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26.  A novel denaturing heteroduplex tracking assay for genotypic prediction of HIV-1 tropism 
Journal of virological methods  2012;185(1):108-117.
Human immunodeficiency virus type 1 (HIV-1) is characterized by sequence variability. The third variable region (V3) of the HIV-1 envelope glycoprotein gp120 plays a key role in determination of viral coreceptor usage (tropism) and pathogenesis. This report describes a novel denaturing heteroduplex tracking assay (HTA) to analyze the genetic variation of HIV-1 V3 DNA. It improved upon previous non-denaturing HTA approaches to distinguish HIV-1 CCR5 and CXCR4 tropic viruses in mixed populations. The modifications included the use of a single-stranded fluorescent probe based on the consensus V3 sequence of HIV-1 CCR5 tropic viruses, Locked Nucleic Acid (LNA) “clamps” at both ends of heteroduplex DNA, and denaturing gel electrophoresis using Mutation Detection Enhancement (MDE®) as matrix. The analysis demonstrated that the LNA “clamps” increased its melting temperature (Tm) and the thermal stability of heteroduplex DNA. The partially denaturing gel used a defined concentration of formamide, and significantly induced mobility shifts of heteroduplex DNA that was dependent on the number and patterns of DNA mismatches and insertions/deletions. This new technique successfully detected tropisms of 53 HIV-1 V3 clones of known tropism, and was able to separate and detect multiple V3 DNA variants encoding tropisms for CCR5 or CXCR4 in a mixture. The assay had the sensitivity to detect 0.5% minority species. This method may be useful as a research tool for analysis of viral quasispecies and for genotypic prediction of HIV-1 tropism in clinical specimens.
doi:10.1016/j.jviromet.2012.06.013
PMCID: PMC3417067  PMID: 22728273
HIV-1 gp120 V3; denaturing heteroduplex tracking assay; Locked Nucleic Acid clamps; viral tropism
27.  Cervicovaginal HPV Infection Before and After Hysterectomy: Evidence of Different Tissue Tropism for Oncogenic and Non-Oncogenic HPV Types in a Cohort of HIV-positive and HIV-negative Women 
Human papillomavirus (HPV) is detected in nearly all cervical cancers and approximately half of vaginal cancers. However, vaginal cancer is an order of magnitude less common than cervical cancer, not only in the general population but also among women with HIV/AIDS. It is interesting therefore that recent studies found that HPV was common in both normal vaginal and cervical tissue, with higher prevalence of non-oncogenic HPV types in the vagina. In the current investigation, we prospectively examined HPV infection in 86 HIV-positive and 17 HIV-negative women who underwent hysterectomy during follow-up in a longitudinal cohort. Cervicovaginal lavage specimens were obtained semi-annually and tested for HPV DNA by PCR. To address possible selection biases associated with having a hysterectomy, subjects acted as their own comparison group – before versus after hysterectomy. The average HPV prevalence was higher in HIV-positive than HIV-negative women both before (59% versus 12%; P<0.001) and after hysterectomy (56% versus 6%; P<0.001). Multivariate random effects models (within-individual comparisons) demonstrated significantly lower HPV prevalence (odds ratio [OR]=0.71; 95% confidence interval [CI]=0.59-0.85) after hysterectomy. The association of HPV prevalence with hysterectomy was similar among HIV-positive and HIV-negative women. However, hysterectomy had greater effects on oncogenic (OR=0.48; 95%CI=0.35-0.66) than non-oncogenic HPV types (OR=0.89; 95%CI=0.71-1.11; Pinteraction=0.002). Overall, we observed greater reductions in oncogenic than non-oncogenic HPV prevalence following hysterectomy. If correct, these data could suggest that oncogenic HPV have greater tropism for cervical compared with vaginal epithelium, consistent with the lower incidence of vaginal than cervical cancer.
doi:10.1002/ijc.27363
PMCID: PMC3321069  PMID: 22120980
vaginal; HPV; hysterectomy; viral tropism; HIV
28.  Interleukin 10 Responses Are Associated With Sustained CD4 T-Cell Counts in Treated HIV Infection 
The Journal of Infectious Diseases  2012;206(5):780-789.
Background.Inflammation persists in treated human immunodeficiency virus (HIV) infection and may contribute to an increased risk for non–AIDS-related pathologies. We investigated the correlation of cytokine responses with changes in CD4 T-cell levels and coinfection with hepatitis C virus (HCV) during highly active antiretroviral treatment (HAART).
Methods.A total of 383 participants in the Women's Interagency HIV Study (212 with HIV monoinfection, 56 with HCV monoinfection, and 115 with HIV/HCV coinfection) were studied. HIV-infected women had <1000 HIV RNA copies/mL, 99.7% had >200 CD4 T cells/μL; 98% were receiving HAART at baseline. Changes in CD4 T-cell count between baseline and 2–4 years later were calculated. Peripheral blood mononuclear cells (PBMCs) obtained at baseline were used to measure interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 12 (IL-12), and tumor necrosis factor α (TNF-α) responses to Toll-like receptor (TLR) 3 and TLR4 stimulation.
Results.Undetectable HIV RNA (<80 copies/mL) at baseline and secretion of IL-10 by PBMCs were positively associated with gains in CD4 T-cell counts at follow-up. Inflammatory cytokines (IL-1β, IL-6, IL-12, and TNF-α) were also produced in TLR-stimulated cultures, but only IL-10 was significantly associated with sustained increases in CD4 T-cell levels. This association was significant only in women with HIV monoinfection, indicating that HCV coinfection is an important factor limiting gains in CD4 T-cell counts, possibly by contributing to unbalanced persistent inflammation.
Conclusions.Secreted IL-10 from PBMCs may balance the inflammatory environment of HIV, resulting in CD4 T-cell stability.
doi:10.1093/infdis/jis380
PMCID: PMC3491747  PMID: 22693231
29.  Evolution and Taxonomic Classification of Alphapapillomavirus 7 Complete Genomes: HPV18, HPV39, HPV45, HPV59, HPV68 and HPV70 
PLoS ONE  2013;8(8):e72565.
Background
The species Alphapapillomavirus 7 (alpha-7) contains human papillomavirus genotypes that account for 15% of invasive cervical cancers and are disproportionately associated with adenocarcinoma of the cervix. Complete genome analyses enable identification and nomenclature of variant lineages and sublineages.
Methods
The URR/E6 region was sequenced to screen for novel variants of HPV18, 39, 45, 59, 68, 70, 85 and 97 from 1147 cervical samples obtained from multiple geographic regions that had previously been shown to contain an alpha-7 HPV isolate. To study viral heterogeneity, the complete 8 kb genome of 128 isolates, including 109 sequenced for this analysis, were annotated and analyzed. Viral evolution was characterized by constructing phylogenic trees using maximum-likelihood and Bayesian algorithms. Global and pairwise alignments were used to calculate total and ORF/region nucleotide differences; lineages and sublineages were assigned using an alphanumeric system. The prototype genome was assigned to the A lineage or A1 sublineage.
Results
The genomic diversity of alpha-7 HPV types ranged from 1.1% to 6.7% nucleotide sequence differences; the extent of genome-genome pairwise intratype heterogeneity was 1.1% for HPV39, 1.3% for HPV59, 1.5% for HPV45, 1.6% for HPV70, 2.1% for HPV18, and 6.7% for HPV68. ME180 (previously a subtype of HPV68) was designated as the representative genome for HPV68 sublineage C1. Each ORF/region differed 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.
Conclusions
These data provide estimates of the maximum viral genomic heterogeneity of alpha-7 HPV type variants. The proposed taxonomic system facilitates the comparison of variants across epidemiological and molecular studies. Sequence diversity, geographic distribution and phylogenetic topology of this clinically important group of HPVs suggest an independent evolutionary history for each type.
doi:10.1371/journal.pone.0072565
PMCID: PMC3745470  PMID: 23977318
30.  Detectability and reproducibility of plasma levels of chemokines and soluble receptors☆ 
Results in Immunology  2013;3:79-84.
Background: Multiplex assays are available to measure an array of circulating chemokines, soluble cytokine receptors and growth factors. However, there is limited information regarding whether these analytes are suitable for large-scale epidemiological studies to assess their relationships with chronic diseases, including cancer.
Methods: We examined detectability, assay repeatability, and 3-year within-subject reproducibility of plasma levels of 25 chemokines and 11 soluble receptors of cytokines and growth factors selected from the Human Millipore Panels. Plasma samples were obtained from 36 men (average age 62 years) and 17 women (average age 32 years) who participated in two epidemiological studies. Inter-assay and within-subject reproducibility were assessed by intraclass correlation coefficients (ICC).
Results: All analytes, except lymphotactin (47% detectability), were detectable in >90% of plasma samples. Inter-assay reproducibility for all analytes in 36 men tested three times on separate days were good to excellent (ICCs: 0.71–1.00). Within-subject reproducibility in 17 women sampled three times in three years were excellent (ICC ≥ 0.75) for five chemokines (eotaxin, fractalkine, 6Ckine, eotaxin 3, and SDF-1α+β) and three soluble receptors (sIL-1R2, sIL-4R and sVEGFR2); ICCs were fair to good (0.4 ≤ ICC < 0.75) for 15 chemokines and eight soluble receptors. However, five chemokines (GRO, IP-10, MIP-1β, BCA-1, and MIP-3α) had ICC < 0.4, suggesting biological variability.
Conclusion: Multiplex assays for plasma levels of selected chemokines and soluble receptors showed good to excellent assay detectability and repeatability. Most analytes also had good 3-year within-subject reproducibility, indicating that a single measurement of these analytes may be used to assess biomarker-disease associations.
doi:10.1016/j.rinim.2013.07.001
PMCID: PMC3908322  PMID: 24600562
Chemokines; Soluble receptors; Within-subject variability; Biomarker; Limit of detection
31.  Potential cardiovascular disease risk markers among HIV-infected women initiating antiretroviral treatment 
Background
Inflammation and hemostasis perturbation may be involved in vascular complications of HIV infection. We examined atherogenic biomarkers and subclinical atherosclerosis in HIV-infected adults before and after beginning highly-active antiretroviral therapy (HAART).
Methods
In the Women's Interagency HIV Study (WIHS), 127 HIV-infected women studied pre- and post-HAART were matched to HIV-uninfected controls. Six semi-annual measurements of soluble CD14, tumor necrosis factor (TNF)-alpha, soluble interleukin (IL)-2 receptor, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, D-dimer, and fibrinogen were obtained. Carotid artery intima-media thickness (CIMT) was measured by B-mode ultrasound.
Results
Relative to HIV-uninfected controls, HAART-naïve HIV-infected women had elevated levels of soluble CD14 (1945 vs 1662 ng/mL, Wilcoxon signed rank P<0.0001), TNF-alpha (6.3 vs 3.4 pg/mL, P<0.0001), soluble IL-2 receptor (1587 vs 949 pg/mL, P<0.0001), IL-10 (3.3 vs 1.9 pg/mL, P<0.0001), MCP-1 (190 vs 163 pg/mL, P<0.0001) and D-dimer (0.43 vs 0.31 µg/mL, P<0.01). Elevated biomarker levels declined after HAART. While most biomarkers normalized to HIV-uninfected levels, in women on effective HAART, TNF-alpha levels remained elevated compared to HIV-uninfected women (+0.8 pg/mL, P=0.0002). Higher post-HAART levels of soluble IL-2 receptor (P=0.02), IL-6 (P=0.05), and D-dimer (P=0.03) were associated with increased CIMT.
Conclusions
Untreated HIV infection is associated with abnormal hemostasis (e.g., D-dimer), and pro-atherogenic (e.g., TNF-alpha) and anti-atherogenic (e.g., IL-10) inflammatory markers. HAART reduces most inflammatory mediators to HIV-uninfected levels. Increased inflammation and hemostasis are associated with subclinical atherosclerosis in recently treated women. These findings have potential implications for long-term risk of cardiovascular disease in HIV-infected patients, even with effective therapy.
doi:10.1097/QAI.0b013e31825b03be
PMCID: PMC3400505  PMID: 22592585
antiretroviral therapy; cardiovascular diseases; cytokines; hemostasis; HIV; inflammation
32.  Circulating Vitamin D Correlates with Serum Anti-Mullerian Hormone Levels in Late Reproductive-Aged Women: Women’s Interagency HIV Study 
Fertility and Sterility  2012;98(1):228-234.
Objective
To study the correlation between circulating 25 hydroxy-vitamin D (25OH-D) levels and serum AMH in women enrolled in the Women’s Interagency HIV Study (WIHS).
Design
A cross-sectional study.
Setting
WIHS, a multicenter prospective study.
Patient(s)
All premenopausal women (n=388) with regular menstrual cycles were included and subdivided into three groups: group 1 with age <35 (N=128), group 2 with age 35 to 39 (N=119), and group 3 with age ≥ 40 (N=141).
Intervention(s)
Serum for 25OH-D, AMH, fasting glucose and insulin, and creatinine levels.
Main Outcome Measure(s)
Correlation between 25OH-D and AMH before and after adjusting for HIV status, BMI, race, smoking, illicit drug use, glucose and insulin levels, estimated glomerular filtration rate and geographic site of participation.
Result(s)
After adjusting for all covariates, the regression slope in all participants for total 25OH-D predicting log10AMH for 25-year-olds (youngest participant) was −0.001 (SE=0.008, p=0.847); and for 45-year-olds (oldest participant), the corresponding slope was +0.011 (SE=0.005, p=0.021). Fasting insulin level was negatively correlated with serum AMH (p=0.016). The regression slope for the correlation between 25OH-D and AMH in group 1 was +0.002 (SE=0.006, p=0.764); in group 2 was +0.006 (SE=0.005, p=0.269); and in group 3 was +0.011 (SE=0.005, p=0.022). There was no association between HIV and AMH.
Conclusion(s)
A novel relationship is reported between circulating 25OH-D and AMH in women aged = 40 suggesting that 25OH-D deficiency might be associated with lower ovarian reserve in late reproductive-aged women.
doi:10.1016/j.fertnstert.2012.03.029
PMCID: PMC3389125  PMID: 22494925
Vitamin D; anti-mullerian hormonem mullerian inhibiting substance; HIV; ovarian reserve; insulin resistance; obesity
33.  Insulin Resistance and Cognition Among HIV-Infected and HIV-Uninfected Adult Women: The Women's Interagency HIV Study 
Abstract
Cognitive impairment remains prevalent in the era of combination antiretroviral therapy (cART) and may be partially due to comorbidities. We postulated that insulin resistance (IR) is negatively associated with cognitive performance. We completed a cross-sectional analysis among 1547 (1201 HIV+) women enrolled in the Women's Interagency HIV Study (WIHS). We evaluated the association of IR with cognitive measures among all WIHS women with concurrent fasting bloods and cognitive testing [Trails A, Trails B, and Symbol Digit Modalities Test (SDMT)] using multiple linear regression models. A smaller subgroup also completed the Stroop test (n=1036). IR was estimated using the Homeostasis Model Assessment (HOMA). Higher HOMA was associated with poorer performance on the SDMT, Stroop Color-Naming (SCN) trial, and Stroop interference trial, but remained statistically significant only for the SCN in models adjusting for important factors [β=3.78 s (95% CI: 0.48–7.08), p=0.025, for highest vs. lowest quartile of HOMA]. HIV status did not appear to substantially impact the relationship of HOMA with SCN. There was a small but statistically significant association of HOMA and reduced neuropsychological performance on the SCN test in this cohort of women.
doi:10.1089/aid.2011.0159
PMCID: PMC3332367  PMID: 21878059
34.  Hepatitis C Viremia Is Associated with Cytomegalovirus IgG Antibody Levels in HIV-Infected Women 
PLoS ONE  2013;8(4):e61973.
Background
Individuals with HIV infection exhibit high cytomegalovirus (CMV) IgG levels, but there are few data regarding the association of hepatitis C virus (HCV) with the immune response against CMV.
Methods
Associations of HCV with CMV seropositivity and CMV IgG levels were studied in 635 HIV-infected women, 187 of whom were HCV-seropositive, with adjustment in multivariable models for age, race/ethnicity, and HIV disease characteristics. Eighty one percent of the women reported receipt of highly active antiretroviral therapy (HAART) prior to or at CMV testing.
Results
In adjusted models women with chronic HCV had higher CMV IgG levels than those without HCV RNA (β = 2.86, 95% CI:0.89 – 4.83; P = 0.004). The association of HCV RNA with CMV IgG differed by age (Pinteraction = 0.0007), with a strong association observed among women in the low and middle age tertiles (≤45.3 years of age; β = 6.21, 95% CI:3.30 – 9.11, P<0.0001) but not among women in the high age tertile. CMV IgG levels were not associated with non-invasive measures of liver disease, APRI and FIB-4, or with HCV RNA level and adjustment for Epstein-Barr virus (EBV) IgG levels did not affect the association between HCV and CMV.
Conclusions
CMV IgG levels are higher in HCV/HIV co-infected women than in HIV mono-infected women. Further research on the association of HCV with CMV IgG is indicated because prior studies have found CMV IgG to be associated with morbidity and mortality in the general population and subclinical carotid artery disease in HIV-infected patients.
doi:10.1371/journal.pone.0061973
PMCID: PMC3629158  PMID: 23613990
35.  CHRONIC DEPRESSIVE SYMPTOMS AND FRAMINGHAM CORONARY RISK IN HIV- INFECTED AND UNINFECTED WOMEN 
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.
doi:10.1080/09540121.2011.608791
PMCID: PMC3243818  PMID: 21902560
36.  Marginal Structural Models for Case-Cohort Study Designs to Estimate the Association of Antiretroviral Therapy Initiation With Incident AIDS or Death 
American Journal of Epidemiology  2012;175(5):381-390.
To estimate the association of antiretroviral therapy initiation with incident acquired immunodeficiency syndrome (AIDS) or death while accounting for time-varying confounding in a cost-efficient manner, the authors combined a case-cohort study design with inverse probability-weighted estimation of a marginal structural Cox proportional hazards model. A total of 950 adults who were positive for human immunodeficiency virus type 1 were followed in 2 US cohort studies between 1995 and 2007. In the full cohort, 211 AIDS cases or deaths occurred during 4,456 person-years. In an illustrative 20% random subcohort of 190 participants, 41 AIDS cases or deaths occurred during 861 person-years. Accounting for measured confounders and determinants of dropout by inverse probability weighting, the full cohort hazard ratio was 0.41 (95% confidence interval: 0.26, 0.65) and the case-cohort hazard ratio was 0.47 (95% confidence interval: 0.26, 0.83). Standard multivariable-adjusted hazard ratios were closer to the null, regardless of study design. The precision lost with the case-cohort design was modest given the cost savings. Results from Monte Carlo simulations demonstrated that the proposed approach yields approximately unbiased estimates of the hazard ratio with appropriate confidence interval coverage. Marginal structural model analysis of case-cohort study designs provides a cost-efficient design coupled with an accurate analytic method for research settings in which there is time-varying confounding.
doi:10.1093/aje/kwr346
PMCID: PMC3282878  PMID: 22302074
acquired immunodeficiency syndrome; case-cohort studies; cohort studies; confounding bias; HIV; pharmacoepidemiology; selection bias
37.  Effects of hepatitis C and HIV on cognition in women: Data from the Women’s Interagency HIV Study 
Objective
To compare neuropsychological scores in women infected with HIV, women infected with both HIV and hepatitis C, and uninfected subjects.
Background
Some, but not all, studies have demonstrated that dual infection with HCV and HIV has worse effects on cognition than infection with HIV alone.
Design/Methods
The Women’s Interagency HIV Study (WIHS) is an ongoing prospective study of the natural history of HIV in women where participants are reevaluated every 6 months. In a cross-sectional analysis, we evaluated the effects of active HIV and HCV-infections on scores on symbol-digit test (SDMT), the Stroop interference test, and trails A and B after controlling for age, ethnicity, education, depression, liver disease, and current or past substance abuse.
Results
Data were available for 1338 women – 17.8 % had detectable hepatitis C virus and 67% were HIV-seropositive. In fully adjusted general linear models, HCV viremia was not associated with scores on any of the cognitive tests.
Conclusion
In this large sample of women, active HCV infection was not associated with scores on a small battery of neuropsychological tests.
doi:10.1097/QAI.0b013e318240566b
PMCID: PMC3319079  PMID: 22107817
Hepatitis C; HIV; neurocognition; women
38.  Risk of Cervical Pre-Cancer and Cancer Among HIV-Infected Women With Normal Cervical Cytology and No Evidence of Oncogenic HPV Infection 
Context
U.S. cervical cancer screening guidelines for HIV-uninfected women 30 years of age and older have recently been revised, increasing the suggested interval between Pap tests from three years to five years among those with normal cervical cytology (the Pap test) who test negative for oncogenic human papillomavirus (HPV). Whether a three-year or five-year screening interval might be used in HIV-infected women who are cytologically normal and oncogenic HPV-negative is unknown.
Objective
To determine the risk of cervical pre-cancer or cancer defined cytologically (high-grade squamous intraepithelial lesions or greater [HSIL+]) or histologically (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), as two separate endpoints, in HIV-infected women and HIV-uninfected women who at baseline had a normal Pap test and were negative for oncogenic HPV.
Design, Setting and Participants
Participants included 420 HIV-infected women and 279 HIV-uninfected women with normal cervical cytology at their enrollment in a multi-institutional cohort, between October 1, 2001 and September 30, 2002, with follow-up through April 30, 2011. Clinical sites were in the Bronx, Brooklyn, Chicago, Los Angeles, San Francisco, and Washington, DC. Semi-annual visits included Pap testing and, if indicated, cervical biopsy. Cervicovaginal lavage specimens from enrollment were tested for HPV DNA using PCR. The primary analysis was truncated at five years of follow-up.
Main Outcome Measure
The five-year cumulative incidence of cervical pre-cancer and cancer.
Results
No oncogenic HPV was detected in 369 (88%; 95% CI, 84%-91%) of the HIV-infected women and 255 (91%; 95% CI, 88%-94%) of the HIV-uninfected women with normal cervical cytology at enrollment. Among these oncogenic HPV-negative women two cases of HSIL+ were observed; an HIV-uninfected woman and an HIV-infected woman with a CD4 cell count of 500/μL or greater. Histologic data were obtained from four of the six sites. There were six cases of CIN-2+ in N=145 HIV-uninfected women (cumulative incidence = 5% [95% CI, 1%-8%]) and nine cases in N=219 HIV-infected women (cumulative incidence = 5% [95% CI, 2%-8%]). This included one case of CIN-2+ in N=44 oncogenic HPV-negative HIV-infected women with CD4 cell counts less than 350/μL (cumulative incidence = 2% [95% CI, 0%-7%]), one case in N=47 women with CD4 cell counts of 350 to 499/μL (cumulative incidence = 2% [95% CI, 0%-7%]), and seven cases in N=128 women with CD4 cell counts of 500/μL or greater (cumulative incidence = 6% [95% CI, 2%-10%]). One HIV-infected and one HIV-uninfected woman had CIN-3, but none had cancer.
Conclusion
The five-year cumulative incidence of HSIL+ and CIN-2+ was similar in HIV-infected women and HIV-uninfected women who were cytologically normal and oncogenic HPV-negative at enrollment.
doi:10.1001/jama.2012.5664
PMCID: PMC3556987  PMID: 22820789
39.  A C17T polymorphism in the mu opiate receptor is associated with quantitative measures of drug use in African-American women 
Addiction biology  2010;17(1):181-191.
Previous studies of the association of the C17T polymorphism of the mu opiate receptor gene with substance dependence compared cases with substance dependence to controls and usually found no significant association. However, the studies were limited by small sample size - no study had more than 12 subjects with the TT genotype, a genotype that is rare in white and Asian subjects. Moreover, drug use is not dichotomous but follows a spectrum from non-use to modest, intermittent use, to use several times daily. We asked whether the Kreek-McHugh-Schluger-Kellogg (KMSK) scales for alcohol, cocaine, opiates, and tobacco that quantify substance use during the time of a subject's maximal use might be more sensitive measures than dichotomous outcomes. We administered the KMSK scales and completed C17T genotyping on 1009 HIV-infected and 469 HIV-uninfected women in The Women's Interagency HIV Study (WIHS), an ongoing study of HIV in women. Forty-two of 697 African-American, 1 of 182 Hispanic, and none of 161 white women had the TT genotype. KMSK cocaine, alcohol, and tobacco scores were significantly higher in African-American women with the TT genotype (p =0.008, 0.0001, and 0.006 respectively) but opiate scores were not. Ordinal regression models controlling for HIV-serostatus, age, education, and income had odds ratios for the TT genotype for predicting alcohol, tobacco, cocaine, and opiates scores of 2.1 (p = 0.02), 2.4 (p = 0.0004), 2.0 (p = 0.03), and 1.9 (p = 0.07). We conclude that the TT genotype of OPRM1 may increase the risk of substance use and abuse.
doi:10.1111/j.1369-1600.2010.00265.x
PMCID: PMC3117061  PMID: 21070507
C17T polymorphism; HIV; mu opioid receptor gene; quantitative measures; substance abuse; substance dependence
40.  Differences in the Nonuse of any Contraception and Use of Specific Contraceptive Methods in HIV Positive and HIV Negative Rwandan Women 
AIDS Research and Treatment  2012;2012:367604.
Contraception can reduce the dual burden of high fertility and high HIV prevalence in sub-Sahara Africa, but significant barriers remain regarding access and use. We describe factors associated with nonuse of contraception and with use of specific contraceptive methods in HIV positive and HIV negative Rwandan women. Data from 395 HIV-positive and 76 HIV-negative women who desired no pregnancy in the previous 6 months were analyzed using univariate and multivariate logistic regression models to identify clinical and demographic characteristics that predict contraceptive use. Differences in contraceptive methods used were dependent on marital/partner status, partner's knowledge of a woman's HIV status, and age. Overall, condoms, abstinence, and hormonal methods were the most used, though differences existed by HIV status. Less than 10% of women both HIV+ and HIV− used no contraception. Important differences exist between HIV-positive and HIV-negative women with regard to contraceptive method use that should be addressed by interventions seeking to improve contraceptive prevalence.
doi:10.1155/2012/367604
PMCID: PMC3533450  PMID: 23304468
41.  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.
doi:10.1007/s13365-011-0052-3
PMCID: PMC3509940  PMID: 22006469
Cognition; HIV; Women; Hypertension; Atherosclerosis; Middle-Aged
42.  The insulin-like growth factor axis and risk of liver disease in hepatitis C virus/HIV-co-infected women 
AIDS (London, England)  2008;22(4):527-531.
Objective
Insulin-like growth factor (IGF) I stimulates the proliferation of hepatic stellate cells (HSC), the primary source of extracellular matrix accumulation in liver fibrosis. In contrast, insulin-like growth factor binding protein (IGFBP) 3, the most abundant IGFBP in circulation, negatively modulates HSC mitogenesis. To investigate the role of the IGF axis in hepatitis C virus (HCV)-related liver disease among high-risk patients, we prospectively evaluated HCV-viremic/HIV-positive women.
Design
A cohort investigation.
Methods
Total IGF-I and IGFBP-3 were measured in baseline serum specimens obtained from 472 HCV-viremic/HIV-positive subjects enrolled in the Women's Inter-agency HIV Study, a large multi-institutional cohort. The aspartate aminotransferase to platelet ratio index (APRI), a marker of liver fibrosis, was assessed annually.
Results
Normal APRI levels (< 1.0) at baseline were detected in 374 of the 472 HCV-viremic/HIV-positive subjects tested, of whom 302 had complete liver function test data and were studied. IGF-I was positively associated [adjusted odds ratio comparing the highest and lowest quartiles (AORq4–q1), 5.83; 95% confidence interval (CI) 1.17–29.1; Ptrend = 0.03], and IGFBP-3 was inversely associated (AORq4–q1, 0.13; 95% CI 0.02–0.76; Ptrend = 0.04), with subsequent (incident) detection of an elevated APRI level(> 1.5), after adjustment for the CD4 T-cell count, alcohol consumption, and other risk factors.
Conclusion
High IGF-I may be associated with increased risk and high IGFBP-3 with reduced risk of liver disease among HCV-viremic/HIV-positive women.
doi:10.1097/QAD.0b013e3282f22cdf
PMCID: PMC3507535  PMID: 18301066
aspartate aminotransferase to platelet ratio index; APRI; hepatitis C virus (HCV); HIV; IGFBP-3; IGF; liver disease
43.  Assessment of haematological parameters in HIV-infected and uninfected Rwandan women: a cross-sectional study 
BMJ Open  2012;2(6):e001600.
Objectives
Although haematological abnormalities are common manifestations of HIV infection, few studies on haematological parameters in HIV-infected persons have been undertaken in sub-Saharan Africa. The authors assessed factors associated with haematological parameters in HIV-infected antiretroviral-naïve and HIV-uninfected Rwandan women.
Study design
Cross-sectional analysis of a longitudinal cohort.
Setting
Community-based women's associations.
Participants
710 HIV-infected (HIV+) antiretroviral-naïve and 226 HIV-uninfected (HIV−) women from the Rwanda Women's Interassociation Study Assessment. Haematological parameters categorised as (abnormal vs normal) were compared by HIV status and among HIV+ women by CD4 count category using proportions. Multivariate logistic regression models using forward selection were fit.
Results
Prevalence of anaemia (haemoglobin (Hb) <12.0 g/dl) was higher in the HIV+ group (20.5% vs 6.3%; p<0.001), and increased with lower CD4 counts: ≥350 (7.6%), 200–349 (16%) and <200 cells/mm3 (32.2%). Marked anaemia (Hb <10.0 g/dl) was found in 4.2% of HIV+ and none of the HIV− women (p<0.001), and was highest in HIV+ women with CD4 <200 cells/mm3 (8.4%). The HIV+ were more likely than HIV− women (4.2 vs 0.5%, respectively, p=0.002) to have moderate neutropenia with white blood cells <2.0×103 cells/mm3 and 8.4% of HIV+ women with CD4 <200 cells/mm3 had moderate neutropenia. In multivariate logistic regression analysis, BMI (OR 0.87/kg/m2, 95% CI 0.82 to 0.93; p<0.001), CD4 200–350 vs HIV− (OR 3.59, 95% CI 1.89 to 6.83; p<0.001) and CD4 <200 cells/mm3 vs HIV− (OR 8.09, 95% CI 4.37 to 14.97; <0.001) had large independent associations with anaemia. There were large independent associations of CD4 <200 cells/mm3 vs HIV− (OR 7.18, 95% CI 0.78 to 65.82; p=0.081) and co-trimoxazole and/or dapsone use (OR 5.69, 95% CI 0.63 to 51.45; p=0.122) with moderate neutropenia.
Conclusions
Anaemia was more common than neutropenia or thrombocytopenia in the HIV-infected Rwandan women. Future comparisons of haematological parameters in HIV-infected patients before and after antiretroviral therapy initiation are warranted.
doi:10.1136/bmjopen-2012-001600
PMCID: PMC3533001  PMID: 23169875
44.  Identification and Characterization of Bacterial Vaginosis-Associated Pathogens Using a Comprehensive Cervical-Vaginal Epithelial Coculture Assay 
PLoS ONE  2012;7(11):e50106.
Bacterial vaginosis (BV) is the most commonly treated female reproductive tract affliction, characterized by the displacement of healthy lactobacilli by an overgrowth of pathogenic bacteria. BV can contribute to pathogenic inflammation, preterm birth, and susceptibility to sexually transmitted infections. As the bacteria responsible for BV pathogenicity and their interactions with host immunity are not understood, we sought to evaluate the effects of BV-associated bacteria on reproductive epithelia. Here we have characterized the interaction between BV-associated bacteria and the female reproductive tract by measuring cytokine and defensin induction in three types of FRT epithelial cells following bacterial inoculation. Four BV-associated bacteria were evaluated alongside six lactobacilli for a comparative assessment. While responses differed between epithelial cell types, our model showed good agreement with clinical BV trends. We observed a distinct cytokine and human β-defensin 2 response to BV-associated bacteria, especially Atopobium vaginae, compared to most lactobacilli. One lactobacillus species, Lactobacillus vaginalis, induced an immune response similar to that elicited by BV-associated bacteria, stimulating significantly higher levels of cytokines and human β-defensin 2 than other lactobacilli. These data provide an important prioritization of BV-associated bacteria and support further characterization of reproductive bacteria and their interactions with host epithelia. Additionally, they demonstrate the distinct immune response potentials of epithelial cells from different locations along the female reproductive tract.
doi:10.1371/journal.pone.0050106
PMCID: PMC3499514  PMID: 23166828
45.  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.
Abstract
Objective
To estimate the association between vitamin D deficiency and bacterial vaginosis (BV) among nonpregnant HIV-infected and uninfected women.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1089/jwh.2010.2685
PMCID: PMC3233211  PMID: 21875343
46.  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.
Objective
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).
Methods
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).
Results
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.
Conclusion
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.
doi:10.1097/QAD.0b013e3283489d1f
PMCID: PMC3314300  PMID: 21572306
HIV; CD4+ T cells; cytokines; chemokines; HAART
47.  Improvement in Posttraumatic Stress Disorder in Postconflict Rwandan Women 
Journal of Women's Health  2011;20(9):1325-1332.
Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1089/jwh.2010.2404
PMCID: PMC3168969  PMID: 21732802
48.  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.
doi:10.1093/infdis/jir192
PMCID: PMC3100515  PMID: 21606539
49.  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.
doi:10.1093/cid/cir131
PMCID: PMC3079399  PMID: 21507924
50.  Association of Serum Albumin with Markers of Nutritional Status among HIV-Infected and Uninfected Rwandan Women 
PLoS ONE  2012;7(4):e35079.
Introduction
The objectives of this study are to address if and how albumin can be used as an indication of malnutrition in HIV infected and uninfected Africans.
Methods
In 2005, 710 HIV-infected and 226 HIV-uninfected women enrolled in a cohort study. Clinical/demographic parameters, CD4 count, albumin, liver transaminases; anthropometric measurements and Bioelectrical Impedance Analysis (BIA) were performed. Malnutrition outcomes were defined as body mass index (BMI), Fat-free mass index (FFMI) and Fat mass index (FMI). Separate linear predictive models including albumin were fit to these outcomes in HIV negative and HIV positive women by CD4 strata (CD4>350,200–350 and <200 cells/µl).
Results
In unadjusted models for each outcome in HIV-negative and HIV positive women with CD4>350 cells/µl, serum albumin was not significantly associated with BMI, FFMI or FMI. Albumin was significantly associated with all three outcomes (p<0.05) in HIV+ women with CD4 200–350 cells/µl, and highly significant in HIV+ women with CD4<200 cells/µl (P<0.001). In multivariable linear regression, albumin remained associated with FFMI in women with CD4 count<200 cells/µl (p<0.01) but not in HIV+ women with CD4>200.
Discussion
While serum albumin is widely used to indicate nutritional status it did not consistently predict malnutrition outcomes in HIV- women or HIV+ women with higher CD4. This result suggests that albumin may measure end stage disease as well as malnutrition and should not be used as a proxy for nutritional status without further study of its association with validated measures.
doi:10.1371/journal.pone.0035079
PMCID: PMC3331977  PMID: 22532840

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