Twelve-year neurocognitive decline in HIV is associated with comorbidities, not age: a CHARTER study.

Modern antiretroviral therapy (ART) has increased longevity of people with HIV and shifted the age distribution of the HIV pandemic upward toward that of the general population. This positive development has also led to concerns about premature and/or accelerated neurocognitive and physical ageing due to the combined effects of chronic HIV, accumulating comorbidities, adverse effects or possible toxicities of ART and biological ageing. Here we present results of comprehensive assessments over 12 years of 402 people with HIV in the CNS HIV ART Effects Research (CHARTER) programme, who at follow-up were composed of younger (<60 years) and older (≥60 years) subgroups. Over the 12 years, ART use and viral suppression increased in both subgroups as did systemic and psychiatric comorbidities; participants in both subgroups also evidenced neurocognitive decline beyond what is expected in typical ageing. Contrary to expectations, all these adverse effects were comparable in the younger and older CHARTER subgroups, and unrelated to chronological age. Neurocognitive decline was unrelated to HIV disease or treatment characteristics but was significantly predicted by the presence of comorbid conditions, specifically diabetes, hypertension, chronic pulmonary disease, frailty, neuropathic pain, depression and lifetime history of cannabis use disorder. These results are not consistent with premature or accelerated neurocognitive ageing due to HIV itself but suggest important indirect effects of multiple, potentially treatable comorbidities that are more common among people with HIV than in the general population. Good medical management of HIV disease did not prevent these adverse outcomes, and increased attention to a range of comorbid conditions in people with HIV may be warranted in their care.

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.

Concurrent validity and reliability of at-home teleneuropsychological evaluations among people with and without HIV.

OBJECTIVE: To determine the reliability of teleneuropsychological (TNP) compared to in-person assessments (IPA) in people with HIV (PWH) and without HIV (HIV-). METHODS: Participants included 80 PWH (Mage = 58.7, SDage = 11.0) and 23 HIV- (Mage = 61.9, SDage = 16.7). Participants completed two comprehensive neuropsychological IPA before one TNP during the COVID-19 pandemic (March-December 2020). The neuropsychological tests included: Hopkins Verbal Learning Test-Revised (HVLT-R Total and Delayed Recall), Controlled Oral Word Association Test (COWAT; FAS-English or PMR-Spanish), Animal Fluency, Action (Verb) Fluency, Wechsler Adult Intelligence Scale 3rd Edition (WAIS-III) Symbol Search and Letter Number Sequencing, Stroop Color and Word Test, Paced Auditory Serial Addition Test (Channel 1), and Boston Naming Test. Total raw scores and sub-scores were used in analyses. In the total sample and by HIV status, test-retest reliability and performance-level differences were evaluated between the two consecutive IPA (i.e., IPA1 and IPA2), and mean in-person scores (IPA-M), and TNP. RESULTS: There were statistically significant test-retest correlations between IPA1 and IPA2 (r or ρ = .603-.883, ps < .001), and between IPA-M and TNP (r or ρ = .622-.958, ps < .001). In the total sample, significantly lower test-retest scores were found between IPA-M and TNP on the COWAT (PMR), Stroop Color and Word Test, WAIS-III Letter Number Sequencing, and HVLT-R Total Recall (ps < .05). Results were similar in PWH only. CONCLUSIONS: This study demonstrates reliability of TNP in PWH and HIV-. TNP assessments are a promising way to improve access to traditional neuropsychological services and maintain ongoing clinical research studies during the COVID-19 pandemic.

Influence of Educational Background, Childhood Socioeconomic Environment, and Language Use on Cognition among Spanish-Speaking Latinos Living Near the US-Mexico Border.

OBJECTIVES: We investigated the impact of culturally relevant social, educational, and language factors on cognitive test performance among Spanish speakers living near the US-Mexico border. METHODS: Participants included 254 healthy native Spanish speakers from the Neuropsychological Norms for the US-Mexico Border Region in Spanish (NP-NUMBRS) project (Age: M = 37.3, SD = 10.4; Education: M = 10.7, SD = 4.3; 59% Female). A comprehensive neuropsychological battery was administered in Spanish. Individual test scaled scores and T-scores (based on region-specific norms adjusted for age, education, and sex) were averaged to create Global Mean Scaled and T-scores. Measures of culturally relevant factors included a self-reported indicator of educational quality/access (proportion of education in Spanish-speaking country, quality of school/classroom setting, stopped attending school to work), childhood socioeconomic environment (parental education, proportion of time living in Spanish-speaking country, childhood socioeconomic and health status, access to basic resources, work as a child), and Spanish/English language use and fluency. RESULTS: Several culturally relevant variables were significantly associated with unadjusted Global Scaled Scores in univariable analyses. When using demographically adjusted T-scores, fewer culturally relevant characteristics were significant. In multivariable analyses, being bilingual (p = .04) and working as a child for one's own benefit compared to not working as a child (p = .006) were significantly associated with higher Global Mean T-score, accounting for 9% of variance. CONCLUSIONS: Demographically adjusted normative data provide a useful tool for the identification of brain dysfunction, as these account for much of the variance of sociocultural factors on cognitive test performance. Yet, certain culturally relevant variables still contributed to cognitive test performance above and beyond basic demographics, warranting further investigation.

Evidence for a novel subcortical mechanism for posterior cingulate cortex atrophy in HIV peripheral neuropathy.

We previously reported that neuropathic pain was associated with smaller posterior cingulate cortical (PCC) volumes, suggesting that a smaller/dysfunctional PCC may contribute to development of pain via impaired mind wandering. A gap in our previous report was lack of evidence for a mechanism for the genesis of PCC atrophy in HIV peripheral neuropathy. Here we investigate if volumetric differences in the subcortex for those with neuropathic paresthesia may contribute to smaller PCC volumes, potentially through deafferentation of ascending white matter tracts resulting from peripheral nerve damage in HIV neuropathy. Since neuropathic pain and paresthesia are highly correlated, statistical decomposition was used to separate pain and paresthesia symptoms to determine which regions of brain atrophy are associated with both pain and paresthesia and which are associated separately with pain or paresthesia. HIV+ individuals (N = 233) with and without paresthesia in a multisite study underwent structural brain magnetic resonance imaging. Voxel-based morphometry and a segmentation/registration tool were used to investigate regional brain volume changes associated with paresthesia. Analysis of decomposed variables found that smaller midbrain and thalamus volumes were associated with paresthesia rather than pain. However, atrophy in the PCC was related to both pain and paresthesia. Peak thalamic atrophy (p = 0.004; MNI x = - 14, y = - 24, z = - 2) for more severe paresthesia was in a region with reciprocal connections with the PCC. This provides initial evidence that smaller PCC volumes in HIV peripheral neuropathy are related to ascending white matter deafferentation caused by small fiber damage observed in HIV peripheral neuropathy.

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.

Evaluating the accuracy of self-report for the diagnosis of HIV-associated neurocognitive disorder (HAND): defining "symptomatic" versus "asymptomatic" HAND.

The criteria for differentiating symptomatic from asymptomatic HIV-associated neurocognitive disorder require evaluation of (1) cognitive impairment, (2) daily functioning declines, and (3) whether the functional declines are attributable to cognitive versus physical problems. Many providers rely only on self-report to evaluate these latter criteria. However, the accuracy of patient-provided information may be limited. This study evaluated the validity of self-assessment for HIV-associated neurocognitive disorder (HAND) diagnoses by comparing objective findings with self-report of criteria 2 and 3 above. Self-reports were used to stratify 277 cognitively impaired HIV+ individuals into functionally dependent (n = 159) and independent (n = 118) groups, followed by group comparisons of objective functional problems. The dependent group was then divided into those who self-attributed their functional dependence to only cognitive (n = 80) versus only physical (n = 79) causes, for further comparisons on objective findings. The functionally dependent group was significantly worse than the independent group on all objective disability characteristics except severity of cognitive impairment, while those who attributed their dependence to physical (versus cognitive) factors were similar on all objective physical, cognitive, and functioning variables. Of note, 28 % of physical attributors showed no physical abnormalities on neuromedical examinations. Results suggest that patient report is consistently associated with objective measures of functional loss; in contrast, patient identification of physical versus cognitive causes is poorly associated with objective criteria. These findings caution against relying solely on patient self-report to determine whether functional disability in cognitively impaired HIV+ individuals can be attributed to strictly physical causes.

Use of Western Neuropsychological Test Battery in Detecting HIV-Associated Neurocognitive Disorders (HAND) in Zambia.

This is a study of neuroAIDS in sub-Saharan Africa, involving 266 Zambian adults infected with the human immunodeficiency virus (HIV), clade C. All HIV+ participants were receiving combination antiretroviral therapy (CART), and were administered a comprehensive neuropsychological (NP) test battery covering seven ability domains that are frequently affected by neuroAIDS. The battery was developed in the U.S. but has been validated in other international settings and has demographically-corrected normative standards based upon 324 healthy Zambian adults. Compared to the healthy Zambian controls, the HIV+ sample performed worse on the NP battery with a medium effect size (Cohen's d = 0.64). 34.6 % of the HIV+ individuals had global NP impairment and met criteria for HIV associated neurocognitive disorder (HAND). The results indicate that the Western-developed NP test battery is appropriate for use in Zambia and can serve as a viable HIV and AIDS management tool.

HIV Distal Neuropathic Pain Is Associated with Smaller Ventral Posterior Cingulate Cortex.

Objective: . Despite modern antiretroviral therapy, HIV-associated neuropathy is one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of distal neuropathic pain is not fully explained by the degree of peripheral nerve damage. A better understanding of brain structure in HIV distal neuropathic pain may help explain why some patients with HIV neuropathy report pain while the majority does not. Previously, we reported that more intense distal neuropathic pain was associated with smaller total cerebral cortical gray matter volumes. The objective of this study was to determine which parts of the cortex are smaller. Methods: . HIV positive individuals with and without distal neuropathic pain enrolled in the multisite (N = 233) CNS HIV Antiretroviral Treatment Effects (CHARTER) study underwent structural brain magnetic resonance imaging. Voxel-based morphometry was used to investigate regional brain volumes in these structural brain images. Results: . Left ventral posterior cingulate cortex was smaller for HIV positive individuals with versus without distal neuropathic pain (peak P = 0.017; peak t = 5.15; MNI coordinates x = -6, y = -54, z = 20). Regional brain volumes within cortical gray matter structures typically associated with pain processing were also smaller for HIV positive individuals having higher intensity ratings of distal neuropathic pain. Conclusions: . The posterior cingulate is thought to be involved in inhibiting the perception of painful stimuli. Mechanistically a smaller posterior cingulate cortex structure may be related to reduced anti-nociception contributing to increased distal neuropathic pain.

Anemia and Red Blood Cell Indices Predict HIV-Associated Neurocognitive Impairment in the Highly Active Antiretroviral Therapy Era.

BACKGROUND: Anemia has been linked to adverse human immunodeficiency virus (HIV) outcomes, including dementia, in the era before highly active antiretroviral therapy (HAART). Milder forms of HIV-associated neurocognitive disorder (HAND) remain common in HIV-infected persons, despite HAART, but whether anemia predicts HAND in the HAART era is unknown. METHODS: We evaluated time-dependent associations of anemia and cross-sectional associations of red blood cell indices with neurocognitive impairment in a multicenter, HAART-era HIV cohort study (N = 1261), adjusting for potential confounders, including age, nadir CD4(+) T-cell count, zidovudine use, and comorbid conditions. Subjects underwent comprehensive neuropsychiatric and neuromedical assessments. RESULTS: HAND, defined according to standardized criteria, occurred in 595 subjects (47%) at entry. Mean corpuscular volume and mean corpuscular hemoglobin were positively associated with the global deficit score, a continuous measure of neurocognitive impairment (both P < .01), as well as with all HAND, milder forms of HAND, and HIV-associated dementia in multivariable analyses (all P < .05). Anemia independently predicted development of HAND during a median follow-up of 72 months (adjusted hazard ratio, 1.55; P < .01). CONCLUSIONS: Anemia and red blood cell indices predict HAND in the HAART era and may contribute to risk assessment. Future studies should address whether treating anemia may help to prevent HAND or improve cognitive function in HIV-infected persons.

Genome-wide association study of HIV-associated neurocognitive disorder (HAND): A CHARTER group study.

HIV-associated neurocognitive disorder (HAND) often complicates HIV infection despite combination antiretroviral therapy (ART) and may be influenced by host genomics. We performed a genome-wide association study (GWAS) of HAND in 1,050 CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) Study participants. All participants underwent standardized, comprehensive neurocognitive, and neuromedical assessments to determine if they had cognitive impairment as assessed by the Global Deficit Score (GDS), and individuals with comorbidities that could confound diagnosis of HAND were excluded. Neurocognitive outcomes included GDS-defined neurocognitive impairment (NCI; binary GDS, 366 cases with GDS ≥ 0.5 and 684 controls with GDS < 0.5, and GDS as a continuous variable) and Frascati HAND definitions that incorporate assessment of functional impairment by self-report and performance-based criteria. Genotype data were obtained using the Affymetrix Human SNP Array 6.0 platform. Multivariable logistic or linear regression-based association tests were performed for GDS-defined NCI and HAND. GWAS results did not reveal SNPs meeting the genome-wide significance threshold (5.0 × 10-8 ) for GDS-defined NCI or HAND. For binary GDS, the most significant SNPs were rs6542826 (P = 8.1 × 10-7 ) and rs11681615 (1.2 × 10-6 ), both located on chromosome 2 in SH3RF3. The most significant SNP for continuous GDS was rs11157436 (P = 1.3 × 10-7 ) on chromosome 14 in the T-cell-receptor alpha locus; three other SNPs in this gene were also associated with binary GDS (P ≤ 2.9 × 10-6 ). This GWAS, conducted among ART-era participants from a single cohort with robust neurological phenotyping, suggests roles for several biologically plausible loci in HAND that deserve further exploration. © 2017 Wiley Periodicals, Inc.

Mitochondrial DNA Haplogroups and Neurocognitive Impairment During HIV Infection.

BACKGROUND: Neurocognitive impairment (NCI) remains an important complication in persons infected with human immunodeficiency virus (HIV). Ancestry-related mitochondrial DNA (mtDNA) haplogroups have been associated with outcomes of HIV infection and combination antiretroviral therapy (CART), and with neurodegenerative diseases. We hypothesize that mtDNA haplogroups are associated with NCI in HIV-infected adults and performed a genetic association study in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort. METHODS: CHARTER is an observational study of ambulatory HIV-infected adults. Haplogroups were assigned using mtDNA sequence, and principal components were derived from ancestry-informative nuclear DNA variants. Outcomes were cross-sectional global deficit score (GDS) as a continuous measure, GDS impairment (GDS ≥ 0.50), and HIV-associated neurocognitive disorder (HAND) using international criteria. Multivariable models were adjusted for comorbidity status (incidental vs contributing), current CART, plasma HIV RNA, reading ability, and CD4 cell nadir. RESULTS: Haplogroups were available from 1027 persons; median age 43 years, median CD4 nadir 178 cells/mm(3), 72% on CART, and 46% with HAND. The 102 (9.9%) persons of genetically determined admixed Hispanic ancestry had more impairment by GDS or HAND than persons of European or African ancestry (P < .001 for all). In multivariate models including persons of admixed Hispanic ancestry, those with haplogroup B had lower GDS (ß = -0.34; P = .008) and less GDS impairment (odds ratio = 0.16; 95% confidence interval, .04, .63; P = .009) than other haplogroups. There were no significant haplogroup associations among persons of European or African ancestry. CONCLUSIONS: In these mostly CART-treated persons, mtDNA haplogroup B was associated with less NCI among persons of genetically determined Hispanic ancestry. mtDNA variation may represent an ancestry-specific factor influencing NCI in HIV-infected persons.

Neurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study.

BACKGROUND: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) can show variable clinical trajectories. Previous longitudinal studies of HAND typically have been brief, did not use adequate normative standards, or were conducted in the context of a clinical trial, thereby limiting our understanding of incident neurocognitive (NC) decline and recovery. METHODS: We investigated the incidence and predictors of NC change over 16-72 (mean, 35) months in 436 HIV-infected participants in the CNS HIV Anti-Retroviral Therapy Effects Research cohort. Comprehensive laboratory, neuromedical, and NC assessments were obtained every 6 months. Published, regression-based norms for NC change were used to generate overall change status (decline vs stable vs improved) at each study visit. Survival analysis was used to examine the predictors of time to NC change. RESULTS: Ninety-nine participants (22.7%) declined, 265 (60.8%) remained stable, and 72 (16.5%) improved. In multivariable analyses, predictors of NC improvements or declines included time-dependent treatment status and indicators of disease severity (current hematocrit, albumin, total protein, aspartate aminotransferase), and baseline demographics and estimated premorbid intelligence quotient, non-HIV-related comorbidities, current depressive symptoms, and lifetime psychiatric diagnoses (overall model P < .0001). CONCLUSIONS: NC change is common in HIV infection and appears to be driven by a complex set of risk factors involving HIV disease, its treatment, and comorbid conditions.

Neurocognitive functioning in a Romanian cohort of young adults with parenterally-acquired HIV-infection during childhood.

The Romanian cohort can provide valuable information about the effect of chronic HIV-infection and exposure to combined antiretroviral therapy (cART) on the developing brain, based on its unique characteristics: young adults infected parenterally with HIV clade F in the late 1980s and exposed to cART for a decade. We conducted a prospective study using a neuropsychological test battery validated in other international HIV cohorts, in order to evaluate the rate and severity of neurocognitive impairment in a group of young Romanian adults. The 49 HIV-infected (HIV+) participants and the 20 HIV negative (HIV-) controls were similar for age and gender, although the HIV- group tended to be more educated. We found higher cognitive impairment prevalence in the HIV+ group (59.1 %) versus the HIV- group (10 %), and the impairment rate remained significantly higher even when the groups were matched based on the educational level (38.7 % for the HIV+ group vs. 10.0 % for the HIV- controls; p = 0.025). The nadir CD4 count was <200 in 71.4 % of patients, but at the time of neurocognitive assessment, 89.5 % of patients had normal immunological status and 81.8 % undetectable HIV load. Among the HIV-impaired group, 26 % of the participants had syndromic impairment while the other 74 % had asymptomatic neurocognitive impairment. We found a high prevalence of neurocognitive dysfunction in the Romanian young adults growing-up with HIV. The greatest HIV-related cognitive deficits were in the domains of executive and motor functioning, consistent with a frontosubcortical pattern.

HIV-associated distal neuropathic pain is associated with smaller total cerebral cortical gray matter.

Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50 % of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling, and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Anti-Retroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (r = -0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.

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.

Biopsychosocial phenotypes in people with HIV in the CHARTER cohort.

Neuropsychiatric complications such as neurocognitive impairment and depression are common in people with HIV despite viral suppression on antiretroviral therapy, but these conditions are heterogeneous in their clinical presentations and associated disability. Identifying novel biopsychosocial phenotypes that account for neurocognitive performance and depressive and functional symptoms will better reflect the complexities encountered in clinical practice and may have pathological and therapeutic implications. We classified 1580 people with HIV based on 17 features, including 7 cognitive domains, 4 subscales of the Beck depression inventory-II, 5 components of the patient's assessment of own functioning inventory, and dependence in instrumental and basic activities of daily living. A two-stage clustering procedure consisting of dimension reduction with self-organizing maps and Mahalanobis distance-based k-means clustering algorithms was applied to cross-sectional data. Baseline demographic and clinical characteristics were compared between the phenotypes, and their prediction on the biopsychosocial phenotypes was evaluated using multinomial logistic regression. Four distinct phenotypes were identified. Participants in Phenotype 1 overall did well in all domains. Phenotype 2 had mild-to-moderate depressive symptoms and the most substance use disorders. Phenotype 3 had mild-to-moderate cognitive impairment, moderate depressive symptoms, and the worst daily functioning; they also had the highest proportion of females and non-HIV conditions that could affect cognition. Phenotype 4 had mild-to-moderate cognitive impairment but with relatively good mood, and daily functioning. Multivariable analysis showed that demographic characteristics, medical conditions, lifetime cocaine use disorder, triglycerides, and non-antiretroviral therapy medications were important variables associated with biopsychosocial phenotype. We found complex, multidimensional biopsychosocial profiles in people with HIV that were associated with different risk patterns. Future longitudinal work should determine the stability of these phenotypes, assess factors that influence transitions from one phenotype to another, and characterize their biological associations.

Genetic Variations in EIF2AK3 are Associated with Neurocognitive Impairment in People Living with HIV.

Based on emerging evidence on the role for specific single-nucleotide variants (SNVs) in EIF2AK3 encoding the integrated stress response kinase PERK, in neurodegeneration, we assessed the association of EIF2AK3 SNVs with neurocognitive performance in people with HIV (PWH) using a candidate gene approach. This retrospective study included the CHARTER cohort participants, excluding those with severe neuropsychiatric comorbidities. Genome-wide data previously obtained for 1047 participants and targeted sequencing of 992 participants with available genomic DNA were utilized to interrogate the association of three noncoding and three coding EIF2AK3 SNVs with the continuous global deficit score (GDS) and global neurocognitive impairment (NCI; GDS ≥ 0.5) using univariable and multivariable methods, with demographic, disease-associated, and treatment characteristics as covariates. The cohort characteristics were as follows: median age, 43.1 years; females, 22.8%; European ancestry, 41%; median CD4 + T cell counts, 175/µL (nadir) and 428/µL (current). At first assessment, 70.5% used ART and 68.3% of these had plasma HIV RNA levels ≤ 200 copies/mL. All three noncoding EIF2AK3 SNVs were associated with GDS and NCI (all p < 0.05). Additionally, 30.9%, 30.9%, and 41.2% of participants had at least one risk allele for the coding SNVs rs1805165 (G), rs867529 (G), and rs13045 (A), respectively. Homozygosity for all three coding SNVs was associated with significantly worse GDS (p < 0.001) and more NCI (p < 0.001). By multivariable analysis, the rs13045 A risk allele, current ART use, and Beck Depression Inventory-II value > 13 were independently associated with GDS and NCI (p < 0.001) whereas the other two coding SNVs did not significantly correlate with GDS or NCI after including rs13045 in the model. The coding EIF2AK3 SNVs were associated with worse performance in executive functioning, motor functioning, learning, and verbal fluency. Coding and non-coding SNVs of EIF2AK3 were associated with global NC and domain-specific performance. The effects were small-to-medium in size but present in multivariable analyses, raising the possibility of specific SNVs in EIF2AK3 as an important component of genetic vulnerability to neurocognitive complications in PWH.

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.

Disparities in Metabolic Syndrome and Neurocognitive Function Among Older Hispanics/Latinos with Human Immunodeficiency Virus.

Neurocognitive impairment and metabolic syndrome (MetS) are prevalent in persons with HIV (PWH). We examined disparities in HIV-associated neurocognitive function between Hispanic and non-Hispanic White older PWH, and the role of MetS in explaining these disparities. Participants included 116 community-dwelling PWH aged 50-75 years enrolled in a cohort study in southern California [58 Hispanic (53% Spanish speaking) and 58 age-comparable non-Hispanic White; overall group: age: M = 57.9, standard deviation (SD) = 5.7; education (years): M = 13, SD = 3.4; 83% male, 58% AIDS, 94% on antiretroviral therapy]. Global neurocognition was derived from T-scores adjusted for demographics (age, education, sex, ethnicity, language) on a battery of 10 cognitive tests. MetS was ascertained via standard criteria that considered central obesity, and fasting elevated triglycerides, low high-density lipoprotein cholesterol and elevated glucose, or medical treatment for these conditions. Covariates examined included sociodemographic, psychiatric, substance use and HIV disease characteristics. Compared with non-Hispanic Whites, Hispanics showed worse global neurocognitive function (Cohen's d = 0.56, p < 0.05) and had higher rates of MetS (38% vs. 56%, p < 0.05). A stepwise regression model including ethnicity and significant covariates showed Hispanic ethnicity was the sole significant predictor of worse global neurocognition (B = -3.82, SE = 1.27, p < 0.01). A model also including MetS showed that both Hispanic ethnicity (B = -3.39, SE = 1.31, p = 0.01) and MetS (B = -2.73, SE = 1.31, p = 0.04) were independently associated with worse neurocognition. In conclusion, findings indicate that increased MetS is associated with worse neurocognitive function in both Hispanic and non-Hispanic White older PWH, but does not explain neurocognitive disparities. MetS remains an important target for intervention efforts to ameliorate neurocognitive dysfunction among diverse older PWH.