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.

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.

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.

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.

Hearing loss among HIV-seropositive and HIV-seronegative men and women.

IMPORTANCE: Age-related hearing loss affects quality of life. Data on hearing loss among aging human immunodeficiency virus-seropositive (HIV+) adults are limited. OBJECTIVE: To evaluate pure-tone hearing thresholds among HIV+ and HIV-seronegative (HIV-) adults and to determine whether HIV disease variables and antiretroviral therapy are associated with pure-tone threshold levels. DESIGN, SETTING, AND PARTICIPANTS: A total of 262 men (117 HIV+) from the Baltimore, Maryland/Washington, DC, site of the Multicenter AIDS Cohort Study and 134 women (105 HIV+) from the Washington, DC, site of the Women's Interagency HIV Study participated. Pure-tone air conduction thresholds were collected in a sound-treated room for each ear at frequencies from 250 through 8000 Hz. Linear mixed regression models tested the effect of HIV on hearing after adjustment for age, sex, race, and noise exposure history. MAIN OUTCOMES AND MEASURES: Low-frequency pure-tone average (LPTA) at 250, 500, 1000, and 2000 Hz and high-frequency PTA (HPTA) at 3000, 4000, 6000, and 8000 Hz. Differential HIV effects for LPTA and HPTA and better/worse ear were also examined. CD4⁺ and CD8⁺ T-cell counts, log10 plasma HIV RNA concentrations, receipt of AIDS diagnosis, and cumulative duration of antiretroviral therapy were included in the models for HIV+ participants only. RESULTS: HPTA and LPTA were significantly higher (18%: estimated ratio, 1.18 [95% CI, 1.02-1.36]; P = .02; and 12%: estimated ratio, 1.12 [95% CI, 1.00-1.26]; P = .05, respectively) for HIV+ participants compared with HIV- participants for the better ear. The direction of the effect was consistent across both the better and worse ears. There were no significant associations between HIV disease variables or treatment variables and LPTA or HPTA. CONCLUSIONS AND RELEVANCE: The HIV+ adults had significantly poorer lower-frequency and higher-frequency hearing than HIV- adults. High-frequency hearing loss is consistent with an accelerated aging (presbycusis); low-frequency hearing loss in middle age is unexpected. Because some vowels and consonants have predominantly low-frequency acoustic energy, poor low-frequency hearing may impair communication in HIV+ individuals.

Retrospective mortality study among employees occupationally exposed to toner.

OBJECTIVE: This cohort study examined the effects of occupational exposure to toner, a particulate material with widespread use in today's society, on mortality. METHODS: The study included 33,671 employees of a xerographic company employed between 1960 and 1982 as manufacturing workers or customer service engineers. Vital status was tracked through 1999. Standardized mortality ratios (SMRs) were calculated using the US population for comparison. RESULTS: All-cause SMRs for toner-exposed populations were 0.65 and 0.84 for White men and women, respectively, and 0.37 and 0.74 for non-White men and women, respectively. SMRs for all cancers, lung cancer, respiratory disease, and cardiovascular disease in toner-exposed men were lower than 1.0. CONCLUSIONS: Results are consistent with general mortality patterns among healthy working populations. There was no evidence that toner exposure increases the risk of all-cause mortality or cause-specific mortality for the 23 categories of death analyzed.

Incidence and risk factors for verrucae in women.

OBJECTIVES: To describe the incidence and risk factors for verrucae in HIV-infected and uninfected women. DESIGN AND METHODS: A prospective study of 1790 HIV-infected and 772 uninfected women. Skin examinations and interviews were performed every 6 months over an 8-year study period. Data collected at each visit included antiretroviral therapy use since the prior visit, CD4 counts, HIV RNA loads, and location, description, and diagnosis of verrucae. Incidence rates of cutaneous and anogenital warts were determined. RESULTS: Unadjusted cumulative incidence of cutaneous warts for HIV-uninfected women was 6.6%, 6.7% for HIV-infected women who initiated HAART, and 8.4% for HIV-infected, HAART-naïve women. The unadjusted cumulative incidence of anogenital verrucae for HIV-uninfected women was 9.3%, 28.4% for HIV-infected women who initiated HAART, and 25.1% for HIV-infected women who were HAART-naïve. Multivariate proportional hazard models revealed the following significant factors for the development of cutaneous verrucae among HIV-infected women: Black race [relative hazard (RH) = 0.50] and Hispanic ethnicity (RH = 0.38), compared to White race. Risk factors for anogenital verrucae were: more recent recruitment (RH = 0.63), human papillomavirus infection at baseline (RH = 1.85), decade of age (RH = 0.82), current smoker (RH = 1.40), lowest CD4 count (per 100 cells/microl) in the past 4 years (RH = 0.85), and log10 higher HIV viral load at the prior visit (RH = 1.34). CONCLUSION: HIV-infected women had a significantly increased cumulative incidence of anogenital verrucae compared to HIV-uninfected women. Although HAART did not alter the risk of developing skin or anogenital warts, those with higher CD4 cell counts and lower HIV RNA levels had a lower risk of developing anogenital warts.

The occurrence of vaginal infections among HIV-infected and high-risk HIV-uninfected women: longitudinal findings of the women's interagency HIV study.

OBJECTIVES: To evaluate changes over time in rates of bacterial vaginosis (BV), trichomoniasis (TV), and yeast vaginitis (YV) among HIV-infected and similar HIV-uninfected women. METHODS: Two thousand fifty-six HIV-infected women and 554 HIV-uninfected women were evaluated semiannually from 1994 until March 2003 in a prospective cohort study. BV was diagnosed by Gram stain, TV by wet mount, and YV by symptoms with microscopically visible hyphae or positive culture. Trends were assessed using Poisson models. RESULTS: At baseline, BV was present in 42.8% and 47.0% of HIV-infected and uninfected women (P = 0.21), TV in 6.1% and 7.8% (P = 0.17), and YV in 10.0% and 3.8% (P < 0.001). Over time, rates of BV and TV decreased significantly in both groups, whereas rates of YV declined only among HIV-infected women. Risk of BV was not associated with HIV status, whereas HIV-infected women had a lower risk of TV. Highly active antiretroviral therapy (HAART) use was associated with decreased risk of all 3 infections. CONCLUSIONS: : Declines in BV, TV, and YV represent decreased morbidity for HIV-infected women and, potentially, decreased risk of transmission of HIV, because each has been associated with increased genital detection of HIV.

Effect of antiretroviral therapy on the incidence of genital warts and vulvar neoplasia among women with the human immunodeficiency virus.

OBJECTIVE: The purpose of this study was to determine the incidence and predictors of genital warts and vulvar intraepithelial neoplasia among women with the human immunodeficiency virus. STUDY DESIGN: This was a multicenter prospective cohort study comprised of women without warts or vulvar intraepithelial neoplasia at baseline who underwent CD4 count, human immunodeficiency virus RNA measurement, examination, Papanicolaou test, and biopsy, as indicated, every 6 months. Human papillomavirus DNA typing was examined at baseline. RESULTS: The incidence of warts among women who were human immunodeficiency virus seronegative was 1.31 versus 5.01 per 100 person-years among women who were seropositive (P < .001). Incidence of vulvar intraepithelial neoplasia among women who were seronegative was 1.31 versus 4.67 per 100 person-years among women who were seropositive (P < .001). In multivariable analysis, warts were associated with highly active antiretroviral therapy (relative hazard, 0.76), CD4 count (relative hazard, 0.91/100 cell/cm(2) increase), acquired immunodeficiency syndrome (relative hazard, 1.25), abnormal Papanicolaou test results (relative hazard, 2.18), high- or medium-risk human papillomavirus types (relative hazard, 1.91), low-risk human papillomavirus types (relative hazard, 1.48), smoking (relative hazard, 1.43), having 1 child (relative hazard, 1.54), and age (relative hazard, 0.74/10 years). Vulvar intraepithelial neoplasia was linked to highly active antiretroviral therapy (relative hazard, 0.65), CD4 count (relative hazard, 0.92), abnormal Papanicolaou test results (relative hazard, 16.03), high- or medium-risk human papillomavirus types (relative hazard, 1.37), and age (relative hazard, 0.85/10 years). CONCLUSION: Warts and vulvar intraepithelial neoplasia are common among women with human immunodeficiency virus. Highly active antiretroviral therapy decreases their incidence.