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1.  Elevated Levels of Asymmetric Dimethylarginine are Associated With Lower CD4+ Count and Higher Viral Load in HIV-Infected Individuals 
Atherosclerosis  2013;229(1):246-252.
To compare asymmetric dimethylarginine (ADMA) among HIV-infected and uninfected individuals and to evaluate predictors of ADMA in HIV infection.
HIV-infected individuals have high rates of atherosclerosis. Endothelial dysfunction is central to atherogenesis and is one possible mechanism underlying this increased cardiovascular risk. ADMA is an endogenous inhibitor of endothelial nitric oxide synthase. Among uninfected individuals, higher ADMA levels predict cardiovascular events and mortality. The association between HIV infection, HIV-related factors, and ADMA has not been well described.
We compared ADMA in 248 HIV-infected individuals and 50 uninfected controls. We performed multivariable analysis using traditional cardiovascular and HIV-specific factors as covariates to identify factors associated with ADMA.
HIV-infected men were older, less often Caucasian, more hypertensive, and had lower HDL than uninfected men. The median duration of HIV infection was 13 years, median CD4+ count was 592 cells/μL, 76% had an undetectable viral load, and 76% were on antiretroviral therapy. ADMA levels were modestly higher in HIV-infected individuals than controls [median (IQR): 0.46μM (0.41–0.52) vs. 0.44μM (0.38–0.46), p=0.019], but the association lost statistical significance after controlling for cardiovascular risk factors (+0.028μM, p=0.054). Lower CD4+ count and both detectable and higher viral load were independently associated with increased ADMA.
ADMA levels were modestly elevated in the setting of HIV infection. Notably, a greater HIV-associated inflammatory burden, as evidenced by lower CD4+ counts and higher viral loads, was associated with increased ADMA levels. Our findingssuggest that HIV infection impairs endothelial function and predisposes to atherosclerosis through chronic inflammation and subsequent accumulation of ADMA.
PMCID: PMC3691342  PMID: 23711612
HIV; Asymmetric dimethylarginine; Endothelial dysfunction; Nitric oxide
2.  Serum albumin and short-term risk for mortality and cardiovascular disease among HIV-infected veterans 
AIDS (London, England)  2013;27(8):1339-1343.
We examined the short-term and long-term associations of serum albumin with mortality and cardiovascular disease among HIV-infected veterans.
Retrospective cohort analysis using a national database of US veterans with HIV infection.
This analysis evaluated all HIV-infected veterans in the Department of Veterans Affairs HIV Clinical Case Registry (CCR), a national database consisting of demographic, clinical, laboratory, pharmaceutical, and viral status data. There were 25 522 patients enrolled between 1986 and 2007. We evaluated the associations of baseline and time-updated serum albumin levels with all-cause mortality, atherosclerotic cardiovascular disease, and heart failure by multivariate proportional hazards models.
Over 21 years, there were 10 869 deaths; the cumulative mortality was 73.2 per 1000 person-years. After multivariate adjustment for covariates measured at baseline, the lowest category of serum albumin (<2.5 g/dl) was associated with a higher mortality risk compared with the highest category (>4 g/dl; hazard ratio 3.00; 2.67–3.37). When analyzed as a time-dependent model, the association strengthened substantially (15.1; 14.0–16.4). Findings were similar for atherosclerotic cardiovascular disease and heart failure. We stratified the baseline mortality model by year of follow-up and found that albumin was more strongly associated with deaths that occurred within 1 year of baseline (9.29; 7.85–11.0) than in the second (1.66; 1.18–2.33) or third (1.22; 0.77–1.96) year after measurement.
Among ambulatory HIV-infected patients, lower serum albumin levels are strongly predictive of mortality risk, particularly within 1 year.
PMCID: PMC4026018  PMID: 23343914
albumin; cardiovascular disease; end-stage renal disease; glomerular filtration rate; kidney
3.  Does HIV infection promote early kidney injury in women? 
Antiviral therapy  2013;19(1):79-87.
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.
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.
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.
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.
PMCID: PMC3933452  PMID: 23970313
4.  Decreased limb muscle and increased central adiposity are associated with 5-year all-cause mortality in HIV infection 
AIDS (London, England)  2011;25(11):1405-1414.
Unintentional loss of weight and muscle due to aging and disease has been associated with increased mortality. Wasting and weight loss occur in HIV infection even in the modern era of effective antiretroviral therapy.
We determined the association of MRI-measured regional and total skeletal muscle and adipose tissue with 5-year, all-cause mortality in 922 HIV-infected persons in the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM).
After 5 years of follow-up, HIV-infected participants with arm skeletal muscle in the lowest tertile had a mortality rate of 23%, compared with 11 and 8% for those in the middle and highest tertiles. After multivariable adjustment for demographics, cardiovascular risk factors, HIV-related factors, inflammatory markers, and renal disease, we found that lower arm skeletal muscle, lower leg skeletal muscle and higher visceral adipose tissue (VAT) were each independently associated with increased mortality. Those in the lowest tertile of arm or leg skeletal muscle had higher odds of death [arm: odds ratio (OR)=2.0, 95% confidence interval (CI) 0.96–4.0; leg: OR=2.4, 95% CI 1.2–4.8] compared with the highest respective tertiles. Those in the highest tertile of VAT had 2.1-fold higher odds of death (95% CI 1.1–4.0) compared with the lowest VAT tertile.
Lower muscle mass and central adiposity appear to be important risk factors for mortality in HIV-infected individuals. A substantial proportion of this risk may be unrecognized because of the current reliance on body mass index in clinical practice.
PMCID: PMC3933309  PMID: 21572308
body composition; cachexia; fat redistribution; HIV infection; lipoatrophy; lipodystrophy; mortality; sarcopenia
5.  Comparisons of creatinine and cystatin C for detection of kidney disease and prediction of all-cause mortality in HIV-infected women 
AIDS (London, England)  2013;27(14):2291-2299.
Cystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine.
Retrospective cohort analysis.
Cystatin C and creatinine were measured from specimens taken and stored during the 1999–2000 exam among 908 HIV-infected participants in the Women’s Interagency HIV study (WIHS). Mean follow-up was 10.2 years. The associations of baseline categories (<60, 60–90, and >90 mL/min/1.73m2) of creatinine eGFR (eGFRcr), cystatin C eGFR (eGFRcys), and combined creatinine-cystatin C eGFR (eGFRcr-cys) with all-cause mortality were evaluated using multivariable Cox regression. The net reclassification index (NRI) was calculated to evaluate the effect of cystatin C on reclassification of CKD staging.
The prevalence of CKD (eGFR<60) at baseline was higher with eGFRcys (10.1%) compared to eGFRcr (6.7%, p=0.0006) and eGFRcr-cys (7.5%, p=0.011). Relative to eGFR >90, the eGFR <60 category by eGFRcys (Adjusted HR: 2.56; 95% CI: 1.63, 4.02), eGFRcr-cys (3.11; 1.94–5.00), and eGFRcr (2.34; 1.44–3.79) was associated with increased mortality risk. However, the eGFR 60–90 category was associated with increased mortality risk for eGFRcys (1.80; 1.28–2.53) and eGFRcr-cys (1.91; 1.38–2.66) but not eGFRcr (1.20; 0.85–1.67). The overall NRI for mortality was 26% when reclassifying from eGFRcr to eGFRcys (p<0.001) and was 20% when reclassifying from eGFRcr to eGFRcr-cys (p<0.001).
Cystatin C detected a higher prevalence of CKD relative to creatinine and improves CKD staging relative to creatinine by reclassifying individuals at the highest mortality risk to lower eGFR categories.
PMCID: PMC3919542  PMID: 23669156
Creatinine; Cystatin C; Glomerular Filtration Rate; HIV; Mortality; Kidney; Women
6.  Doppler Echocardiography Does Not Accurately Estimate Pulmonary Artery Systolic Pressure in HIV-Infected Patients 
AIDS (London, England)  2012;26(15):1967-1969.
PMCID: PMC3897275  PMID: 22781217
HIV; pulmonary hypertension; Doppler echocardiography; right heart catheterization
8.  Urinary Markers of Kidney Injury and Kidney Function Decline in HIV-Infected Women 
HIV-infected persons have substantially higher risk of kidney failure than persons without HIV, but serum creatinine levels are insensitive for detecting declining kidney function. We hypothesized that urine markers of kidney injury would be associated with declining kidney function among HIV-infected women.
In the Women's Interagency HIV Study (WIHS), we measured concentrations of albumin-to-creatinine ratio (ACR), interleukin-18 (IL-18), kidney injury marker-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) from stored urine among 908 HIV-infected and 289 uninfected participants. Primary analyses used cystatin C based estimated glomerular filtration rate (CKD-EPI eGFRcys) as the outcome, measured at baseline and two follow-up visits over eight years; secondary analyses used creatinine (CKD-EPI eGFRcr). Each urine biomarker was categorized into tertiles, and kidney decline was modeled with both continuous and dichotomized outcomes.
Compared with the lowest tertiles, the highest tertiles of ACR (−0.15ml/min/1.73m2, p<0.0001), IL-18 (−0.09ml/min/1.73m2, p<0.0001) and KIM-1 (−0.06ml/min/1.73m2, p<0.001) were independently associated with faster eGFRcys decline after multivariate adjustment including all three biomarkers among HIV-infected women. Among these biomarkers, only IL-18 was associated with each dichotomized eGFRcys outcome: ≥3% (Relative Risk 1.40; 95%CI 1.04-1.89); ≥5% (1.88; 1.30-2.71); and ≥10% (2.16; 1.20-3.88) for the highest versus lowest tertile. In alternative models using eGFRcr, the high tertile of KIM-1 had independent associations with 5% (1.71; 1.25-2.33) and 10% (1.78; 1.07-2.96) decline, and the high IL-18 tertile with 10% decline (1.97; 1.00-3.87).
Among HIV-infected women in the WIHS cohort, novel urine markers of kidney injury detect risk for subsequent declines in kidney function.
PMCID: PMC3509242  PMID: 23023103
HIV; KIM-1; NGAL; IL-18; albumin-to-creatinine ratio; cystatin C; kidney injury
9.  A Randomized, Controlled Trial Assessing the Effects of Raltegravir Intensification on Endothelial Function in Treated HIV Infection 
To determine whether intensification with raltegravir improves endothelial function in antiretroviral-treated, HIV-infected individuals.
Randomized, double-blinded, placebo-controlled study.
Fifty-six subjects with treatment-mediated viral suppression for at least one year were randomized to add raltegravir 400 mg twice daily or matching placebo for 24 weeks. The primary endpoint was the difference in rate of change in endothelial function (as assessed by flow-mediated vasodilation of the brachial artery [FMD]) from baseline to week 24 between the raltegravir and placebo groups. Linear mixed models were used to evaluate the association of treatment group with changes in FMD, immune activation, and measures of viral persistence.
At baseline, the median CD4+ T cell count was 498 cells/mm3, nadir CD4+ T cell count was 191 cells/mm3, duration of HIV infection was 18 years, FMD was 3.3%, and hyperemic velocity (a marker of microvascular function) was 68.3 cm. There were no significant differences between treatment groups in rate of change in FMD (raltegravir group +0.032% per week, placebo group +0.023% per week; p=0.60). There were also no differences between treatment groups in rate of change in hyperemic velocity, immune activation, or viral persistence. In multivariable analysis, older age, longer duration of HIV infection, and current abacavir use were associated with lower FMD. Lower CD4+ T cell count and current abacavir use were associated with lower hyperemic velocity.
The addition of raltegravir to suppressive antiretroviral therapy did not have a significant impact on cardiovascular risk, as assessed by endothelial function ( NCT00843713).
PMCID: PMC3480968  PMID: 22918156
HIV; raltegravir intensification; endothelial function; flow-mediated vasodilation
10.  Weight change following GPi or STN deep brain stimulation in Parkinson’s disease and dystonia 
Weight gain has been described in Parkinson’s disease (PD) patients after subthalamic nucleus (STN) deep brain stimulation (DBS).
We examined change in weight following DBS in both PD and dystonia patients to further investigate the role of disease and brain target (STN or GPi) specificity.
Data was retrospectively collected on 61 PD DBS patients (STN (n=31) or GPi (n=30)) and on 36 dystonia DBS patients (STN (n=9) and GPi (n=27)) before and after surgery. Annual change in body mass index (BMI) was evaluated with non-parametric tests between groups and multiple quantile regression.
PD patients treated with STN DBS had a small increase in median BMI while those with GPi had a small decrease in BMI. Dystonia patients treated with STN DBS had a greater increase in BMI per year compared to those treated with GPi. Multivariable regression analyses for each disease showed little difference between targets in weight gain in those with PD, but STN target was strongly associated with weight gain in dystonia patients (STN vs. GPi, +7.99 kg, p=0.012).
Our results support previous reports of weight gain after DBS in PD. This is the first report to suggest a target-specific increase in weight following STN DBS in dystonia patients.
PMCID: PMC3698968  PMID: 22922491
deep brain stimulation; Parkinson’s disease; dystonia; Subthalamic Nucleus; Globus Pallidus; weight change
11.  Association of Tenofovir Exposure with Kidney Disease Risk in HIV Infection 
AIDS (London, England)  2012;26(7):867-875.
Despite widespread highly active antiretroviral therapy use, HIV disease remains associated with increased risk of kidney disease. Whether tenofovir use is associated with higher risk of kidney disease is controversial.
We evaluated the association of cumulative and ever exposure to tenofovir on kidney outcomes in 10,841 HIV-infected patients from the Veterans Health Administration who initiated antiretroviral therapy from 1997-2007.
Cox proportional hazards and marginal structural models evaluated associations between tenofovir and time to first occurrence of 1) proteinuria (two consecutive urine dipstick measurements ≥30mg/dL), 2) rapid decline in kidney function (≥3ml/min/1.73m2 annual decline), and 3) CKD (estimated glomerular filtration rate <60ml/min/1.73m2).
Median follow-up ranged from 3.9 years (proteinuria) to 5.5 years (CKD), during which 3400 proteinuria, 3078 rapid decline, and 533 CKD events occurred. After multivariable adjustment, each year of exposure to tenofovir was associated with 34% increased risk of proteinuria (95%CI 25-45%, p<0.0001), 11% increased risk of rapid decline (3-18%, p=0.0033), and 33% increased risk of CKD (18-51%; p<0.0001). Pre-existing renal risk factors did not appear to worsen the effects of tenofovir. Other ARVs showed weaker or inconsistent associations with kidney disease events. Among those who discontinued tenofovir use, risk of kidney disease events did not appear to decrease during follow-up.
Tenofovir exposure was independently associated with increased risk for three types of kidney disease events, and did not appear to be reversible. Because subtle kidney function decline affects long-term morbidity and mortality, the balance between efficacy and probable adverse effects requires further study.
PMCID: PMC3736566  PMID: 22313955
HIV; antiretroviral therapy; kidney disease; tenofovir
12.  Intermuscular Adipose Tissue and Metabolic Associations in HIV Infection 
Obesity (Silver Spring, Md.)  2010;19(2):283-291.
Intermuscular adipose tissue (IMAT) is associated with metabolic abnormalities similar to those associated with visceral adipose tissue (VAT). Increased IMAT has been found in obese human immunodeficiency virus (HIV)-infected women. We hypothesized that IMAT, like VAT, would be similar or increased in HIV-infected persons compared with healthy controls, despite decreases in subcutaneous adipose tissue (SAT) found in HIV infection. In the second FRAM (Study of Fat Redistribution and Metabolic Change in HIV infection) exam, we studied 425 HIV-infected subjects and 211 controls (from the Coronary Artery Risk Development in Young Adults study) who had regional AT and skeletal muscle (SM) measured by magnetic resonance imaging (MRI). Multivariable linear regression identified factors associated with IMAT and its association with metabolites. Total IMAT was 51% lower in HIV-infected participants compared with controls (P = 0.003). The HIV effect was attenuated after multivariable adjustment (to −28%, P < 0.0001 in men and −3.6%, P = 0.70 in women). Higher quantities of leg SAT, upper-trunk SAT, and VAT were associated with higher IMAT in HIV-infected participants, with weaker associations in controls. Stavudine use was associated with lower IMAT and SAT, but showed little relationship with VAT. In multivariable analyses, regional IMAT was associated with insulin resistance and triglycerides (TGs). Contrary to expectation, IMAT is not increased in HIV infection; after controlling for demographics, lifestyle, VAT, SAT, and SM, HIV+ men have lower IMAT compared with controls, whereas values for women are similar. Stavudine exposure is associated with both decreased IMAT and SAT, suggesting that IMAT shares cellular origins with SAT.
PMCID: PMC3731045  PMID: 20539305
13.  HIV viremia and changes in kidney function 
AIDS (London, England)  2009;23(9):1089-1096.
To evaluate the effect of HIV infection on longitudinal changes in kidney function and to identify independent predictors of kidney function changes in HIV-infected individuals.
A prospective cohort.
Cystatin C was measured at baseline and at the 5-year follow-up visit of the Study of Fat Redistribution and Metabolic Change in HIV infection in 554 HIV-infected participants and 230 controls. Control participants were obtained from the Coronary Artery Risk Development in Young Adults study. Glomerular filtration rate (eGFRcys) was estimated using the formula 76.7 × cysC−1.19.
Compared with controls, HIV-infected participants had a greater proportion of clinical decliners (annual decrease in eGFRcys > 3 ml/min per 1.73 m2; 18 versus 13%, P=0.002) and clinical improvers (annual increase in eGFRcys > 3 ml/min per 1.73 m2; 26 versus 6%, P< 0.0001). After multivariable adjustment, HIV infection was associated with higher odds of both clinical decline (odds ratio 2.2; 95% confidence interval 1.3, 3.9, P = 0.004) and clinical improvement (odds ratio 7.3; 95% confidence interval 3.9, 13.6, P ≤ 0.0001). Among HIV-infected participants, a decrease in HIV viral load during follow-up was independently associated with clinical improvement; conversely, higher baseline and an increase in viral load during follow-up were associated with clinical decline. No individual antiretroviral drug or drug class appeared to be substantially associated with clinical decline or improvement.
Compared with controls, HIV-infected persons were more likely both to have clinical decline and clinical improvement in kidney function during 5 years of follow-up. The extent of viremic control had a strong association with longitudinal changes in kidney function.
PMCID: PMC3725756  PMID: 19352136
cystatin C; glomerular filtration rate; HIV; kidney; viral load
14.  HIV Infection Is Associated With Decreased Thrombin Generation 
HIV infection is associated with decreased thrombin generation and an increased antithrombin level. These data suggest that HIV infection may not be associated with an increased propensity towards clotting.
Background. Excess risk of cardiovascular disease occurs in effectively treated individuals with human immunodeficiency virus (HIV) infection. Although elevated plasma D-dimer levels are associated with increased morbidity and mortality, the impact of HIV infection on coagulation in vivo has not been well studied.
Methods. We measured D-dimers, antithrombin, endogenous thrombin potential (ETP; a functional measure of thrombin generation in vitro), thrombin/antithrombin complexes (TAT; a measure of thrombin generation in vivo), tissue factor, prothrombin fragment 1 + 2 (F1+2), and normalized APC sensitivity ratio (nAPCsr) in 199 HIV-positive men who were receiving antiretroviral therapy and had an undetectable HIV RNA level, in 79 HIV-positive untreated men, and in 39 uninfected controls.
Results. Median antithrombin levels were higher while the ETP was lower among HIV-infected adults (treated and untreated), compared with controls. There were few differences between coagulation markers in the 2 HIV groups. Compared with controls, the nAPCsr was lower in treated men and the TAT level was lower in untreated individuals. We observed little difference among measured levels of D-dimer, tissue factor, or F1+2 between HIV-infected individuals and controls. Antiretroviral therapy exposure was associated with a lower antithrombin level, a lower nAPCsr, and a lower ETP, while history of opportunistic infection was associated with a higher nAPCsr.
Conclusions. HIV infection is associated with decreased thrombin generation, as measured by the ETP, and an increased antithrombin level. These data suggest that HIV infection may not be associated with increased propensity toward clotting, as has been suggested on the basis of isolated measures of D-dimer levels.
PMCID: PMC3309887  PMID: 22438347
15.  Genes Linked to Energy Metabolism and Immunoregulatory Mechanisms are Associated with Subcutaneous Adipose Tissue Distribution in HIV-infected Men 
Pharmacogenetics and genomics  2011;21(12):798-807.
Genetic studies may help explain abnormalities of fat distribution in HIV-infected patients treated with antiretroviral therapy (ARV).
Subcutaneous adipose tissue (SAT) volume measured by magnetic resonance imaging (MRI) in leg, lower trunk, upper trunk, and arm was examined in 192 HIV-infected Caucasian men, ARV-treated from the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study. Single nucleotide polymorphisms (SNPs) were assayed using the Illumina HumanCNV370-quad beadchip. Multivariate and univariate genome wide association analyses of the four SAT depots were implemented in PLINK software adjusted for age and ARV duration. Functional annotation analysis (FAA) using Ingenuity Systems Pathway Analysis tool (IPA) was carried out for markers with P<10-3 near known genes identified by multivariate analysis.
Loci (rs10504906, rs13267998, rs921231) in or near the anion exchanger solute carrier family 26, member 7 isoform a (SLC26A7) were strongly associated with upper trunk and arm SAT (9.8*10-7≤P<7.8*10-6). Loci (rs193139, rs7523050, rs1761621) in and near a gene rich region including G-protein-signaling modulator 2 (GPSM2) and syntaxin binding protein 3 (STXBP3) were significantly associated with lower body SAT depots (9.9*10-7≤P<9.5*10-6). GPSM2 is associated with cell division and cancer while STXBP3 is associated with glucose metabolism in adipoctyes. IPA identified atherosclerosis, mitochondrial function and T-Cell mediated apoptosis as processes related to SAT volume in HIV-infected individuals (P<5*10-3).
Our results are limited by the small sample size and replication is needed, however this genomic scan uncovered new genes associated with metabolism and inflammatory pathways that may affect SAT volume in ARV-treated HIV-infected patients.
PMCID: PMC3210910  PMID: 21897333
HIV; HAART; GWAS; Subcutaneous Fat; SAT
16.  Association of Increased Upper Trunk and Decreased Leg Fat With 2-h Glucose in Control and HIV-Infected Persons 
Diabetes Care  2011;34(11):2448-2453.
Changes in body fat distribution and abnormal glucose metabolism are common in HIV-infected patients. We hypothesized that HIV-infected participants would have a higher prevalence of impaired glucose tolerance (IGT) compared with control subjects.
A total of 491 HIV-infected and 187 control participants from the second examination of the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) underwent glucose tolerance testing (GTT). Multivariable regression was used to identify factors associated with GTT parameters.
The prevalence of impaired fasting glucose (IFG) (>110 mg/dL) was similar in HIV-infected and control participants (21 vs. 25%, P = 0.23). In those without IFG, the prevalence of IGT was slightly higher in HIV-infected participants compared with control subjects (13.1 vs. 8.2%, P = 0.14) and in HIV+ participants with lipoatrophy versus without (18.1 vs. 11.5%, P = 0.084). Diabetes detected by GTT was rare (HIV subjects 1.3% and control subjects 0%, P = 0.65). Mean 2-h glucose levels were 7.6 mg/dL higher in the HIV-infected participants (P = 0.012). Increased upper trunk subcutaneous adipose tissue (SAT) and decreased leg SAT were associated with 2-h glucose and IGT in both HIV-infected and control participants. Adjusting for adipose tissue reduced the estimated effects of HIV. Exercise, alcohol use, and current tenofovir use were associated with lower 2-h glucose levels in HIV-infected participants.
In HIV infection, increased upper trunk SAT and decreased leg SAT are associated with higher 2-h glucose. These body fat characteristics may identify HIV-infected patients with normal fasting glucose but nonetheless at increased risk for diabetes.
PMCID: PMC3198295  PMID: 21926283
17.  Regional Anthropometry Changes in Antiretroviral-Naïve Persons Initiating a Zidovudine-Containing Regimen in Mbarara, Uganda 
Lipodystrophy is commonly reported in Africa after antiretroviral therapy (ART) is initiated, but few studies have objectively measured changes in body composition. Body composition was determined in 76 HIV-infected participants from Mbarara, Uganda after starting a thymidine-analog regimen, and annual change was determined using repeated measures analysis. We measured skinfolds (tricep, thigh, subscapular, and abdomen), circumferences (arm, hip, thigh, waist), and total lean and fat mass (using bioelectric impedance analysis). A cross-sectional sample of 49 HIV-uninfected participants was studied for comparison. At baseline, most body composition measures were lower in HIV-infected than uninfected participants, but waist circumference was similar. After 12 months on ART, there was little difference in body composition measures between HIV-infected and uninfected participants; median waist circumference appeared higher in HIV-infected participants (79 vs. 75 cm; p = 0.090). Among HIV-infected participants, increases were observed in total lean and fat mass, circumference, and skinfold measures; only the increase in tricep skinfold did not reach statistical significance (+1.05 mm; 95% confidence interval: −0.24, 2.34; p = 0.11). Regional anthropometry in peripheral and central body sites increased over 12 months after ART initiation in HIV-infected persons from southwestern Uganda, suggesting a restoration to health. Gains in the tricep skinfold, a reliable marker of subcutaneous fat, appeared blunted, which could indicate an inhibitory effect of zidovudine on peripheral subcutaneous fat recovery.
PMCID: PMC3159125  PMID: 21128866
18.  Reduced Kidney Function and Preclinical Atherosclerosis in HIV-Infected Individuals: The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) 
American Journal of Nephrology  2011;33(5):453-460.
Reduced kidney function and albuminuria are associated with higher risk for cardiovascular disease (CVD) and mortality in HIV-infected individuals. We investigated whether reduced estimated glomerular filtration rate (eGFR) and albuminuria are associated with subclinical vascular disease, as assessed by carotid intima-medial thickness (cIMT).
Cross-sectional analysis of 476 HIV-infected individuals without clinical evidence of CVD enrolled in the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study, using multivariable linear regression. eGFRCys and eGFRCr were calculated from cystatin C and creatinine levels. Albuminuria was defined as a positive urine dipstick (≥1+) or urine albumin-to-creatinine ratio ≥30 mg/g. Common and internal cIMT were measured by high-resolution B-mode ultrasound.
In unadjusted analyses, eGFRCys and eGFRCr were strongly associated with common and internal cIMT. Each 10 ml/min/1.73 m2 decrease in eGFRCys and eGFRCr was associated with a 0.008 mm higher common cIMT (p = 0.003, p = 0.01) and a 0.024 and 0.029 mm higher internal cIMT (p = 0.003), respectively. These associations were eliminated after adjustment for age, gender, and race. Albuminuria showed little association with common or internal cIMT in all models.
In HIV-infected individuals without prior CVD, reduced kidney function and albuminuria were not independently associated with subclinical vascular disease, as assessed by cIMT. These results suggest that research should focus on searching for novel mechanisms by which kidney disease confers cardiovascular risk in HIV-infected individuals.
PMCID: PMC3100378  PMID: 21508633
Cystatin C; Intima-medial thickness; HIV; Atherosclerosis; Cardiovascular disease; Kidney
19.  Carotid Intima-Media Thickness Progression in HIV-Infected Adults Occurs Preferentially at the Carotid Bifurcation and Is Predicted by Inflammation 
Shear stress gradients and inflammation have been causally associated with atherosclerosis development in carotid bifurcation regions. The mechanism underlying higher levels of carotid intima-media thickness observed among HIV-infected individuals remains unknown.
Methods and Results
We measured carotid intima-media thickness progression and development of plaque in the common carotid, bifurcation region, and internal carotid artery in 300 HIV-infected persons and 47 controls. The median duration of follow-up was 2.4 years. When all segments were included, the rate of intima-media thickness progression was greater in HIV-infected subjects compared with controls after adjustment for traditional risk factors (0.055 vs. 0.024 mm/year, P=0.016). Rate of progression was also greater in the bifurcation region (0.067 vs. 0.025 mm/year, P=0.042) whereas differences were smaller in the common and internal regions. HIV-infected individuals had a greater incidence of plaque compared with controls in the internal (23% vs. 6.4%, P=0.0037) and bifurcation regions (34% vs. 17%, P=0.014). Among HIV-infected individuals, the rate of progression in the bifurcation region was more rapid compared with the common carotid, internal, or mean intima-media thickness; in contrast, progression rates among controls were similar at all sites. Baseline hsCRP was elevated in HIV-infected persons and was a predictor of progression in the bifurcation region.
Atherosclerosis progresses preferentially in the carotid bifurcation region in HIV-infected individuals. hsCRP, a marker of inflammation, is elevated in HIV and is associated with progression in the bifurcation region. These data are consistent with a model in which the interplay between hemodynamic shear stresses and HIV-associated inflammation contribute to accelerated atherosclerosis. (J Am Heart Assoc. 2012;1:jah3-e000422 doi: 10.1161/JAHA.111.000422.)
Clinical Trial Registration
URL: Unique identifier: NCT01519141
PMCID: PMC3487373  PMID: 23130122
AIDS; carotid arteries; inflammation; atherosclerosis
21.  Age-Related Skeletal Muscle Decline Is Similar in HIV-Infected and Uninfected Individuals 
Skeletal muscle (SM) mass decreases with advanced age and with disease in HIV infection. It is unknown whether age-related muscle loss is accelerated in the current era of antiretroviral therapy and which factors might contribute to muscle loss among HIV-infected adults. We hypothesized that muscle mass would be lower and decline faster in HIV-infected adults than in similar-aged controls.
Whole-body 1H-magnetic resonance imaging was used to quantify regional and total SM in 399 HIV-infected and 204 control men and women at baseline and 5 years later. Multivariable regression identified associated factors.
At baseline and Year 5, total SM was lower in HIV-infected than control men. HIV-infected women were similar to control women at both time points. After adjusting for demographics, lifestyle factors, and total adipose tissue, HIV infection was associated with lower Year 5 SM in men and higher SM in women compared with controls. Average overall 5-year change in total SM was small and age related, but rate of change was similar in HIV-infected and control men and women. CD4 count and efavirenz use in HIV-infected participants were associated with increasing SM, whereas age and stavudine use were associated with decreasing SM.
Muscle mass was lower in HIV-infected men compared with controls, whereas HIV-infected women had slightly higher SM than control women after multivariable adjustment. We found evidence against substantially faster SM decline in HIV infected versus similar-aged controls. SM gain was associated with increasing CD4 count, whereas stavudine use may contribute to SM loss.
PMCID: PMC3041474  PMID: 21310810
Sarcopenia; Lipoatrophy; Fat redistribution; Body composition
22.  Associations of antiretroviral drug use and HIV-specific risk factors with carotid intima–media thickness 
AIDS (London, England)  2010;24(14):2201-2209.
Previous research has demonstrated an increase in carotid intima–media thickness (cIMT) in HIV-infected individuals compared to controls. However, the reason for this increased level of subclinical vascular disease is unknown.
To identify HIV-related risk factors for increased cIMT.
We evaluated the relationship between HIV-related characteristics (including markers of HIV disease severity and use of antiretroviral therapy) and cIMT measurements in the internal/bulb and common carotid regions among 538 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). We used Bayesian model averaging to estimate the posterior probability of candidate HIV and non-HIV-related risk factors being true predictors of increased cIMT. Variables with a posterior probability of more than 50% were used to develop a selected regression model for each of the anatomic regions.
For common cIMT, the Bayesian model selection process identified age, African-American race, and systolic and diastolic blood pressure with probability more than 95%, HDL cholesterol with probability 85% and Hispanic ethnicity with probability 51%. Among the HIV-related factors included in the analysis, only tenofovir use was selected (51% probability). In the selected model, duration of tenofovir use was associated with lower common cIMT (−0.0094 mm/year of use; 95% confidence interval: −0.0177 to −0.0010). For internal cIMT, no HIV-related risk factors were above the 50% posterior probability threshold.
We observed an inverse association between duration of tenofovir use and common carotid cIMT. Whether this association is causal or due to confounding by indication needs further investigation.
PMCID: PMC3224487  PMID: 20671544
atherosclerosis; carotid intima–media thickness; HIV; tenofovir
23.  Association of Low Level Viremia with Inflammation and Mortality in HIV-Infected Adults 
PLoS ONE  2011;6(11):e26320.
Whether HIV viremia, particularly at low levels is associated with inflammation, increased coagulation, and all-cause mortality is unclear.
The associations of HIV RNA level with C-reactive protein (CRP), fibrinogen, interleukin (IL)-6 and mortality were evaluated in 1116 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV infection. HIV RNA level was categorized as undetectable (i.e., “target not detected”), 1–19, 20–399, 400–9999, and ≥10,000 copies/ml. Covariates included demographics, lifestyle, adipose tissue, and HIV-related factors.
HIV RNA level had little association with CRP. Categories of HIV RNA below 10,000 copies/ml had similar levels of IL-6 compared with an undetectable HIV RNA level, while HIV RNA ≥10,000 copies/ml was associated with 89% higher IL-6 (p<0.001). This association was attenuated by ∼50% after adjustment for CD4+ cell count. Higher HIV RNA was associated with higher fibrinogen. Compared to an undetectable HIV RNA level, fibrinogen was 0.6%, 1.9%, 4.5%, 4.6%, and 9.4% higher across HIV RNA categories, respectively, and statistically significant at the highest level (p = 0.0002 for HIV RNA ≥10,000 copies/ml). Higher HIV RNA was associated with mortality during follow-up in unadjusted analysis, but showed little association after adjustment for CD4+ cell count and inflammation.
HIV RNA ≥10,000 copies/ml was associated with higher IL-6 and fibrinogen, but lower levels of viremia appeared similar, and there was little association with CRP. The relationship of HIV RNA with IL-6 was strongly affected by CD4 cell depletion. After adjustment for CD4+ cell count and inflammation, viremia did not appear to be substantially associated with mortality risk over 5 years.
PMCID: PMC3206804  PMID: 22073156
24.  Inflammation and Mortality in HIV-infected Adults: Analysis of the FRAM Study Cohort 
To determine the association of inflammatory markers, fibrinogen and C-reactive protein (CRP), with 5-year mortality risk.
Vital status was ascertained in 922 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV infection. Multivariable logistic regression estimated odds ratios (OR) after adjustment for demographic, cardiovascular and HIV-related factors.
Over a 5-year period, HIV-infected participants with fibrinogen levels in the highest tertile(>406mg/dL) had 2.6-fold higher adjusted odds of death than those with fibrinogen in the lowest tertile(<319mg/dL). Those with high CRP(>3mg/L) had 2.7-fold higher adjusted odds of death than those with CRP<1mg/L. When stratified by CD4 count category, fibrinogen (as a linear variable) remained independently associated [OR(95% confidence intervals) per 100mg/dL increase in fibrinogen: 1.93(1.57,2.37);1.43(1.14,1.79);1.43(1.14,1.81);and 1.30(1.04,1.63) for CD4 <200,200–350,>350–500, and >500cells/μL, respectively. Higher CRP also remained associated with higher odds of death overall and within each CD4 subgroup.
Fibrinogen and CRP are strong and independent predictors of mortality in HIV-infected adults. Our findings suggest that even in those with relatively preserved CD4 counts >500cells/μL, inflammation remains an important risk factor for mortality. Further investigation should determine whether interventions to reduce inflammation might decrease mortality risk in HIV-infected individuals.
PMCID: PMC2955817  PMID: 20581689
HIV; inflammation; C-reactive protein; fibrinogen; mortality
25.  Cystatin C, Albuminuria, and 5-Year All-Cause Mortality in HIV-Infected Persons 
Compared with controls, HIV-infected persons have a greater prevalence of kidney disease as assessed by high levels of cystatin C and albuminuria, but not as assessed by creatinine level. However, the clinical importance of elevated cystatin C and albuminuria in the HIV-infected population has not been studied.
Study Design
We conducted an observational cohort study to determine the association of kidney disease (measured by albuminuria, cystatin C, and serum creatinine) with mortality.
Setting & Participants
922 HIV-infected persons enrolled in the FRAM (Fat Redistribution and Metabolic Change in HIV infection) study.
Serum cystatin C and serum creatinine were used to estimate glomerular filtration rate (eGFR). Albuminuria was defined as a positive urine dipstick (≥1+) or a urine albumin-creatinine ratio > 30 mg/g.
5-year mortality
At baseline, reduced kidney function (eGFRSCysC <60 mL/min/1.73m2) or albuminuria was present in 28% of participants. After five years of follow-up, mortality was 48% among those with both eGFRSCysC <60 mL/min/1.73m2 and albuminuria, 23% in those with eGFRSCysC <60 mL/min/1.73m2 alone, 20% in those with albuminuria alone, and 9% in those with neither condition. After multivariable adjustment for demographics, cardiovascular risk factors, HIV-related factors, and inflammatory markers, eGFRSCysC <60 mL/min/1.73m2 and albuminuria were associated with nearly a twofold increase in mortality, whereas eGFRSCr <60 mL/min/1.73m2 did not appear to have any substantial association with mortality. Together, eGFRSCysC <60 mL/min/1.73m2 and albuminuria accounted for 17% of the population-level attributable risk for mortality.
Vital status was unknown in 261 participants from the original cohort.
Kidney disease marked by albuminuria or increased cystatin C levels appears to be an important risk factor for mortality in HIV-infected individuals. A substantial proportion of this risk may be unrecognized because of the current reliance on serum creatinine to estimate kidney function in clinical practice.
PMCID: PMC3164880  PMID: 20709438
kidney disease; mortality; HIV infection

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