High Incidence Rate of Computed Tomography-Measured Steatotic Liver Disease in Men With and Without HIV Infection.

INTRODUCTION: We determined steatotic liver disease (SLD) incidence in a prospective cohort of men with HIV (MWH) and men without HIV (MWOH). METHODS: Incident SLD was defined using paired noncontrast computed tomography scans performed during 2010-2013 and repeated during 2015-2017. RESULTS: Of 268 men, 173 MWH and 95 MWOH, 33 had incident SLD (11.1%, incidence rate 2.4 and 2.7/100 person-years for MWH and MWOH, respectively). Overall, higher abdominal visceral adipose tissue was independently associated with increased SLD risk. In MWH, increased visceral adipose tissue, insulin resistance, chronic hepatitis B, and cumulative etravirine use were associated with SLD. DISCUSSION: Metabolic factors, but not HIV, were associated with incident SLD. The high incidence rate suggests that SLD will continue to increase in PWH.

Trauma Across the Life Span and Multisystem Morbidity in Women With HIV.

OBJECTIVE: Sexual and physical abuse are highly prevalent among women living with HIV (WLWH) and are risk factors for the development of mental health and substance use disorders (MHDs, SUDs), and cognitive and medical comorbidities. We examined empirically derived patterns of trauma, MHD, and SUD, and associations with later cognitive and health outcomes. METHODS: A total of 1027 WLWH (average age = 48.6 years) in the Women's Interagency HIV Study completed the World Mental Health Composite International Diagnostic Interview from 2010 to 2013 to identify MHDs, SUDs, and age at onset of sexual and physical abuse. Then, cognitive impairment, cardiovascular/metabolic conditions, and HIV disease outcomes were assessed for up to 8.8 years. Latent class analysis identified patterns of co-occurring trauma, MHDs, and/or SUDs. Generalized estimating equations determined associations between these patterns and midlife cognitive and medical outcomes. RESULTS: Six distinct profiles emerged: no/negligible sexual/physical trauma, MHD, or SUD (39%); preadolescent/adolescent sexual trauma with anxiety and SUD (22%); SUD only (16%); MHD + SUD only (12%); early childhood sexual/physical trauma only (6%); and early childhood sexual/physical trauma with later MHD + SUD (4%). Profiles including early childhood trauma had the largest number of midlife conditions (i.e., cognitive, cardiovascular, HIV-related). Preadolescent/adolescent sexual trauma with anxiety and SUD predicted both global and domain-specific cognitive declines. Only SUD without trauma predicted lower CD4, whereas childhood trauma with MHD + SUD predicted increased CD8. CONCLUSIONS: WLWH have complex multisystem profiles of abuse, MHD, and/or SUD that predict midlife cognitive, metabolic/cardiovascular, and HIV outcomes. Understanding the interplay between these factors over time can identify risks and personalize preventative and treatment interventions.

Gap detection responses modelled using the Hill equation in adults with well-controlled HIV.

OBJECTIVE: This study's objective was determining whether gap detection deficits are present in a longstanding cohort of people living with HIV (PLWH) compared to those living without HIV (PLWOH) using a new gap detection modelling technique (i.e. fitting gap responses using the Hill equation and analysing the individual gap detection resulting curves with non-linear statistics). This approach provides a measure of both gap threshold and the steepness of the gap length/correct detection relationship. DESIGN: The relationship between the correct identification rate at each gap length was modelled using the Hill equation. Results were analysed using a nonlinear mixed-effect regression model. STUDY SAMPLE: 45 PLWH (age range 41-78) and 39 PLWOH (age range 38-79) were enrolled and completed gap detection testing. RESULTS: The likelihood ratio statistic comparing the full regression model with the HIV effects to the null model, assuming one population curve for both groups, was highly significant (p < 0.001), suggesting a less precise relationship between gap length and correct detection in PLWH. CONCLUSIONS: PLWH showed degraded gap detection ability compared to PLWOH, likely due to central nervous system effects of HIV infection or treatment. The Hill equation provided a new approach for modelling gap detection ability.

Glucocorticoid Receptor Function and Cognitive Performance in Women With HIV.

OBJECTIVE: Alterations in glucocorticoid receptor (GCR) function may be a risk factor for cognitive complications among older people with human immunodeficiency virus (HIV). We evaluated whether HIV serostatus and age modify the GCR function-cognition association among women. METHODS: Eighty women with HIV ( n = 40, <40 years of age [younger]; n = 40, >50 years of age [older]) and 80 HIV-uninfected women ( n = 40 older, n = 40 younger) enrolled in the Women's Interagency HIV Study completed a comprehensive neuropsychological test battery. Peripheral blood mononuclear cells collected concurrent with neuropsychological testing were assessed for GCR function. Multivariable linear regression analyses were conducted to examine whether a) HIV serostatus and age were associated with GCR function, and b) GCR function-cognition associations are moderated by HIV serostatus and age adjusting for relevant covariates. RESULTS: Among older women, higher baseline FKBP5 expression level was associated with lower attention/working memory performance among women with HIV ( B = 6.4, standard error = 1.7, p = .0003) but not in women without HIV infection ( B = -1.7, standard error = 1.9, p = .37). There were no significant HIV serostatus by age interactions on dexamethasone (DEX)-stimulated expression of the genes regulated by the GCR or lipopolysaccharide-stimulated tumor necrosis factor α levels (with or without DEX stimulation; p values > .13). HIV serostatus was associated with GC target genes PER1 ( p = .006) and DUSP1 ( p = .02), but not TSC22D3 ( p = .32), after DEX stimulation. CONCLUSIONS: Collectively, these data suggest that HIV serostatus and age may modify the influence of the GCR, such that the receptor is likely engaged to a similar extent, but the downstream influence of the receptor is altered, potentially through epigenetic modification of target genes.

Degree of Polypharmacy and Cognitive Function in Older Women with HIV.

The number of people with HIV (PWH) experiencing age-associated comorbidities including those treated with medications and cognitive impairment is increasing. We examined associations between polypharmacy and cognition in older women with HIV (WWH) given their vulnerability to this comorbidity. Cross-sectional analysis capitalizing on Women's Interagency HIV Study data collected between 2014 and 2017. WWH meeting the following criteria were analyzed: age ≥50 years; availability of self-reported non-antiretroviral therapy (ART) medications data; and neuropsychological data. The number of non-ART medications used regularly in the prior 6 months was summed. Polypharmacy was categorized as none/low (0-4), moderate (5-9), or severe (≥10). Multivariable linear regression analyses examined polypharmacy-cognition (T-score) associations in the total sample and among virally suppressed (VS; < 20 copies/mL)-WWH after covariate adjustment for enrollment site, income, depressive symptoms, substance use (smoking, heavy alcohol, marijuana, crack, cocaine, and/or heroin), the Veterans Aging Cohort Study index (indicators of HIV disease and organ system function, hepatitis C virus serostatus), ART use, nadir CD4 count, and specific ART drugs (efavirenz, integrase inhibitors). We included 637 women (median age = 55 years; 72% Black). Ninety-four percent reported ART use in the past 6 months and 75% had HIV RNA <20 copies/mL. Comorbidity prevalence was high (61% hypertension; 26% diabetes). Moderate and severe polypharmacy in WWH were 34% and 24%. In WWH, severe polypharmacy was associated with poorer executive function (p = .007) and processing speed (p = .01). The same pattern of findings remained among VS-WWH. Moderate polypharmacy was not associated with cognition. Moderate and severe polypharmacy were common and associated with poorer executive function and processing speed in WWH. Severe polypharmacy may be a major contributor to the persistence of domain-specific cognitive complications in older WWH above and beyond the conditions that these medications are used to treat.

Patterns and Predictors of Cognitive Function Among Virally Suppressed Women With HIV.

Cognitive impairment remains frequent and heterogeneous in presentation and severity among virally suppressed (VS) women with HIV (WWH). We identified cognitive profiles among 929 VS-WWH and 717 HIV-uninfected women from 11 Women's Interagency HIV Study sites at their first neuropsychological (NP) test battery completion comprised of: Hopkins Verbal Learning Test-Revised, Trail Making, Symbol Digit Modalities, Grooved Pegboard, Stroop, Letter/Animal Fluency, and Letter-Number Sequencing. Using 17 NP performance metrics (T-scores), we used Kohonen self-organizing maps to identify patterns of high-dimensional data by mapping participants to similar nodes based on T-scores and clustering those nodes. Among VS-WWH, nine clusters were identified (entropy = 0.990) with four having average T-scores ≥45 for all metrics and thus combined into an "unimpaired" profile (n = 311). Impaired profiles consisted of weaknesses in: (1) sequencing (Profile-1; n = 129), (2) speed (Profile-2; n = 144), (3) learning + recognition (Profile-3; n = 137), (4) learning + memory (Profile-4; n = 86), and (5) learning + processing speed + attention + executive function (Profile-5; n = 122). Sociodemographic, behavioral, and clinical variables differentiated profile membership using Random Forest models. The top 10 variables distinguishing the combined impaired vs. unimpaired profiles were: clinic site, age, education, race, illicit substance use, current and nadir CD4 count, duration of effective antiretrovirals, and protease inhibitor use. Additional variables differentiating each impaired from unimpaired profile included: depression, stress-symptoms, income (Profile-1); depression, employment (Profile 2); depression, integrase inhibitor (INSTI) use (Profile-3); employment, INSTI use, income, atazanavir use, non-ART medications with anticholinergic properties (Profile-4); and marijuana use (Profile-5). Findings highlight consideration of NP profile heterogeneity and potential modifiable factors contributing to impaired profiles.

Cognitive changes during the menopausal transition: a longitudinal study in women with and without HIV.

OBJECTIVE: To assess longitudinal changes in cognitive performance across menopause stages in a sample comprised primarily of low-income women of color, including women with HIV (WWH). METHODS: A total of 443 women (291 WWH; 69% African American; 18% Hispanic; median age = 42 y) from the Women's Interagency HIV Study completed tests of verbal learning and memory, attention/working memory, processing speed, verbal fluency, motor skills, and executive function first at an index premenopausal visit and thereafter once every 2 years for up to six visits (mean follow-up = 5.7 y). General linear-mixed effects regression models were run to estimate associations between menopause stages and cognition, in the overall sample and in WWH. We examined both continuous scores and categorical scores of cognitive impairment (yes/no >1 standard deviation below the mean). RESULTS: Adjusting for age and relevant covariates, the overall sample and WWH showed longitudinal declines in continuous measures of learning, memory, and attention/working memory domains from the premenopause to the early perimenopause and from the premenopause to the postmenopause, Ps < 0.05 to < 0.001. Effects on those same domains were also evident in categorical scores of cognitive impairment, with the increased odds of impairment ranging from 41% to 215%, Ps < 0.05 to < 0.001. The increase in predicted probability of impairment by menopausal stage (% affected) ranged from 4% to 13%. CONCLUSIONS: Menopause stage was a key determinant of cognition in a sample of low-income women of color, including WWH. Many of these changes reached a clinically significant level of cognitive impairment.

Factors Predicting Detrimental Change in Declarative Memory Among Women With HIV: A Study of Heterogeneity in Cognition.

OBJECTIVE: Statistical techniques used to study cognitive function in HIV typically yield normative estimates and can mask the heterogeneity in cognitive trajectories over time. We applied a novel statistical approach to identify clusters of individuals with distinct patterns of change in declarative memory in HIV-seropositive (HIV+) and HIV-seronegative (HIV-) women. METHODS: 1731 women from the Women's Interagency HIV Study, a multi-center, prospective cohort study, completed the Hopkins Verbal Learning Test-Revised (HLVT-R) at >2 visits. To derive subgroups with similar patterns of decline by HIV-serostatus, we used a mixed-effects framework that modeled the trajectory of multiple declarative memory outcomes over time, while simultaneously clustering individuals. RESULTS: Of the 1731 participants, 1149 were HIV+ (70% Black/African American [AA]; 30% White/Other [W/O]) and 582 were HIV- (68% AA; 32% W/O). Race stratification was necessary to optimize clustering. Among HIV+AA's, four subgroups emerged: a subgroup with minimal decline, two with accelerated decline, and one with stable but low performance. In HIV- AA, three subgroups emerged: one with minimal decline and two with accelerated decline. In multivariable-adjusted models among HIV+, individuals with accelerated decline were less educated (P < 0.001) and more likely to have a history of depression (P < 0.001) versus those with minimal decline. Similar subgroups were identified in W/O HIV+ and W/O HIV- participants. CONCLUSION: We identified clinically meaningful subgroups of women with distinct phenotypes of declarative memory decline, which depend on race and HIV-serostatus using a data driven approach. Identification of underlying mechanisms and risk factors contributing to the observed differences are warranted. More broadly our modeling approach could be other populations to identify risk factors for accelerated cognitive decline and to personalize interventions.

COVID-19 symptoms and SARS-CoV-2 infection among people living with HIV in the US: the MACS/WIHS combined cohort study.

BACKGROUND: SARS-CoV-2 infection among People Living With HIV (PLWH) is not well-described. OBJECTIVE: To study COVID-19 symptoms and SARS-CoV-2 PCR-based swab testing among participants of the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS). METHODS: A telephone survey was collected April-June 30, 2020. Symptom and testing prevalence were explored. Multivariable logistic regression was used to examine the factors associated with SARS-CoV-2 positivity. RESULTS: The survey was completed by 3411 participants, including 2078 (61%) PLWH and 1333 HIV-seronegative (SN) participants from across the US. Thirteen percent (n = 441) were tested for SARS-CoV-2 infection (13.4% of PLWH vs 12.2% of SN). Among those tested, positivity was higher in PLWH than SN (11.2% vs 6.1%, p = 0.08). Reasons for not being tested included testing not being available (30% of participants) and not knowing where to get tested (16% of participants). Most symptoms reported since January 2020 were similar in PLWH and SN, including headache (23% vs. 24%), myalgias (19% vs 18%), shortness of breath (14% vs 13%), chills (12% vs 10%), fever (6% vs 6%) and loss of taste or smell (6% vs 7%). Among PLWH who tested positive for SARS-CoV-2 DNA, the most common symptoms were headache (71%), myalgia (68%), cough (68%) and chills (65%). In multivariable analysis among those tested, the odds of SARS-CoV-2 positivity were higher among PLWH than SN (aOR = 2.22 95%CI = 01.01-4.85, p = 0.046) and among those living with others versus living alone (aOR = 2.95 95%CI = 1.18-7.40). CONCLUSION: Prevalence and type of COVID-19 symptoms were similar in PLWH and SN. SARS-CoV-2 infection may be elevated among PLWH.

Vestibular and oculomotor abnormalities among HIV-infected and HIV-uninfected men and women: A pilot study.

OBJECTIVE: To determine if middle-aged and aging men and women with HIV disease (HIV+) should be screened for vestibular and oculomotor dysfunction. METHODS: Age- and sociodemographically matched HIV+ and HIV- men and women were tested on vestibular evoked myogenic potential (VEMP), bi-thermic caloric testing, Dix-Hallpike maneuvers and saccades. RESULTS: HIV+ men had more caloric weakness than HIV- men. HIV+ subjects had more saccade abnormalities than HIV- subjects. A saccade abnormality was positively associated with being HIV+. Among the HIV+ sample, abnormalities were associated with increasing age, being male, ever taking monotherapy, and having an undetectable viral load. Only being male and having an undetectable viral load were statistically significant. Unilateral caloric weakness had a decreased prevalence with age per 10 years, and being HIV+ showed an increased prevalence. In HIV+ subjects only, these abnormalities decreased with age and being male but increased with undetectable viral load and ever taking antiretroviral monotherapy. No statistically significant differences were found. CONCLUSION: Women are at greater risk of vestibular and oculomotor abnormalities than men. HIV+ adults are at greater risk than HIV- adults. Physicians who care for HIV+ men and women should monitor the symptoms of vestibular and oculomotor impairment.

Early Inflammatory Signatures Predict Subsequent Cognition in Long-Term Virally Suppressed Women With HIV.

Immunologic function is an important determinant of cognition. Here we examined the contribution of early immune signatures to cognitive performance among HIV-infected, virally suppressed women (HIV+VS) and in HIV-uninfected (HIV-) women. Specifically, we measured serum inflammatory markers, developed combinatory immune signatures, and evaluated their associations with cognition. Forty-nine HIV+VS women in the Women's Interagency HIV Study (WIHS) who achieved viral suppression shortly after effective antiretroviral therapy (ART) initiation, and 56 matched HIV- women were selected. Forty-two serum inflammatory markers were measured within 2 years of effective ART initiation for HIV+VS women, and at an initial timepoint for HIV- women. The same inflammatory markers were also measured approximately 1, 7, and 12 years later for all women. Of the 105 women with complete immune data, 83 (34 HIV+VS, 49 HIV-) also had cognitive data available 12 years later at ≥1 time points (median = 3.1). We searched for combinatory immune signatures by adapting a dynamic matrix factorization analytic method that builds upon Tucker decomposition followed by Ingenuity® Pathway Analysis to facilitate data interpretation. Seven combinatory immune signatures emerged based on the Frobenius residual. Three signatures were common between HIV+VS and HIV- women, while four signatures were unique. These inflammatory signatures predicted subsequent cognitive performance in both groups using mixed-effects modeling, but more domain-specific associations were significant in HIV+VS than HIV- women. Leukocyte influx into brain was a major contributor to cognitive function in HIV+VS women, while T cell exhaustion, inflammatory response indicative of depressive/psychiatric disorders, microglial activity, and cytokine signaling predicted both global and domain-specific performance for HIV- women. Our findings suggest that immune signatures may be useful diagnostic, prognostic, and immunotherapeutic targets predictive of subsequent cognitive performance. Importantly, they also provide insight into common and distinct inflammatory mechanisms underlying cognition in HIV- and HIV+VS women.

Genetic and clinical predictors of CD4 lymphocyte recovery during suppressive antiretroviral therapy: Whole exome sequencing and antiretroviral therapy response phenotypes.

Increase of peripheral blood CD4 lymphocyte counts is a key goal of combined antiretroviral therapy (cART); most, but not all, recipients respond adequately and promptly. A small number of studies have examined specific genetic factors associated with the extent of CD4 recovery. We report a genome-wide examination of factors that predict CD4 recovery in HIV-infected women. We identified women in in a cohort study who were on cART with viral load below 400 copies, and drew racially and ethnically matched samples of those with good CD4 response over 2 years or poor response. We analyzed the exomes of those women employing next generation sequencing for genes associated with CD4 recovery after controlling for non-genetic factors identified through forward stepwise selection as important. We studied 48 women with good CD4 recovery and 42 with poor CD4 recovery during virologically-suppressive cART. Stepwise logistic regression selected only age as a statistically significant (p<0.05) non-genetic predictor of response type (each additional year of age reduced the odds of good recovery by 11% (OR = 0.89, CI = 0.84-0.96, p = 0.0009). After adjustment for age and genomic estimates of race and ethnicity, 41 genes harbored variations associated with CD4 recovery group (p≤0.001); 5 of these have been previously reported to be associated with HIV infection, 4 genes would likely influence CD4 homeostasis, and 13 genes either had known functions or were members of product families that had functions for which interactions with HIV or effects on lymphocyte homeostasis were biologically plausible. Greater age was the strongest acquired factor that predicted poor CD4 cell recovery. Sequence variations spanning 41 genes were independently predictive of CD4 recovery. Many of these genes have functions that impact the cell cycle, apoptosis, lymphocyte migration, or have known interactions with HIV. These findings may help inform new hypotheses related to responses to HIV therapy and CD4 lymphocyte homeostasis.

Elevated Depressive Symptoms Are a Stronger Predictor of Executive Dysfunction in HIV-Infected Women Than in Men.

BACKGROUND: HIV-infected (HIV+) women seem to be more vulnerable to neurocognitive impairment (NCI) than HIV+ men, perhaps in part due to mental health factors. We assessed the association between elevated depressive symptoms and NCI among HIV+ and HIV-uninfected (HIV-) women and men. SETTING: Women's Interagency HIV Study and Multicenter AIDS Cohort Study. METHODS: Eight hundred fifty-eight HIV+ (429 women; 429 men) and 562 HIV- (281 women; 281 men) completed the Center for Epidemiologic Studies Depression (16 cutoff) Scale and measures of psychomotor speed/attention, executive, and motor function over multiple visits (or time points). Women's Interagency HIV Study and Multicenter AIDS Cohort Study participants were matched according to HIV status, age, race/ethnicity, and education. Generalized linear mixed models were used to examine interactions between biological sex, HIV serostatus, and depression on impairment (T-scores <40) after covariate adjustment. RESULTS: Despite a higher frequency of depression among men, the association between depression and executive function differed by sex and HIV serostatus. HIV+ women with depression had 5 times the odds of impairment on a measure of executive control and inhibition versus HIV- depressed women and 3 times the odds of impairment on that measure versus HIV+ depressed men. Regardless of group status, depression was associated with greater impairment on processing speed, executive (mental flexibility), and motor function (P's < 0.05). CONCLUSIONS: Depression contributes to NCI across a broad range of cognitive domains in HIV+ and HIV- individuals, but HIV+ depressed women show greater vulnerabilities in executive function. Treating depression may help to improve cognition in patients with HIV infection.

Cognitive Burden of Common Non-antiretroviral Medications in HIV-Infected Women.

OBJECTIVE: The aging HIV population has increased comorbidity burden and consequently non-antiretroviral medication utilization. Many non-antiretroviral medications have known neurocognitive-adverse effects ("NC-AE medications"). We assessed the cognitive effects of NC-AE medications in HIV+ and HIV- women. METHODS: One thousand five hundred fifty-eight participants (1037 HIV+; mean age 46) from the Women's Interagency HIV Study completed a neuropsychological test battery between 2009 and 2011. The total number of NC-AE medications and subgroups (eg, anticholinergics) were calculated based on self-report. Generalized linear models for non-normal data were used to examine the cognitive burden of medications and factors that exacerbate these effects. RESULTS: HIV+ women reported taking more NC-AE medications vs. HIV- women (P < 0.05). NC-AE medication use altogether was not associated with cognitive performance. However, among NC-AE medication subgroups, anticholinergic-acting medications, but not opioids or anxiolytics/anticonvulsants, were negatively associated with performance. HIV status moderated the association between these NC-AE medication subgroups and performance (P's < 0.05). HIV-serostatus differences (HIV- < HIV+) in global, learning, fluency, and motor function were greatest among women taking >1 anticholinergic medications. HIV-serostatus differences in performance on learning and psychomotor speed were also greatest among women taking 1 or more anxiolytics/anticonvulsants and 1 or more opioids, respectively. CONCLUSIONS: HIV+ women have increased cognitive vulnerabilities to anticholinergic, anxiolytic/anticonvulsant, and opioid medications. Potential synergy between these medications and HIV may explain some HIV-related cognitive impairments. It may be important clinically to consider these specific types of medications as a contributor to impaired cognitive performance in HIV+ women and assess the cost/benefit of treatment dosage for underlying conditions.

Differences in Cognitive Function Between Women and Men With HIV.

BACKGROUND: Women may be more vulnerable to HIV-related cognitive dysfunction compared with men because of sociodemographic, lifestyle, mental health, and biological factors. However, studies to date have yielded inconsistent findings on the existence, magnitude, and pattern of sex differences. We examined these issues using longitudinal data from 2 large, prospective, multisite, observational studies of US women and men with and without HIV. SETTING: The Women's Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS). METHODS: HIV-infected (HIV+) and uninfected (HIV-) participants in the Women's Interagency HIV Study and Multicenter AIDS Cohort Study completed tests of psychomotor speed, executive function, and fine motor skills. Groups were matched on HIV status, sex, age, education, and black race. Generalized linear mixed models were used to examine group differences on continuous and categorical demographically corrected T-scores. Results were adjusted for other confounding factors. RESULTS: The sample (n = 1420) included 710 women (429 HIV+) and 710 men (429 HIV+) (67% non-Hispanic black; 53% high school or less). For continuous T-scores, sex by HIV serostatus interactions were observed on the Trail Making Test parts A & B, Grooved Pegboard, and Symbol Digit Modalities Test. For these tests, HIV+ women scored lower than HIV+ men, with no sex differences in HIV- individuals. In analyses of categorical scores, particularly the Trail Making Test part A and Grooved Pegboard nondominant, HIV+ women also had a higher odds of impairment compared with HIV+ men. Sex differences were constant over time. CONCLUSIONS: Although sex differences are generally understudied, HIV+ women vs men show cognitive disadvantages. Elucidating the mechanisms underlying these differences is critical for tailoring cognitive interventions.

Carotid Artery Stiffness and Cognitive Decline Among Women With or at Risk for HIV Infection.

BACKGROUND: Vascular stiffness is associated with aging and cognitive impairment in older populations without HIV. HIV has been linked to increased vascular stiffness. We examined whether vascular stiffness relates to cognitive decline at younger ages in women with or at risk for HIV. METHODS: We evaluated the association of carotid artery stiffness with decline in neuropsychological test performance among participants in the Women's Interagency HIV Study and assessed whether HIV modified the association. Baseline carotid stiffness, defined by the distensibility index, was determined at a single visit using carotid artery ultrasound. Longitudinal neuropsychological testing from 2004-2016 included Trail Making Tests A and B and the Symbol Digit Modalities Test. Relationships were assessed with linear mixed-effect models adjusted for demographic, behavioral, cardiometabolic, and neuropsychological factors. RESULTS: Among 1662 women (1192 [72%] HIV+), median baseline age was 41 years (interquartile range 34-47), with 60% non-Hispanic black and 28% Hispanic. Lower baseline distensibility (greater carotid stiffness) was associated with greater decline in neuropsychological test scores over 10-year follow-up as measured by Symbol Digit Modalities Test (adjusted ß = -0.06 per SD, P < 0.001), Trail Making Test A (ß = -0.08 per SD; P < 0.001), and Trail Making Test B (ß = -0.08 per SD; P < 0.001). Changes in cognitive function did not differ by HIV serostatus, or HIV-related factors. CONCLUSIONS: Higher carotid stiffness was independently associated with faster decline in executive functioning, information processing, and psychomotor speed even in mostly middle-aged minority women and regardless of HIV serostatus. Our study highlights the need for cardiovascular risk factor modification to prevent premature cognitive deterioration in this at-risk population.

Variability in C-reactive protein is associated with cognitive impairment in women living with and without HIV: a longitudinal study.

Despite the availability of effective antiretroviral therapies, cognitive impairment (CI) remains prevalent in HIV-infected (HIV+) individuals. Evidence from primarily cross-sectional studies, in predominantly male samples, implicates monocyte- and macrophage-driven inflammatory processes linked to HIV-associated CI. Thus, peripheral systemic inflammatory markers may be clinically useful biomarkers in tracking HIV-associated CI. Given sex differences in immune function, we focused here on whether mean and intra-individual variability in inflammatory marker-predicted CI in HIV+ and HIV- women. Seventy-two HIV+ (36 with CI) and 58 HIV- (29 with CI) propensity-matched women participating in the Women's Interagency HIV Study completed a neuropsychological battery once between 2009 and 2011, and performance was used to determine CI status. Analysis of 13 peripheral immune markers was conducted on stored biospecimens at three time points (7 and 3.5 years before neuropsychological data collection and concurrent with data collection). HIV+ women showed alterations in 8 immune markers compared to HIV- women. The strongest predictors of CI across HIV+ and HIV- women were lower mean soluble tumor necrosis factor receptor I (sTNFRI) levels, higher mean interleukin (IL)-6 levels, and greater variability in C-reactive protein (CRP) and matrix metalloproteinase (MMP)-9 (p values < 0.05). Stratified by HIV, the only significant predictor of CI was greater variability in CRP for both HIV+ and HIV- women (p values < 0.05). This variability predicted lower executive function, attention/working memory, and psychomotor speed in HIV+ but only learning in HIV- women (p values < 0.05). Intra-individual variability in CRP levels over time may be a good predictor of CI in predominately minority low-socioeconomic status midlife women.

Cognitive trajectories over 4 years among HIV-infected women with optimal viral suppression.

OBJECTIVE: To determine whether persistent viral suppression alters cognitive trajectories among HIV-infected (HIV+) women on combination antiretroviral therapy (cART) by investigating performance longitudinally in uninfected (HIV-) and 3 groups of HIV+ women: those with consistent viral suppression after continuous cART use (VS), those without consistent virologic suppression despite continuous cART use (NVS), and those without consistent virologic suppression after intermittent cART use (Int NVS). METHODS: Two hundred thirty-nine VS, 220 NVS, 172 Int NVS, and 301 HIV- women from the Women's Interagency HIV Study (WIHS) completed neuropsychological testing every 2 years for 3 visits between 2009 and 2013. Mixed-effects regressions were used to examine group differences on continuous T scores and categorical measures of impairment (T score <40). RESULTS: On global function, VS women demonstrated lower scores and were more likely to score in the impaired range than HIV- women (p = 0.01). These differences persisted over time (group × time, p > 0.39). VS women demonstrated lower learning and memory scores than HIV- women (p < 0.05) and lower attention/working memory and fluency scores than HIV- and NVS women (p < 0.05). Group differences in scores persisted over time. Categorically, VS women were more likely to be impaired on attention/working memory and executive function than HIV- women (p < 0.05). On motor skills, VS and NVS women showed a greater decline and were more likely to be impaired than HIV- women (p < 0.05). CONCLUSIONS: Cognitive difficulties remain among HIV+ women despite persistent viral suppression. In some instances, VS women are worse than NVS women, reinforcing the need for novel adjunctive therapies to attenuate cognitive problems.

Perceived and post-traumatic stress are associated with decreased learning, memory, and fluency in HIV-infected women.

OBJECTIVE: Psychological risk factors (PRFs) are associated with impaired learning and memory in HIV-infected (HIV+) women. We determined the dynamic nature of the effects of PRFs and HIV serostatus on learning and memory over time. DESIGN: Multi-center, prospective cohort study METHODS:: Every two years between 2009 and 2013 (3 times), 646 HIV+ and 300 demographically-similar HIV-uninfected (HIV-) women from the Women's Interagency HIV Study completed neuropsychological (NP) testing and questionnaires measuring PRFs (perceived stress, post-traumatic stress disorder (PTSD) symptoms, depressive symptoms). Using mixed-effects regressions, we examined separate and interactive associations between HIV-serostatus and PRFs on performance over time. RESULTS: HIV+ and HIV- women had similar rates of PRFs. Fluency was the only domain where performance over time depended on the combined influence of HIV-serostatus and stress or PTSD (p's < 0.05); not depression. In HIV, higher stress and PTSD were associated with a greater cognitive decline in performance (p's < 0.05) versus lower stress and PTSD. Irrespective of time, performance on learning and memory depended on the combined influence of HIV-serostatus and stress or PTSD (p's ≤ 0.05). In the context of HIV, stress and PTSD were negatively associated with performance. Effects were pronounced on learning among HIV+ women without effective treatment or viral suppression. Regardless of time or HIV-serostatus, all PRFs were associated with lower speed, global NP, and executive function. CONCLUSIONS: More than depression, perceived stress and PTSD symptoms are treatment targets to potentially improve fluency, learning, and memory in women living with HIV particularly when HIV treatment is not optimal.

Speech audiometry findings from HIV+ and HIV- adults in the MACS and WIHS longitudinal cohort studies.

The purpose of this study was to compare various speech audiometry measures between HIV+ and HIV- adults and to further evaluate the association between speech audiometry and HIV disease variables in HIV+ adults only. Three hundred ninety-six adults from the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) completed speech audiometry testing. There were 262 men, of whom 117 (44.7%) were HIV+, and 134 women, of whom 105 (78.4%) were HIV+. Speech audiometry was conducted as part of the standard clinical audiological evaluation that included otoscopy, tympanometry, and pure-tone air- and bone-conduction thresholds. Specific speech audiometry measures included speech recognition thresholds (SRT) and word recognition scores in quiet presented at 40dB sensation level (SL) in reference to the SRT. SRT data were categorized in 5-dB steps from 0 to 25dB hearing level (HL) with one category as ≥30dB HL while word recognition scores were categorized as <90%, 90-99%, and 100%. A generalized estimating equations model was used to evaluate the association between HIV status and both ordinal outcomes. The SRT distributions across HIV+ and HIV- adults were similar. HIV+ and HIV- adults had a similar percentages of word recognition scores <90%, a lower percentage of HIV- adults had 90-99%, but HIV- adults had a higher percentage of 100%. After adjusting for covariables, HIV+ adults were borderline significantly more likely to have a higher SRT than HIV- adults (odds ratio [OR]=1.45, p=0.06). Among HIV+ adults, HIV-related variables (i.e., CD4+ T-cell counts, HIV viral load, and ever history of clinical AIDS) were not significantly associated with either SRT or word recognition score data. There was, however, a ceiling effect for word recognition scores, probably the result of obtaining this measure in quiet with a relatively high presentation level. A more complex listening task, such as speech-in-noise testing, may be a more clinically informative test to evaluate the effects of HIV on speech communication.