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1.  Genetic Predictor of Working Memory and Prefrontal Function in Women with HIV 
Journal of neurovirology  2014;21(1):81-91.
The Val158Met (rs4680) single nucleotide polymorphism (SNP) of the catechol-O-methyltransferase gene (COMT) influences executive function and prefrontal function through its effect on dopamine (DA) metabolism. Both HIV and the Val allele of the Val158Met SNP are associated with compromised executive function and inefficient prefrontal function. The present study used behavioral and neuroimaging techniques to determine independent and interactive associations between HIV serostatus and COMT genotype on working memory and prefrontal function in women. For the behavioral study, 54 HIV-infected and 33 HIV-uninfected women completed the 0-, 1- and 2-back conditions of the verbal N-back, a working memory test. For the imaging study, 36 women (23 HIV-infected, 13 HIV-uninfected) underwent functional magnetic resonance imaging (fMRI) assessments while completing the N-back task. HIV-infected women demonstrated significantly worse N-back performance compared to HIV-uninfected women (p<0.05). A significant serostatus by genotype interaction (p<0.01) revealed that, among Val/Val, but not Met allele carriers, HIV-infected women performed significantly worse than HIV-uninfected controls across N-back conditions (p<0.01). Analogous to behavioral findings, a serostatus by genotype interaction revealed that HIV-infected, Val/Val carriers showed significantly greater prefrontal activation compared to HIV-uninfected, Val/Val carriers (p<0.01). Conversely, HIV-uninfected, Met allele carriers demonstrated significantly greater prefrontal activation compared to HIV-infected, Met allele carriers. Findings suggest that the combination of HIV infection and the Val/Val COMT genotype leads to working memory deficits and altered prefrontal function in HIV-infected individuals.
doi:10.1007/s13365-014-0305-z
PMCID: PMC4319991  PMID: 25515329
HIV; COMT genotype; single nucleotide polymorphism (SNP); working memory; prefrontal function; dopamine
2.  Long-term cumulative detection of human papillomavirus among HIV seropositive women 
AIDS (London, England)  2014;28(17):2601-2608.
Objective
To estimate the effects of infection by human immunodeficiency virus (HIV) on the type-specific cumulative detection of cervicovaginal infection by human papillomavirus (HPV).
Design
Retrospective assessment of prospectively collected data in a multicenter U.S. cohort.
Methods
HIV seropositive and at-risk seronegative participants in the Women's Interagency HIV Study were followed semiannually for up to 11 years. HPV typing was determined from cervicovaginal lavage specimens by polymerase chain reaction; types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 were considered carcinogenic.
Results
Among 3438 women enrolled, (2543 HIV seropositive, 895 seronegative), the cumulative detection of any HPV infection rose among HIV seropositive women from 53% at baseline to 92% at 8 years and among seronegative women from 22% to 66% (P < 0.0001 for HIV seropositive vs seronegative women). The 8-year cumulative detection of carcinogenic and noncarcinogenic HPV was 67% and 89% among HIV seropositive and 36% and 56% among seronegative women (P = 0.001 for both carcinogenic and noncarcinogenic HPV). The 8-year cumulative detection of HPV16 and HPV 18 was 15.2% and 15.0% in HIV seropositive and 6.7% and 6.1% in HIV seronegative women (P < 0.0001 for both). In multivariable regression analyses, lower CD4 count, age under 30 years, and smoking but not number of lifetime sexual partners were significant correlates of cumulative HPV detection.
Conclusion
More than 90% of HIV seropositive women have HPV detected during long follow-up. Rates are lower among at-risk HIV seronegative women, though most also develop HPV infections.
doi:10.1097/QAD.0000000000000455
PMCID: PMC4289460  PMID: 25188771
Human papillomavirus; HIV in women; immunodeficiency
3.  Association of Markers of Hemostasis with Death in HIV-infected Women 
In HIV-negatives, markers of hemostasis including D-dimer, Factor VIII, plasminogen activator inhibitor-1 antigen (PAI-1) and total protein S are associated with all-cause and cardiovascular disease mortality. In HIV-positives, studies of D-dimer and Factor VIII with death were limited to short follow-up; associations of PAI-1 and total protein S with death have not been examined.
In 674 HIV-infected women from the Women’s Interagency HIV Study (WIHS), markers from the first visit after enrollment were exposures of interest in multivariate analyses of death (AIDS and non-AIDS) in separate models at 5 and 16 years.
There were 87 AIDS and 44 non-AIDS deaths at 5 years, and 159 AIDS and 113 non-AIDS deaths at 16 years. An inverse association of total protein S quartiles with non-AIDS deaths was observed at 5 (p-trend=0.002) and 16 years (p-trend=0.02); there was no association with AIDS deaths. The 3rd quartile of PAI-1 was associated with AIDS deaths at 5 (hazard ratio (HR)=4.0, 95% confidence interval (CI)=1.9–8.4) and 16 years (HR=3.4, 95% CI=1.9–5.9); and with non-AIDS deaths at 5 years (HR=4.8, 95%CI=1.6,13.9). D-dimer and Factor VIII were not associated with AIDS or non-AIDS death at 5 or 16 years.
Lower total Protein S was a consistent marker of non-AIDS death. We found no association between D-dimer with AIDS or non-AIDS death, in contrast to previous studies showing increased short term (<5 years) mortality, which may represent sex differences or population heterogeneity. Given longer survival on HAART, further studies of these markers are needed to determine their prognostic value.
doi:10.1097/QAI.0000000000000306
PMCID: PMC4197808  PMID: 25314249
4.  Investigating the Effects of Metabolic Dysregulation on Hair Follicles: A Comparison of HIV-Infected Women With and Without Central Lipohypertrophy 
International journal of dermatology  2013;53(10):e443-e448.
Background
Normal lipid metabolism and functioning of the peroxisome proliferator activated receptor gamma (PPAR-gamma) in the sebaceous gland is critical to maintaining a normal hair follicle. Human immunodeficiency virus (HIV) infection affects lipid metabolism; some have hypothesized a link between PPAR-gamma function and lipodystrophy in HIV infection. Our objective was to determine whether lipodystrophy is associated with altered hair characteristics in HIV-infected women from the Women’s Interagency HIV Study (WIHS).
Methods
Hair characteristics and scalp inflammation were assessed by an interviewer-administered questionnaire. Central lipohypertrophy and peripheral lipoatrophy was defined by self report of moderate to severe fat gain in central body sites and fat loss in peripheral body sites, respectively confirmed by clinical examination. Additional covariates considered in the analyses included demographics, behavioral characteristics, medical history, and HIV-related factors.
Results
There were 1037 women with data on all study variables. 76 women reported central lipohypertrophy; only 4 women reported lipoatrophy. Women with central lipohypertrophy were more likely to be older, have a self-reported history of injection drug use, statin medication use, diabetes, elevated cholesterol, and have self-reported less hair and shorter eyelashes. After adjustment for age, central lipohypertrophy was associated with shorter eyelashes (OR 2.3; 95% CI 1.4-3.8).
Conclusions
Central lipohypertrophy was not associated with change in scalp hair texture or scalp inflammation in this cohort. Rather, we found an association between central lipohypertrophy and shorter eyelash length. This finding may be explained by an influence of prostaglandin E2 mediators on eyelash follicles.
doi:10.1111/ijd.12044
PMCID: PMC3785560  PMID: 23786579
eyelash; hair; HIV
5.  Serum Albumin and Kidney Function Decline in HIV-Infected Women 
Background
Serum albumin concentrations are a strong predictor of mortality and cardiovascular disease in HIV-infected individuals. We studied the longitudinal associations between serum albumin levels and kidney function decline in a population of HIV-infected women.
Study Design
Retrospective cohort analysis.
Setting & Participants
The study participants were recruited from the Women’s Interagency HIV Study (WIHS), a large observational study designed to understand risk factors for the progression of HIV infection in women living in urban communities. 908 participants had baseline assessment of kidney function and two follow-up measures over an average of 8 years.
Predictor
The primary predictor was serum albumin concentration.
Outcomes
We examined annual change in kidney function. Secondary outcomes included rapid kidney function decline and incident reduced estimated glomerular filtration rate (eGFR).
Measurements
Kidney function decline was determined by cystatin C–based (eGFRcys) and creatinine-based eGFR (eGFRcr) at baseline and follow up. Each model was adjusted for kidney disease and HIV-related risk factors using linear and relative risk regression.
Results
After multivariate adjustment, each 0.5-g/dL decrement in baseline serum albumin concentration was associated with a 0.56-mL/min faster annual decline in eGFRcys (P<0.001), which was only slightly attenuated to 0.55-mL/min/1.73 m2 after adjustment for albuminuria. Results were similar whether using eGFRcys or eGFRcr. In adjusted analyses, each 0.5-g/dL lower baseline serum albumin was associated with a 1.71-fold greater risk of rapid kidney function decline (p<0.001) and a 1.72-fold greater risk of incident reduced eGFR (p<0.001).
Limitations
The cohort is composed of only female participants from urban communities within the United States.
Conclusions
Lower levels of serum albumin were strongly associated with kidney function decline and incident reduced eGFR in HIV-infected women, independent of HIV disease status, BMI and albuminuria.
doi:10.1053/j.ajkd.2014.05.015
PMCID: PMC4177337  PMID: 25059222
albumin; kidney function; HIV; incident reduced eGFR; albuminuria; disease trajectory; chronic kidney disease (CKD) progression
6.  The association of perceived stress and verbal memory is greater in HIV-infected versus HIV-uninfected women 
Journal of neurovirology  2015;21(4):422-432.
In contrast to findings from cohorts comprised primarily of HIV-infected men, verbal memory deficits are the largest cognitive deficit found in HIV-infected women from the Women’s Interagency HIV Study (WIHS), and this deficit is not explained by depressive symptoms or substance abuse. HIV-infected women may be at greater risk for verbal memory deficits due to a higher prevalence of cognitive risk factors such as high psychosocial stress and lower socioeconomic status. Here, we investigate the association between perceived stress using the Perceived Stress Scale (PSS-10) and verbal memory performance using the Hopkins Verbal Learning Test (HVLT) in 1009 HIV-infected and 496 at-risk HIV-uninfected WIHS participants. Participants completed a comprehensive neuropsychological test battery which yielded seven cognitive domain scores, including a primary outcome of verbal memory. HIV infection was not associated with a higher prevalence of high perceived stress (i.e., PSS-10 score in the top tertile) but was associated with worse performance on verbal learning (p<0.01) and memory (p<0.001), as well as attention (p=0.02). Regardless of HIV status, high stress was associated with poorer performance in those cognitive domains (p’s< 0.05) as well as processing speed (p=0.01) and executive function (p<0.01). A significant HIV by stress interaction was found only for the verbal memory domain (p=0.02); among HIV-infected women only, high stress was associated with lower performance (p’s<0.001). That association was driven by the delayed verbal memory measure in particular. These findings suggest that high levels of perceived stress contribute to the deficits in verbal memory observed in WIHS women.
doi:10.1007/s13365-015-0331-5
PMCID: PMC4562210  PMID: 25791344
HIV; Verbal memory; Stress; Women; Cognition
7.  An investigation of menopausal stage and symptoms on cognition in HIV-infected women 
Menopause (New York, N.Y.)  2014;21(9):997-1006.
Objective:
We evaluated the separate and interactive associations of menopausal stage, menopausal symptoms, and HIV infection on cognition. We hypothesized that HIV-infected, perimenopausal women would show the greatest cognitive difficulties and that menopausal symptoms would be inversely associated with cognition.
Methods:
This cross-sectional study included 708 HIV-infected and 278 HIV-uninfected, pre-, peri-, or postmenopausal women (64% African-American; median age 44 years) from the Women’s Interagency HIV Study. Participants completed tests of verbal learning and memory, attention/processing speed, and executive function. We administered a menopausal symptom questionnaire that assessed anxiety, vasomotor, and sleep symptoms and obtained measures of depressive symptoms.
Results:
In multivariable regression analyses controlling for relevant covariates, HIV infection, but not menopausal stage, was associated with worse performance on all cognitive measures (p’s<0.05). Depressive symptoms were associated with lower cognitive performance on measures of verbal learning and memory, attention, and executive function (p’s<0.05); anxiety symptoms were associated with lower performance on measures of verbal learning and memory (p’s<0.05). Vasomotor symptoms were associated with worse attention (p<0.05). HIV and anxiety symptoms interacted to influence verbal learning (p’s<0.05); elevated anxiety was associated with worse verbal learning in HIV-infected women only.
Conclusion:
Vasomotor, depressive, and anxiety symptoms, but not menopausal stage, were associated with worse cognitive performance in both HIV-infected and uninfected women, although elevated anxiety symptoms were associated with verbal learning deficits more in HIV-infected women. Since cognitive problems can interfere with everyday functioning including treatment adherence, it may be important to screen and treat anxiety in HIV-infected women.
doi:10.1097/GME.0000000000000203
PMCID: PMC4119867  PMID: 24496085
HIV; Verbal Learning; Menopause; Mood; Anxiety; African American
9.  Crack cocaine use impairs anterior cingulate and prefrontal cortex function in women with HIV infection 
Journal of neurovirology  2014;20(4):352-361.
Objective
Crack cocaine use is associated with impaired verbal memory in HIV-infected women more than -uninfected women. To understand the neural basis for this impairment, this study examined the effects of crack cocaine use on activation of the prefrontal cortex (PFC) and strategic encoding during a verbal memory task in HIV-infected women.
Methods
Three groups of HIV-infected women from the Chicago Consortium of the Women’s Interagency HIV Study were compared: current users of crack cocaine (n=10), former users of cocaine (n=11), and women who had never used cocaine (n=9). Participants underwent functional magnetic resonance imaging during a verbal memory task and completed a neuropsychological test of verbal memory.
Results
On the neuropsychological test, current crack users performed significantly worse than other groups on semantic clustering, a measure of strategic encoding, p < .05. During encoding, activation in left anterior cingulate cortex (ACC) was lower in current and former cocaine users compared to never users. During recognition, activation in bilateral PFC, specifically left dorsal medial PFC and bilateral dorsolateral PFC, was lower in current and former users compared to women who had never used cocaine. Lower activation in left dorsolateral PFC was correlated with worse performance on the recognition task, p < .05.
Conclusion
The verbal learning and memory deficits associated with cocaine use in women with HIV may be partially accounted for by alterations in ACC and PFC function.
doi:10.1007/s13365-014-0250-x
PMCID: PMC4090256  PMID: 24760360
HIV; crack cocaine; African American; verbal memory; fMRI; prefrontal cortex
10.  Sexual Minority Status and Violence Among HIV Infected and At-Risk Women 
Journal of General Internal Medicine  2014;29(8):1131-1138.
ABSTRACT
IMPORTANCE
Sexual minority women with and at-risk for human immunodeficiency virus (HIV) may face increased risks of violence.
OBJECTIVE
To understand the relationship between sexual minority status and violence; and how high-risk sex and substance use mediate that relationship among women with and at-risk for HIV.
DESIGN & PARTICIPANTS
Longitudinal study of 1,235 HIV infected and 508 uninfected women of the Women's Interagency HIV Study (WIHS) cohort, from New York City, NY, Chicago, IL, Washington D.C., and San Francisco, CA, 1994–2012.
MAIN MEASURES
Primary exposures are sexual identity (heterosexual, bisexual, lesbian/gay) and sexual behavior (male, female, or male & female partners). Primary outcomes are sexual abuse, intimate partner violence (IPV) and physical violence; high-risk sex and substance use were examined as mediators.
KEY RESULTS
Bisexual women were at increased odds for sexual abuse [aOR 1.56 (1.00, 2.44)], IPV [aOR 1.50 (1.08, 2.09)], and physical violence [aOR 1.77 (1.33, 2.37)] compared to heterosexual women. In a separate analysis, women who reported sex with men and women (WSMW) had increased odds for sexual abuse [aOR 1.65 (0.99, 2.77], IPV [aOR 1.50 (1.09, 2.06)] and physical violence [aOR 2.24 (1.69, 2.98)] compared to women having sex only with men (WSM). Using indirect effects, multiple sex partners, cocaine and marijuana were significant mediators for most forms of abuse. Transactional sex was only a mediator for bisexual women. Women who reported sex only with women (WSW) had lower odds of sexual abuse [aOR 0.23 (0.06, 0.89)] and physical violence [aOR 0.42 (0.21, 0.85)] compared to WSM.
CONCLUSIONS
Women who identify as bisexual or report both male and female sex partners are most vulnerable to violence; multiple recent sex partners, transactional sex and some types of substance use mediate this relationship. Acknowledging sexual identity and behavior, while addressing substance use and high-risk sex in clinical and psychosocial settings, may help reduce violence exposure among women with and at-risk for HIV.
doi:10.1007/s11606-014-2832-y
PMCID: PMC4099466  PMID: 24700180
gay and lesbian health; IPV; sexual assault; HIV/AIDS; women’s health
11.  Antiretroviral Therapy Modifies the Genetic Effect of Known Type 2 Diabetes-Associated Risk Variants in the Women’s Interagency HIV Study 
AIDS (London, England)  2014;28(12):1815-1823.
Objective
Type 2 diabetes (DM) incidence is increased in HIV-infected persons. We examined the associations of DM with known DM-risk alleles from the general population in the context of HIV infection and explored effect modification by combination antiretroviral treatment (cART).
Methods
The Women’s Interagency HIV Study (WIHS) is a prospective cohort of HIV-infected women. Seventeen European-derived DM-risk polymorphisms were genotyped in eligible WIHS participants. Analyses were run separately for non-African-Americans (Whites, Hispanics, Asians, and other; n=378, 49 with incident DM) and African-Americans (n=591, 49 with incident DM). Cox proportional hazards models were fit to estimate hazard ratios (HRs) for DM overall and within strata of cART.
Results
In non-African-Americans, heterogeneity across cART regimen was observed for 9 of 14 polymorphisms (phet<0.05). One polymorphism was statistically significantly inversely associated with DM risk among women taking 2 NRTIs+NNRTI. Five polymorphisms were statistically significantly associated with DM among women treated with ≥2 NRTIs + ≥1 PI and one polymorphism was associated with DM among those treated with ≥3 NRTIs ± NNRTI. The HR per risk allele for IGF2BP2 rs1470579 was 2.67 (95% CI 1.67–4.31) for women taking cART with ≥2 NRTIs+≥1 PI and 2.45 (95% CI 1.08–5.53) in women taking ≥3 NRTIs±NNRTI (phet=2.50×10−3). No such associations were observed in African-Americans.
Conclusions
Genetic susceptibility to DM, based on the variants studied, is substantially elevated among HIV-infected women using cART containing three or more NRTI/PI components. A personalized medicine approach to cART selection may be indicated for HIV-infected persons carrying these DM-risk variants.
doi:10.1097/QAD.0000000000000366
PMCID: PMC4269472  PMID: 24932614
type 2 diabetes; genetics; HIV; women; antiretroviral therapy
12.  Smoking Cessation and Recidivism in the Women's Interagency Human Immunodeficiency Virus Study 
Background
Smoking increases the risk of morbidity and mortality and is particularly harmful to HIV-infected people.
Purpose
To explore smoking trends and longitudinal factors associated with smoking cessation and recidivism among participants in the Women's Interagency HIV Study.
Methods
From 1994 through 2011, 2,961 HIV-infected and 981 HIV-uninfected women were enrolled and underwent semi-annual interviews and specimen collection. Smoking prevalence was evaluated annually and risk factors associated with time to smoking cessation and recidivism were analyzed in 2013 using survival models.
Results
The annual cigarette smoking prevalence declined from 57% in 1995 to 39% in 2011 (p-trend<0.0001). Among smokers, factors significantly associated with a longer time to smoking cessation included less education, alcohol use, having health insurance, >10-year smoking duration, self-reported poor health rating, and having hypertension. Pregnancy in the past 6 months was associated with a shorter time to cessation. Among HIV-infected women, additional risk factors for longer time to cessation included lower household income, use of crack/cocaine/heroin, CD4 cell count ≤200, and highly active antiretroviral therapy (HAART) use. Predictors of smoking recidivism included marijuana use, enrollment in 1994–1996, and not living in one's own place. Among HIV-infected women, enrollment in 2001-2002 and crack/cocaine/heroin use were associated with a shorter time to recidivism, whereas older age and HAART use were associated with a longer time to recidivism.
Conclusions
Despite declining rates of cigarette smoking, integrated interventions are needed to help women with and at risk for HIV infection to quit smoking and sustain cessation.
doi:10.1016/j.amepre.2014.02.010
PMCID: PMC4065848  PMID: 24746376
13.  Effect of HIV Infection on Body Composition and Fat Distribution in Rwandan Women 
Objective
To assess the association of HIV infection with body weight and composition in Rwandan women.
Design
Body weight and composition, the latter determined by bioelectrical impedance analysis (BIA) and by anthropometry, were compared in 620 HIV-positive and 211 HIV-negative participants. Associations of HIV with body composition were assessed, and t tests compared the groups.
Results
HIV-positive women were younger (−7.0 years, P < .001) and shorter (− 2.1 cm, P < .001). Mean body weight, body mass index (BMI), total body fat, and waist-to-hip ratio (WHR) were similar. Mean fat-free mass was 2.5% greater in HIV-negative participants, and 19% of HIV-positive group had BMI <18.5 kg/m2 versus 26% of the HIV-negative group (P < .05). CD4 counts and body composition were not associated.
Conclusions
Malnutrition was common in this cohort of Rwandan women. However, HIV infection was not associated with nutritional status. Factors other than malnutrition may influence quality-of-life outcomes in HIV-infected Rwandan women. Initiatives to improve nutritional status should be population-wide and not restricted to the HIV-infected population.
doi:10.1177/1545109710366472
PMCID: PMC4460979  PMID: 20530472
HIV; malnutrition; body composition; Rwanda; women; fat distribution
14.  Urinary Biomarkers of Kidney Injury Are Associated with All-Cause Mortality in the Women’s Interagency HIV Study (WIHS) 
HIV medicine  2013;15(5):291-300.
Objectives
Chronic kidney disease (CKD) is common in HIV; CKD is associated with mortality. Urinary markers of tubular injury have been associated with future kidney disease risk, but associations with mortality are unknown.
Methods
We evaluated the association of urinary interleukin-18(IL-18), liver fatty acid binding protein(L-FABP), kidney injury molecule-1(KIM-1), neutrophil gelatinase-associated lipocalin(NGAL), albumin-to-creatinine ratio(ACR) with 10-year, all-cause death in 908 HIV-infected women. Kidney function was estimated using cystatin C (eGFRcys).
Results
There were 201 deaths during 9,269 person-years of follow-up. After demographic adjustment, compared to the lowest tertile, highest tertiles of IL-18 (HR 2.54,95%CI 1.75–3.68), KIM-1 (2.04,1.44–2.89), NGAL(1.50,1.05–2.14), and ACR(1.63,1.13–2.36) were associated with higher mortality. After multivariable adjustment including eGFRcys, only the highest tertiles of IL-18, (1.88,1.29–2.74) and ACR (1.46,1.01–2.12) remained independently associated with mortality. Findings with KIM-1 were borderline (1.41, 0.99–2.02). We found a J-shaped association between L-FABP and mortality. Compared to persons in the lowest tertile, HR for middle tertile of L-FABP was 0.67 (0.46–0.98) after adjustment. Findings were stronger when IL-18, ACR and L-FABP were simultaneously included in models.
Conclusions
Among HIV-infected women, some urinary markers of tubular injury are associated with mortality risk, independently of eGFRcys and ACR. These markers represent potential tools to identify early kidney injury in persons with HIV.
doi:10.1111/hiv.12113
PMCID: PMC3975680  PMID: 24313986
HIV; IL-18; KIM-1; L-FABP; NGAL; urinary biomarkers
15.  Psychosocial Correlates of Gender-Based Violence Among HIV-Infected and HIV-Uninfected Women in Three US Cities 
AIDS Patient Care and STDs  2014;28(5):260-267.
Abstract
Gender-based violence (GBV) is common among women with and at risk for HIV, yet little is known about the GBV associated psychological factors that could be modifiable through behavioral interventions. The current study examined the associations between some of these psychological factors (i.e., hopelessness, consideration of future consequences, self esteem), mental health symptoms, substance abuse, and GBV among a sample of 736 HIV-infected and sociodemographically similar uninfected participants in the Women's Interagency HIV Study (WIHS). Results indicated high rates of lifetime GBV among the sample (58%), as well as high rates of childhood sexual abuse (CSA) (22.2%). HIV-infected women were more likely to be hopeless and to experience lower consideration of future consequences as compared to uninfected women. Multivariable analysis indicated that current non-injection drug use and a history of injection drug use were the main correlates of GBV and CSA, even when other psychosocial variables were included in analytic models. Being born outside of the US reduced the likelihood of GBV and CSA. Future research directions and intervention implications are discussed.
doi:10.1089/apc.2013.0342
PMCID: PMC4011431  PMID: 24724987
16.  Macrophage inflammatory markers are associated with subclinical carotid artery disease in women with HIV or HCV infection 
Objective
Infection with hepatitis C (HCV) or human immunodeficiency virus (HIV) may be associated with atherosclerosis and vascular disease. Macrophages are a major component of atherosclerotic plaque, and classically activated (M1) macrophages contribute to plaque instability. Our goal was to identify plasma biomarkers that reflect macrophage inflammation and are associated with subclinical atherosclerosis.
Approach and results
We tested whether M1 macrophages produce galectin-3 binding protein (Gal-3BP) in-vitro. Then we measured Gal-3BP and the soluble macrophage biomarkers sCD163 and sCD14 in 264 participants in the Women’s Interagency HIV Study. Women were positive for HIV, HCV, both, or neither (66 in each group, matched for age, race/ethnicity and smoking status). Carotid artery disease was assessed by ultrasound measurement of right distal common carotid artery intima-media thickness (cIMT), distensibility, and presence of atherosclerotic lesions (IMT>1.5 mm). Plasma Gal-3BP was higher in HCV+ than HCV− women (p<0.01), but did not differ by HIV status. The three inflammatory macrophage markers were significantly correlated with each other and negatively correlated with CD4+ counts in HIV-infected women. We defined a macrophage score as 1, 2 or 3 biomarkers elevated above the median. In models adjusted for traditional risk factors, higher macrophage scores were significantly associated with increased atherosclerotic lesions and lower carotid distensibility. Receiver-operator curve analysis of lesions revealed that the markers added predictive value beyond traditional risk factors and C-reactive protein.
Conclusions
The macrophage inflammatory markers Gal-3BP, sCD163 and sCD14 are significantly associated with carotid artery disease in the setting of HIV and HCV infection.
doi:10.1161/ATVBAHA.113.303153
PMCID: PMC4067091  PMID: 24651679
atherosclerosis; women; AIDS; immune system; risk factors
17.  Insulin Resistance Change and Antiretroviral Therapy Exposure in HIV-Infected and Uninfected Rwandan Women: A Longitudinal Analysis 
PLoS ONE  2015;10(4):e0123936.
Background
We longitudinally assessed predictors of insulin resistance (IR) change among HIV-uninfected and HIV-infected (ART-initiators and ART-non-initiators) Rwandan women.
Methodology
HIV-infected (HIV+) and uninfected (HIV-) women provided demographic and clinical measures: age, body mass index (BMI) in Kg/(height in meters)2, Fat-Mass (FMI) and Fat-Free-Mass (FFMI) index, fasting serum glucose and insulin. Homeostasis Model Assessment (HOMA) was calculated to estimate IR change over time in log10 transformed HOMA measured at study enrollment or prior to ART initiation in 3 groups: HIV- (n = 194), HIV+ ART-non-initiators (n=95) and HIV+ ART-initiators (n=371). ANCOVA linear regression models of change in log10-HOMA were fit with all models included the first log10 HOMA as a predictor.
Results
Mean±SD log10-HOMA was -0.18±0.39 at the 1st and -0.21±0.41 at the 2nd measure, with mean change of 0.03±0.44. In the final model (all women) BMI at 1st HOMA measure (0.014; 95% CI=0.006-0.021 per kg/m2; p<0.001) and change in BMI from 1st to 2nd measure (0.024; 95% CI=0.013-0.035 per kg/m2; p<0.001) predicted HOMA change. When restricted to subjects with FMI measures, FMI at 1st HOMA measure (0.020; 95% CI=0.010-0.030 per kg/m2; p<0.001) and change in FMI from 1st to 2nd measure (0.032; 95% CI=0.020-0.043 per kg/m2; p<0.0001) predicted change in HOMA. While ART use did not predict change in log10-HOMA, untreated HIV+ women had a significant decline in IR over time. Use or duration of AZT, d4T and EFV was not associated with HOMA change in HIV+ women.
Conclusions
Baseline BMI and change in BMI, and in particular fat mass and change in fat mass predicted insulin resistance change over ~3 years in HIV-infected and uninfected Rwandan women. Exposure to specific ART (d4T, AZT, EFV) did not predict insulin resistance change in ART-treated HIV-infected Rwandan women.
doi:10.1371/journal.pone.0123936
PMCID: PMC4400132  PMID: 25880634
18.  INCREASE IN SINGLE-TABLET REGIMEN USE AND ASSOCIATED IMPROVEMENTS IN ADHERENCE-RELATED OUTCOMES IN HIV-INFECTED WOMEN 
Introduction
The use of single-tablet ART regimens and its implications on adherence among HIV-infected women have not been well-described.
Methods
Participants were enrolled in the Women’s Interagency HIV Study (WIHS), a longitudinal study of HIV infection in U.S. women. We examined semiannual trends in single-tablet regimen use and ART adherence, defined as self-reported 95% adherence in the past 6 months, during 2006–2013. In a nested cohort study, we assessed the comparative effectiveness of a single-tablet versus a multiple-tablet regimen with respect to adherence, virologic suppression, quality of life, and AIDS-defining events, using propensity score matching to account for demographic, behavioral, and clinical confounders. We also examined these outcomes in a subset of women switching from a multiple- to single-tablet regimen, using a case-crossover design.
Results
15,523 person-visits, representing 1,727 women (53% black, 29% Hispanic, 25% IDU, median age 47), were included. Use of single-tablet regimens among ART users increased from 7% in 2006 to 27% in 2013; adherence increased from 78% to 85% during the same period (both p<0.001). Single-tablet regimen use was significantly associated with increased adherence (adjusted RR 1.05, 95% CI 1.03–1.08) and virologic suppression (RR 1.06, 95% CI 1.01–1.11), while associations with improved quality of life and fewer AIDS-defining events did not achieve statistical significance. Similar findings were observed among the subset of switchers.
Conclusion
Single-tablet regimen use was associated with increased adherence and virologic suppression. Despite this, 15% of women prescribed ART were still not optimally adherent; additional interventions are needed to maximize therapeutic benefits.
doi:10.1097/QAI.0000000000000082
PMCID: PMC3999284  PMID: 24326606
adherence; antiretroviral therapy; HIV; time factors; United States; viral load; women
19.  RYR3 gene variants in subclinical atherosclerosis among HIV-infected women in the Women’s Interagency HIV Study (WIHS) 
Atherosclerosis  2014;233(2):666-672.
Background
Single nucleotide polymorphisms (SNPs) in the Ryanodine receptor 3 (RYR3) gene are associated with common carotid intima media thickness (CCA cIMT) in HIV-infected men. We evaluated SNPs in the RYR3 gene among HIV-infected women participating in Women’s Interagency HIV Study (WIHS).
Methods
CCA cIMT was measured using B-mode ultrasound and the 838 SNPs in the RYR3 gene region were genotyped using the Illumina HumanOmni2.5-quad beadchip. The CCA cIMT genetic association was assessed using linear regression analyses among 1213 women and also separately among White (n=139), Black (n=720) and Hispanic (n=354) women after adjusting for confounders. A summary measure of pooled association was estimated using a meta-analytic approach by combining the effect estimates from the three races. Haploblocks were inferred using Gabriel’s method and haplotype association analyses were conducted among the three races separately.
Results
SNP rs62012610 was associated with CCA cIMT among the Hispanics (p=4.41× 10−5), rs11856930 among Whites (p=5.62× 10−4), and rs2572204 among Blacks (p=2.45× 10−3). Meta-analysis revealed several associations of SNPs in the same direction and of similar magnitude, particularly among Blacks and Hispanics. Additionally, several haplotypes within three haploblocks containing SNPs previously related with CCA cIMT were also associated in Whites and Hispanics.
Discussion
Consistent with previous research among HIV-infected men, SNPs within the RYR3 region were associated with subclinical atherosclerosis among HIV-infected women. Allelic heterogeneity observed across the three races suggests that the contribution of the RYR3 gene to CCA cIMT is complex, and warrants future studies to better understand regional SNP function.
doi:10.1016/j.atherosclerosis.2014.01.035
PMCID: PMC3965606  PMID: 24561552
RYR3; single nucleotide polymorphisms; HIV infection; CCA; cIMT; subclinical atherosclerosis
20.  Abuse and Resilience in Relation to HAART Medication Adherence and HIV Viral Load Among Women with HIV in the United States 
AIDS Patient Care and STDs  2014;28(3):136-143.
Abstract
Abuse is highly prevalent among HIV+ women, leading to behaviors, including lower adherence to highly active antiretroviral therapy (HAART) that result in poor health outcomes. Resilience (functioning competently despite adversity) may buffer the negative effects of abuse. This study investigated how resilience interacted with abuse history in relation to HAART adherence, HIV viral load (VL), and CD4+ cell count among a convenience sample of 138 HIV+ women from the Ruth M. Rothstein CORE Center/Cook County Health and Hospital Systems site of the Women's Interagency HIV Study (WIHS). Resilience was measured by the 10-item Connor-Davidson Resilience Scale (CD-RISC). HAART adherence (≥95% vs. <95% self reported usage of prescribed medication) and current or prior sexual, physical, or emotional/domestic abuse, were reported during structured interviews. HIV viral load (≥20 vs. <20 copies/mL) and CD4+ count (200 vs. <200 cells/mm) were measured with blood specimens. Multiple logistic regressions, controlling for age, race, income, enrollment wave, substance use, and depressive symptoms, indicated that each unit increase in resilience was significantly associated with an increase in the odds of having ≥95% HAART adherence and a decrease in the odds of having a detectable viral load. Resilience-Abuse interactions showed that only among HIV+ women with sexual abuse or multiple abuses did resilience significantly relate to an increase in the odds of ≥95% HAART adherence. Interventions to improve coping strategies that promote resilience among HIV+ women may be beneficial for achieving higher HAART adherence and viral suppression.
doi:10.1089/apc.2013.0329
PMCID: PMC3948478  PMID: 24568654
21.  Resilience among women with HIV: Impact of silencing the self and socioeconomic factors 
Sex roles  2014;70(5-6):221-231.
In the U.S., women account for over a quarter of the approximately 50,000 annual new HIV diagnoses and face intersecting and ubiquitous adversities including gender inequities, sexism, poverty, violence, and limited access to quality education and employment. Women are also subjected to prescribed gender roles such as silencing their needs in interpersonal relationships, which may lessen their ability to be resilient and function adaptively following adversity. Previous studies have often highlighted the struggles encountered by women with HIV without focusing on their strengths. The present cross-sectional study investigated the relationships of silencing the self and socioeconomic factors (education, employment, and income) with resilience in a sample of women with HIV. The sample consisted of 85 women with HIV, diverse ethnic/racial groups, aged 24 – 65 enrolled at the Chicago site of the Women’s Interagency HIV Study in the midwestern region of the United States. Measures included the Connor-Davidson Resilience Scale -10 item and the Silencing the Self Scale (STSS). Participants showed high levels of resilience. Women with lower scores on the STSS (lower self-silencing) reported significantly higher resilience compared to women with higher STSS scores. Although employment significantly related to higher resilience, silencing the self tended to predict resilience over and above the contributions of employment, income, and education. Results suggest that intervention and prevention efforts aimed at decreasing silencing the self and increasing employment opportunities may improve resilience.
doi:10.1007/s11199-014-0348-x
PMCID: PMC4051411  PMID: 24932061
resilience; silencing the self; HIV; women; socioeconomic factors
22.  The Vaginal Microbiota over an 8- to 10-Year Period in a Cohort of HIV-Infected and HIV-Uninfected Women 
PLoS ONE  2015;10(2):e0116894.
Background
We identified predominant vaginal microbiota communities, changes over time, and how this varied by HIV status and other factors in a cohort of 64 women.
Methods
Bacterial DNA was extracted from reposited cervicovaginal lavage samples collected annually over an 8–10 year period from Chicago Women’s Interagency HIV Study participants: 22 HIV-negative, 22 HIV-positive with stable infection, 20 HIV-positive with progressive infection. The vaginal microbiota was defined by pyrosequencing of the V1/V2 region of the 16S rRNA gene. Scheduled visits included Bacterial vaginsosis (BV) screening; clinically detected cases were referred for treatment. Hierarchical clustering identified bacterial community state types (CST). Multinomial mixed effects modeling determined trends over time in CST, by HIV status and other factors.
Results
The median follow-up time was 8.1 years (range 5.5–15.3). Six CSTs were identified. The mean relative abundance (RA) of Lactobacillus spp. by CST (with median number of bacterial taxa) was: CST-1–25.7% (10), CST-2–27.1% (11), CST-3–34.6% (9), CST-4–46.8% (9), CST-5–57.9% (4), CST-6–69.4% (2). The two CSTs representing the highest RA of Lactobacillus and lowest diversity increased with each additional year of follow-up (CST-5, adjusted odds ratio (aOR) = 1.62 [95% CI: 1.34–1.94]; CST-6, aOR = 1.57 [95 CI: 1.31–1.89]), while the two CSTs representing lowest RA of Lactobacillus and higher diversity decreased with each additional year (CST-1, aOR = 0.89 [95% CI: 0.80–1.00]; CST-2, aOR = 0.86 [95% CI: 0.75–0.99]). There was no association between HIV status and CST at baseline or over time. CSTs representing lower RA of Lactobacillus were associated with current cigarette smoking.
Conclusions
The vaginal microbial community significantly improved over time in this cohort of women with HIV and at high risk for HIV who had regular detection and treatment referral for BV.
doi:10.1371/journal.pone.0116894
PMCID: PMC4326357  PMID: 25675346
23.  Echolucency of the Carotid Artery Intima‐Media Complex and Intima‐Media Thickness Have Different Cardiovascular Risk Factor Relationships: The Women's Interagency HIV Study 
Background
Adults infected with HIV have increased atherosclerosis potentially associated with both HIV and non‐HIV associated factors. We characterized risk factors for atherosclerosis as measured by noninvasive vascular imaging.
Methods and Results
We used B‐mode ultrasound to examine levels and correlates of echogenicity and vessel wall thickness of the carotid artery intima‐media complex in 1282 HIV‐infected and 510 HIV‐uninfected women of the Women's Interagency HIV Study. Levels of gray scale median (GSM, a measure of echogenicity) did not vary between HIV infection groups. In both groups, smokers had increased GSM, whereas age, diabetes, elevated blood pressure, and high BMI were associated with lower (rather than higher) GSM. Each of these non‐lipid CVD risk factors, especially age and blood pressure, was also associated with higher levels of carotid artery intima‐media thickness (cIMT). Higher serum triglyceride levels were associated with lower GSM in both HIV‐infected and HIV‐uninfected groups. Additional lipid risk factors for low GSM including high LDL cholesterol and low HDL cholesterol levels were identified in HIV uninfected but not in HIV infected women. In contrast to findings for GSM, among the lipid parameters only LDL cholesterol level had an association with cIMT, which was observed only in the HIV uninfected group.
Conclusions
Lipid and non‐lipid risk factor associations with echolucency of the carotid artery and the thickness of the common carotid artery intima‐media layer suggest that these measures capture different aspects of atherosclerosis.
doi:10.1161/JAHA.114.001405
PMCID: PMC4345869  PMID: 25699995
carotid arteries; epidemiology; immune system; risk factors; ultrasonics
24.  Cleavage/Alteration of Interleukin-8 by Matrix Metalloproteinase-9 in the Female Lower Genital Tract 
PLoS ONE  2015;10(1):e0116911.
Objective
Interleukin-8 (IL-8, CXCL8) plays important roles in immune responses at mucosal sites including in the lower genital tract. Since several types of bacteria produce proteases that cleave IL-8 and many types of bacteria can be present in lower genital tract microbiota, we assessed genital fluids for IL-8 cleavage/alteration.
Study Design
Genital fluids collected by lavage from 200 women (23 HIV-seronegative and 177 HIV-seropositive) were tested for IL-8 cleavage/alteration by ELISA.
Results
IL-8 cleaving/altering activity was observed in fluids from both HIV-positive (28%) and HIV-negative women (35%). There was no clear relationship between the activity and the types of bacteria present in the lower genital tract as determined by high-throughput sequencing of the 16S rRNA gene. Protease inhibitors specific for matrix metalloproteinases (MMPs) reduced the activity and a multiplex assay that detects both inactive and active MMPs showed the presence of multiple MMPs, including MMP-1, -3, -7, -8, -9, -10 and -12 in genital secretions from many of the women. The IL-8-cleaving/altering activity significantly correlated with active MMP-9 as well as with cleavage of a substrate that is acted on by several active MMPs.
Conclusions
These studies show that multiple MMPs are present in the genital tract of women and strongly suggest that MMP-9 in genital secretions can cleave IL-8 at this mucosal site. These studies suggest that MMP-mediated cleavage of IL-8 can modulate inflammatory responses in the lower genital tract.
doi:10.1371/journal.pone.0116911
PMCID: PMC4303271  PMID: 25611319
25.  Common Clinical Conditions – Age, Low BMI, Ritonavir Use, Mild Renal Impairment - Affect Tenofovir Pharmacokinetics in a Large Cohort of HIV-Infected Women 
AIDS (London, England)  2014;28(1):59-66.
Objective
Tenofovir is used commonly in HIV treatment and prevention settings, but factors that correlate with tenofovir exposure in real-world setting are unknown.
Design
Intensive pharmacokinetic (PK) studies of tenofovir in a large, diverse cohort of HIV-infected women over 24-hours at steady-state were performed and factors that influenced exposure (assessed by areas-under-the-time-concentration curves, AUCs) identified
Methods
HIV-infected women (n=101) on tenofovir-based therapy underwent intensive 24-hour PK sampling. Data on race/ethnicity, age, exogenous steroid use, menstrual cycle phase, concomitant medications, recreational drugs and/or tobacco, hepatic and renal function, weight and body mass index (BMI) were collected. Multivariable models using forward stepwise selection identified factors associated with effects on AUC. Glomerular filtration rates (GFR) prior to starting tenofovir were estimated by the CKD-EPI equation using both creatinine and cystatin-C measures
Results
The median (range) of tenofovir AUCs was 3350 (1031–13,911) ng x h/mL. Higher AUCs were associated with concomitant ritonavir use (1.33-fold increase, p 0.002), increasing age (1.21-fold increase per decade, p=0.0007) and decreasing BMI (1.04-fold increase per 10% decrease in BMI). When GFR was calculated using cystatin-C measures, mild renal insufficiency prior to tenofovir initiation was associated with higher subsequent exposure (1.35-fold increase when pre-tenofovir GFR <70mL/min, p=0.0075).
Conclusions
Concomitant ritonavir use, increasing age, decreasing BMI and lower GFR prior to tenofovir initiation as estimated by cystatin C were all associated with elevated tenofovir exposure in a diverse cohort of HIV-infected women. Clinicians treating HIV-infected women should be aware of common clinical conditions that affect tenofovir exposure when prescribing this medication.
doi:10.1097/QAD.0000000000000033
PMCID: PMC3956315  PMID: 24275255
Tenofovir; pharmacokinetics; HIV-infected women; diverse populations; GFR; cystatin C

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