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1.  Changes in weight and weight distribution across the lifespan among HIV-infected and -uninfected men and women 
Medicine  2016;95(46):e5399.
Supplemental Digital Content is available in the text
Abstract
Examine body composition changes across the lifespan of HIV-infected compared to uninfected adults. Longitudinal study of antiretroviral therapy (ART)-treated HIV-infected and uninfected participants from the Multicenter AIDS Cohort Study and Women's Interagency HIV Study. Body mass index (BMI), waist (WC), hip circumference (HC), and waist-to-height ratio (WHtR) measured at semiannual visits from 1999 to 2014. The age effect on outcomes over time was investigated using multivariate, piecewise, linear mixed-effect regression models adjusted for demographics, substance use, and comorbidities. Person-visits from 2363 men (1059 HIV-infected/1304 HIV-uninfected) and 2200 women (1455 HIV-infected/745 HIV-uninfected), median ages 45 [IQR 39,51] and 40 [32,46], respectively, were included. BMI gains were slower among HIV-infected participants of 40 years or less (P < 0.001), similar between HIV-infected and uninfected persons 40 to 60 years of age, and plateaued after age 60 in both groups. WC and WHtR increased across the age spectrum (P < 0.001) regardless of HIV serostatus, with significantly greater gains in HIV-infected men more than 60. Black race and Hispanic ethnicity were associated with greater BMI and WC. Lower BMI, WC, hip circumference, and WHtR were associated with hepatitis C infection among women only, and with substance use among all participants, and with lower CD4+ cell count and shorter ART duration among HIV-infected participants. Slower BMI gain among younger HIV-infected adults may be partly explained by substance use and hepatitis C infection, and suggests that lower BMI does not represent improved health. Further analysis of muscle and fat abundance and quality will advance understanding of metabolic risk over the lifespan, a key to reducing morbidity in an aging population.
doi:10.1097/MD.0000000000005399
PMCID: PMC5120935  PMID: 27861378
body composition; body mass index; HIV; HIV wasting syndrome; obesity; waist circumference; weight-to-height ratio
2.  Metabolic Syndrome, Diabetes, and Cardiovascular Risk in HIV 
Current HIV/AIDS reports  2014;11(3):271-278.
HIV infection and its treatment have been associated with adipose tissue changes and disorders of glucose and lipid metabolism. The proportion of HIV-infected adults over the age of 50 is also growing placing HIV-infected adults at particular risk for metabolic perturbations and cardiovascular disease. The metabolic syndrome in HIV-infected adults has been increasingly studied but whether HIV is associated with greater risk remains unclear, likely because of the interplay of host, viral and antiretroviral factors that are associated with the components of the metabolic syndrome. While the Framingham Risk Score is a well-accepted measure of 10-year cardiovascular risk in the general population, it may not accurately predict risk in the HIV setting due to HIV-related factors such as inflammation that are not accounted for. The relationship between HIV and diabetes mellitus (DM) risk has also been debated. We summarize the recent literature on metabolic syndrome, DM, and cardiovascular risk in HIV-infected adults.
doi:10.1007/s11904-014-0219-7
PMCID: PMC4138538  PMID: 25027062
HIV; Metabolic Syndrome; Diabetes; Cardiovascular Risk; Framingham Risk Score; Lipodystrophy Syndrome
3.  Antiretroviral Therapy Modifies the Genetic Effect of Known Type 2 Diabetes-Associated Risk Variants in the Women’s Interagency HIV Study 
AIDS (London, England)  2014;28(12):1815-1823.
Objective
Type 2 diabetes (DM) incidence is increased in HIV-infected persons. We examined the associations of DM with known DM-risk alleles from the general population in the context of HIV infection and explored effect modification by combination antiretroviral treatment (cART).
Methods
The Women’s Interagency HIV Study (WIHS) is a prospective cohort of HIV-infected women. Seventeen European-derived DM-risk polymorphisms were genotyped in eligible WIHS participants. Analyses were run separately for non-African-Americans (Whites, Hispanics, Asians, and other; n=378, 49 with incident DM) and African-Americans (n=591, 49 with incident DM). Cox proportional hazards models were fit to estimate hazard ratios (HRs) for DM overall and within strata of cART.
Results
In non-African-Americans, heterogeneity across cART regimen was observed for 9 of 14 polymorphisms (phet<0.05). One polymorphism was statistically significantly inversely associated with DM risk among women taking 2 NRTIs+NNRTI. Five polymorphisms were statistically significantly associated with DM among women treated with ≥2 NRTIs + ≥1 PI and one polymorphism was associated with DM among those treated with ≥3 NRTIs ± NNRTI. The HR per risk allele for IGF2BP2 rs1470579 was 2.67 (95% CI 1.67–4.31) for women taking cART with ≥2 NRTIs+≥1 PI and 2.45 (95% CI 1.08–5.53) in women taking ≥3 NRTIs±NNRTI (phet=2.50×10−3). No such associations were observed in African-Americans.
Conclusions
Genetic susceptibility to DM, based on the variants studied, is substantially elevated among HIV-infected women using cART containing three or more NRTI/PI components. A personalized medicine approach to cART selection may be indicated for HIV-infected persons carrying these DM-risk variants.
doi:10.1097/QAD.0000000000000366
PMCID: PMC4269472  PMID: 24932614
type 2 diabetes; genetics; HIV; women; antiretroviral therapy
4.  Increased fracture incidence in middle-aged HIV-infected and uninfected women: updated results from the Women’s Interagency HIV Study 
Background
We previously reported that fracture incidence rates did not differ by HIV status among predominantly premenopausal Women's Interagency HIV Study (WIHS) participants. We now conduct a follow-up study with 5 additional observation years, to further characterize fracture risk associated with HIV infection in women as they age.
Methods
We measured time to first new fracture at any site in 2375 (1713 HIV-infected, 662 HIV-uninfected) WIHS participants, with median 10 years follow-up. Fractures were self-reported semiannually. Proportional Hazards models assessed predictors of incident fracture.
Results
At index visit, HIV-infected women were older (median age 40 yrs (IQR 34–46) vs. 35 (27–43), p<0.0001) and more likely to be postmenopausal, HCV-infected, and weigh less than HIV-uninfected women. Among HIV-infected women, mean CD4+ count was 480 cells/µL and 63% were taking HAART. Unadjusted incidence rates of any fracture were higher in HIV-infected than uninfected women (2.19/100 person-years (py) vs 1.54/100py, p=0.002). In multivariate models, HIV status, older age, white (vs. black) race, prior fracture, history of cocaine use, and history of injection drug use were significant predictors of incident fracture. Among HIV-infected women, age, white race, prior fracture, smoking, and prior AIDS were predictors of new fracture.
Conclusion
Middle-aged HIV-infected women had a higher adjusted fracture rate than uninfected women. Cocaine use and injection drug use were also associated with a greater risk of incident fracture. Further research is needed to understand whether the risk of fracture associated with cocaine use relates to increased rate of falls, or direct effects on bone metabolism.
doi:10.1097/QAI.0000000000000674
PMCID: PMC4557627  PMID: 26322667
HIV; women; bone; fracture; fragility fracture
5.  HIV Infection Is Associated With Progression of Subclinical Carotid Atherosclerosis 
Human immunodeficiency virus (HIV) infection was associated with greater increases in focal carotid artery plaque over 7 years among both women and men, particularly among those with lower CD4+ counts. Increased plaque was observed even among HIV-infected individuals with persistent virologic suppression.
Background. Individuals infected with human immunodeficiency virus (HIV) live longer as a result of effective treatment, but long-term consequences of infection, treatment, and immunological dysfunction are poorly understood.
Methods. We prospectively examined 1011 women (74% HIV-infected) in the Women's Interagency HIV Study and 811 men (65% HIV-infected) in the Multicenter AIDS Cohort Study who underwent repeated B-mode carotid artery ultrasound imaging in 2004–2013. Outcomes included changes in right common carotid artery intima-media thickness (CCA-IMT) and new focal carotid artery plaque formation (IMT >1.5 mm) over median 7 years. We assessed the association between HIV serostatus and progression of subclinical atherosclerosis, adjusting for demographic, behavioral, and cardiometabolic risk factors.
Results. Unadjusted mean CCA-IMT increased (725 to 752 µm in women, 757 to 790 µm in men), but CCA-IMT progression did not differ by HIV serostatus, either in combined or sex-specific analyses. Focal plaque prevalence increased from 8% to 15% in women and 25% to 34% in men over 7 years. HIV-infected individuals had 1.6-fold greater risk of new plaque formation compared with HIV-uninfected individuals (relative risk [RR] 1.61, 95% CI, 1.12–2.32), adjusting for cardiometabolic factors; the association was similar by sex. Increased plaque occurred even among persistently virologically suppressed HIV-infected individuals compared with uninfected individuals (RR 1.56, 95% CI, 1.07–2.27). HIV-infected individuals with baseline CD4+ ≥500 cells/µL had plaque risk not statistically different from uninfected individuals.
Conclusions. HIV infection is associated with greater increases in focal plaque among women and men, potentially mediated by factors associated with immunodeficiency or HIV replication at levels below current limits of detection.
doi:10.1093/cid/civ325
PMCID: PMC4607734  PMID: 25904369
HIV infection; cardiovascular disease; atherosclerosis; intima-media thickness; viral load
6.  Association of HIV, HCV and Liver Fibrosis Severity with IL-6 and CRP levels 
AIDS (London, England)  2015;29(11):1325-1333.
Background
Hepatitis C infection (HCV) is associated with chronic inflammation; yet studies show greater IL-6 but lower CRP levels. We determined whether liver fibrosis severity and HCV replication affect the ability of IL-6 to stimulate production of CRP from the liver.
Methods
We used multivariable generalized linear regression to examine the association of HIV, HCV and transient elastography-measured liver stiffness (LS) with IL-6 and CRP in participants (164 HIV-monoinfected; 10 HCV-monoinfected; 73 HIV/HCV-coinfected; 59 neither infection) of the Women's Interagency HIV Study. Significant fibrosis was defined as LS>7.1 kiloPascals.
Results
IL-6 was positively correlated with CRP levels in all women, but CRP levels were lower in HCV-infected women (with and without HIV infection) at all levels of IL-6. HCV-infected women with fibrosis had nearly 2.7-fold higher IL-6 levels compared to controls (95% Confidence Interval [CI]:146%, 447%); HCV-infected women without fibrosis had IL-6 levels that were similar to controls. By contrast, CRP was 28% lower in HCV-infected women with fibrosis (95% CI:-55%, 15%) and 47% lower in HCV-infected women without fibrosis (95% CI:-68%,-12%). Among the HCV-infected women, higher HCV RNA levels were associated with 9% lower CRP levels per doubling (95% CI: -18%, 0%).
Conclusion
Liver fibrosis severity is associated with greater IL-6 levels, but the stimulatory effect of IL-6 on CRP appears to be blunted by HCV replication rather than by liver fibrosis severity. Investigation of the potential CRP rebound after HCV RNA eradication and persistent liver fibrosis on organ injury is needed.
doi:10.1097/QAD.0000000000000654
PMCID: PMC4478137  PMID: 25870985
HIV; HCV; transient elastography; CRP; IL-6
7.  Anthropometric measures and cognition in middle-aged HIV-infected and uninfected women. The Women's Interagency HIV Study 
Journal of neurovirology  2013;19(6):574-585.
Objective
To explore the relationship of body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) with cognition in women with (HIV+) and without HIV (HIV-) infection.
Design/Methods
1690 participants (1196 HIV+, 494 HIV-) in the Women's Interagency HIV Study (WIHS) with data available on anthropometric measures comprise the analytical sample. Cross-sectional analyses using linear regression models estimated the relationship between anthropometric variables and Trails A, Trails B, Stroop interference time, Stroop word recall, Stroop color naming and reading, and Symbol Digit Modalities Test (SDMT) with consideration for age, HIV infection status, Wide Range Achievement Test score, CD4 count, insulin resistance, drug use, and race/ethnicity.
Results
Among HIV+ women, BMI < 18.5 kg/m2 was associated with poorer cognitive performance evidenced by longer Trails A and Trails B and shorter SDMT completion times. An obese BMI (30 kg/m2 or higher) was related to better performance on Trails B and worse performance on the Stroop Interference test. Among HIV- women, an obese BMI was related to worse performance on the Stroop – Color naming test. Few and inconsistent associations were observed between WC, WHR and cognition.
Conclusion
Among women at mid-life with chronic (at least 10 years) HIV infection, common anthropometric measures, primarily BMI, were differentially related to cognitive test performance by cognitive domain. Higher levels of BMI were associated with better cognitive function. In this era of antiretroviral therapies, restoration of health evidenced as higher BMI due to effective antiretroviral therapies, may improve cognitive function in middle-aged HIV infected women.
doi:10.1007/s13365-013-0219-1
PMCID: PMC3957488  PMID: 24338243
Cognition; HIV; Women; Overweight; Obesity; Middle-Aged
8.  Differences in Response to Antiretroviral Therapy by Sex and Hepatitis C Infection Status 
AIDS Patient Care and STDs  2015;29(7):370-378.
Abstract
Hepatitis C virus (HCV) co-infection and biological sex may each affect response to antiretroviral therapy (ART), yet no studies have examined HIV-associated outcomes by both HCV status and sex. We conducted a cohort study of HIV-infected adults initiating ART in Kaiser Permanente California during 1996–2011. We used piecewise linear regression to assess CD4 changes by sex and HCV status over 5 years. We used Cox regression to estimate hazard ratios (HR) by sex and HCV status for HIV RNA <500 copies/mL over 1 year, and for AIDS and death over the follow-up period. Among 12,865 subjects, there were 154 HIV/HCV-co-infected women, 1000 HIV/HCV-co-infected men, 1088 HIV-mono-infected women, and 10,623 HIV-mono-infected men. CD4 increases were slower in the first year for HIV/HCV-co-infected women (75 cells/μL) and men (70 cells/μL) compared with HIV-mono-infected women (145 cells/μL) and men (120 cells/μL; p<0.001). After 5 years, women had higher CD4 than men in both HIV-mono-infected (598 vs. 562 cells/μL, p=0.003) and HIV/HCV-co-infected individuals (567 vs. 509 cells/μL, p=0.003). Regardless of sex, HIV/HCV co-infection was associated with 40% higher mortality [95% confidence interval (CI): 1.2–1.6] compared with HIV mono-infection, but was not associated with AIDS (HR 1.1, 95% CI: 0.9–1.3) or achieving HIV RNA <500 copies/mL (HR 1.0, 95% CI: 0.9–1.1). HIV/HCV-co-infected men and women have slower CD4 recovery after starting ART and have increased mortality compared with HIV-mono-infected men and women. HCV should be aggressively treated in HIV/HCV-co-infected adults, regardless of sex.
doi:10.1089/apc.2015.0040
PMCID: PMC4808272  PMID: 26061798
9.  Prevalence and Long-Term Effects of Occult Hepatitis B Virus Infection in HIV-Infected Women 
Occult hepatitis B virus (HBV) infection is of concern in human immunodeficiency virus (HIV)–infected persons. We observed that 2% of 400 HIV-infected women with antibodies to hepatitis B core antigen alone had occult HBV infection (i.e., detectable HBV DNA in the absence of HBV surface antigen). CD4 cell counts of <200 cells/mm3 were more common among occult HBV-infected women than among those without occult HBV infection. Aminotransferase levels did not appear to be associated with being positive for HBV DNA.
doi:10.1086/520989
PMCID: PMC4142488  PMID: 17712758
10.  APOL1 Genotype and Glomerular and Tubular Kidney Injury in Women With HIV 
Background
APOL1 genotype is associated with advanced kidney disease in African-Americans, but the pathogenic mechanisms are unclear. Here, associations of APOL1 genotype with urine biomarkers of glomerular and tubular injury, and with kidney function decline, were evaluated.
Study Design
Observational study.
Setting & Participants
431 HIV-infected African-American women enrolled in Women's Interagency HIV Study (WIHS).
Predictor
APOL1 genotype.
Outcomes
Albumin-creatinine ratio (ACR), four tubular injury biomarkers (interleukin 18 [IL-18], kidney injury molecule 1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL], and α1-microglobulin [α1m]), and kidney function estimated using the CKD-EPI cystatin C equation.
Measurements
Participants were genotyped for APOL1 single-nucleotide polymorphisms rs73885319 (G1 allele) and rs71785313 (G2 allele). Urine biomarker levels were measured using stored samples from 1999-2000. Cystatin C was measured using serum collected at baseline and 4- and 8-year follow-up.
Results
At baseline, ACR levels were higher among 47 women with 2 APOL1 risk alleles versus 384 women with 0/1 risk allele (median, 24 vs. 11 mg/g; p < 0.001). Compared to women with 0/1 risk allele, women with 2 risk alleles had 104% higher ACR (95% CI, 29-223 mg/g) and 2-fold greater risk of ACR > 30 mg/g (95% CI, 1.17-3.44) after multivariable adjustment. APOL1 genotype showed little association with urine IL-18:Cr, KIM-1:Cr, and NGAL:Cr (estimates of -5% [95% CI, -24% to 18%], -20% [95% CI, -36% to 1%], and 10% [95% CI, -26% to 64%], respectively), or detectable urine α1m (prevalence ratio, 1.13; 95% CI, 0.65-1.97) in adjusted analyses. Compared to women with 0/1 allele, women with 2 risk alleles had faster eGFR decline, by 1.2 (95% CI, -2.2 to -0.2) ml/min/1.73 m2 per year, and had 1.7- and 3.4-fold greater rates of incident chronic kidney disease (95% CI, 1.1-2.5) and 10% annual eGFR decline (95% CI, 1.7-6.7), respectively, with minimal attenuation after adjustment for glomerular and tubular injury biomarkers.
Limitations
Results may not be generalizable to men.
Conclusions
Among HIV-infected African-American women, APOL1-associated kidney injury appears to localize to the glomerulus, rather than the tubules.
doi:10.1053/j.ajkd.2015.02.329
PMCID: PMC4615696  PMID: 25921719
APOL1 genotype; risk variant; risk allele; G1 allele; G2 allele; single-nucleotide polymorphism (SNP); albumin-creatinine ratio (ACR); proteinuria; tubular injury biomarker; apolipoprotein L1; kidney disease; renal function; glomerular injury; African American; Women's Interagency HIV Study (WIHS)
11.  Mechanisms for the Negative Effects of Internalized HIV-Related Stigma on Antiretroviral Therapy Adherence in Women: The Mediating Roles of Social Isolation and Depression 
Supplemental Digital Content is Available in the Text.
Background:
Internalization of HIV-related stigma may inhibit a person's ability to manage HIV disease through adherence to treatment regimens. Studies, mainly with white men, have suggested an association between internalized stigma and suboptimal adherence to antiretroviral therapy (ART). However, there is a scarcity of research with women of different racial/ethnic backgrounds and on mediating mechanisms in the association between internalized stigma and ART adherence.
Methods:
The Women's Interagency HIV Study (WIHS) is a multicenter cohort study. Women living with HIV complete interviewer-administered questionnaires semiannually. Cross-sectional analyses for the current article included 1168 women on ART for whom data on medication adherence were available from their last study visit between April 2013 and March 2014, when the internalized stigma measure was initially introduced.
Results:
The association between internalized stigma and self-reported suboptimal ART adherence was significant for those in racial/ethnic minority groups (AOR = 0.69, P = 0.009, 95% CI: 0.52 to 0.91), but not for non-Hispanic whites (AOR = 2.15, P = 0.19, 95% CI: 0.69 to 6.73). Depressive symptoms, loneliness, and low perceived social support mediated the association between internalized stigma and suboptimal adherence in the whole sample, as well as in the subsample of minority participants. In serial mediation models, internalized stigma predicted less-perceived social support (or higher loneliness), which in turn predicted more depressive symptoms, which in turn predicted suboptimal medication adherence.
Conclusions:
Findings suggest that interconnected psychosocial mechanisms affect ART adherence, and that improvements in adherence may require multifaceted interventions addressing both mental health and interpersonal factors, especially for minority women.
doi:10.1097/QAI.0000000000000948
PMCID: PMC4868649  PMID: 26885803
adherence; stigma; depression; social support; loneliness
12.  Oral Glucose Tolerance Testing identifies HIV+ infected women with Diabetes Mellitus (DM) not captured by standard DM definition 
Objective
HIV-infected (HIV+) individuals may have differential risk of diabetes mellitus (DM) compared to the general population, and the optimal diagnostic algorithm for DM in HIV+ persons remains unclear. We aimed to assess the utility of oral glucose tolerance testing (OGTT) for DM diagnosis in a cohort of women with or at risk for HIV infection.
Methods
Using American Diabetic Association DM definitions, DM prevalence and incidence were assessed among women enrolled in the Women’s Interagency HIV Study. DM was defined by 2-hour OGTT ≥ 200 mg/dL (DM_OGTT) or a clinical definition (DM_C) that included any of the following: (i) anti-diabetic medication use or self-reported DM confirmed by either fasting glucose (FG) ≥126 mg/dL or HbA1c ≥ 6.5%, (ii) FG ≥ 126 mg/dL confirmed by a second FG ≥ 126 mg/dL or HbA1c 6.5%, or (iii) HbA1c 6.5% confirmed by FG ≥ 126 mg/dL cohort.
Results
Overall, 390 women (285 HIV+, median age 43 years; 105 HIV−, median age 37 years) were enrolled between 2003-2006. Over half of all women were African American. Using DM_C, DM prevalence rates were 5.6% and 2.8% among HIV+ and HIV− women, respectively. Among HIV+ women, adding DM_OGTT to DM_C increased DM prevalence from 5.6% to 7.4%, a 31% increase in the number of diabetes cases diagnosed (p=0.02). In HIV− women, no additional cases were diagnosed by DM-OGTT.
Conclusion
In HIV+ women, OGTT identified DM cases that were not identified by a standardized clinical definition. Further investigation is needed to determine whether OGTT should be considered as an adjunctive tool for DM diagnosis in the setting of HIV infection.
doi:10.4172/2155-6113.1000545
PMCID: PMC4825684  PMID: 27066296
HIV; Women; Diabetes mellitus; Oral glucose tolerance test
15.  The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM): Methods, Design, and Sample Characteristics 
American journal of epidemiology  2006;163(9):860-869.
The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM), initiated in 2000, investigates the prevalence and correlates of changes in fat distribution, insulin resistance, and dyslipidemia among human immunodeficiency virus (HIV)-infected men and women compared with a population-based group of control men and women. Between June 2000 and September 2002, 1,480 participants (1,183 HIV-infected persons and 297 controls) were enrolled in FRAM. Measurements taken included whole-body magnetic resonance imaging for quantification of regional fat, anthropometric measurements, central laboratory analysis of metabolites, and assessment of symptoms, sociodemographic factors, and lifestyle. Similar measurements were repeated among FRAM participants 4 years later (FRAM 2) for investigation of the progression of fat distribution changes, insulin resistance, and hyperlipidemia. In FRAM 2, which is ongoing, investigators are also determining the associations of subclinical cardiovascular disease, as measured by carotid intimal-medial wall thickness, with HIV infection, fat distribution changes, insulin resistance, and other proatherogenic changes in serum lipid levels. The demographic characteristics of HIV-infected FRAM men and women were comparable to those reported from a national random sampling of HIV-infected men and women receiving medical care in the United States. The representativeness of the FRAM sample increases its value as a resource for studies on fat distribution, metabolic changes, and atherosclerosis in HIV infection.
doi:10.1093/aje/kwj111
PMCID: PMC3170407  PMID: 16524955
body fat distribution; dyslipidemias; HIV infections; insulin resistance; lipodystrophy; metabolism
16.  Factors Associated with Seronegative Chronic Hepatitis C Virus Infection in HIV Infection 
Background
Chronic seronegative hepatitis C virus (HCV) infection is defined as being HCV antibody (anti-HCV) negative, but HCV RNA positivity occurs in individuals infected with human immunodeficiency virus (HIV). However, associated factors are not well established because of the small number of reported cases.
Methods
Multivariate logistic regression analysis of HIV-infected subjects from 4 cohorts (Tien et al., 2006; Bonacini et al., 2001; George et al., 2002; and Hall et al., 2004) determined factors associated with HCV RNA positivity in anti-HCV–negative subjects. HCV enzyme immunoassay 2.0 was used to determine anti-HCV status.
Results
Among 1174 anti-HCV–negative, HIV-infected subjects, the prevalence of seronegative HCV infection was 3.2% (95% confidence interval [CI], 2.2%–4.3%). History of injection drug use (IDU; OR, 5.8; 95% CI, 2.7–12.8), higher alanine aminotransferase (ALT) level (OR, 2.0 per doubling; 95% CI, 1.3–3.2), and CD4 cell count <200 cells/μL (OR, 2.3; 95% CI, 1.1–4.8) were associated with HCV RNA positivity in anti-HCV–negative subjects. Among those with a history of IDU who had either a CD4 cell count <200 cells/μL or an ALT level greater than the upper limit of normal, the prevalence of seronegative HCV infection was 24% (95% CI, 13%–39%).
Conclusions
Detectable HCV RNA in the context of a negative HCV enzyme immunoassay 2.0 result in HIV-infected patients is low, but higher than the reported prevalence in HIV-uninfected patients. Our findings suggest that HCV RNA testing should be performed in anti-HCV–negative, HIV-infected patients, especially those with a history of IDU and either a CD4 cell count <200 cells/μL or an abnormal ALT level.
doi:10.1086/511038
PMCID: PMC3170414  PMID: 17243063
17.  Association Between Hepatitis C Virus Coinfection and Regional Adipose Tissue Volume in HIV-Infected Men and Women 
Objective
Coinfection with hepatitis C virus (HCV) is reported to be associated with a higher prevalence of lipodystrophy than HIV infection alone. We examine the association between HCV and adipose tissue volume in HIV-infected men and women.
Methods
Cross-sectional analysis of HIV-infected subjects from the study of Fat Redistribution and Metabolic Change in HIV Infection. MRI measured regional adipose tissue volume. Detectable HCV RNA defined HCV infection.
Results
Twenty percent of 792 men and 26% of 329 women were HIV/HCV-coinfected. HIV/HCV-coinfected and HIV-monoinfected women had similar amounts of subcutaneous adipose tissue (SAT) in the leg, lower trunk, upper trunk, and arm and similar amounts of visceral adipose tissue (VAT). Similar findings were seen in men, except in the leg and VAT. After adjustment, HCV infection remained associated with more leg fat in men (12.2%, 95% confidence interval [CI]: 0.3 to 25.3; P = 0.043). Among those on stavudine, HIV-monoinfected men had less leg fat (−7% effect per year of stavudine use, 95% CI: −9 to −5; P < 0.001); a weaker association was seen in HIV/HCV-coinfected men (−2% effect, 95% CI: −7 to 3; P = 0.45). Indinavir was associated with less leg fat (−4% in HIV-monoinfected men, 95% CI: −6 to −1; P = 0.002; −5% in HIV/HCV-coinfected men, 95% CI: −11 to 2; P = 0.14).
Conclusions
Our findings suggest that HIV/HCV coinfection is not associated with less SAT in men and women. HCV infection seems to mitigate the loss of leg fat seen in HIV-infected men on stavudine.
doi:10.1097/QAI.0b013e3180423a95
PMCID: PMC3164885  PMID: 17356466
adipose tissue volume; fat distribution; hepatitis C virus; HIV; lipodystrophy
18.  Antiretroviral Therapies Associated with Lipoatrophy in HIV-Infected Women 
AIDS patient care and STDs  2007;21(5):297-305.
We previously demonstrated that HIV infection is associated with peripheral and central lipoatrophy in women. We now describe the association of specific antiretroviral drugs (ARV) with body fat changes over a four-year period from 1999 to 2003. 775 HIV-positive and 205 HIV-negative women in the Women’s Interagency HIV Study with anthropometric measurements, weight, bioelectric impedance analysis and ARV collected semiannually were included in analysis. Exposure to ARV was defined as report of use for 3 consecutive semiannual study visits. The average 6–month change in weight, percent total body fat, and circumference measurements (i.e., hip, waist, chest, arm, and thigh) was compared between those exposed and those unexposed to the specific ARV for any of the same three consecutive visits. Weight, percent total body fat, and hip, waist, thigh, chest, and arm circumferences decreased in HIV-positive women, but increased in HIV-negative women on average for every six-month interval over the 4-year study period. Among the HIV-positive women, didanosine was the only ARV associated with decreases in circumference measures in the hip (−0.65 cm, 95% confidence interval [CI]: −1.18, −0.12), waist (−0.71 cm, 95% CI: −1.37, −0.04), chest (−0.71 cm, 95% CI: −1.17, −0.26), and arm (−0.23 cm, 95% CI: −0.48, 0.03; p = 0.08). These prospective data suggest that fat loss continues to predominate in HIV-positive women and exposure to didanosine for at least 12 months may further worsen fat loss.
doi:10.1089/apc.2006.128
PMCID: PMC3133726  PMID: 17518522
19.  Association between Syphilis, Antibodies to Herpes Simplex Virus Type 2, and Recreational Drug Use and Hepatitis B Virus Infection in the Women’s Interagency HIV Study 
Background
Liver disease is a leading cause of death in human immunodeficiency virus (HIV)–infected women; however, risk factors for hepatitis B virus (HBV) infection in this population have not been well studied.
Methods
We describe the seroprevalence and predictors of HBV infection in a cross-sectional analysis of 2132 women with and at risk for HIV infection enrolled in the Women’s Interagency HIV Study during the periods 1994–95 and 2001–02. Any test result positive for antibody to hepatitis B core antigen defined infection; those women with serological evidence of vaccine immunity were excluded from analysis. Women were stratified into those with a history of injection drug use (IDU), those with a history of noninjection drug use (non-IDU), and those with no history of illicit drug use.
Results
Of 1606 HIV-infected and 526 HIV-uninfected women, 7% and 12%, respectively, appeared to be vaccine immune. After exclusion of these women, 43% of 1500 HIV-infected and 22% of 461 HIV-uninfected women had HBV infection. HBV infection prevalence differed among the IDU, non-IDU, and no illicit drug use groups (76%, 30%, and 17%, respectively; P < .0001). HBV infection was strongly associated with herpes simplex virus 2 (HSV-2) seropositivity in the IDU group (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.6–5.4) and with a history of syphilis in the non-IDU group (OR, 2.7; 95% CI, 1.4–5.0).
Discussion
We found a high prevalence of HBV infection in our cohort of women with and at risk for HIV infection. HSV-2 seropositivity and a history of syphilis appeared to be important correlates of HBV infection. Sexual transmission of HBV, particularly in those with a history of genital ulcer disease, should be a major focus of education in all high-risk groups.
doi:10.1086/424879
PMCID: PMC3118996  PMID: 15494914
20.  Relationship between Body Mass Index and Mortality in HIV-Infected HAART Users in the Women's Interagency HIV Study 
PLoS ONE  2015;10(12):e0143740.
Background
Early HIV studies suggested protective associations of overweight against mortality, yet data are lacking for the era of potent highly active antiretroviral therapy (HAART). We evaluated associations of pre-HAART initiation body mass index (BMI) with mortality among HAART-using women.
Methods
Prospective study of time to death after HAART initiation among continuous HAART users in the Women’s Interagency HIV Study. Unadjusted Kaplan–Meier and adjusted proportional hazards survival models assessed time to AIDS and non-AIDS death by last measured pre-HAART BMI.
Results
Of 1428 continuous HAART users 39 (2.7%) were underweight, 521 (36.5%) normal weight, 441 (30.9%) overweight, and 427 (29.9%) obese at time of HAART initiation. A total of 322 deaths occurred during median follow-up of 10.4 years (IQR 5.9–14.6). Censoring at non-AIDS death, the highest rate of AIDS death was observed among underweight women (p = 0.0003 for all 4 categories). In multivariate models, women underweight prior to HAART died from AIDS more than twice as rapidly vs. normal weight women (aHR 2.04, 95% CI 1.03, 4.04); but being overweight or obese (vs. normal weight) was not independently associated with AIDS death. Cumulative incidence of non-AIDS death was similar across all pre-HAART BMI categories.
Conclusions
Among continuous HAART-using women, being overweight prior to initiation was not associated with lower risk of AIDS or non-AIDS death. Being underweight prior to HAART was associated with over double the rate of AIDS death in adjusted analyses. Although overweight and obesity may be associated with many adverse health conditions, neither was predictive of mortality among the HAART-using women.
doi:10.1371/journal.pone.0143740
PMCID: PMC4689347  PMID: 26699870
21.  Antiretroviral Therapy Exposure and Insulin Resistance in the Women’s Interagency HIV Study 
Background
Evidence suggesting an increased risk of cardiovascular disease in HIV-infected individuals has heightened the need to understand the relation of HIV infection, antiretroviral therapy use, and non–HIV-related factors with insulin resistance (IR).
Methods
Prospective study of 1614 HIV-infected and 604 HIV-uninfected participants from the Women’s Interagency HIV Study between October 2000 and March 2007. Homeostasis model assessment (HOMA)–estimated IR at 11,019 semiannual visits.
Results
HIV-infected women reporting highly active antiretroviral therapy (HAART) had higher median HOMA than HIV-uninfected women {1.20 [95% confidence interval (CI): 1.11 to 1.30] times higher for those reporting protease inhibitor–containing HAART; 1.10 (95% CI: 1.01 to 1.20) times higher for those reporting non–protease inhibitor–containing HAART}. Among HIV-infected, cumulative exposure to nucleoside reverse transcriptase inhibitors (NRTIs) of >3 years was associated with HOMA 1.13 (95% CI: 1.02 to 1.25) times higher than the HOMA without any cumulative NRTI exposure. Cumulative exposure to the NRTI stavudine of >1 year was associated with HOMA 1.15 (95% CI: 1.05 to 1.27) times higher than the HOMA without any cumulative stavudine use. Family history of diabetes, hepatitis C virus seropositivity, higher body mass index, or reporting menopause was associated with higher HOMA.
Conclusions
Longer cumulative exposure to NRTI; in particular, stavudine is associated with greater IR in HIV-infected women.
PMCID: PMC2889144  PMID: 19186350
antiretroviral therapy; HIV; HOMA; insulin resistance; nucleoside reverse transcriptase inhibitor; protease inhibitor
22.  Regional Adipose Tissue and Lipid and Lipoprotein Levels in HIV-Infected Women 
Background
HIV infection and antiretroviral therapy are associated with dyslipidemia, but the association between regional body fat and lipid levels is not well described.
Methods
Multivariable linear regression analyzed the association between magnetic resonance imaging–measured regional adipose tissue and fasting lipids in 284 HIV-infected and 129 control women.
Results
Among African Americans, HIV-infected women had higher triglyceride (116 vs. 83 mg/dL; P < 0.001), similar high-density lipoprotein (HDL; 52 vs. 50 mg/dL; P = 0.60), and lower low-density lipoprotein (LDL; 99 vs. 118 mg/dL; P = 0.008) levels than controls. Among whites, HIV-infected women had higher triglyceride (141 vs. 78 mg/dL; P < 0.001), lower HDL (46 vs. 57 mg/dL; P < 0.001), and slightly lower LDL (100 vs. 107 mg/dL; P = 0.059) levels than controls. After adjustment for demographic and lifestyle factors, the highest tertile of visceral adipose tissue (VAT) was associated with higher triglyceride (+85%, 95% confidence interval [CI]: 55 to 121) and lower HDL (−9%, 95% CI: −18 to 0) levels in HIV-infected women; the highest tertile of leg subcutaneous adipose tissue (SAT) was associated with lower triglyceride levels in HIV-infected women (−28%, 95% CI: −41 to −11) and controls (−39%, 95% CI: −5 to −18). After further adjustment for adipose tissue, HIV infection remained associated with higher triglyceride (+40%, 95% CI: 21 to 63) and lower LDL (−17%, 95% CI: −26 to −8) levels, whereas HIV infection remained associated with lower HDL levels (−21%, 95% CI: −29 to −12) in whites but not in African Americans (+8%, 95% CI: −2 to 19).
Conclusions
HIV-infected white women are more likely to have proatherogenic lipid profiles than HIV-infected African American women. Less leg SAT and more VAT are important factors associated with adverse lipid levels. HIV-infected women may be at particular risk for dyslipidemia because of the risk for HIV-associated lipoatrophy.
doi:10.1097/QAI.0b013e318164227f
PMCID: PMC2776070  PMID: 18197118
dyslipidemia; fat distribution; HIV infection; lipid levels; lipodystrophy; women
23.  Regional Adipose Tissue and Elevations in Serum Aminotransferases in HIV-Infected Individuals 
Background
The association of fat distribution with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations is not well-defined in HIV-infected individuals. Obesity is associated with hepatic steatosis, and ALT is a marker of steatosis in the general population.
Methods
Cross-sectional analysis of 1119 HIV-infected and 284 control subjects. Hepatitis C virus (HCV) RNA testing determined HCV infection. Magnetic resonance imaging measured regional adipose tissue volume.
Results
After adjustment for demographic and lifestyle factors, visceral adipose tissue (VAT) was positively associated with ALT in HIV/HCV-coinfected subjects (+9.8%, 95% confidence interval [CI]: 2.8 to 17.6), HIV-monoinfected subjects (+8.0%, 95% CI: 4.2 to 12.1), and controls (+5.9%, 95% CI: 2.0 to 10.1). In contrast, lower trunk subcutaneous adipose tissue (SAT) was negatively associated with ALT in HIV/HCV-coinfected subjects (−14.3%, 95% CI: −24.7 to −4.2) and HIV-monoinfected subjects (−11.9%, 95% CI: −18.4 to −5.3); there was a trend toward an association in controls (−7.1%, 95% CI: −22.7 to 5.9). Estimated associations between regional adipose tissue and AST were small and did not reach statistical significance.
Conclusions
More VAT and less lower trunk SAT are associated with elevated ALT, which likely reflects the presence of steatosis. There was little association with AST. HCV infection and having more VAT or less lower trunk SAT are independently associated with elevated ALT in HIV infection. Study regarding the association between VAT, trunk SAT, HCV, and progression of steatosis and fibrosis is needed in HIV-infected individuals.
doi:10.1097/QAI.0b013e3181685700
PMCID: PMC2776053  PMID: 18285711
adipose tissue; aminotransferase levels; hepatitis C virus; HIV; lipodystrophy
24.  T-cell Activation, Both Pre- and Post-HAART Levels, Correlates with Carotid Artery Stiffness over 6.5 years among HIV-infected Women in the WIHS 
Objective
T-cell activation is a major pathway driving HIV disease progression. Little is known regarding the impact of T-cell activation on HIV-associated atherosclerosis and cardiovascular disease, a common co-morbidity in HIV infection. We hypothesized that T-cell activation will predict vascular stiffness, a measure of subclinical atherosclerosis.
Design
Linear regression models evaluated the covariate-adjusted association of T-cell activation with vascular stiffness.
Methods
CD38 and HLA-DR expression on CD4+ and CD8+ T-cells was assessed by flow cytometry among 59 HIV-negative and 376 HIV-infected (185 hepatitis-C co-infected) women in the Women's Interagency HIV Study (WIHS). T-cell activation was defined by CD8+CD38+DR+ and CD4+CD38+DR+. Multiple activation assessments over 6.5 years were averaged. In 140 women, T-cell activation was measured before and after HAART initiation. Carotid artery ultrasounds were completed a median of 6.5 years after last measurement of T- cell activation and carotid artery stiffness including distensibility and elasticity were calculated.
Results
Percentages of CD4+ and CD8+ T-cell activation were significantly higher in HIV- infected compared to HIV-negative women. Among HIV-negative women, T-cell activation was not associated with carotid artery stiffness. Among HIV-infected women, higher CD4+ T-cell activation significantly predicted increased arterial stiffness independent of CD4 cell count and HIV RNA. The association was stronger among HIV/HCV co-infected compared to HIV-mono- infected women; however, the difference was not statistically significant (p-for interaction>0.05). Pre- and post-HAART levels of CD4+ T-cell activation significantly predicted carotid artery stiffness.
Conclusions
Persistent T-cell activation, even after HAART initiation, can contribute to structural and/or functional vascular damage accelerating atherogenesis in HIV infection. These results need to be confirmed in a longitudinal prospective study.
doi:10.1097/QAI.0000000000000311
PMCID: PMC4197806  PMID: 25314253
T-cell activation; arterial stiffness; HIV-infection
25.  Investigating the Effects of Metabolic Dysregulation on Hair Follicles: A Comparison of HIV-Infected Women With and Without Central Lipohypertrophy 
International journal of dermatology  2013;53(10):e443-e448.
Background
Normal lipid metabolism and functioning of the peroxisome proliferator activated receptor gamma (PPAR-gamma) in the sebaceous gland is critical to maintaining a normal hair follicle. Human immunodeficiency virus (HIV) infection affects lipid metabolism; some have hypothesized a link between PPAR-gamma function and lipodystrophy in HIV infection. Our objective was to determine whether lipodystrophy is associated with altered hair characteristics in HIV-infected women from the Women’s Interagency HIV Study (WIHS).
Methods
Hair characteristics and scalp inflammation were assessed by an interviewer-administered questionnaire. Central lipohypertrophy and peripheral lipoatrophy was defined by self report of moderate to severe fat gain in central body sites and fat loss in peripheral body sites, respectively confirmed by clinical examination. Additional covariates considered in the analyses included demographics, behavioral characteristics, medical history, and HIV-related factors.
Results
There were 1037 women with data on all study variables. 76 women reported central lipohypertrophy; only 4 women reported lipoatrophy. Women with central lipohypertrophy were more likely to be older, have a self-reported history of injection drug use, statin medication use, diabetes, elevated cholesterol, and have self-reported less hair and shorter eyelashes. After adjustment for age, central lipohypertrophy was associated with shorter eyelashes (OR 2.3; 95% CI 1.4-3.8).
Conclusions
Central lipohypertrophy was not associated with change in scalp hair texture or scalp inflammation in this cohort. Rather, we found an association between central lipohypertrophy and shorter eyelash length. This finding may be explained by an influence of prostaglandin E2 mediators on eyelash follicles.
doi:10.1111/ijd.12044
PMCID: PMC3785560  PMID: 23786579
eyelash; hair; HIV

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