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AIDS Care  2011;24(3):394-403.
Depression is common in people with cardiovascular diseases (CVD) and those with HIV, and is a risk factor for CVD-related mortality. However, little is known about whether HIV influences the relationship between depression and cardiovascular risk. 526 HIV-infected and 132 uninfected women from the Women’s Interagency HIV Study were included in an analysis of women who completed twice-yearly study visits over 9.5 years. CVD risk was calculated at baseline and approximately 9.5 years later using the Framingham Risk Score (FRS). Chronic depressive symptoms were defined as Center for Epidemiologic Studies Depression Scale scores of 16 or greater at ≥75% of study visits. Over the follow-up period, 22.8% of HIV-infected women and 15.9% of HIV-uninfected women had chronic depressive symptoms (p=0.08). Baseline FRS were similar between HIV infected and uninfected women (M=−5.70±SE=0.30 vs. M=−6.90± SE=0.60, p=0.07) as was follow-up FRS (M=0.82±SE=0.30 vs. M=−0.44± SE=0.73, p=0.11). Among HIV-infected and uninfected women, together, follow-up FRS were higher among women with chronic depressive symptoms as compared to those without (M=1.3± SE=0.6 vs. M=−0.3± SE=0.40, p<0.01), after adjusting for baseline FRS and other covariates. HIV status did not modify the relationship between chronic depressive symptoms and FRS. Chronic depressive symptoms accelerated CVD risk scores to a similar extent in both HIV infected and uninfected women. This implies that the diagnosis and treatment of depression may be an important consideration in CV risk reduction in the setting of HIV-infection. The determination of factors that mediate the depression/CVD relationship merits further study.
PMCID: PMC3243818  PMID: 21902560
2.  Associations of cardiovascular variables and HAART with cognition in middle-aged HIV-infected and uninfected women 
Journal of neurovirology  2011;17(5):469-476.
Despite use of HAART, cognitive impairment remains prevalent in HIV. Indeed, a recent study suggested that in certain instances, stopping HAART was associated with improved cognitive function (Robertson et al. 2010). HAART is occasionally associated with cardiovascular pathology and such pathology may be associated with cognitive impairment. To explore these associations, we assessed the relative contributions of cardiovascular variables such as hypertension and atherosclerosis, of HIV and HAART to cognition. Participants were members of the Women’s Interagency HIV Study (WIHS). In analysis of cross-sectional data using general linear models we assessed the relationship between each cardiovascular variable and Stroop interference time and symbol digit modalities test while adjusting for age, HIV, education, depression, and race/ethnicity. We also analyzed the association of summary measures of HAART use with cognition. In multivariate models significance was limited to carotid lesions and carotid intima-medial thickness quintile (CIMT) with Stroop interference time (for carotid lesions, coefficient = 10.5, CI: 3.5 to 17.5, p = 0.003, N = 1130; for CIMT quintile, coefficient = 8.6, CI = 1.7 to 15.4, p = 0.025, N = 1130). Summary measures of protease inhibitor use and other HAART measures were in most cases not associated with cognitive score in multivariate models. We conclude that in the HAART era among middle-aged women with HIV, carotid disease may be significantly associated with some measures of cognitive impairment. In this cross-sectional study, we could detect neither positive nor negative effects of HAART on cognition.
PMCID: PMC3509940  PMID: 22006469
Cognition; HIV; Women; Hypertension; Atherosclerosis; Middle-Aged
3.  The Association of HIV Status with Bacterial Vaginosis and Vitamin D in the United States 
Journal of Women's Health  2011;20(10):1497-1503.
To estimate the association between vitamin D deficiency and bacterial vaginosis (BV) among nonpregnant HIV-infected and uninfected women.
In a substudy of the Women's Interagency HIV Study, including women from Chicago and New York, the association between BV and vitamin D deficiency, demographics, and disease characteristics was tested using generalized estimating equations. Deficiency was defined as <20 ng/mL 25 (OH) vitamin D and insufficiency as >20 and ≤30 ng/mL. BV was defined by the Amsel criteria.
Among 602 observations of nonpregnant women (480 HIV infected and 122 uninfected), BV was found in 19%. Vitamin D deficiency was found in 59.4%, and insufficiency was found in 24.4%. In multivariable analysis, black race was the most significant predictor of BV (adjusted odds ratio [AOR] 5.90, (95% confidence interval [CI] 2.52-13.8). Vitamin D deficiency was independently associated with BV among HIV-infected women (AOR 3.12, 95% CI 1.16-8.38) but not among HIV-uninfected women. There was a negative linear correlation between vitamin D concentration and prevalence of BV in HIV-infected women (r=−0.15, p=0.001).
Vitamin D deficiency was very common in this cohort and significantly associated with BV among HIV-infected women. These preliminary findings suggest that further epidemiologic and mechanistic exploration of the relationship between vitamin D and BV in HIV-infected women is warranted.
PMCID: PMC3233211  PMID: 21875343
4.  The effect of HIV infection and HAART on inflammatory biomarkers in a population-based cohort of US women 
AIDS (London, England)  2011;25(15):1823-1832.
HIV causes inflammation that can be at least partially corrected by HAART. To determine the qualitative and quantitative nature of cytokine perturbation, we compared cytokine patterns in three HIV clinical groups including HAART responders (HAART), untreated HIV non-controllers (NC), and HIV-uninfected (NEG).
Multiplex assays were used to measure 32 cytokines in a cross-sectional study of participants in the Women's Interagency HIV Study (WIHS). Participants from 3 groups were included: HAART (n=17), NC (n=14), and HIV NEG (n=17).
Several cytokines and chemokines showed significant differences between NC and NEG participants, including elevated IP-10 and TNF-α and decreased IL-12(p40), IL-15, and FGF-2 in NC participants. Biomarker levels among HAART women more closely resembled the NEG, with the exception of TNF-α and FGF-2. Secondary analyses of the combined HAART and NC groups revealed that IP-10 showed a strong, positive correlation with viral load and negative correlation with CD4+ T cell counts. The growth factors VEGF, EGF, and FGF-2 all showed a positive correlation with increased CD4+ T cell counts.
Untreated, progressive HIV infection was associated with decreased serum levels of cytokines important in T cell homeostasis (IL-15) and T cell phenotype determination (IL-12), and increased levels of innate inflammatory mediators such as IP-10 and TNF-α. HAART was associated with cytokine profiles that more closely resembled those of HIV uninfected women. The distinctive pattern of cytokine levels in the 3 study groups may provide insights into HIV pathogenesis, and responses to therapy.
PMCID: PMC3314300  PMID: 21572306
HIV; CD4+ T cells; cytokines; chemokines; HAART
5.  Improvement in Posttraumatic Stress Disorder in Postconflict Rwandan Women 
Journal of Women's Health  2011;20(9):1325-1332.
Depression and posttraumatic stress disorder (PTSD) are common in developing and postconflict countries. The purpose of this study is to examine longitudinal changes in PTSD in HIV-infected and uninfected Rwandan women who experienced the 1994 genocide.
Five hundred thirty-five HIV-positive and 163 HIV-negative Rwandan women in an observational cohort study were followed for 18 months. Data on PTSD symptoms were collected longitudinally by the Harvard Trauma Questionnaire (HTQ) and analyzed in relationship to demographics, HIV status, antiretroviral treatment (ART), and depression. PTSD was defined as a score on the HTQ of ≥2.
There was a continuing reduction in HTQ scores at each follow-up visit. The prevalence of PTSD symptoms changed significantly, with 61% of the cohort having PTSD at baseline vs. 24% after 18 months. Women with higher HTQ score were most likely to have improvement in PTSD symptoms (p<0.0001). Higher rate of baseline depressive symptoms (p<0.0001) was associated with less improvement in PTSD symptoms. HIV infection and ART were not found to be consistently related to PTSD improvement.
HIV care settings can become an important venue for the identification and treatment of psychiatric problems affecting women with HIV in postconflict and developing countries. Providing opportunities for women with PTSD symptoms to share their history of trauma to trained counselors and addressing depression, poverty, and ongoing violence may contribute to reducing symptoms.
PMCID: PMC3168969  PMID: 21732802
6.  The Relation of HLA Genotype to Hepatitis C Viral Load and Markers of Liver Fibrosis in HIV-Infected and HIV-Uninfected Women 
The Journal of Infectious Diseases  2011;203(12):1807-1814.
Background. Human leukocyte antigen (HLA) class I and II genotype is associated with clearance of hepatitis C virus (HCV) infection, but little is known regarding its relation with HCV viral load or risk of liver disease in patients with persistent HCV infection.
Methods. High-resolution HLA class I and II genotyping was conducted in a prospective cohort of 519 human immunodeficiency virus (HIV)–seropositive and 100 HIV-seronegative women with persistent HCV infection. The end points were baseline HCV viral load and 2 noninvasive indexes of liver disease, fibrosis-4 (FIB-4), and the aspartate aminotransferase to platelet ratio index (APRI), measured at baseline and prospectively.
Results. DQB1*0301 was associated with low baseline HCV load (β = −.4; 95% confidence interval [CI], −.6 to −.3; P < .00001), as well as with low odds of FIB-4–defined (odds ratio [OR], .5; 95% CI, .2–.9; P = .02) and APRI-defined liver fibrosis (OR, .5; 95% CI, .3–1.0; P = .06) at baseline and/or during follow-up. Most additional associations with HCV viral load also involved HLA class II alleles. Additional associations with FIB-4 and APRI primarily involved class I alleles, for example, the relation of B*1503 with APRI-defined fibrosis had an OR of 2.0 (95% CI, 1.0–3.7; P = .04).
Conclusions. HLA genotype may influence HCV viral load and risk of liver disease, including DQB1*0301, which was associated with HCV clearance in prior studies.
PMCID: PMC3100515  PMID: 21606539
7.  Atazanavir Concentration in Hair Is the Strongest Predictor of Outcomes on Antiretroviral Therapy 
In a longitudinal study of outcomes on atazanavir-based therapy in a large cohort of HIV-infected women, hair levels of atazanavir were the strongest independent predictor of virologic suppression. Hair antiretroviral concentrations may serve as a useful tool in HIV care.
Background. Adequate exposure to antiretrovirals is important to maintain durable responses, but methods to assess exposure (eg, querying adherence and single plasma drug level measurements) are limited. Hair concentrations of antiretrovirals can integrate adherence and pharmacokinetics into a single assay.
Methods. Small hair samples were collected from participants in the Women's Interagency HIV Study (WIHS), a large cohort of human immunodeficiency virus (HIV)-infected (and at-risk noninfected) women. From 2003 through 2008, we analyzed atazanavir hair concentrations longitudinally for women reporting receipt of atazanavir-based therapy. Multivariate random effects logistic regression models for repeated measures were used to estimate the association of hair drug levels with the primary outcome of virologic suppression (HIV RNA level, <80 copies/mL).
Results. 424 WIHS participants (51% African-American, 31% Hispanic) contributed 1443 person-visits to the analysis. After adjusting for age, race, treatment experience, pretreatment viral load, CD4 count and AIDS status, and self-reported adherence, hair levels were the strongest predictor of suppression. Categorized hair antiretroviral levels revealed a monotonic relationship to suppression; women with atazanavir levels in the highest quintile had odds ratios (ORs) of 59.8 (95% confidence ratio, 29.0–123.2) for virologic suppression. Hair atazanavir concentrations were even more strongly associated with resuppression of viral loads in subgroups in which there had been previous lapses in adherence (OR, 210.2 [95% CI, 46.0–961.1]), low hair levels (OR, 132.8 [95% CI, 26.5–666.0]), or detectable viremia (OR, 400.7 [95% CI, 52.3–3069.7]).
Conclusions. Antiretroviral hair levels surpassed any other predictor of virologic outcomes to HIV treatment in a large cohort. Low antiretroviral exposure in hair may trigger interventions prior to failure or herald virologic failure in settings where measurement of viral loads is unavailable. Monitoring hair antiretroviral concentrations may be useful for prolonging regimen durability.
PMCID: PMC3079399  PMID: 21507924
8.  Human Leukocyte Antigen Genotype and Risk of HIV Disease Progression before and after Initiation of Antiretroviral Therapy▿‡ 
Journal of Virology  2011;85(20):10826-10833.
While the human leukocyte antigen (HLA) genotype has been associated with the rate of HIV disease progression in untreated patients, little is known regarding these relationships in patients using highly active antiretroviral therapy (HAART). The limited data reported to date identified few HLA-HIV disease associations in patients using HAART and even occasional associations that were opposite of those found in untreated patients. We conducted high-resolution HLA class I and II genotyping in a random sample (n = 860) of HIV-seropositive women enrolled in a long-term cohort initiated in 1994. HLA-HIV disease associations before and after initiation of HAART were examined using multivariate analyses. In untreated HIV-seropositive patients, we observed many of the predicted associations, consistent with prior studies. For example, HLA-B*57 (β = −0.7; 95% confidence interval [CI] = −0.9 to −0.5; P = 5 × 10−11) and Bw4 (β = −0.2; 95% CI = −0.4 to −0.1; P = 0.009) were inversely associated with baseline HIV viral load, and B*57 was associated with a low risk of rapid CD4+ decline (odds ratio [OR] = 0.2; 95% CI = 0.1 to 0.6; P = 0.002). Conversely, in treated patients, the odds of a virological response to HAART were lower for B*57:01 (OR = 0.2; 95% CI = 0.0 to 0.9; P = 0.03), and Bw4 (OR = 0.4; 95% CI = 0.1 to 1.0; P = 0.04) was associated with low odds of an immunological response. The associations of HLA genotype with HIV disease are different and sometimes even opposite in treated and untreated patients.
PMCID: PMC3187522  PMID: 21849458
9.  The Impact of the AIDS Drug Assistance Program (ADAP) on Use of Highly Active Antiretroviral and Antihypertensive Therapy among HIV-Infected Women 
To evaluate the association between enrollment into an AIDS Drug Assistance Program (ADAP) and use of highly active antiretroviral therapy (HAART) and antihypertensive therapy.
Cross-sectional analyses of data were performed on HAART-eligible women enrolled in the California (n=439), Illinois (n=168), and New York (n=487) Women’s Interagency HIV Study (WIHS) sites. A subset of HIV-infected women with hypertension (n=395) was also analyzed. Unadjusted and adjusted backward stepwise elimination logistic regression measured the association between demographic, behavioral, and health service factors and non-use of HAART or antihypertensive medication.
In adjusted analysis of HAART non-use, women without ADAP were significantly more likely not to use HAART (odds ratio [OR] = 2.4, 95% confidence interval [CI] = 1.5–3.7) than women with ADAP. In adjusted analysis of antihypertensive medication non-use, women without ADAP had an increased but not significant odds of antihypertensive medication non-use (OR = 2.4, 95% CI = 0.93–6.0) than women with ADAP.
Government-funded programs for prescription drug coverage, such as ADAP, may play an important role in how HIV-positive women to access and use essential medications for chronic diseases.
PMCID: PMC3042745  PMID: 21239994
AIDS; antiretroviral therapy; hypertension; women; healthcare disparity; prescription insurance
Antiviral therapy  2011;16(4):591-596.
We previously reported an increased risk of all-cause and AIDS mortality among HIV-infected women with albuminuria (proteinuria or microalbuminuria) enrolled in the Women’s Interagency HIV Study (WIHS) prior to the introduction of highly active antiretroviral therapy (HAART).
The current analysis includes 1,073 WIHS participants who subsequently initiated HAART. Urinalysis for proteinuria and semi-quantitative testing for microalbuminuria from two consecutive study visits prior to HAART initiation were categorized as follows: confirmed proteinuria (both specimens positive for protein), confirmed microalbuminuria (both specimens positive with at least one microalbuminuria), unconfirmed albuminuria (one specimen positive for proteinuria or microalbuminuria), or negative (both specimens negative). Time from HAART initiation to death was modeled using proportional hazards analysis.
Compared to the reference group of women with two negative specimens, the hazard ratio (HR) for all-cause mortality was significantly elevated for women with confirmed microalbuminuria (HR 1.9; 95% CI 1.2–2.9). Confirmed microalbuminuria was also independently associated with AIDS death (HR 2.3; 95% CI 1.3–4.3), while women with confirmed proteinuria were at increased risk for non-AIDS death (HR 2.4; 95% CI 1.2–4.6).
In women initiating HAART, pre-existing microalbuminuria independently predicted increased AIDS mortality, while pre-existing proteinuria predicted increased risk of non-AIDS death. Urine testing may identify HIV-infected individuals at increased risk for mortality even after the initiation of HAART. Future studies should consider whether these widely available tests can identify individuals who would benefit from more aggressive management of HIV infection and comorbid conditions associated with mortality in this population.
PMCID: PMC3119869  PMID: 21685547
HIV; microalbuminuria; proteinuria; mortality; non-AIDS death
11.  Association of Pre-Treatment Nutritional Status with Change in CD4 Count after Antiretroviral Therapy at 6, 12, and 24 Months in Rwandan Women 
PLoS ONE  2011;6(12):e29625.
Body mass index (BMI) independently predicts mortality in studies of HIV infected patients initiating antiretroviral therapy (ART). We hypothesized that poorer nutritional status would be associated with smaller gains in CD4 count in Rwandan women initiating ART.
Methods and Findings
The Rwandan Women's Interassociation Study and Assessment, enrolled 710 ART-naïve HIV-positive and 226 HIV-negative women in 2005 with follow-up every 6 months. The outcome assessed in this study was change in CD4 count at 6, 12, and 24 months after ART initiation. Nutritional status measures taken prior to ART initiation were BMI; height adjusted fat free mass (FFMI); height adjusted fat mass (FMI), and sum of skinfold measurements. 475 women initiated ART. Mean (within 6 months) pre-ART CD4 count was 216 cells/µL. Prior to ART initiation, the mean (±SD) BMI was 21.6 (±3.78) kg/m2 (18.3% malnourished with BMI<18.5); and among women for whom the following were measured, mean FFMI was 17.10 (±1.76) kg/m2; FMI 4.7 (±3.5) kg/m2 and sum of skinfold measurements 4.9 (±2.7) cm. FFMI was significantly associated with a smaller change in CD4 count at 6 months in univariate analysis (−6.7 cells/uL per kg/m2, p  = 0.03) only. In multivariate analysis after adjustment for covariates, no nutritional variable was associated with change in CD4 count at any follow up visit.
In this cohort of African women initiating ART, no measure of malnutrition prior to ART was consistently associated with change in CD4 count at 6, 12, and 24 months of follow up, suggesting that poorer pre-treatment nutritional status does not prevent an excellent response to ART.
PMCID: PMC3247268  PMID: 22216334
12.  Adherence to Highly Active Antiretroviral Treatment in HIV-Infected Rwandan Women 
PLoS ONE  2011;6(11):e27832.
Scale-up of highly active antiretroviral treatment therapy (HAART) programs in Rwanda has been highly successful but data on adherence is limited. We examined HAART adherence in a large cohort of HIV+ Rwandan women.
The Rwanda Women's Interassociation Study Assessment (RWISA) was a prospective cohort study that assessed effectiveness and toxicity of ART. We analyzed patient data 12±3 months after HAART initiation to determine adherence rates in HIV+ women who had initiated HAART.
Of the 710 HIV+ women at baseline, 490 (87.2%) initiated HAART. Of these, 6 (1.2%) died within 12 months, 15 others (3.0%) discontinued the study and 80 others (19.0%) remained in RWISA but did not have a post-HAART initiation visit that fell within the 12±3 month time points leaving 389 subjects for analysis. Of these 389, 15 women stopped their medications without being advised to do so by their doctors. Of the remaining 374 persons who reported current HAART use 354 completed the adherence assessment. All women, 354/354, reported 100% adherence to HAART at the post-HAART visit. The high self-reported level of adherence is supported by changes in laboratory measures that are influenced by HAART. The median (interquartile range) CD4 cell count measured within 6 months prior to HAART initiation was 185 (128, 253) compared to 264 (182, 380) cells/mm3 at the post-HAART visit. Similarly, the median (interquartile range) MCV within 6 months prior to HAART initiation was 88 (83, 93) fL compared to 104 (98, 110) fL at the 12±3 month visit.
Self-reported adherence to antiretroviral treatment 12±3 months after initiating therapy was 100% in this cohort of HIV-infected Rwandan women. Future studies should explore country-specific factors that may be contributing to high levels of adherence to HAART in this population.
PMCID: PMC3219684  PMID: 22114706
13.  Evolution and Taxonomic Classification of Human Papillomavirus 16 (HPV16)-Related Variant Genomes: HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67 
PLoS ONE  2011;6(5):e20183.
Human papillomavirus 16 (HPV16) species group (alpha-9) of the Alphapapillomavirus genus contains HPV16, HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67. These HPVs account for 75% of invasive cervical cancers worldwide. Viral variants of these HPVs differ in evolutionary history and pathogenicity. Moreover, a comprehensive nomenclature system for HPV variants is lacking, limiting comparisons between studies.
DNA from cervical samples previously characterized for HPV type were obtained from multiple geographic regions to screen for novel variants. The complete 8 kb genomes of 120 variants representing the major and minor lineages of the HPV16-related alpha-9 HPV types were sequenced to capture maximum viral heterogeneity. Viral evolution was characterized by constructing phylogenic trees based on complete genomes using multiple algorithms. Maximal and viral region specific divergence was calculated by global and pairwise alignments. Variant lineages were classified and named using an alphanumeric system; the prototype genome was assigned to the A lineage for all types.
The range of genome-genome sequence heterogeneity varied from 0.6% for HPV35 to 2.2% for HPV52 and included 1.4% for HPV31, 1.1% for HPV33, 1.7% for HPV58 and 1.1% for HPV67. Nucleotide differences of approximately 1.0% - 10.0% and 0.5%–1.0% of the complete genomes were used to define variant lineages and sublineages, respectively. Each gene/region differs in sequence diversity, from most variable to least variable: noncoding region 1 (NCR1) /noncoding region 2 (NCR2) >upstream regulatory region (URR)> E6/E7 > E2/L2 > E1/L1.
These data define maximum viral genomic heterogeneity of HPV16-related alpha-9 HPV variants. The proposed nomenclature system facilitates the comparison of variants across epidemiological studies. Sequence diversity and phylogenies of this clinically important group of HPVs provides the basis for further studies of discrete viral evolution, epidemiology, pathogenesis and preventative/therapeutic interventions.
PMCID: PMC3103539  PMID: 21673791
14.  Prevalence of Kidney Disease in HIV-Infected and Uninfected Rwandan Women 
PLoS ONE  2011;6(3):e18352.
In the United States, HIV-related kidney disease disproportionately affects individuals of African descent; however, there are few estimates of kidney disease prevalence in Africa. We evaluated the prevalence of kidney disease among HIV-infected and uninfected Rwandan women.
The Rwandan Women's Interassociation Study and Assessment prospectively enrolled 936 women. Associations with estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 and proteinuria were assessed in separate logistic regression models.
Among 891 non-pregnant women with available data, 2.4% had an eGFR<60 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease equation, MDRD eGFR) and 8.7% had proteinuria ≥1+. The prevalence of decreased eGFR varied markedly depending on the estimating method used, with the highest prevalence by Cockcroft-Gault. Regardless of the method used to estimate GFR, the proportion with decreased eGFR or proteinuria did not differ significantly between HIV-infected and -uninfected women in unadjusted analysis. After adjusting for age and blood pressure, HIV infection was associated with significantly higher odds of decreased MDRD eGFR but not proteinuria.
In a well-characterized cohort of Rwandan women, HIV infection was associated with decreased MDRD eGFR. The prevalence of decreased eGFR among HIV-infected women in our study was lower than that previously reported in African-Americans and in other Central and East African HIV populations, although there was substantial variability depending on the equation used to estimate GFR. Future studies are needed to optimize GFR estimates and to determine the impact of antiretroviral therapy on kidney disease in this population.
PMCID: PMC3065469  PMID: 21464937

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