (aß=0.15, p = 0.042). SNRI use was associated with higher values of CSF and plasma neopterin and CSF sTNFR-II (aß=0.22, p = 0.004). Statins and ACEIs showed no association. CONCLUSIONS: SSRIs and SNRIs had distinct biomarker signatures. SSRIs were associated with reduced neurodegeneration, immune activation and oxidative stress in CSF, suggesting a role of SSRIs as adjunctive therapy in PWH.

The clinical utility of three frailty measures in identifying HIV-associated neurocognitive disorders.

OBJECTIVE: Frailty measures vary widely and the optimal measure for predicting HIV-associated neurocognitive disorders (HAND) is unclear. DESIGN: A study was conducted to examine the clinical utility of three widely used frailty measures in identifying HIV-associated neurocognitive disorders. METHODS: The study involved 284 people with HIV (PWH) at least 50 years enrolled at UC San Diego's HIV Neurobehavioral Research Program. Frailty measurements included the Fried Phenotype, the Rockwood Frailty Index, and the Veterans Aging Cohort Study (VACS) Index. HAND was diagnosed according to Frascati criteria. ANOVAs examined differences in frailty severity across HAND conditions. ROC analyses evaluated sensitivity and specificity of each measure to detect symptomatic HAND [mild neurocognitive disorder (MND) and HIV-associated dementia (HAD)] from no HAND. RESULTS: Across all frailty measures, frailty was found to be higher in HAD compared with no HAND. For Fried and Rockwood (not VACS), frailty was significantly more severe in MND vs. no HAND and in HAD vs. ANI (asymptomatic neurocognitive impairment). For discriminating symptomatic HAND from no HAND, Fried was 37% sensitive and 92% specific, Rockwood was 85% sensitive and 43% specific, and VACS was 58% sensitive and 65% specific. CONCLUSION: These findings demonstrate that Fried and Rockwood outperform VACS in predicting HAND. However, ROC analyses suggest none of the indices had adequate predictive validity in detecting HAND. The results indicate that the combined use of the Rockwood and Fried indices may be an appropriate alternative.

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.

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.

Increasing Neuroinflammation Relates to Increasing Neurodegeneration in People with HIV.

BACKGROUND: HIV infection causes neuroinflammation and immune activation (NIIA) and systemic inflammation and immune activation (SIIA), which in turn drive neurodegeneration (ND). Cross-sectionally, higher levels of NIIA biomarkers correlate with increased biomarkers of ND. A more convincing confirmation would be a longitudinal demonstration. METHODS: PWH in the US multisite CHARTER Aging project were assessed at a baseline visit and after 12 years using standardized evaluations. We measured a panel of 14 biomarkers of NIIA, SIIA, and ND in plasma and CSF at two time points and calculated changes from baseline to the 12-year visit. Factor analysis yielded simplified indices of NIIA, SIIA, and ND. RESULTS: The CSF NIIA factor analysis yielded Factor1 loading on soluble tumor necrosis factor type-2 (sTNFR-II) and neopterin, and Factor2, loading on MCP1, soluble CD14, and IL-6. The SIIA factor analysis yielded Factor1 loading on CRP, D-dimer, and Neopterin; Factor2 loading on sTNFR-II. The ND analysis yielded Factor1 loading on Phosphorylated tau (p-tau) and Aß42; Factor2 loading on NFL. NIIA Factor1, but not Factor2, correlated with increases in CSF NFL (r = 0.370, p = 0.0002). CONCLUSIONS: Increases in NIIA and SIIA in PWH were associated with corresponding increases in ND, suggesting that reducing neuro/systemic inflammation might slow or reverse neurodegeneration.

Reply to Augello, P.A.; Wu, J. Comment on "Rogers et al. The Combined Effects of Cannabis, Methamphetamine, and HIV on Neurocognition. Viruses 2023, 15, 674".

We thank Augello and Wu [...].

Combined effects of loneliness and inflammation on depression in people with HIV.

OBJECTIVE: Loneliness is prevalent in people with HIV (PWH) and associated with adverse health-related consequences, including depression. Chronic inflammation has been linked to depression in PWH, though its association with loneliness is less well established. Simultaneous examination of inflammation, loneliness and depression is needed to clarify these relationships. This study investigated the relationship between loneliness and inflammation, and the effects of loneliness and inflammation on depression in PWH. METHODS: 82 PWH who were on suppressive ART (mean age [SD] = 53.2 [9.0]) completed the UCLA Loneliness Scale-Version 3 and the Center for Epidemiologic Studies Depression Scale as part of a comprehensive evaluation. Biomarkers of systemic inflammation (CRP, IL-6, CCL2/MCP-1, sCD14) and coagulation (D-dimer) were measured in blood using commercial immunoassays. RESULTS: Multivariable linear regression analyses revealed that higher D-dimer, CCL2/MCP-1, and sCD14 were significant predictors of loneliness (ps < .05) while accounting for relevant covariates. Stepwise multiple linear regression models that included loneliness, biomarkers, and their interactions as predictors of depressive symptoms revealed significant main effects of loneliness and CCL2/MCP-1 levels (ps < .05), and a significant loneliness by D-dimer interaction (p < .05) whereby higher D-dimer was associated with increased depressive symptoms only at higher levels of loneliness. CONCLUSIONS: Increased coagulation activity is associated with loneliness, and in the context of loneliness, may increase risk for depression. Increased inflammation was associated with depression suggesting potentially dissociable underlying biological processes. To the extent that these processes are modifiable, such findings could have important implications in the treatment of loneliness and depression in PWH.

Beyond the Syndemic of Opioid Use Disorders and HIV: The Impact of Opioids on Viral Reservoirs.

People with HIV are more likely to have opioid use disorder and to be prescribed opioids for chronic pain than the general population; however, the effects of opioids on the immune system and HIV persistence have not been fully elucidated. Opioids may affect HIV reservoirs during their establishment, maintenance, and reactivation by enhancing HIV infectivity and replication due to upregulation of co-receptors and impairment of innate antiviral responses. Opioids may also modulate immune cell functioning and microbial translocation and can reverse viral latency. In this review, we summarize the current findings for and against the modulating effects of opioids on HIV cellular and anatomical reservoirs, highlighting the current limitations that affect in vitro, ex vivo, and in vivo studies in the field. We propose further research targets and potential strategies to approach this topic.

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.

Antiretroviral Therapy Intensification for Neurocognitive Impairment in Human Immunodeficiency Virus.

BACKGROUND: Neurocognitive impairment (NCI) in people with HIV (PWH) on antiretroviral therapy (ART) is common and may result from persistent HIV replication in the central nervous system. METHODS: A5324 was a randomized, double-blind, placebo-controlled, 96-week trial of ART intensification with dolutegravir (DTG) + MVC, DTG + Placebo, or Dual - Placebo in PWH with plasma HIV RNA <50 copies/mL on ART and NCI. The primary outcome was the change on the normalized total z score (ie, the mean of individual NC test z scores) at week 48. RESULTS: Of 357 screened, 191 enrolled: 71% male, 51% Black race, 22% Hispanic ethnicity; mean age 52 years; mean CD4+ T-cells 681 cells/µL. Most (65%) had symptomatic HIV-associated NC disorder. Study drug was discontinued due to an adverse event in 15 (8%) and did not differ between arms (P = .17). Total z score, depressive symptoms, and daily functioning improved over time in all arms with no significant differences between them at week 48 or later. Adjusting for age, sex, race, study site, efavirenz use, or baseline z score did not alter the results. Body mass index modestly increased over 96 weeks (mean increase 0.32 kg/m2, P = .006) and did not differ between arms (P > .10). CONCLUSIONS: This is the largest, randomized, placebo-controlled trial of ART intensification for NCI in PWH. The findings do not support empiric ART intensification as a treatment for NCI in PWH on suppressive ART. They also do not support that DTG adversely affects cognition, mood, or weight.

The Combined Effects of Cannabis, Methamphetamine, and HIV on Neurocognition.

OBJECTIVE: Methamphetamine and cannabis are two widely used substances among people living with HIV (PLWH). Whereas methamphetamine use has been found to worsen HIV-associated neurocognitive impairment, the effects of combined cannabis and methamphetamine use disorder on neurocognition in PLWH are not understood. In the present study, we aimed to determine the influence of these substance use disorders on neurocognition in PLWH and to explore if methamphetamine-cannabis effects interacted with HIV status. METHOD AND PARTICIPANTS: After completing a comprehensive neurobehavioral assessment, PLWH (n = 472) were stratified by lifetime methamphetamine (M-/M+) and cannabis (C-/C+) DSM-IV abuse/dependence disorder into four groups: M-C- (n = 187), M-C+ (n = 68), M+C-, (n = 82), and M+C+ (n = 135). Group differences in global and domain neurocognitive performances and impairment were examined using multiple linear and logistic regression, respectively, while holding constant other covariates that were associated with study groups and/or cognition. Data from participants without HIV (n = 423) were added, and mixed-effect models were used to examine possible interactions between HIV and substance use disorders on neurocognition. RESULTS: Compared with M+C+, M+C- performed worse on measures of executive functions, learning, memory, and working memory and were more likely to be classified as impaired in those domains. M-C- performed better than M+C+ on measures of learning and memory but worse than M-C+ on measures of executive functions, learning, memory, and working memory. Detectable plasma HIV RNA and nadir CD4 < 200 were associated with lower overall neurocognitive performance, and these effects were greater for M+C+ compared with M-C-. CONCLUSIONS: In PLWH, lifetime methamphetamine use disorder and both current and legacy markers of HIV disease severity are associated with worse neurocognitive outcomes. There was no evidence of an HIV × M+ interaction across groups, but neurocognition was most impacted by HIV among those with polysubstance use disorder (M+C+). Better performance by C+ groups is consistent with findings from preclinical studies that cannabis use may protect against methamphetamine's deleterious effects.

Time of Day Influences Concentrations of Total Protein and Albumin in Cerebrospinal Fluid in HIV.

The accumulation of soluble proteins and metabolites during wakefulness and their clearance during sleep via the glymphatic system occurs in healthy adults and is disturbed in some neurological conditions. Such diurnal variations in the cerebrospinal fluid (CSF) proteins produced outside the central nervous system and entering via the blood-brain barrier (BBB) have not been evaluated in people with HIV (PWH). CSF and blood were collected in 165 PWH at six US centers between 2003 and 2007. The time of collection was compared to CSF albumin, globulin, and total protein concentrations using bivariate and multivariate regression. Participants all took antiretroviral therapy (ART) and were mostly middle-aged (median age 44.0 years) men (78.8%), with AIDS (77.0%), plasma HIV RNA ≤ 200 copies/mL (75.8%), and immune recovery (median CD4+ T-cell count 414/µL). CSF was collected at median 1:10 p.m. (range 9:00 a.m. to 5:20 p.m.) and within a median of 15 min of blood collection. A later time of CSF collection was associated with higher total protein (p = 0.0077) and albumin (p = 0.057) in CSF but not in serum, and was additionally associated with higher CSF globulin (p = 0.013). The glymphatic clearance of albumin, globulin, and total protein is preserved in PWH. The analyses of soluble biomarkers in CSF should account for the time of collection.

Higher Levels of Cerebrospinal Fluid and Plasma Neurofilament Light in Human Immunodeficiency Virus-Associated Distal Sensory Polyneuropathy.

BACKGROUND: Neurofilament light (NFL) chain concentrations, reflecting axonal damage, are seen in several polyneuropathies but have not been studied in human immunodeficiency virus (HIV) distal sensory polyneuropathy (DSP). We evaluated NFL in cerebrospinal fluid (CSF) and plasma in relation to DSP in people with HIV (PWH) from 2 independent cohorts and in people without HIV (PWoH). METHODS: Cohort 1 consisted of PWH from the CHARTER Study. Cohort 2 consisted of PWH and PWoH from the HIV Neurobehavioral Research Center (HNRC). We evaluated DSP signs and symptoms in both cohorts. Immunoassays measured NFL in CSF for all and for plasma as well in Cohort 2. RESULTS: Cohort 1 consisted of 111 PWH, mean ± SD age 56.8 ± 8.32 years, 15.3% female, 38.7% Black, 49.6% White, current CD4+ T-cells (median, interquartile range [IQR]) 532/µL (295, 785), 83.5% with plasma HIV RNA ≤50 copies/mL. Cohort 2 consisted of 233 PWH of similar demographics to PWH in Cohort 1 but also 51 PWoH, together age 58.4 ± 6.68 years, 41.2% female, 18.0% Black, Hispanic, non-Hispanic White 52.0%, 6.00% White. In both cohorts of PWH, CSF and plasma NFL were significantly higher in both PWH with DSP signs. Findings were similar, albeit not significant, for PWoH. The observed relationships were not explained by confounds. CONCLUSIONS: Both plasma and CSF NFL were elevated in PWH and PWoH with DSP. The convergence of our findings with others demonstrates that NFL is a reliable biomarker reflecting peripheral nerve injury. Biomarkers such as NFL might provide, validate, and optimize clinical trials of neuroregenerative strategies in HIV DSP.

Anemia and Erythrocyte Indices Are Associated With Neurocognitive Performance Across Multiple Ability Domains in Adults With HIV.

BACKGROUND: Anemia is linked to neurocognitive impairment (NCI) in people with HIV (PWH), but its impact within specific ability domains, and in diverse populations with HIV, is uncertain. METHODS: Participants included 1339 PWH enrolled in observational HIV cohort studies with a mean of 3 comprehensive neurocognitive assessments over 30 months. Global and domain-specific neurocognitive function were assessed by the global deficit score and domain deficit score (GDS and DDS, respectively) or as GDS-defined or DDS-defined NCI (GDS ≥ 0.5, DDS > 0.5). Time-dependent associations of anemia or red-cell indices with neurocognitive function were evaluated by multivariable regression. RESULTS: The mean age at entry was 43.6 years (85% male, 23.9% Hispanic, 16.7% African ancestry by self-report, and 69.8% virally suppressed). Anemia occurred at entry in 297 (22.2%) and developed subsequently in another 129 (9.6%). Anemia (present in 26.8% of cognitively impaired PWH at entry) and lower hemoglobin were associated with higher (worse) GDS values; the association for anemia persisted after multivariable adjustment and in virally suppressed persons ( P < 0.0001). Anemia was also associated with reduced processing speed, motor function, learning, delayed recall, working memory (all P < 0.01), executive function ( P = 0.021), and verbal fluency ( P = 0.035), and these findings persisted in longitudinal analyses (adjusted P < 0.01 for all domains, except verbal fluency). Higher mean corpuscular volume and mean corpuscular hemoglobin were associated with less impairment in learning and recall (all P < 0.05). CONCLUSIONS: Anemia in diverse and virally suppressed PWH associates with reduced neurocognitive performance in multiple domains, cross-sectionally and over time. The impact of identifying and treating anemia to prevent or slow neurocognitive decline in PWH should be prospectively evaluated.

Current Challenges and Solutions for Clinical Management and Care of People with HIV: Findings from the 12th Annual International HIV and Aging Workshop.

People with HIV on combination antiretroviral therapy (ART) have longer life expectancy and are increasingly experiencing age-related comorbidities. Thus, aging with HIV has become a central issue in clinical care and research, which has been particularly challenging with the intersection of the ongoing coronavirus (COVID)-19 pandemic. Since 2009, the International Workshop on HIV and Aging has served as a multidisciplinary platform to share research findings from cross-disciplinary fields along with community advocates to address critical issues in HIV and aging. In this article, we summarize the key oral presentations from the 12th Annual International Workshop on HIV and Aging, held virtually on September 23rd and 24th, 2021. The topics ranged from basic science research on biological mechanisms of aging to quality of life and delivery of care under the COVID-19 pandemic. This workshop enriched our understanding of HIV and aging under the COVID-19 pandemic, identified challenges and opportunities to combat the impact of COVID-19 on HIV communities, and also provided updated research and future directions of the field to move HIV and aging research forward, with the ultimate goal of successful aging for older people with HIV.