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1.  Association of HIV infection with Incident Diabetes Mellitus: Impact of using Hemoglobin A1C as a Criterion for Diabetes 
Background
Data regarding the association between HIV and DM are conflicting, with little known regarding the impact of including hemoglobin A1C (A1C) as a criterion for DM.
Methods
Pooled logistic regression was used to quantify the association between HIV and DM in 1501 HIV-infected and 550 HIV-uninfected participants from the Women’s Interagency HIV Study. Incident DM was defined using three DM definitions: (I) fasting glucose (FG) ≥126mg/dl, anti-DM medication, or reporting DM diagnosis (with confirmation by FG≥126mg/dl or anti-DM medication); (II) confirmation with a second FG≥126mg/dl; and (III) addition of A1C≥6.5% confirmed by FG≥126mg/dl or anti-DM medication.
Results
DM incidence per 100 person-years was 2.44, 1.55, and 1.70 for HIV-infected women; 1.89, 0.85, and 1.13 for HIV-uninfected women, using definition I, II, and III, respectively. After adjustment for traditional DM risk factors, HIV infection was associated with 1.23, 1.90, and 1.38-fold higher risk of incident DM, respectively; the association reached statistical significance only when confirmation with a second FG≥126mg/dl was required. Older age, obesity, and a family history of DM were each consistently and strongly associated with increased DM risk.
Conclusions
HIV infection is consistently associated with greater risk of DM. Inclusion of an elevated A1C to define DM increases the accuracy of the diagnosis and only slightly attenuates the magnitude of the association otherwise observed between HIV and DM. By contrast, a DM diagnosis made without any confirmatory criteria for FG ≥126mg/dl overestimates the incidence, while also underestimating the effects of HIV on DM risk, and should be avoided.
doi:10.1097/QAI.0b013e31826bfc32
PMCID: PMC3480977  PMID: 22878421
Diabetes mellitus; HIV; Women; Hemoglobin A1C
2.  The Effects of Opiate Use and Hepatitis C Virus Infection on Risk of Diabetes Mellitus in the Women’s Interagency HIV Study 
Background
Opiate use is common in HIV- and hepatitis C virus (HCV)-infected individuals, however its contribution to the risk of diabetes mellitus is not well understood.
Methods
Prospective study of 1,713 HIV-infected and 652 uninfected participants from the Women’s Interagency HIV Study between October 2000 and March 2006. Diabetes defined as fasting glucose ≥126 mg/dl, or self-report of diabetes medication use or confirmed diabetes diagnosis. Opiate use determined using an interviewer-administered questionnaire. Detectable plasma HCV RNA confirmed HCV infection.
Results
Current opiate users had a higher prevalence of diabetes (15%) than non-users (10%, p=.03), as well as a higher risk of incident diabetes (adjusted relative hazard [RHadj] 1.58, 95% CI 1.01, 2.46), after controlling for HCV infection, HIV/antiretroviral therapy status and diabetes risk factors including age, race/ethnicity, family history of diabetes and body mass index. HCV infection was also an independent risk factor for diabetes (RHadj 1.61, 95% CI 1.02, 2.52). HCV-infected women reporting current opiate use had the highest diabetes incidence (4.83 cases/100 person-years).
Conclusions
Among women with or at-risk for HIV, opiate use is associated with increased diabetes risk independently of HCV infection. Diabetic screening should be part of care for opiate users, and those infected with HCV.
doi:10.1097/QAI.0b013e3181d0c911
PMCID: PMC3069645  PMID: 20190642
opiate use; diabetes mellitus; fasting glucose; Hepatitis C virus; HIV; women
3.  Hormonal Contraception and Metabolic Outcomes in Women with or at Risk for HIV Infection 
Introduction
The use of hormonal contraception (HC) is increasing in HIV-infected women. Both HC and HIV infection have been associated with adverse metabolic outcomes. We investigated the association of progestin-only and combined (estrogen/progestin) HC with disorders of glucose and lipid metabolism in HIV-infected and uninfected women.
Methods
Linear mixed models evaluated the association of HC type with fasting HDL, LDL, triglycerides, the homeostasis model assessment estimate of insulin resistance (HOMA-IR), and glucose in 885 HIV-infected and 408 HIV-uninfected women from the Women's Interagency HIV Study seen between October 2000 and September 2005.
Results
Compared to non-HC users, progestin-only HC was independently associated with lower HDL (-3mg/dL;95% confidence interval[CI]:-5,-1 in HIV-infected and -6mg/dL;95% CI:-9,-3 in HIV-uninfected women), greater HOMA (+0.86;95% CI:0.51,1.22 and +0.56;95% CI:0.12,1.01). Combined HC was associated with higher HDL(+5mg/dL;95% CI:2,7 and +5mg/dL;95% CI:3,7).
Conclusion
Progestin–only HC is associated with lower HDL and greater HOMA-IR than non-HC users. Combined HC may be preferred in HIV-infected women of reproductive age at risk for cardiovascular disease, but interactions with antiretroviral therapy that may impair contraceptive efficacy have been reported. Alternative HC methods that minimize adverse outcomes but maintain efficacy require further study.
PMCID: PMC2886798  PMID: 19950431
HIV/AIDS; hormonal contraception; Depo Provera®; HDL; triglycerides
4.  Associations of HIV infection with insulin and glucose levels in antiretroviral-naïve Rwandan women: a cross-sectional analysis 
BMJ Open  2013;3(12):e003879.
Objectives
The purpose of these analyses was to determine the associations of HIV infection and related immune dysfunction with a glucose homeostasis in the population of antiretroviral-naïve HIV-infected and uninfected Rwandan women. We hypothesise that insulin resistance and its consequences in the developing countries may be further elevated with HIV infection itself regardless of antiretroviral therapy.
Study design
Cross-sectional analysis of a longitudinal cohort.
Setting
Community-based women's associations.
Participants
In 2005, 710 HIV-infected (HIV positive) antiretroviral naïve and 226 HIV-uninfected (HIV negative) women were enrolled in the Rwanda Women's Interassociation Study and Assessment (RWISA). Clinical and demographic parameters, CD4 count, fasting insulin and glucose levels, anthropometric measurements and Bioelectrical Impedance Analysis (BIA) were obtained. Linear models were fit to log-transformed Homeostasis Model Assessment (HOMA) with results exponentiated back to a multiplicative effect on the original scale.
Primary outcome measures
The outcome, insulin resistance, was measured by the HOMA, calculated as fasting insulin (μU/mL)×fasting glucose (mmol/L)⁄22.5.
Results
In adjusted models, HIV-positive women were less insulin resistant than HIV-negative; an HIV-positive woman tended to have 0.728 times as much (95% CI 0.681 to 0.861) HOMA than a comparable HIV-negative woman. Among the HIV-positive women, those with CD4 <200 cells/µL tended to have 0.741 times as much HOMA (95% CI 0.601 to 0.912) as did comparable women with CD4 >350 cells/µL. The older age was independently associated with a lower HOMA insulin resistance. After adjusting for body mass index, fat and fat-free mass were not independently associated with HOMA.
Conclusions
This study found that HIV infection and more advanced HIV infection (CD4 counts <200 cells/µL) were associated with greater insulin sensitivity in antiretroviral naïve African women. These findings provide baseline information for the interpretation of future studies on the effect of antiretroviral therapy on metabolic insulin sensitivity derangements in African population.
doi:10.1136/bmjopen-2013-003879
PMCID: PMC3855496  PMID: 24319275
Diabetes & Endocrinology; Epidemiology
5.  Cytomegalovirus Immunoglobulin G Antibody Is Associated With Subclinical Carotid Artery Disease Among HIV-Infected Women 
The Journal of Infectious Diseases  2012;205(12):1788-1796.
Background. Cytomegalovirus (CMV) infection has been implicated in immune activation and accelerated progression of immunodeficiency from human immunodeficiency virus (HIV) coinfection. We hypothesized that CMV is associated with vascular disease in HIV-infected adults.
Methods. In the Women's Interagency HIV Study, we studied 601 HIV-infected and 90 HIV-uninfected participants. We assessed the association of CMV immunoglobulin G (IgG) level with carotid artery intima-media thickness, carotid artery distensibility, Young's elastic modulus, and blood pressures. Multivariable models adjusted for age, race/ethnicity, smoking, diabetes, and body mass index.
Results. Mean CMV IgG levels were higher in HIV-infected women compared with HIV-uninfected women (P < .01). Among HIV-infected women, higher CMV IgG level was associated with decreased carotid artery distensibility (P < .01) and increased Young's modulus (P = .02). Higher CMV IgG antibody level was associated with increased prevalence of carotid artery lesions among HIV-infected women who achieved HIV suppression on antiretroviral therapy, but not among viremic or untreated HIV-infected women. Adjustment for Epstein–Barr virus antibody levels and C-reactive protein levels had no effect on the associations between CMV IgG levels and vascular parameters.
Conclusions. Cytomegalovirus antibody titers are increased in HIV-infected women and associated with subclinical cardiovascular disease. Host responses to CMV may be abnormal in HIV infection and associated with clinical disease.
doi:10.1093/infdis/jis276
PMCID: PMC3415890  PMID: 22492856
6.  A1C Underestimates Glycemia in HIV Infection 
Diabetes Care  2009;32(9):1591-1593.
OBJECTIVE
The objective of this study was to determine the relationship between A1C and glycemia in HIV infection.
RESEARCH DESIGN AND METHODS
We completed a prospective cross-sectional study of 100 HIV-infected adults with type 2 diabetes (77%) or fasting hyperglycemia (23%) with measured glucose, A1C, mean corpuscular volume (MCV), and fructosamine. A total of 200 HIV-uninfected type 2 diabetic subjects matched for key demographic characteristics served as control subjects.
RESULTS
Relative to the control subjects, A1C underestimated glucose by 29 ± 4 mg/dl in the HIV-infected subjects. Current nucleoside reverse transcriptase inhibitors (NRTIs), higher MCV and hemoglobin, and lower HIV RNA and haptoglobin were associated with greater A1C-glucose discordance. However, only MCV and current NTRI use, in particular abacavir, remained significant predictors in multivariate analyses. Fructosamine more closely reflected glycemia in the HIV-infected subjects.
CONCLUSIONS
A1C underestimates glycemia in HIV-infected patients and is related to NRTI use. Use of abacavir and increased MCV were key correlates in multivariate analyses. Fructosamine may be more appropriate in this setting.
doi:10.2337/dc09-0177
PMCID: PMC2732167  PMID: 19502538
7.  Elevated NT-pro-BNP Levels Are Associated with Comorbidities among HIV-Infected Women 
AIDS research and human retroviruses  2009;25(10):997-1004.
HIV infection is associated with left ventricular (LV) dysfunction and accelerated atherosclerosis. These conditions result in elevation of plasma natriuretic peptide (NP) levels. The present study compares N-terminal-pro-BNP (NT-pro-BNP) levels in HIV-infected and -uninfected women and identifies factors influencing NT-pro-BNP levels in HIV-infected women. A total of 454 HIV-infected and 200 HIV-uninfected participants from the Women’s Interagency HIV Study (WIHS) had NT-pro-BNP determination. Elevated NT-pro-BNP level was defined using previously determined age stratified cut-off values of >164 ng/liter (age <60 years) and >225 (age ≥60 years). HIV-infected women were older (41.6 ± 8.9 vs. 38.9 ± 10.5 years, p <0.01) and were more likely to have anemia, hepatitis C virus (HCV) antibodies, and kidney dysfunction than HIV-uninfected women. HIV-infected women had significantly higher NT-pro-BNP levels (142.4 ± 524.8 vs. 73.6 ± 115.1 ng/liter, p = 0.01) and a higher prevalence of elevated NT-pro-BNP (12.1% vs. 7.5%; p = 0.08). In univariate analyses, elevated NT-pro-BNP was significantly associated with age, systolic BP, hypertension, anemia, triglyceride levels, kidney disease, and HCV seropositivity, but not HIV infection. In multivariate analysis, elevated NT-pro-BNP levels were significantly associated with anemia and kidney function, and had a borderline association with the presence of HCV antibodies. Among HIV-infected women, NT-pro-BNP levels were not independently associated with measures of severity of infection or with HAART use. Although HIV-infected women have higher NT-pro-BNP levels than HIV-uninfected women, the differences are due to non-HIV factors such as anemia, kidney disease, and HCV coinfection. These findings suggest that natriuretic peptide levels are a global marker of comorbidity in the setting of HIV infection.
doi:10.1089/aid.2009.0038
PMCID: PMC2791362  PMID: 19803714
8.  Elevated NT-pro-BNP Levels Are Associated with Comorbidities among HIV-Infected Women 
AIDS Research and Human Retroviruses  2009;25(10):997-1004.
Abstract
HIV infection is associated with left ventricular (LV) dysfunction and accelerated atherosclerosis. These conditions result in elevation of plasma natriuretic peptide (NP) levels. The present study compares N-terminal-pro-BNP (NT-pro-BNP) levels in HIV-infected and -uninfected women and identifies factors influencingNT-pro-BNP levels in HIV-infected women. A total of 454 HIV-infected and 200 HIV-uninfected participants from the Women's Interagency HIV Study (WIHS) had NT-pro-BNP determination. Elevated NT-pro-BNP level was defined using previously determined age stratified cut-off values of >164 ng/liter (age <60 years) and >225 (age ≥ 60 years). HIV-infected women were older (41.6 ± 8.9 vs. 38.9 ± 10.5 years, p < 0.01) and were more likely to have anemia, hepatitis C virus (HCV) antibodies, and kidney dysfunction than HIV-uninfected women. HIV-infected women had significantly higher NT-pro-BNP levels (142.4 ± 524.8 vs. 73.6 ± 115.1 ng/liter, p = 0.01) and a higher prevalence of elevated NT-pro-BNP (12.1% vs. 7.5%; p = 0.08). In univariate analyses, elevated NT-pro-BNP was significantly associated with age, systolic BP, hypertension, anemia, triglyceride levels, kidney disease, and HCV seropositivity, but not HIV infection. In multivariate analysis, elevated NT-pro-BNP levels were significantly associated with anemia and kidney function, and had a borderline association with the presence of HCV antibodies. Among HIV-infected women, NT-pro-BNP levels were not independently associated with measures of severity of infection or with HAART use. Although HIV-infected women have higher NT-pro-BNP levels than HIV-uninfected women, the differences are due to non-HIV factors such as anemia, kidney disease, and HCV coinfection. These findings suggest that natriuretic peptide levels are a global marker of comorbidity in the setting of HIV infection.
doi:10.1089/aid.2009.0038
PMCID: PMC2791362  PMID: 19803714
9.  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
10.  Factors associated with hepatitis C viremia in a large cohort of HIV-infected and - uninfected women 
Background
Coinfection with hepatitis C virus (HCV) is common among HIV-infected women.
Objective
To further our understanding of the risk factors for HCV viremia and the predictors of HCV viral load among women.
Study design
We investigated sociodemographic, immunologic, and virologic factors associated with presence and level of HCV viremia among 882 HIV-infected and 167 HIV-uninfected HCV-seropositive women at entry into the Women's Interagency HIV Study.
Results
Plasma HCV RNA was detected in 852 (81%) of these 1,049 women (range: 1.2–7.8 log10 copies/ml). HCV-viremic women were more likely to have an HIV RNA level >100,000 copies/ml (P =0.0004), have reported smoking (P =0.01), or to be Black (P =0.005). They were less likely to have current or resolved hepatitis B infection. HCV RNA levels were higher in women who were >35 years old, or HIV-infected. Current smoking and history of drug use (crack/freebase cocaine, marijuana, amphetamines, or heroin) were each associated with both presence and level of viremia.
Conclusions
Substance abuse counseling aimed at eliminating ongoing use of illicit drugs and tobacco may reduce clinical progression, improve response to treatment, and decrease HCV transmission by lowering levels of HCV viremia in women.
doi:10.1016/j.jcv.2007.08.021
PMCID: PMC3493623  PMID: 18243785
Hepatitis C; Hepatitis C RNA levels; Hepatitis C viremia; HIV/hepatitis C virus coinfection
11.  Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Nondiabetic Adults 
The New England journal of medicine  2010;362(9):800-811.
Background
Fasting glucose is the standard measure used to diagnose diabetes in the United States. Recently, glycated hemoglobin was also recommended for this purpose.
Methods
We compared the prognostic value of glycated hemoglobin and fasting glucose for identifying adults at risk for diabetes or cardiovascular disease. We measured glycated hemoglobin in whole-blood samples from 11,092 black or white adults who did not have a history of diabetes or cardiovascular disease and who attended the second visit (occurring in the 1990–1992 period) of the Atherosclerosis Risk in Communities (ARIC) study.
Results
The glycated hemoglobin value at baseline was associated with newly diagnosed diabetes and cardiovascular outcomes. For glycated hemoglobin values of less than 5.0%, 5.0 to less than 5.5%, 5.5 to less than 6.0%, 6.0 to less than 6.5%, and 6.5% or greater, the multivariable-adjusted hazard ratios (with 95% confidence intervals) for diagnosed diabetes were 0.52 (0.40 to 0.69), 1.00 (reference), 1.86 (1.67 to 2.08), 4.48 (3.92 to 5.13), and 16.47 (14.22 to 19.08), respectively. For coronary heart disease, the hazard ratios were 0.96 (0.74 to 1.24), 1.00 (reference), 1.23 (1.07 to 1.41), 1.78 (1.48 to 2.15), and 1.95 (1.53 to 2.48), respectively. The hazard ratios for stroke were similar. In contrast, glycated hemoglobin and death from any cause were found to have a J-shaped association curve. All these associations remained significant after adjustment for the baseline fasting glucose level. The association between the fasting glucose levels and the risk of cardiovascular disease or death from any cause was not significant in models with adjustment for all covariates as well as glycated hemoglobin. For coronary heart disease, measures of risk discrimination showed significant improvement when glycated hemoglobin was added to models including fasting glucose.
Conclusions
In this community-based population of nondiabetic adults, glycated hemoglobin was similarly associated with a risk of diabetes and more strongly associated with risks of cardiovascular disease and death from any cause as compared with fasting glucose. These data add to the evidence supporting the use of glycated hemoglobin as a diagnostic test for diabetes.
doi:10.1056/NEJMoa0908359
PMCID: PMC2872990  PMID: 20200384
12.  Racial Differences in Glycemic Markers: A Cross-sectional Analysis of Community-Based Data 
Annals of internal medicine  2011;154(5):303-309.
Background
Although black and white differences in hemoglobin A1c (HbA1c) values are well established, recent studies suggest that the difference might not reflect differences in glycemia.
Objective
To investigate racial disparities in glycemic markers, including those that reflect biological processes independent of hemoglobin glycation and erythrocyte turnover.
Design
Cross-sectional.
Setting
Community-based.
Participants
1376 nondiabetic and 343 diabetic adults in a substudy of the Atherosclerosis Risk in Communities Study.
Measurements
Hemoglobin A1c, fasting glucose, glycated albumin, fructosamine, and 1,5-anhydroglucitol levels.
Results
In persons with and without diabetes, black persons had significantly higher values of HbA1c, glycated albumin, and fructosamine levels compared with white persons before and after adjustment for covariates and fasting glucose concentration. Serum 1,5-anhydroglucitol, which is reduced in the setting of hyperglycemia-induced glycosuria, was lower in black persons compared with white persons, although this difference was statistically significant only in nondiabetic adults.
Limitation
The design was cross-sectional, a limited number of participants with a history of diabetes were included, and the study did not include integrated measures of circulating nonfasting glycemia
Conclusion
Black and white differences in glycated albumin, fructosamine, and 1,5-anhydroglucitol parallel black and white differences in HbA1c values. Racial differences in hemoglobin glycation and erythrocyte turnover cannot explain racial disparities in these serum markers. The possibility that black persons have systematically higher levels of nonfasting glycemia deserves further study.
doi:10.1059/0003-4819-154-5-201103010-00004
PMCID: PMC3131743  PMID: 21357907
13.  Does HIV infection promote early kidney injury in women? 
Antiviral therapy  2013;19(1):79-87.
Background
In HIV-infected women, urine concentrations of novel tubulointerstitial injury markers, interleukin-18 (IL-18) and kidney injury marker-1 (KIM-1) are associated with kidney function decline and all-cause mortality. We hypothesized that HIV-infected individuals with preserved kidney filtration function would have more extensive kidney injury, as determined by urine injury markers, compared to the uninfected controls, and that risk factors for tubulointerstitial injury would differ from risk factors for albuminuria.
Methods
In this cross-sectional study, we compared urine concentrations of IL-18, KIM-1, and ACR in 908 HIV-infected and 289 HIV-uninfected women enrolled in the Women’s Interagency HIV Study, utilizing stored urine specimens from visits between 1999 and 2000.
Results
After multivariate-adjusted linear regression analysis, mean urine concentrations were higher in HIV-infected individuals by 38% for IL-18 (p<0.0001), 12% for KIM-1 (p=0.081), and 47% for ACR (p<0.0001). Higher HIV RNA level (15% per 10-fold increase, p<0.0001), lower CD4 count (8% per doubling, p=0.0025), HCV infection (30%, p=0.00018), and lower HDL (5% per 10 mg/dL, p=0.0024) were each associated with higher IL-18 concentrations. In contrast, hypertension (81%, p<0.0001) and diabetes (47%, p=0.018) were among the strongest predictors of higher ACR, though HIV RNA level (15% per 10-fold increase, p=0.0004) was also associated with higher ACR.
Conclusions
HIV-infected women had more extensive tubulointerstitial and glomerular injury than uninfected women, but the associated factors differed among the urine biomarkers. Combinations of urinary biomarkers should be investigated to further characterize early kidney injury in HIV-infected women.
doi:10.3851/IMP2677
PMCID: PMC3933452  PMID: 23970313
14.  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
15.  Fracture incidence in HIV-infected women: results from the Women’s Interagency HIV Study 
AIDS (London, England)  2010;24(17):2679-2686.
Background
The clinical importance of the association of HIV infection and antiretroviral therapy (ART) with low bone mineral density (BMD) in premenopausal women is uncertain because BMD stabilizes on established ART and fracture data are limited.
Methods
We measured time to first new fracture at any site with median follow-up of 5.4 years in 2391 (1728 HIV-infected, 663 HIV-uninfected) participants in the Women’s Interagency HIV Study (WIHS). Self-report of fracture was recorded at semiannual visits. Proportional hazard models assessed predictors of incident fracture.
Results
At baseline, HIV-infected women were older (40 ± 9 vs. 36 ± 10 years, P <0.0001), more likely to report postmenopausal status and be hepatitis C virus-infected, and weighed less than HIV-uninfected women. Among HIV-infected women, mean CD4+ cell count was 482 cells/μl; 66% were taking ART. Unadjusted incidence of fracture did not differ between HIV-infected and uninfected women (1.8 vs. 1.4/100 person-years, respectively, P = 0.18). In multivariate models, white (vs. African-American) race, hepatitis C virus infection, and higher serum creatinine, but not HIV serostatus, were statistically significant predictors of incident fracture. Among HIV-infected women, older age, white race, current cigarette use, and history of AIDS-defining illness were associated with incidence of new fracture.
Conclusion
Among predominantly premenopausal women, there was little difference in fracture incidence rates by HIV status, rather traditional risk factors were important predictors. Further research is necessary to characterize fracture risk in HIV-infected women during and after the menopausal transition.
doi:10.1097/QAD.0b013e32833f6294
PMCID: PMC3108019  PMID: 20859192
fracture; fragility fracture; HIV-infected women; premenopausal
16.  Negative-Strand Hepatitis C Virus (HCV) RNA in Peripheral Blood Mononuclear Cells from Anti-HCV–Positive/HIV-Infected Women 
The Journal of Infectious Diseases  2006;195(1):124-133.
Background
Hepatitis C virus (HCV) has been reported to replicate in peripheral blood mononuclear cells (PBMCs), particularly in patients coinfected with HCV and human immunodeficiency virus (HIV). However, there are limited data regarding the prevalence of and the factors associated with extrahepatic replication.
Methods
The presence of negative-strand HCV RNA in PBMCs was evaluated by a strand-specific assay for 144 anti-HCV–positive/HIV-infected women enrolled in the Women’s Interagency HIV Study. One to 5 PBMC samples obtained from each woman were tested. Multivariate analyses were used to assess for associations with the clinical and demographic characteristics of the women.
Results
Negative-strand HCV RNA was detected in 78 (25%) of 315 specimens, and, for 61 women (42%), ≥1 specimen was found to have positive results. The presence of negative-strand HCV RNA in PBMCs was significantly positively associated with an HCV RNA plasma level of ≥6.75 log copies/mL (P =.04) and consumption of ≥7 alcoholic drinks per week (P =.02). It was also negatively associated with injection drug use occurring in the past 6 months (P =.03). A negative association with a CD4+CD38+DR+ cell percentage of >10% and a positive association with acquired immunodeficiency syndrome were borderline significant (P =.05).
Conclusions
HCV replication in PBMCs is common among HIV-coinfected women and appears to be a dynamic process related to lifestyle, virologic, and immunologic factors.
doi:10.1086/509897
PMCID: PMC3319123  PMID: 17152016
17.  Smoking Cessation Among Women with and at Risk for HIV: Are They Quitting? 
BACKGROUND
Cigarette smoking is an important risk factor for adverse health events in HIV-infected populations. While recent US population-wide surveys report annual sustained smoking cessation rates of 3.4–8.5%, prospective data are lacking on cessation rates for HIV-infected smokers.
OBJECTIVE
To determine the sustained tobacco cessation rate and predictors of cessation among women with or at risk for HIV infection.
DESIGN
Prospective cohort study.
PARTICIPANTS
A total of 747 women (537 HIV-infected and 210 HIV-uninfected) who reported smoking at enrollment (1994–1995) in the Women’s Interagency HIV Study (WIHS) and remained in follow-up after 10 years. The participants were mostly minority (61% non-Hispanic Blacks and 22% Hispanics) and low income (68% with reported annual incomes of less than or equal to $12,000).
MEASUREMENTS AND MAIN RESULTS
The primary outcome was defined as greater than 12 months continuous cessation at year 10. Multivariate logistic regression was used to identify independent baseline predictors of subsequent tobacco cessation. A total of 121 (16%) women reported tobacco cessation at year 10 (annual sustained cessation rate of 1.8%, 95% CI 1.6–2.1%). Annual sustained cessation rates were 1.8% among both HIV-positive and HIV-negative women (p = 0.82). In multivariate analysis, the odds of tobacco cessation were significantly higher in women with more years of education (p trend = 0.02) and of Hispanic origin (OR = 1.87, 95% CI = 1.4–2.9) compared to Black women. Cessation was significantly lower in current or former illicit drug users (OR = 0.42 95% CI = 0.24–0.74 and OR = 0.65, 95% CI = 0.49–0.86, respectively, p trend = 0.03) and women reporting a higher number of cigarettes per day at baseline (p trend < 0.001).
CONCLUSIONS
HIV-infected and at-risk women in this cohort have lower smoking cessation rates than the general population. Given the high prevalence of smoking, the high risk of adverse health events from smoking, and low rates of cessation, it is imperative that we increase efforts and overcome barriers to help these women quit smoking.
doi:10.1007/s11606-009-1150-2
PMCID: PMC2811601  PMID: 19921113
smoking cessation; HIV/AIDS; clinical epidemiology; vulnerable populations
18.  Perinatal Depressive Symptoms in HIV-Infected Versus HIV-Uninfected Women: A Prospective Study from Preconception to Postpartum 
Journal of Women's Health  2011;20(9):1287-1295.
Abstract
Objective
Depression is common among HIV-infected women, predicts treatment nonadherence, and consequently may impact vertical transmission of HIV. We report findings from a study evaluating preconception, pregnancy, and postpartum depressive symptoms in HIV-infected vs. at-risk, HIV-uninfected women.
Methods
We examined the prevalence and predictors of elevated perinatal (i.e., pregnancy and/or postpartum) depressive symptoms using a Center for Epidemiological Studies-Depression (CES-D) scale score of ≥16 in 139 HIV-infected and 105 HIV-uninfected women (62% African American) from the Women's Interagency HIV Study (WIHS).
Results
The prevalence of elevated perinatal depressive symptoms did not differ by HIV serostatus (HIV-infected 44%, HIV-uninfected 50%, p=0.44). Among HIV-infected women, the strongest predictor of elevated symptoms was preconception depression (odds ratio [OR] 5.71, 95% confidence interval [CI] 2.67-12.19, p<0.001); crack, cocaine, and/or heroin use during preconception was marginally significant (OR 3.10, 95% CI 0.96-10.01, p=0.06). In the overall sample, additional significant predictors of perinatal depression included having multiple sex partners preconception (OR 2.20, 95% CI 1.12-4.32, p=0.02), use of preconception mental health services (OR 2.51, 95% CI 1.03-6.13, p=0.04), and not graduating from high school (OR 1.92, 95% CI 1.06-3.46, p=0.03).
Conclusions
Elevated perinatal depressive symptoms are common among HIV-infected and at-risk HIV-uninfected women. Depressive symptoms before pregnancy were the strongest predictor of perinatal symptoms. Findings underscore the importance of early and ongoing assessment and treatment to ensure low vertical transmission rates and improving postpregnancy outcomes for mothers and children.
doi:10.1089/jwh.2010.2485
PMCID: PMC3168970  PMID: 21732738
19.  The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts 
PLoS ONE  2013;8(3):e58812.
Objective
To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART).
Design
Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women’s Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively.
Methods
Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era.
Results
Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2–2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3–1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8–2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02–8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3–1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5–2.4; p<0.001).
Conclusion
HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality.
doi:10.1371/journal.pone.0058812
PMCID: PMC3595204  PMID: 23554932
20.  Increased Non-Enzymatic Glycation of Plasma Proteins and Hemoglobin in Non-Diabetic Patients with Acute Myocardial Infarction (MI) 
Background: Glycation is known to play a key role in complications of many pathophysiological processes. The present study was carried out to assess whether there are abnormalities of non-enzymatic glycation of proteins and hemoglobin in acute Myocardial Infarction (MI) patients.
Methods: Eighteen acute Myocardial Infarction (MI) patients and 20 healthy controls were enrolled for the present study. Fasting plasma glucose, fructosamine, glycated hemoglobin were evaluated.
Results: A significant rise in the mean values of fructosamine and glycated hemoglobin was found in acute myocardial patients when compared with controls. When Pearson’s correlation analysis was performed, no significant correlation was found between fasting plasma glucose with either fructosamine or glycated hemoglobin levels.
Conclusion: This data suggests an increased glycation of both plasma proteins and glycated hemoglobin in acute myocardial patients, which might be independent of prevailing glucose concentration.
doi:10.7860/JCDR/2013/7331.3884
PMCID: PMC3919377  PMID: 24551614
Glycation; Fructosamine; Hemoglobin; Acute Myocardial Infarction (MI)
21.  Brief Report: Plasma Homocysteine is Not Associated with HIV Serostatus or Antiretroviral Therapy in Women 
Background
The effects of HIV serostatus and combination antiretroviral therapy (cART) on plasma homocysteine (Hcy) are uncertain.
Methods
Plasma Hcy was assayed in a cross-sectional study of 249 HIV-infected and 127 HIV-uninfected women at the Bronx Women’s Interagency HIV Study site.
Results
Mean plasma Hcy was 7.42 ± 2.68 in HIV-infected and 7.18 ± 2.66 µmol/L in HIV-uninfected women (P = 0.40). Hyperhomocysteinemia (defined as Hcy > 10 µmol/L) was seen in 16.9% and 13.4 % of HIV-infected and HIV-uninfected women, respectively (P=0.45). Among HIV-infected women, cART use was not associated with Hcy level. Compared to the lowest quartile, women with Hcy in the highest quartile had lower mean serum vitamin B12 and RBC folate levels. In multivariate analysis that did not include micronutrient levels, age, serum creatinine and lower CD4% were significantly associated with plasma Hcy level in HIV-infected women.
Conclusions
Plasma Hcy was not associated with HIV serostatus or use of cART in this cross-sectional study. Reduced availability of folate cofactors for Hcy remethylation in HIV-infected women with lower folate intake and decreased health status may influence Hcy levels.
doi:10.1097/QAI.0b013e3181a42bdf
PMCID: PMC2755615  PMID: 19333128
Homocysteine; HIV; women; vitamin B12; folate
22.  Oxidant Stress in HIV-Infected Women from the Women’s Interagency HIV Study 
Antiviral therapy  2009;14(6):763-769.
Background
Oxidant stress contributes to the pathogenesis of multiple conditions and can be assessed by measuring plasma F2-isoprostane concentrations. We hypothesized that oxidant stress is associated with plasma homocysteine concentration and risk factors for atherosclerosis in HIV-infected women.
Methods
We measured plasma F2-isoprostane concentrations in a cross-sectional study of 249 HIV-infected women attending the Bronx site of the Women’s Interagency HIV Study and assessed associations with plasma homocysteine concentration and other metabolic parameters by linear regression.
Results
In multivariate analysis, HCV viremia, waist circumference, homocysteine concentration, and serum aspartate transanimase level were positively associated with log F2-isoprostane concentration (all P < 0.005). There was a trend for an inverse association between log F2-isoprostane and CD4% (P = 0.06). Among women with HCV infection, the FIB-4 index, an indirect marker of liver fibrosis derived from routine laboratory tests, was positively associated with log F2-isoprostane concentration.
Conclusion
In this cross-sectional study of HIV-infected women, plasma F2-isoprostane concentration was positively associated with homocysteine concentration, as well as HCV infection, abdominal obesity, and aspartate transaminase level.
doi:10.3851/1290
PMCID: PMC2760028  PMID: 19812438
Oxidant stress; oxidative stress; F2-isoprostanes; homocysteine; HIV; HCV
23.  Can fasting plasma glucose and glycated hemoglobin levels predict oral complications following invasive dental procedures in patients with type 2 diabetes mellitus? A preliminary case-control study 
Clinics  2013;68(3):427-430.
OBJECTIVE:
To evaluate the effects of the levels of glycemic control on the frequency of clinical complications following invasive dental treatments in type 2 diabetic patients and suggest appropriate levels of fasting blood glucose and glycated hemoglobin considered to be safe to avoid these complications.
METHOD:
Type 2 diabetic patients and non-diabetic patients were selected and divided into three groups. Group I consisted of 13 type 2 diabetic patients with adequate glycemic control (fasting blood glucose levels <140 mg/dl and glycated hemoglobin (HbA1c) levels <7%). Group II consisted of 15 type 2 diabetic patients with inadequate glycemic control (fasting blood glucose levels >140 mg/dl and HbA1c levels >7%). Group III consisted of 18 non-diabetic patients (no symptoms and fasting blood glucose levels <100 mg/dl). The levels of fasting blood glucose, glycated HbA1c, and fingerstick capillary glycemia were evaluated in diabetic patients prior to performing dental procedures. Seven days after the dental procedure, the frequency of clinical complications (surgery site infections and systemic infections) was examined and compared between the three study groups. In addition, correlations between the occurrence of these outcomes and the glycemic control of diabetes mellitus were evaluated.
RESULTS:
The frequency of clinical outcomes was low (4/43; 8.6%), and no significant differences between the outcome frequencies of the various study groups were observed (p>0.05). However, a significant association was observed between clinical complications and dental extractions (p = 0.02).
CONCLUSIONS:
Because of the low frequency of clinical outcomes, it was not possible to determine whether fasting blood glucose or glycated HbA1c levels are important for these clinical outcomes.
doi:10.6061/clinics/2013(03)RC01
PMCID: PMC3611742  PMID: 23644869
Type 2 Diabetes Mellitus; Oral Infections; Glycemic Control
24.  Glycated Hemoglobin A1c as Screening for Diabetes Mellitus in HIV-Infected Individuals 
AIDS Patient Care and STDs  2012;26(4):197-201.
Abstract
The American Diabetes Association now recommends hemoglobin A1c (HbA1c) screening for the diagnosis of diabetes. It has been reported that HbA1c levels underestimate glycemic levels in HIV-infected persons. We examined the performance of HbA1c as a screening test for diabetes in a group of HIV-infected people without diabetes. We conducted a retrospective cross-sectional cohort study among HIV-infected patients determining the sensitivity and specificity of HbA1c as a screening test compared to fasting blood glucose (FBG). The effect of treatment regimen on the relationship between HbA1c and FBG was assessed by multiple linear regressions. Twenty-two of the 395 patients included in the study were newly diagnosed with diabetes based on FBG≥126 mg/dL. Using a cutoff of HbA1c≥6.5%, HbA1c had a sensitivity of 40.9% and specificity of 97.5% for identification of incident diabetes. At an HbA1c level of 5.8% the product of sensitivity and specificity was maximized, with values of 88.8% and 77.5% respectively. Higher mean cell volume (MCV) values (p=0.02) and current use of a non-nucleoside reverse transcriptase inhibitors (NNRTIs; p=0.02) significantly increased the slope, while PI use significantly decreased the slope (p<0.001), of the linear regression of HbA1c compared to FBG. Tenofovir use did not significantly alter the slope or y-intercept of the line. Among HIV-infected nondiabetic patients, HbA1c is insensitive, although highly specific for diagnosing diabetes. Current antiretroviral (ART) use has significant and variable influence on the relationship between HbA1c and FBG. The use of HbA1c in conjunction with FBG may be the best modality to screen for diabetes.
doi:10.1089/apc.2011.0379
PMCID: PMC3317391  PMID: 22324292
25.  Novel Association of HK1 with Glycated Hemoglobin in a Non-Diabetic Population: A Genome-Wide Evaluation of 14,618 Participants in the Women's Genome Health Study 
PLoS Genetics  2008;4(12):e1000312.
Type 2 diabetes is a leading cause of morbidity and mortality. While genetic variants have been found to influence the risk of type 2 diabetes mellitus, relatively few studies have focused on genes associated with glycated hemoglobin, an index of the mean blood glucose concentration of the preceding 8–12 weeks. Epidemiologic studies and randomized clinical trials have documented the relationship between glycated hemoglobin levels and the development of long-term complications in diabetes; moreover, higher glycated hemoglobin levels in the subdiabetic range have been shown to predict type 2 diabetes risk and cardiovascular disease. To examine the common genetic determinants of glycated hemoglobin levels, we performed a genome-wide association study that evaluated 337,343 SNPs in 14,618 apparently healthy Caucasian women. The results show that glycated hemoglobin levels are associated with genetic variation at the GCK (rs730497; P = 2.8×10−12), SLC30A8 (rs13266634; P = 9.8×10−8), G6PC2 (rs1402837; P = 6.8×10−10), and HK1 (rs7072268; P = 6.4×10−9) loci. While associations at the GCK, SLC30A8, and G6PC2 loci are confirmatory, the findings at HK1 are novel. We were able to replicate this novel association in an independent validation sample of 455 additional non-diabetic men and women. HK1 encodes the enzyme hexokinase, the first step in glycolysis and a likely candidate for the control of glucose metabolism. This observed genetic association between glycated hemoglobin levels and HK1 polymorphisms paves the way for further studies of the role of HK1 in hemoglobin glycation, glucose metabolism, and diabetes.
Author Summary
Type 2 diabetes is a leading cause of morbidity and mortality in both the developed and developing world. Because the main metabolic characteristic of diabetes is increased blood glucose concentration, we sought to uncover the genetic determinants of glycated hemoglobin, an index of the mean blood glucose concentration of the preceding 8–12 weeks. Taking advantage of new technologies allowing us to interrogate genetic variation on a whole-genome basis, we found that variations in the GCK, SLC30A8, G6PC2, and HK1 genes are important determinants of glycated hemoglobin concentrations. While associations with the GCK, SLC30A8, and G6PC2 genes have previously been identified in genetic studies of diabetes and blood glucose concentration, the findings at HK1 are novel. HK1 encodes the enzyme hexokinase, responsible for the first step in glucose utilization and a likely candidate for the control of glucose metabolism. This observed genetic association between glycated hemoglobin levels and HK1 genetic variants paves the way for further studies of the role of HK1 in glucose metabolism and diabetes.
doi:10.1371/journal.pgen.1000312
PMCID: PMC2596965  PMID: 19096518

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