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1.  Evaluation of a Newly Developed Tobacco Cessation Program for People with Disabilities 
Disability and health journal  2015;9(1):145-149.
Tobacco use is the single most preventable cause of morbidity and mortality, accounting for at least 480,000 deaths in the United States annually. People with disabilities smoke at a rate 1.5 times greater than the able-bodied population. Higher incidence of tobacco use among people with disabilities has been directly related to both unique and universal cessation barriers. Despite increased prevalence of tobacco use and cessation obstacles, evidence is lacking on the development of successful interventions targeting people with disabilities.
We aimed to assess the feasibility, acceptability, and potential effectiveness of a cessation intervention tailored to people with disabilities.
Eighteen tobacco users with disabilities (56% African American, 64% male) participated in a 4-week, 8-session tobacco cessation program consisting of group sessions on managing addiction, relapse, and lifestyle changes specific to people with disabilities. Semi-structured interviews were conducted at the conclusion of the program. A follow-up measure of smoking status, triggers, and nicotine replacement therapy usage was completed at 4 weeks and 6 months.
Sixteen participants completed the intervention (89%), with participants on average attending 86% of sessions. Most participants rated the program as excellent (83%) or good (8%). Qualitative interviews revealed participants value social support, accessibility, and a tailored program. Four participants (22%) reported abstinence at six months, which is greater than the standard quit rate.
This study suggests tailoring a cessation program to the characteristics unique to people with disabilities may be critical in delivering meaningful and effective cessation interventions among this population.
PMCID: PMC4688053  PMID: 26365086
Tobacco Cessation; Disability; CBPR; Intervention
2.  Gender-related risk factors improve mortality predictive ability of VACS Index among HIV-infected women 
Adding gender-related modifiable characteristics or behaviors to the Veterans Aging Cohort Study (VACS) Index might improve the accuracy of predicting mortality among HIV-infected women on treatment. We evaluated the VACS Index in women with HIV, determined whether additional variables would improve mortality prediction, and quantified the potential for improved survival associated with reduction in these additional risk factors.
The VACS Index (based on age, CD4 count, HIV-1 RNA, hemoglobin, AST, ALT, platelets, creatinine and Hepatitis C status) was validated in HIV-infected women in the Women’s Interagency HIV Study (WIHS) who initiated antiretroviral therapy (ART) between January 1996 and December 2007. Models were constructed adding race, depression, abuse, smoking, substance use, transactional sex, and comorbidities to determine whether predictability improved. Population attributable fractions were calculated.
The VACS Index accurately predicted 5-year mortality in 1057 WIHS women with 1 year on HAART with c-index 0.83 (95% CI 0.79–0.87). In multivariate analysis, the VACS Index score (adjusted hazard ratio [aHR] for 5-point increment 1.30; 95% CI 1.25–1.35), depressive symptoms (aHR 1.73; 95% CI 1.17–2.56) and history of transactional sex (aHR 1.93; 95% CI 1.33–1.82) were independent statistically significant predictors of mortality.
Including depression and transactional sex significantly improved the performance of the VACS Index in predicting mortality among HIV-infected women. Providing treatment for depression and addressing economic and psychosocial instability in HIV infected women would improve health and perhaps point to a broader public health approach to reducing HIV mortality.
PMCID: PMC4644433  PMID: 26284531
HIV; Women; Mortality; Depression; Transactional Sex
3.  Clinical Implications of Family-Centered Care in Stroke Rehabilitation 
Background and Purpose
Most stroke survivors will be cared for at home by family caregivers with limited training. Families actively involved in rehabilitation feel more prepared for the new responsibilities of caring for the stroke survivor. The focus of this article is to highlight the relevant concepts of a family-centered model of care and provide general guidance on how integrating a family-centered mindset may be clinically applicable.
Family-Centered Care
Family-centered care is a model of healthcare that encourages collaboration and partnership among patients, families, and providers with respect to the planning, delivery, and evaluation of health care. Care provided within such a model can expand providers’ knowledge of the impact of illness and any issues that may affect eventual transition back home.
Clinical Relevance and Conclusion
Rehabilitation nurses should view stroke patients and family caregivers as a unit. Using family-centered strategies can help nurses provide appropriate, individualized care during rehabilitation.
PMCID: PMC4544639  PMID: 25648522
stroke family caregiver; family-centered care
4.  CCR5 Expression Levels in HIV-Uninfected Women Receiving Hormonal Contraception 
The Journal of Infectious Diseases  2015;212(9):1397-1401.
Human immunodeficiency virus (HIV) infectivity increases as receptor/coreceptor expression levels increase. We determined peripheral CD4, CCR5, and CXCR4 expression levels in HIV-uninfected women who used depot medroxyprogesterone acetate (DMPA; n = 32), the levonorgestrel-releasing intrauterine device (LNG-IUD; n = 27), oral contraceptive pills (n = 32), or no hormonal contraception (n = 33). The use of LNG-IUD increased the proportion of CD4+ and CD8+ T cells that expressed CCR5; increases in the magnitude of T-cell subset CCR5 expression were observed with DMPA and LNG-IUD use (P < .01 for all comparisons). LNG-IUD and, to a lesser extent, DMPA use were associated with increased peripheral T-cell CCR5 expression.
PMCID: PMC4601918  PMID: 25895986
HIV-1; hormonal contraception; CCR5; medroxyprogesterone acetate; levonorgestrel; oral contraceptive pills; peripheral blood mononuclear cells; CD4; CXCR4
5.  Increased fracture incidence in middle-aged HIV-infected and uninfected women: updated results from the Women’s Interagency HIV Study 
We previously reported that fracture incidence rates did not differ by HIV status among predominantly premenopausal Women's Interagency HIV Study (WIHS) participants. We now conduct a follow-up study with 5 additional observation years, to further characterize fracture risk associated with HIV infection in women as they age.
We measured time to first new fracture at any site in 2375 (1713 HIV-infected, 662 HIV-uninfected) WIHS participants, with median 10 years follow-up. Fractures were self-reported semiannually. Proportional Hazards models assessed predictors of incident fracture.
At index visit, HIV-infected women were older (median age 40 yrs (IQR 34–46) vs. 35 (27–43), p<0.0001) and more likely to be postmenopausal, HCV-infected, and weigh less than HIV-uninfected women. Among HIV-infected women, mean CD4+ count was 480 cells/µL and 63% were taking HAART. Unadjusted incidence rates of any fracture were higher in HIV-infected than uninfected women (2.19/100 person-years (py) vs 1.54/100py, p=0.002). In multivariate models, HIV status, older age, white (vs. black) race, prior fracture, history of cocaine use, and history of injection drug use were significant predictors of incident fracture. Among HIV-infected women, age, white race, prior fracture, smoking, and prior AIDS were predictors of new fracture.
Middle-aged HIV-infected women had a higher adjusted fracture rate than uninfected women. Cocaine use and injection drug use were also associated with a greater risk of incident fracture. Further research is needed to understand whether the risk of fracture associated with cocaine use relates to increased rate of falls, or direct effects on bone metabolism.
PMCID: PMC4557627  PMID: 26322667
HIV; women; bone; fracture; fragility fracture
6.  HIV Infection Is Associated With Progression of Subclinical Carotid Atherosclerosis 
Human immunodeficiency virus (HIV) infection was associated with greater increases in focal carotid artery plaque over 7 years among both women and men, particularly among those with lower CD4+ counts. Increased plaque was observed even among HIV-infected individuals with persistent virologic suppression.
Background. Individuals infected with human immunodeficiency virus (HIV) live longer as a result of effective treatment, but long-term consequences of infection, treatment, and immunological dysfunction are poorly understood.
Methods. We prospectively examined 1011 women (74% HIV-infected) in the Women's Interagency HIV Study and 811 men (65% HIV-infected) in the Multicenter AIDS Cohort Study who underwent repeated B-mode carotid artery ultrasound imaging in 2004–2013. Outcomes included changes in right common carotid artery intima-media thickness (CCA-IMT) and new focal carotid artery plaque formation (IMT >1.5 mm) over median 7 years. We assessed the association between HIV serostatus and progression of subclinical atherosclerosis, adjusting for demographic, behavioral, and cardiometabolic risk factors.
Results. Unadjusted mean CCA-IMT increased (725 to 752 µm in women, 757 to 790 µm in men), but CCA-IMT progression did not differ by HIV serostatus, either in combined or sex-specific analyses. Focal plaque prevalence increased from 8% to 15% in women and 25% to 34% in men over 7 years. HIV-infected individuals had 1.6-fold greater risk of new plaque formation compared with HIV-uninfected individuals (relative risk [RR] 1.61, 95% CI, 1.12–2.32), adjusting for cardiometabolic factors; the association was similar by sex. Increased plaque occurred even among persistently virologically suppressed HIV-infected individuals compared with uninfected individuals (RR 1.56, 95% CI, 1.07–2.27). HIV-infected individuals with baseline CD4+ ≥500 cells/µL had plaque risk not statistically different from uninfected individuals.
Conclusions. HIV infection is associated with greater increases in focal plaque among women and men, potentially mediated by factors associated with immunodeficiency or HIV replication at levels below current limits of detection.
PMCID: PMC4607734  PMID: 25904369
HIV infection; cardiovascular disease; atherosclerosis; intima-media thickness; viral load
7.  Human Immunodeficiency Virus (HIV) modulates the associations between insulin resistance and cognition in the current combination antiretroviral therapy (cART) era: A study of the Women’s Interagency HIV Study (WIHS) 
Journal of neurovirology  2015;21(4):415-421.
Cognitive impairment (CI) remains common despite access to cART; it has been linked to HIV-specific, HIV-related and HIV-unrelated factors. Insulin resistance (IR) was associated with CI in the early cART era, when antiretroviral medications had greater mitochondrial and metabolic toxicity. We sought to examine these relationships in the current cART era of reduced antiretroviral toxicities. This study examined IR among non-diabetics in relation to a one-hour neuropsychological test battery among 994 women (659 HIV-infected and 335 HIV-uninfected controls) assessed between 2009 and 2011. The mean (Standard Deviation, SD) age of the sample was 45.1 (9.3) years. The HIV-infected sample had a median interquartile range (IQR) Cluster of Differentiation 4 (CD4) T-lymphocyte count of 502 (310-727) cells/μL and 54% had undetectable plasma HIV RNA levels. Among all, the Homeostasis Model Assessment (HOMA) of IR ranged from 0.25 to 37.14. In adjusted models, increasing HOMA was significantly associated with reduced performance on Letter Number Sequencing (LNS) attention task (β=-0.10, p<0.01) and on Hopkins Verbal Learning Test (HVLT) recognition (β=-0.10, p<0.01) with weaker but statistically significant associations on phonemic fluency (β=-0.09, p=0.01). An HIV*HOMA interaction effect was identified on the LNS attention task and Stroop trials 1 and 2, with worse performance in HIV-infected vs. HIV-uninfected women. In separate analyses, cohort members who had diabetes mellitus (DM) performed worse on the grooved pegboard test of psychomotor speed and manual dexterity. These findings confirm associations between both IR and DM on some neuropsychological tests and identify an interaction between HIV status and IR.
PMCID: PMC4511712  PMID: 25740539
HIV; Insulin Resistance; Dementia; Cognition; cART
8.  A comprehensive assessment of family caregivers of stroke survivors during inpatient rehabilitation 
Disability and rehabilitation  2014;36(22):1892-1902.
PMCID: PMC4959419  PMID: 24467676
stroke caregivers; caregiver assessment; stroke rehabilitation
9.  Mixed-method Exploration of Social Network Links to Participation 
The people who regularly interact with an adolescent form that youth's social network, which may impact participation. We investigated the relationship of social networks to participation using personal network analysis and individual interviews. The sample included 36 youth, age 11 – 16 years. Nineteen had diagnoses of learning disability, attention disorder, or high-functioning autism and 17 were typically developing. Network analysis yielded 10 network variables, of which 8 measured network composition and 2 measured network structure, with significant links to at least one measure of participation using the Children's Assessment of Participation and Enjoyment (CAPE). Interviews from youth in the clinical group yielded description of strategies used to negotiate social interactions, as well as processes and reasoning used to remain engaged within social networks. Findings contribute to understanding the ways social networks are linked to youth participation and suggest the potential of social network factors for predicting rehabilitation outcomes.
PMCID: PMC4659346  PMID: 26594737
personal network analysis; adolescence; community participation; environment; qualitative research
10.  APOL1 Genotype and Glomerular and Tubular Kidney Injury in Women With HIV 
APOL1 genotype is associated with advanced kidney disease in African-Americans, but the pathogenic mechanisms are unclear. Here, associations of APOL1 genotype with urine biomarkers of glomerular and tubular injury, and with kidney function decline, were evaluated.
Study Design
Observational study.
Setting & Participants
431 HIV-infected African-American women enrolled in Women's Interagency HIV Study (WIHS).
APOL1 genotype.
Albumin-creatinine ratio (ACR), four tubular injury biomarkers (interleukin 18 [IL-18], kidney injury molecule 1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL], and α1-microglobulin [α1m]), and kidney function estimated using the CKD-EPI cystatin C equation.
Participants were genotyped for APOL1 single-nucleotide polymorphisms rs73885319 (G1 allele) and rs71785313 (G2 allele). Urine biomarker levels were measured using stored samples from 1999-2000. Cystatin C was measured using serum collected at baseline and 4- and 8-year follow-up.
At baseline, ACR levels were higher among 47 women with 2 APOL1 risk alleles versus 384 women with 0/1 risk allele (median, 24 vs. 11 mg/g; p < 0.001). Compared to women with 0/1 risk allele, women with 2 risk alleles had 104% higher ACR (95% CI, 29-223 mg/g) and 2-fold greater risk of ACR > 30 mg/g (95% CI, 1.17-3.44) after multivariable adjustment. APOL1 genotype showed little association with urine IL-18:Cr, KIM-1:Cr, and NGAL:Cr (estimates of -5% [95% CI, -24% to 18%], -20% [95% CI, -36% to 1%], and 10% [95% CI, -26% to 64%], respectively), or detectable urine α1m (prevalence ratio, 1.13; 95% CI, 0.65-1.97) in adjusted analyses. Compared to women with 0/1 allele, women with 2 risk alleles had faster eGFR decline, by 1.2 (95% CI, -2.2 to -0.2) ml/min/1.73 m2 per year, and had 1.7- and 3.4-fold greater rates of incident chronic kidney disease (95% CI, 1.1-2.5) and 10% annual eGFR decline (95% CI, 1.7-6.7), respectively, with minimal attenuation after adjustment for glomerular and tubular injury biomarkers.
Results may not be generalizable to men.
Among HIV-infected African-American women, APOL1-associated kidney injury appears to localize to the glomerulus, rather than the tubules.
PMCID: PMC4615696  PMID: 25921719
APOL1 genotype; risk variant; risk allele; G1 allele; G2 allele; single-nucleotide polymorphism (SNP); albumin-creatinine ratio (ACR); proteinuria; tubular injury biomarker; apolipoprotein L1; kidney disease; renal function; glomerular injury; African American; Women's Interagency HIV Study (WIHS)
11.  Post-traumatic stress is associated with verbal learning, memory, and psychomotor speed in HIV-infected and HIV-uninfected women 
Journal of neurovirology  2015;22(2):159-169.
The prevalence of post-traumatic stress disorder (PTSD) is higher among HIV-infected (HIV+) women compared with HIV-uninfected (HIV−) women, and deficits in episodic memory are a common feature of both PTSD and HIV infection. We investigated the association between a probable PTSD diagnosis using the PTSD Checklist-Civilian (PCL-C) version and verbal learning and memory using the Hopkins Verbal Learning Test in 1004 HIV+ and 496 at-risk HIV− women. HIV infection was not associated with a probable PTSD diagnosis (17 % HIV+, 16 % HIV−; p=0.49) but was associated with lower verbal learning (p<0.01) and memory scores (p<0.01). Irrespective of HIV status, a probable PTSD diagnosis was associated with poorer performance in verbal learning (p<0.01) and memory (p<0.01) and psychomotor speed (p<0.001). The particular pattern of cognitive correlates of probable PTSD varied depending on exposure to sexual abuse and/or violence, with exposure to either being associated with a greater number of cognitive domains and a worse cognitive profile. A statistical interaction between HIV serostatus and PTSD was observed on the fine motor skills domain (p= 0.03). Among women with probable PTSD, HIV− women performed worse than HIV+ women on fine motor skills (p=0.01), but among women without probable PTSD, there was no significant difference in performance between the groups (p= 0.59). These findings underscore the importance of considering mental health factors as correlates to cognitive deficits in women with HIV.
PMCID: PMC4783199  PMID: 26404435
HIV; Post-traumatic stress disorder; Women; Cognition
12.  Women want Pre-Exposure Prophylaxis but are Advised Against it by Their HIV-positive Counterparts 
The latest advancement in HIV prevention, Pre-Exposure Prophylaxis (PrEP), could reduce incidence among women. However, PrEP uptake has remained low among US women since its approval in 2012, while use has increased among men who have sex with men. This study addresses women’s knowledge, attitudes and potential behaviors regarding PrEP. While HIV-negative women are the potential users of antiretroviral (ARV) medications for PrEP, HIV-positive women who have used ARVs could contribute immensely to our understanding of the complexities related to taking such medications. This study is the first to synthesize the opinions of both groups of women.
We conducted eight focus group discussions, segregated by sero-status; four with at-risk HIV-negative (20) and four with HIV-positive (19) women in Washington DC during 2014. Topics discussed include PrEP awareness, likelihood of use, barriers and target populations.
PrEP awareness was almost non-existent and the HIV-negative women urged publicity. They expressed much enthusiasm about PrEP and wanted to use and recommend it to others despite recognizing potential complexities related to taking PrEP, such as side effects, access, duration and frequency of use. HIV-positive women were less supportive of PrEP for those same reasons based on their experience with taking ARVs. They preferred condoms over PrEP given relative efficacy, affordability, accessibility, and prevention of other STIs.
There is an urgent need for PrEP public health campaigns catered to the needs and concerns of women, most importantly bolster their awareness of PrEP.
PMCID: PMC4807623  PMID: 27019765
Pre-exposure prophylaxis; HIV; Prevention; Women; United States
13.  Systemic Cytokine Levels Do Not Predict CD4+ T-Cell Recovery After Suppressive Combination Antiretroviral Therapy in Chronic Human Immunodeficiency Virus Infection 
Open Forum Infectious Diseases  2016;3(1):ofw025.
Background. Subjects on suppressive combination antiretroviral therapy (cART) who do not achieve robust reconstitution of CD4+ T cells face higher risk of complications and death. We studied participants in the Women's Interagency HIV Study with good (immunological responder [IR]) or poor (immunological nonresponder [INR]) CD4+ T-cell recovery after suppressive cART (n = 50 per group) to determine whether cytokine levels or low-level viral load correlated with INR status.
Methods. A baseline sample prior to viral control and 2 subsequent samples 1 and 2 years after viral control were tested. Serum levels of 30 cytokines were measured at each time point, and low-level human immunodeficiency virus (HIV) viral load and anti-HIV antibody levels were measured 2 years after viral suppression.
Results. There were minimal differences in cytokine levels between IR and INR subjects. At baseline, macrophage inflammatory protein-3β levels were higher in IR subjects; after 1 year of suppressive cART, soluble vascular endothelial growth factor-R3 levels were higher in IR subjects; and after 2 years of suppressive cART, interferon gamma-induced protein 10 levels were higher in INR subjects. Very low-level HIV viral load and anti-HIV antibody levels did not differ between IR and INR subjects.
Conclusions. These results imply that targeting residual viral replication might not be the optimum therapeutic approach for INR subjects.
PMCID: PMC4782066  PMID: 26966697
CD4+ T cells; chemokines; cytokines; cART; HIV
14.  Connecting patients, researchers and clinical genetics services: the experiences of participants in the Australian Ovarian Cancer Study (AOCS) 
Population-based genetic research may produce information that has clinical implications for participants and their family. Researchers notify participants or their next of kin (NoK) about the availability of genetic information via a notification letter; however, many subsequently do not contact a family cancer centre (FCC) to clarify their genetic status. Therefore, the purpose of this study was to examine research participants' experience of receiving a notification letter and the factors that influenced contact with an FCC. Twenty-five semi-structured interviews were conducted with research participants (n=10) or their NoK (n=15) who had received a notification letter following participation in the Australian Ovarian Cancer Study. There were a number of factors which impacted participants' access to genetic counselling at an FCC. Some participants had unmet information and support needs, which were addressed by their participation in this psychosocial interview study. Recruitment and participation in this study therefore inadvertently increased a number of participants' intention to contact an FCC. For others, participation in this study facilitated access to an FCC. Recommendations are proposed regarding future notification as well as implications for clinical practice. An approach that also provides opportunity to address research participants' support and informational needs before contacting a clinical genetics service as well as practical guidance for accessing genetic services would facilitate timely and smooth access for research participants who are interested in following up clinically relevant genetic test results.
PMCID: PMC4297914  PMID: 24824132
15.  Cognitive function in women with HIV 
Neurology  2015;84(3):231-240.
In the largest cohort study of neuropsychological outcomes among HIV-infected women to date, we examined the association between HIV status and cognition in relation to other determinants of cognitive function (aim 1) and the pattern and magnitude of impairment across cognitive outcomes (aim 2).
From 2009 to 2011, 1,521 (1,019 HIV-infected) participants from the Women's Interagency HIV Study (WIHS) completed a comprehensive neuropsychological test battery. We used multivariable regression on raw test scores for the first aim and normative regression-based analyses (t scores) for the second aim. The design was cross-sectional.
The effect sizes for HIV status on cognition were very small, accounting for only 0.05 to 0.09 SD units. The effect of HIV status was smaller than that of years of education, age, race, income, and reading level. In adjusted analyses, HIV-infected women performed worse than uninfected women on verbal learning, delayed recall and recognition, and psychomotor speed and attention. The largest deficit was observed in delayed memory. The association of low reading level with cognition was greater in HIV-infected compared to HIV-uninfected women. HIV biomarkers (CD4 count, history of AIDS-defining illness, viral load) were associated with cognitive dysfunction.
The effect of HIV on cognition in women is very small except among women with low reading level or HIV-related comorbidities. Direct comparisons of rates of impairment in well-matched groups of HIV-infected men and women are needed to evaluate possible sex differences in cognition.
PMCID: PMC4335997  PMID: 25540304
16.  Improving HIV Surveillance Data for Public Health Action in Washington, DC: A Novel Multiorganizational Data-Sharing Method 
The National HIV/AIDS Strategy calls for active surveillance programs for human immunodeficiency virus (HIV) to more accurately measure access to and retention in care across the HIV care continuum for persons living with HIV within their jurisdictions and to identify persons who may need public health services. However, traditional public health surveillance methods face substantial technological and privacy-related barriers to data sharing.
This study developed a novel data-sharing approach to improve the timeliness and quality of HIV surveillance data in three jurisdictions where persons may often travel across the borders of the District of Columbia, Maryland, and Virginia.
A deterministic algorithm of approximately 1000 lines was developed, including a person-matching system with Enhanced HIV/AIDS Reporting System (eHARS) variables. Person matching was defined in categories (from strongest to weakest): exact, very high, high, medium high, medium, medium low, low, and very low. The algorithm was verified using conventional component testing methods, manual code inspection, and comprehensive output file examination. Results were validated by jurisdictions using internal review processes.
Of 161,343 uploaded eHARS records from District of Columbia (N=49,326), Maryland (N=66,200), and Virginia (N=45,817), a total of 21,472 persons were matched across jurisdictions over various strengths in a matching process totaling 21 minutes and 58 seconds in the privacy device, leaving 139,871 uniquely identified with only one jurisdiction. No records matched as medium low or low. Over 80% of the matches were identified as either exact or very high matches. Three separate validation methods were conducted for this study, and they all found ≥90% accuracy between records matched by this novel method and traditional matching methods.
This study illustrated a novel data-sharing approach that may facilitate timelier and better quality HIV surveillance data for public health action by reducing the effort needed for traditional person-matching reviews without compromising matching accuracy. Future analyses will examine the generalizability of these findings to other applications.
PMCID: PMC4869245  PMID: 27227157
HIV; surveillance; data sharing; public health; technology
17.  Timing and context: important considerations in the return of genetic results to research participants 
Journal of Community Genetics  2015;7(1):11-20.
General consensus exists that clinically significant germline genetic research results should be fed back to research participants. A body of literature is emerging about Australian research participants’ experiences of feedback of genetic research results and factors that influence a participant’s actions after receiving such information. This exploratory qualitative study conducted interviews with 11 participants from the International Sarcoma Kindred Study, four probands and seven of their relatives. They had been informed by letter of the availability of clinically significant germline TP53 mutations identified through research. We examined the participants’ views about the feedback of these genetic test results. Thematic (inductive) analysis was used to analyse the data. A number of factors influenced participants’ responses following notification. This included participants’ understanding of the notification letter and their perception of the relevance of the information for them and/or their family. Most notably, timing of the letter in the context of an individual’s current life experiences was important. Timing and context are novel factors identified that may impact on research participants’ understanding or their ability to access clinically significant research results. We outline strategies for disseminating results to research participants and their next of kin that may reduce their uncertainty around the receipt of research results.
PMCID: PMC4715816  PMID: 26004130
Results disclosure; Feedback; Genetics; Sarcoma; Li-Fraumeni; Research results
18.  Risk of Breast Cancer with CXCR4-using HIV Defined by V3-Loop Sequencing  
Evaluate the risk of female breast cancer associated with HIV-CXCR4 (X4) tropism as determined by various genotypic measures.
A breast cancer case-control study, with pairwise comparisons of tropism determination methods, was conducted. From the Women's Interagency HIV Study repository, one stored plasma specimen was selected from 25 HIV-infected cases near the breast cancer diagnosis date and 75 HIV-infected control women matched for age and calendar date. HIVgp120-V3 sequences were derived by Sanger population sequencing (PS) and 454-pyro deep sequencing (DS). Sequencing-based HIV-X4 tropism was defined using the geno2pheno algorithm, with both high-stringency DS [False-Positive-Rate (FPR 3.5) and 2% X4 cutoff], and lower stringency DS (FPR 5.75, 15% X4 cut-off). Concordance of tropism results by PS, DS, and previously performed phenotyping was assessed with kappa (κ) statistics. Case-control comparisons used exact P-values and conditional logistic regression.
In 74 women (19 cases, 55 controls) with complete results, prevalence of HIV-X4 by PS was 5% in cases vs 29% in controls (P=0.06, odds ratio 0.14, confidence interval 0.003-1.03). Smaller case-control prevalence differences were found with high-stringency DS (21% vs 36%, P=0.32), lower-stringency DS (16% vs 35%, P=0.18), and phenotyping (11% vs 31%, P=0.10). HIV-X4-tropism concordance was best between PS and lower-stringency DS (93%, κ=0.83). Other pairwise concordances were 82%-92% (κ=0.56-0.81). Concordance was similar among cases and controls.
HIV-X4 defined by population sequencing (PS) had good agreement with lower stringency deep sequencing and was significantly associated with lower odds of breast cancer.
PMCID: PMC4262599  PMID: 25321183
Chemokine receptors; HIV; AIDS; breast cancer; parallel sequencing; women
19.  Trajectory analyses of virologic outcomes reflecting community-based HIV treatment in Washington DC 1994–2012 
BMC Public Health  2015;15:1277.
Effective treatment of HIV since 1996 has reduced morbidity and mortality through virologic suppression. Combination antiretroviral therapy (cART) has been recognized as key to the prevention of drug resistance and the transmission of infection. We used eighteen years of virologic outcomes in a long-standing cohort of women to describe longitudinal viral load trajectories; and examine factors associated with sustained viremia and mortality.
We analyzed data from DC WIHS women with > four semiannual visits using a group-based logistic trajectory analysis approach to identify patterns of HIV RNA detection (>80 copies/mL or lower assay limit, and >1000 copies/mL). We verified findings using cumulative viral load suppression-years, explored group characteristics using generalized linear modeling with generalized estimating equations for repeated measures, and examined survival using the Kaplan-Meier and Cox proportional hazard analyses.
329 women contributed 6633 visits between 1994 and 2012 and demonstrated high, moderate, and low probability patterns of HIV RNA detection (>80 copies/mL) in 40.7, 35.6, and 23.7 % of participant visits, respectively. Analysis of cumulative years of viral load suppression supported these observations. Kaplan-Meier survival analysis demonstrated high mortality of 31.1 % with sustained viremia, but no significant difference in mortality between intermittent viremia and non-viremia patterns, 6.9 and 4.9 % respectively. Mortality was associated with higher age, lower CD4+ T lymphocyte count, and sustained viremia by Cox multivariate analysis.
This ecologic study demonstrates the effectiveness of viral suppression, and conversely the association between viremia and mortality. In community delivery of cART for HIV care, distinct patterns of sustained viremia, intermittent viremia, and non-viremia were identified over nearly 18 years in the DC WIHS, capturing the dynamics and complexity of sustaining long-term HIV care. Persistent viremia was associated with lower CD4s and mortality, but surprisingly mortality was not different between continuous suppression and intermittent viremia. Classification of long-term virologic patterns such as these observed HIV treatment “careers” may provide a suitable framework to identify modifiable factors associated with treatment resilience and failure. Both individual and population interventions are needed to reduce transmission, prevent the emergence of drug resistance, and improve outcomes of community ART programs.
PMCID: PMC4688953  PMID: 26695971
HIV; Viral suppression; Trajectory analysis; HIV treatment career
20.  Long-term cumulative detection of human papillomavirus among HIV seropositive women 
AIDS (London, England)  2014;28(17):2601-2608.
To estimate the effects of infection by human immunodeficiency virus (HIV) on the type-specific cumulative detection of cervicovaginal infection by human papillomavirus (HPV).
Retrospective assessment of prospectively collected data in a multicenter U.S. cohort.
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.
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.
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.
PMCID: PMC4289460  PMID: 25188771
Human papillomavirus; HIV in women; immunodeficiency
21.  Association of Chronic Hepatitis C Infection with T-Cell Phenotypes in HIV-Negative and HIV-Positive Women 
Hepatitis C virus (HCV) viremia is thought to have broad, systemic effects on the cellular immune system that go beyond its impact on just those T-cells that are HCV-specific. However, prior studies of chronic HCV and circulating T-cell subsets (activation and differentiation phenotypes) in HIV-negatives used general population controls, rather than a risk-appropriate comparison group. Studies in HIV-positives did not address overall immune status (total CD4+ count).
We used fresh blood from HIV-positive and at-risk HIV-negative women, with and without chronic HCV, to measure percentages of activated CD4+ and CD8+ T-cells, Tregs, and T-cell differentiation phenotypes (naïve, central memory (CM), effector memory (EM), and terminally differentiated effector). This included 158 HIV-negatives and 464 HIV-positives, of whom 18 and 63, respectively, were HCV viremic.
In multivariate models of HIV-negatives, HCV viremia was associated with 25% fewer naïve CD4+ (P=0.03), 33% more EM CD4+ (P=0.0002) and 37% fewer CM CD8+ (P=0.02) T-cells. Among HIV-positives we observed only one of these three relationships: higher percentage of EM CD4+ among HCV viremic women. Further, the association with EM CD4+ among HIV-positives was limited to individuals with diminished immune status (total CD4+ count ≤500 cells/μL), as were associations of HCV viremia with higher percentages of activated CD4+ and Tregs. Among HIV-positives with high CD4+ count, no significant associations were observed.
These data suggest that HCV viremia in HIV-negatives is associated with accelerated T-cell differentiation, but among HIV-positives the impact of HCV viremia is less straightforward and varies by total CD4+ count.
PMCID: PMC4197408  PMID: 25314250
hepatitis C virus; HIV; T-cell; phenotype; activation; differentiation
22.  T-cell Activation, Both Pre- and Post-HAART Levels, Correlates with Carotid Artery Stiffness over 6.5 years among HIV-infected Women in the WIHS 
T-cell activation is a major pathway driving HIV disease progression. Little is known regarding the impact of T-cell activation on HIV-associated atherosclerosis and cardiovascular disease, a common co-morbidity in HIV infection. We hypothesized that T-cell activation will predict vascular stiffness, a measure of subclinical atherosclerosis.
Linear regression models evaluated the covariate-adjusted association of T-cell activation with vascular stiffness.
CD38 and HLA-DR expression on CD4+ and CD8+ T-cells was assessed by flow cytometry among 59 HIV-negative and 376 HIV-infected (185 hepatitis-C co-infected) women in the Women's Interagency HIV Study (WIHS). T-cell activation was defined by CD8+CD38+DR+ and CD4+CD38+DR+. Multiple activation assessments over 6.5 years were averaged. In 140 women, T-cell activation was measured before and after HAART initiation. Carotid artery ultrasounds were completed a median of 6.5 years after last measurement of T- cell activation and carotid artery stiffness including distensibility and elasticity were calculated.
Percentages of CD4+ and CD8+ T-cell activation were significantly higher in HIV- infected compared to HIV-negative women. Among HIV-negative women, T-cell activation was not associated with carotid artery stiffness. Among HIV-infected women, higher CD4+ T-cell activation significantly predicted increased arterial stiffness independent of CD4 cell count and HIV RNA. The association was stronger among HIV/HCV co-infected compared to HIV-mono- infected women; however, the difference was not statistically significant (p-for interaction>0.05). Pre- and post-HAART levels of CD4+ T-cell activation significantly predicted carotid artery stiffness.
Persistent T-cell activation, even after HAART initiation, can contribute to structural and/or functional vascular damage accelerating atherogenesis in HIV infection. These results need to be confirmed in a longitudinal prospective study.
PMCID: PMC4197806  PMID: 25314253
T-cell activation; arterial stiffness; HIV-infection
23.  Systemic Cytokine and Interferon Responsiveness Patterns in HIV and HCV Mono and Co-Infections 
The role of host response-related factors in the fast progression of liver disease in individuals co-infected with HIV and HCV viruses remains poorly understood. This study compared patterns of cytokines, caspase-1 activation, endotoxin exposure in plasma as well as interferon signaling in peripheral blood mononuclear cells from HIV/HCV co-infected (HIV+/HCV+), HCV mono-infected (HIV−/HCV+), HIV mono-infected (HIV+/HCV−) female patients and HIV- and HCV-uninfected women (HIV−/HCV−) who had enrolled in the Women's Interagency HIV Study (WIHS). HIV+/HCV+ women had higher plasma levels of pro-inflammatory cytokines as well as caspase-1 compared with other groups. Both HIV+/HCV+ and HIV+/HCV− women had significantly higher sCD14 levels compared with other groups. Peripheral blood mononuclear cells from HCV mono-infected patients had reduced levels of phosphorylation of STAT1 compared with other groups as well as lower basal levels of expression of the IFN-stimulated genes, OAS1, ISG15, and USP18 (UBP43). Basal expression of USP18, a functional antagonist of ISG15, as well as USP18/ISG15 ratios were increased in the HIV+/HCV+ group compared with HIV−/HCV+ and HIV+/HCV− groups. A more pronounced systemic inflammatory profile as well as increased expression ratios of USP18 to ISG15 may contribute to the more rapid progression of liver disease in HIV+/HCV+ individuals.
PMCID: PMC4217006  PMID: 24955730
24.  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.
PMCID: PMC4562210  PMID: 25791344
HIV; Verbal memory; Stress; Women; Cognition
25.  An investigation of menopausal stage and symptoms on cognition in HIV-infected women 
Menopause (New York, N.Y.)  2014;21(9):997-1006.
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.
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.
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.
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.
PMCID: PMC4119867  PMID: 24496085
HIV; Verbal Learning; Menopause; Mood; Anxiety; African American

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