IntroductionAdvanced cognitive aging remains a major concern for people living with HIV (PWH), even in the context of viral suppression. This underscores the need for sensitive tools that can detect subtle cognitive change. Mobile cognitive assessments offer a scalable and ecologically valid approach, yet their sensitivity to longitudinal change in clinical populations is not well established.MethodsWe examined longitudinal performance and predictors of change on a 14-day mobile Verbal Learning Test (mVLT) administered remotely at baseline and again 12–46 months (M = 26.7) later in 24 PWH and 13 HIV-negative controls aged 51–74, and compared these trajectories with change on standard in-person neuropsychological testing.ResultsAggregate mean mVLT performance improved over time among controls, but this was not evident among PWH (i.e., a significant group X time interaction). In contrast, longitudinal trajectories did not differ by group on the standard in-person Hopkins Verbal Learning Test-Revised, suggesting greater sensitivity of the mobile measure in this sample. Age moderated mVLT trajectories, such that increasing age was associated with worse longitudinal trajectories in PWH, whereas age was unrelated to change in controls. Among PWH, worse mVLT trajectories were associated with higher cerebrovascular risk, lower social functioning, and poorer baseline global learning performance, but not depressive symptoms, HIV disease markers, or other medical comorbidities.DiscussionThese preliminary findings suggest that the mVLT captures group-level differences in longitudinal learning trajectories and heterogeneity in performance over time among PWH, in line with contemporary models of cognitive aging in HIV. With replication in larger samples, mobile assessments could support scalable monitoring of cognitive function in PWH.

Chronic pain (CP) is common among people with HIV (PWH), yet its prevalence and associated factors in those receiving modern, virally suppressive antiretroviral therapy (ART) are not well understood. This prospective observational study compared CP frequency and associated outcomes between PWH and people without HIV (PWoH). Participants (40 PWH, 23 PWoH) completed a questionnaire assessing daily pain lasting more than three months. Additional data included pain intensity, interference with daily activities, opioid use, and depressed mood (Beck Depression Inventory-II), as well as HIV clinical markers and comorbidities. Groups were demographically similar; all PWH were virally suppressed, with a mean HIV duration of 27.0 years, median nadir CD4 count of 173 cells/μL, and median current CD4 count of 644 cells/μL. CP was significantly more frequent in PWH (60%) than in PWoH (22%; OR = 5.40, 95% CI [1.67, 17.50]; p = 0.003). Among PWH, CP was associated with greater daily activity interference, higher opioid use, and increased neuropathic pain symptoms. PWH with CP also had higher BDI-II scores, indicating worse mood. These findings suggest that CP remains prevalent and disabling among PWH despite effective modern-day ART, underscoring the need for targeted pain assessment and management in this population.

Background:Neuroinflammation is common in people with HIV (PWH) and may be reflected also in plasma biomarkers; the latter are sometimes used as surrogates for CSF. However, use of plasma biomarkers in this way risks obscuring compartment-specific processes since distribution across the blood-brain barrier (BBB) varies between proteins with some reaching the CNS more readily than others. We tested the hypothesis that BBB and viral suppression status shape cross-compartment biomarker coupling, clarifying when plasma proteins do or do not represent neuroinflammation. Methods:Paired CSF and plasma samples from 567 PWH in the CHARTER cohort were analyzed with the Olink Target-96 Inflammation Panel. Using regression, canonical correlation, and machine learning, we evaluated viral suppression and BBB permeability (indexed by CSF total protein levels, which are more readily available clinically and highly correlated with the CSF to serum albumin ratio) as effect modifiers of CSF-plasma biomarker correlations. Results:Intra-CSF and intra-plasma correlations were consistently strong, but cross-compartment correlations were weak and inconsistent. Some proteins had strong correlations when CSF total protein was high, including CD8A, IL-12B, TNFRSF9, and TNFB. Unsuppressed viremia amplified broader cross-compartment signaling (e.g., IL-12B, CXCL9, CXCL10). Conclusions:BBB permeability and viral suppression moderate biomarker compartmentalization in PWH. These findings support a hypothesis-driven framework in which biomarkers can be classified as CNS-restricted, peripherally driven, or BBB-dependent. This mechanistic structure informs biomarker selection for clinical trials and provides testable models of neuroinflammation in PWH.

Objectives We previously developed a refined longitudinal data harmonization method to address the challenge of nonoverlapping cognitive tests across cohorts, successfully harmonizing data from 5 large-scale US HIV studies. Building on this harmonized data set, we now aim to apply this method to an additional US HIV study and cognitive data from HIV studies in China, India, and Uganda. This effort will result in a more comprehensive data set with a larger, internationally diverse sample that includes both people with HIV and people without HIV. Study Design and Setting The new cohorts to be harmonized included cognitive tests that did not fully overlap across studies, a challenge for traditional harmonization methods. We applied our refined approach, designed for scenarios without direct test linkage. In the Uganda cohort, where a key method assumption was violated, we implemented targeted adjustments. Results The harmonized cognitive domain scores were consistent across cohorts and strongly correlated with raw or log-transformed cognitive test data (eg, timed outcomes). These scores preserved key patterns of variation observed in the raw data for key demographics—such as age, education, and race—and maintained age-related longitudinal trajectories of cognitive performance derived from all participants’ visits. Conclusion The resulting harmonized data set includes 18,270 participants across multiple countries, significantly enhancing its diversity and utility. It lays the groundwork for developing normative data and conducting more robust analyses to address critical neuro-HIV research questions. This study also demonstrates the adaptability of the refined harmonization method in integrating new data and accommodating methodological challenges. Plain Language Summary People with HIV (PWH) often face a variety of cognitive challenges, but these issues can look different for each person. As different studies use different tests to measure cognitive abilities, it is difficult to combine the results from multiple studies and draw clear conclusions. In our previous work, we developed a refined method to harmonize data from 5 large US-based HIV neuro studies. Such method could handle the scenarios where nonoverlapping cognitive tests are used in certain domains across different studies. We now aim to include additional cohorts from the United States, China, India, and Uganda. Because these new cohorts also use nonoverlapping cognitive tests in certain domains, we applied our developed approach to harmonize the new data into our previously harmonized data. Our refined method created “harmonized scores” for cognitive abilities that closely matched the original test results. These scores captured differences related to age, education, and other factors while preserving how each person's cognitive abilities changed over time. By using this method to combine new data with existing data, we were able to create a more comprehensive and diverse data set. This will aid researchers to better understand the wide range of cognitive changes in PWH, leading to stronger, more inclusive studies on the impact of HIV on cognition.

Prevalence and incidence of HIV among people aged 50 years and older continue to rise worldwide, generating increasing awareness among care providers, scientists, and the HIV community about the importance of brain health in older adults with HIV. Many age-related factors that adversely affect brain health can occur earlier and more often among people with HIV, including epigenetic ageing, chronic medical conditions (eg, cardiovascular disease), and age-related syndromes (eg, frailty). Extensive dialogue between HIV community leaders, health-care providers, and scientists has led to the development of a multidimensional response strategy to protect and enhance brain health in people ageing with HIV that spans across public health, clinical spaces, and research spaces. This response strategy was informed by integrated ageing care frameworks and is centred on prevention, early detection, and management of brain health issues associated with HIV (eg, neurocognitive disorders), with specific considerations for low-resource or middle-resource countries. A collaborative, international, and data-informed update of the diagnostic criteria for HIV-associated neurocognitive disorders is a cornerstone of the proposed response strategy. The proposed response strategy includes a dynamic, international, online knowledge hub that will provide a crucial community resource for emerging evidence on the brain health of people ageing with HIV.

Objective: Examine the association between markers of inflammation in the cerebrospinal fluid (CSF) and neurocognitive impairment (NCI) among diverse persons with HIV (PWH). Background: Latino PWH are at higher risk for NCI than non-Latino White PWH (NLW). Evidence of inflammation in cerebrospinal fluid (CSF) can be higher among racial and ethnic minority PWH and has been linked to NCI. Methods: We performed a retrospective cross-sectional analysis of 363 PWH who identified as Latinos or NLW. Neurocognitive performance was measured by a comprehensive battery. A focused panel of biomarkers [interleukin-6 (IL-6), soluble CD14 (sCD14), interferon-γ-inducible protein-10 (IP-10), neurofilament light chain (NFL)] was measured in CSF by immunoassay. Covariates included demographic, HIV disease, medical, psychiatric, and substance use characteristics. Results: The cohort consisted of 126 Latinos and 237 NLW (age: M = 42.5, SD = 11.0, 88% male, 51.5% AIDS history; 64% on antiretroviral therapy). Latinos had significantly higher NFL levels than NLW ( P < 0.0001, adjusted Cohen's d 1.15), but not among virally-suppressed PWH. In the entire cohort, higher sCD14 was associated with NCI (adjusted odds ratio (aOR) = 2.6, confidence interval (CI) = 1.1–6.5] after adjusting for statistically significant covariates. Conclusions: We did not identify a relationship between ethnicity, inflammation and NCI in this cohort. Future studies might examine sociocultural factors leading to increased inflammation in the CSF in diverse PWH.

OBJECTIVE:In this cross-sectional study in Zambia, we examined factors that influence cognitive performance in adults with clade C human immunodeficiency virus-1 (HIV) infection who were on antiretroviral therapy. METHOD:We examined if detectable HIV ribonucleic acid (RNA) in blood plasma, nadir CD4+ T-cell count before antiretroviral therapy, increase in CD4+ T-cell count during antiretroviral therapy, and having pulmonary tuberculosis (TB) influenced cognitive performance. We performed a multilinear regression in which the dependent variable was the global mean cognitive T-score, an overall composite score based on 16 neuropsychological tests that were adjusted for age, sex, and education using normative data from Zambian adults without HIV infection. The 16 tests were merged into seven cognitive domains: Executive Functions, Verbal Fluency, Attention/Working Memory, Learning (immediate recall), Memory (delayed recall), Motor Control, and Speed of Information Processing. RESULTS:When on antiretroviral therapy, a greater increase in CD4+ T-cells was significantly associated with a better global mean cognitive T-score (p = .002). Pulmonary TB was independently associated with worse performance (p = .008). Neither nadir CD4+ T-cell count nor plasma HIV RNA during antiretroviral therapy was associated with cognitive performance. CONCLUSIONS:Accounting for CD4+ T-cell increase after antiretroviral therapy initiation and comorbid pulmonary TB may help explain cognitive outcomes in persons with HIV infection in endemic settings. We suggest that it is essential that those with a low CD4+ T-cell count increase the number of cells as early as possible. Our data suggest that this is important for their cognitive functioning. Future research should determine whether the deleterious effect of pulmonary TB resolves after completion of TB treatment. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Background: Aging-related comorbidities such as cardiovascular disease and neurocognitive impairment are more common among people with HIV (PWH). Hypertension (HTN) has been implicated in cognitive decline, and antihypertensives with anticholinergic properties may exacerbate this decline. Our research probed the relationship between neurocognitive performance and antihypertensives in hypertensive PWH and in those without HIV (PWoH), examining whether increased antihypertensives followed the worsening in neurocognitive performance. Methods: This longitudinal analysis encompassed seven visits over five years, enrolled between 1999 and 2022. Participants were included if they reported HTN or used antihypertensives. All participants underwent comprehensive cognitive assessments, and their global cognitive performance was evaluated using summary, demographically corrected T-scores. The association between the global T-score and the number of antihypertensives was evaluated using generalized linear mixed-effects models. Summary regression-based change score (sRCS) was analyzed as an indicator of global performance over time. Results: Among 1158 hypertensive PWH (79.9% were on ART), worsening cognitive performance was associated with an increased number of antihypertensives (p = 0.012) but not in PWoH (p = 0.58). PWH had lower mean arterial pressure (MAP) than PWoH after adjusting for demographics (β = −5.05, p = 2.3 × 10−11). In PWH, an association between mean arterial pressure (MAP) and sRCS suggested that those with cognitive improvement had lower MAP (p = 0.027). PWH taking more anticholinergics were more likely to have worse cognitive performance over time (p < 0.001). Conclusions: PWH with declining neurocognitive performance over time used increasing numbers of antihypertensives, suggesting that their providers prescribed more antihypertensives because of either treatment refractory HTN or poor adherence. Prescribers should avoid using antihypertensives with anticholinergic properties when possible.

Background In people with HIV (PWH) who are virally suppressed (VS) on antiretroviral therapy (ART), abdominal obesity (AO) is linked to neurocognitive impairment (NCI), potentially due to visceral adiposity, inflammation, and reduced insulin-like growth factor 1 (IGF-1). Tesamorelin, a growth hormone-releasing hormone, reduces AO and increases IGF-1, suggesting it might mitigate NCI in VS PWH. Methods This 6-month, Phase II randomized, open-label clinical trial compared Tesamorelin versus standard-of-care (SOC) for NCI in abdominally obese PWH. Participants had VS, NCI, and AO (elevated waist circumference [WC]). Exclusions included conditions other than HIV causing NCI, active substance use disorder, and malignancy. Results Seventy-three participants were randomized 3:2 to Tesamorelin or SOC (2mg subcutaneously daily). The primary outcome was the change in neurocognitive performance at 6 months, with secondary outcomes including WC, mood, and daily functioning. The groups were well-matched at baseline. The Tesamorelin group showed a trend toward improved neurocognitive performance after 6 months (mean change: 0.146, 95% CI: -0.002 to 0.294, p=0.060), while the SOC group did not (0.103, 95% CI: -0.095 to 0.301, p=0.295), but the between-group difference was not significant (p=0.673). IGF-1 levels increased, but changes did not correlate with sRCS or WC. The Tesamorelin group had a greater reduction in WC than the SOC group (median difference -2.7 cm, p=0.015). Conclusions While tesamorelin reduced WC, the cognitive benefits did not significantly differ between groups. Recognizing the limitations of insufficient power and no placebo arm, this study suggests no clear benefit of short-term AO reduction with tesamorelin on NCI.

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.

We aimed to identify complex, multidimensional, longitudinal biopsychosocial phenotypes (MLBPSPs) in people with HIV (PWH) and evaluate their associations with baseline clinical characteristics. We included 506 PWH in the multi-site CHARTER study who underwent assessments at four visits, six months apart. Using machine learning, we identified four MLBPSP clusters based on means and nonlinear trajectories of biopsychosocial characteristics. These characteristics included neurocognition, depressed mood, self-reported cognitive symptoms, and activities of daily living at each visit. The largest MLBPSP cluster (C1, N = 231) had the best average scores across all domains and remained stable over 18 months of follow-up. Other clusters showed varying degrees of cognitive impairment, depressed mood, and functional disability. In multivariable analyses, several baseline clinical characteristics, including chronic pulmonary disease, distal neuropathic pain, polypharmacy, and creatinine levels, significantly predicted one or more adverse MLBPSP trajectories. These findings have implications for HIV care by identifying PWH at risk for future adverse trajectories. The results may lead to insights informing future personalized interventions targeted to vulnerable subpopulations of PWH.

OBJECTIVE:Diagnosing HIV-Associated Neurocognitive Disorders (HAND) requires attributing neurocognitive impairment and functional decline at least partly to HIV-related brain effects. Depressive symptom severity, whether attributable to HIV or not, may influence self-reported functioning. We examined longitudinal relationships among objective global cognition, depressive symptom severity, and self-reported everyday functioning in people with HIV (PWH). METHODS:Longitudinal data from 894 PWH were collected at a university-based research center (2002-2016). Participants completed self-report measures of everyday functioning to assess both dependence in instrumental activities of daily living (IADL) and subjective cognitive difficulties at each visit, along with depressive symptom severity (BDI-II). Multilevel modeling examined within- and between-person predictors of self-reported everyday functioning outcomes. RESULTS:Participants averaged 6 visits over 5 years. Multilevel regression showed a significant interaction between visit-specific global cognitive performance and mean depression symptom severity on likelihood of dependence in IADL (p = 0.04), such that within-person association between worse cognition and greater likelihood of IADL dependence was strongest among individuals with lower mean depressive symptom severity. In contrast, participants with higher mean depressive symptom severity had higher likelihoods of IADL dependence regardless of cognition. Multilevel modelling of subjective cognitive difficulties showed no significant interaction between global cognition and mean depressive symptom severity (p > 0.05). CONCLUSIONS:The findings indicate a link between cognitive abilities and IADL dependence in PWH with low to moderate depressive symptoms. However, those with higher depressive symptoms severity report IADL dependence regardless of cognitive status. This is clinically significant because everyday functioning is measured through self-report rather than performance-based assessments.

Chronic pain (CP) is common among people with HIV (PWH), yet its prevalence and associated factors in those receiving modern, virally suppressive antiretroviral therapy (ART) are not well understood. This prospective observational study compared CP frequency and associated outcomes between PWH and people without HIV (PWoH). Participants (40 PWH, 23 PWoH) completed a questionnaire assessing daily pain lasting more than three months. Additional data included pain intensity, interference with daily activities, opioid use, and depressed mood (Beck Depression Inventory-II), as well as HIV clinical markers and comorbidities. Groups were demographically similar; all PWH were virally suppressed, with a median HIV duration of 30.6 years, nadir CD4 count of 300 cells/μL, and current CD4 count of 644 cells/μL. CP was significantly more frequent in PWH (60%) than in PWoH (22%; OR = 5.4 [1.67, 17.5]; p = 0.0028). Among PWH, CP was associated with greater daily activity interference, higher opioid use (38% vs. 6%), and increased neuropathic pain symptoms. PWH with CP also had higher BDI-II scores, indicating worse mood. These findings suggest that CP remains prevalent and disabling among PWH despite effective modern-day ART, underscoring the need for targeted pain assessment and management in this population.

This systematic review evaluated the psychometric performance of the National Institutes of Health's Toolbox Cognition Battery (NIHTB-CB) composite scores in older adults with and without Alzheimer's disease and related dementias (ADRD). A systematic literature search was conducted using MEDLINE, Embase, PsycINFO, and CINHAL databases. The evidence quality of NIHTB-CB measurement properties was assessed using integrated Consensus-based Standards for the Selection of Health Measurement Instrument (COSMIN) methodology and the Interpretation/Use Argument framework. Fourteen studies met inclusion criteria for this review of the NIHTB-CB. Evidence supporting the scoring, generalization, and extrapolation inferences of the Total, Crystallized, and Fluid composite scores in older adults ranged from developing through exemplary ratings. Findings indicate additional research is warranted on the NIHTB-CB in older adult and ADRD populations. The present study highlights the importance of continued use and research of the NIHTB-CB in diverse, older populations who are at risk for ADRD. HIGHLIGHTS: Limited research focuses on the National Institutes of Health's Toolbox Cognition Battery (NIHTB-CB) composites in older adults. The general psychometric robustness of the NIHTB-CB has been es. The Crystallized composite shows proficient psychometric evidence. The psychometric evidence of Fluid composite is developing due to limited data.

Background In people with HIV who are virally suppressed with antiretroviral therapy, abdominal obesity (AO) is linked to neurocognitive impairment (NCI), potentially due to visceral adiposity, inflammation, and reduced insulin-like growth factor 1 (IGF-1). Tesamorelin, a growth hormone-releasing hormone, reduces AO and increases IGF-1, suggesting that it might mitigate NCI in people with HIV and viral suppression.Methods This 6-month phase 2 randomized open-label clinical trial compared tesamorelin vs standard of care (SOC) for NCI in people with HIV who were virally suppressed and abdominally obese (elevated waist circumference [WC]). Exclusions included conditions other than HIV causing NCI, active substance use disorder, and malignancy.Results Seventy-three participants were randomized 3:2 to tesamorelin or SOC (2 mg subcutaneously daily). The primary outcome was the change in neurocognitive performance at 6 months, with secondary outcomes including WC, mood, and daily functioning. The groups were well matched at baseline. The tesamorelin group showed a trend toward improved neurocognitive performance after 6 months (mean change, 0.146; 95% CI, -.002 to .294; P = .060) while the SOC group did not (0.103; 95% CI, -.095 to .301; P = .295), but the between-group difference was not significant (P = .673). IGF-1 levels increased, but changes did not correlate with summary regression change score or WC. The tesamorelin group had a greater reduction in WC than the SOC group (median difference, -2.7 cm; P = .015).Conclusions While tesamorelin reduced WC, the cognitive benefits did not significantly differ between groups. Recognizing the limitations of insufficient power and no placebo arm, this study suggests no clear benefit of short-term AO reduction with tesamorelin on NCI. In this clinical trial, tesamorelin reduced waist circumference in patients with HIV and abdominal obesity but did not significantly improve neurocognitive function when compared with standard care, despite increasing levels of insulin-like growth factor 1 over 6 months of treatment.