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1.  Elevated rates of intracerebral hemorrhage in individuals from a US clinical care HIV cohort 
Neurology  2014;83(19):1705-1711.
To compare rates of intracerebral hemorrhage (ICH) in HIV-infected and uninfected individuals in a large clinical care cohort and to assess risk factors associated with ICH.
We identified incident ICH in HIV-infected and uninfected control cohorts from the Partners Health Care system using ICD-9-CM codes. We constructed Cox proportional hazards models to estimate adjusted hazard ratios for HIV infection and other predictors of ICH.
The incidence rate of ICH was 2.29 per 1,000 person-years in HIV-infected individuals compared with 1.23 per 1,000 person-years in uninfected individuals, with an unadjusted incidence rate ratio of 1.85 (95% confidence interval 1.37–2.47, p < 0.001). In a multivariable model, HIV infection was independently associated with a higher hazard of ICH, although its effect diminished with increasing age. Female sex was associated with a lower hazard of ICH in the uninfected cohort but not in the HIV cohort. CD4 count <200 × 106 cells/L and anticoagulant use were predictive of ICH.
HIV infection conferred an increased adjusted hazard of ICH, which was more pronounced in young patients and in women.
PMCID: PMC4239837  PMID: 25280902
2.  Plaque Burden in HIV-Infected Patients is Associated with Serum Intestinal Microbiota-generated Trimethylamine 
AIDS (London, England)  2015;29(4):443-452.
Some intestinal microbiota-generated metabolites of phosphatidylcholine are recognized to be pro-atherogenic. As the HIV population is vulnerable to cardiovascular disease (CVD) and can develop intestinal dysbiosis associated with systemic inflammation, we investigated the novel relationship between microbiota-derived metabolites of phosphatidylcholine and coronary atherosclerosis in HIV.
155 HIV-infected and 67 non-HIV-infected subjects without known history of CVD were previously recruited to assess coronary plaque by CT angiography. In the current study, we evaluate whether serum choline, trimethylamine (TMA), or trimethylamine N-oxide(TMAO) levels are associated with plaque features.
Young, asymptomatic HIV-infected subjects (age 47±7 years) demonstrated significantly higher prevalence of plaque (53 vs. 35%, P=0.01) and number of total plaque segments (1.8±2.5 vs. 1.2±2.2, P=0.03) when compared to well-matched non-infected subjects with similar co-morbidities. TMA was significantly associated with calcium score (r=0.22, P=0.006), number of total (r=0.20, P=0.02) and calcified (r=0.18, P=0.03) plaque segments, and calcium plaque volume (r=0.19, P=0.02) and mass (r=0.22, P=0.009) in the HIV cohort only. In multivariate modeling among HIV-infected subjects, TMA remained significantly associated with calcium score (P=0.008), number of total (P=0.005) and calcified (P=0.02) plaque segments, and calcium plaque volume (P=0.01) and mass (P=0.007), independent of Framingham Risk Score. In contrast, there was no association of TMAO to coronary plaque features in either cohort.
A link between TMA and atherosclerosis has not previously been established. The current study suggests that TMA may be a non-traditional risk factor related to the number of plaque segments and severity of calcified plaque burden in HIV.
PMCID: PMC4410017  PMID: 25565500
HIV; Trimethylamine; Trimethylamine-N-Oxide; Coronary Plaque; Gut Microbiota; Inflammation
3.  Soluble CD163 is Associated with Shortened Telomere Length in HIV-infected Patients 
Telomere length (TL) and immune activation markers were measured in a cohort of HIV-infected (n=102) and age-matched non-HIV-infected (n=41) men. TL was significantly shorter in HIV-infected compared to non-HIV-infected subjects (P = 0.04). Univariate analysis revealed a strong inverse relationship of TL to sCD163, and thus, monocyte/macrophage activation, among the HIV group (ρ = −0.30, P = 0.003). In multivariate modeling among the whole group, HIV positive serostatus (P = 0.06) and sCD163 (P = 0.05) were independent predictors of TL controlling for age and smoking status. Our data demonstrate that increased immune activation relates to shorter TL in HIV.
PMCID: PMC4213298  PMID: 25197827
sCD163; telomeres; HIV; immune activation; immunosenescence; aging
4.  Noncalcified Coronary Atherosclerotic Plaque and Immune Activation in HIV-Infected Women 
The Journal of Infectious Diseases  2013;208(11):1737-1746.
Background. Little is known about coronary plaque in human immunodeficiency virus (HIV)–infected women.
Methods. Sixty HIV-infected and 30 non–HIV-infected women without symptoms or history of cardiovascular disease were recruited to assess coronary plaque with coronary computed tomographic angiography and immune activation. Data from 102 HIV-infected men and 41 non–HIV-infected male controls were compared.
Results. HIV-infected women demonstrated significantly higher percentages of segments with noncalcified plaque (mean ± SD, 74% ± 28% vs 23% ± 39% compared to female control subjects; median [interquartile range], 75% [63%–100%] vs 0% [0%–56%]; P = .007) and more segments with noncalcified plaque (mean ± SD, 0.92 ± 1.48 vs 0.40 ± 1.44; median [interquartile range], 0 [0–2] vs 0 [0–0]; P = .04). Immune activation parameters, including soluble CD163 (sCD163; P = .006), CXCL10 (P = .002), and percentages of CD14+CD16+ monocytes (P = .008), were higher in HIV-infected women than in female control subjects, but no differences were seen in general inflammatory markers. Among HIV-infected women with noncalcified coronary plaque, sCD163 levels were significantly higher than in HIV-infected women without noncalcified plaque (P = .04). In multivariate modeling for sCD163 levels among male and female subjects, significant effects of HIV (P < .0001), age (P = .002), and sex (P = .0002) were seen.
Conclusions. Young, asymptomatic, HIV-infected women, demonstrate increased noncalcified coronary plaque and increased immune activation, particularly monocyte activation. Independent effects of sex, HIV status, and aging on immune activation may contribute to cardiovascular disease in this population.
Clinical Trials Registration. NCT00455793.
PMCID: PMC3814845  PMID: 24041790
HIV; atherosclerosis; cardiovascular disease; non-calcified coronary plaque; immune activation; age
5.  Effects of Aging and Smoking on Carotid Intima Media Thickness in HIV-infection 
AIDS (London, England)  2013;27(1):49-57.
To investigate the effects of aging and smoking on carotid intima-media thickness (cIMT) among patients with and without HIV.
Data from a community sample of HIV-infected and HIV-uninfected participants were analyzed. Carotid intima-media thickness was measured via carotid ultrasound and smoking history was obtained via patient interview.
Data on 166male and female participants with stable HIV-infection and 152 healthy HIV-uninfected participants were analyzed. Among the HIV-infected and HIV-uninfected participants, a significant association was observed between age and cIMT [r=0.51, P<0.0001 (HIV), r=0.39, P<0.0001, (non-HIV)], and between smoking burden and cIMT [r=0.42, P<0.0001 (HIV), r=0.24, P=0.003 (non-HIV)]. In multivariate regression modeling among all participants (HIV and non-HIV), a significant three-way interaction was observed between age, smoking burden, and HIV status with respect to cIMT (P<0.010), controlling for gender, race and traditional cardiovascular disease (CVD) risk factors, such that increased cIMT was associated with increased smoking burden and age to a greater degree among HIV-infected vs. HIV-uninfected participants. Among HIV-infected participants a significant interaction between smoking burden and age with respect to cIMT was seen (P=0.027), controlling for race, gender, CVD risk factors, immunological function and antiretroviral therapy use.
A significant interaction between HIV, age and smoking on cIMT was observed, suggesting that HIV-infection modifies the relationship of age and smoking on cIMT in this population. These findings emphasize the need to encourage smoking cessation in this population, due to its deleterious effect on subclinical atherosclerosis in older HIV-infected patients.
PMCID: PMC3690796  PMID: 22874518
HIV; Aging; Cardiovascular Diseases; Smoking
6.  Reduction in Visceral Adiposity Is Associated With an Improved Metabolic Profile in HIV-Infected Patients Receiving Tesamorelin 
Following treatment with the growth hormone–releasing hormone analogue tesamorelin, patients who experience reduced visceral adiposity have improved lipid levels and relatively unchanged glucose homeostasis, whereas patients who do not experience decreased visceral fat have worsened glucose homeostasis and unchanged lipid levels.
Background. Tesamorelin, a growth hormone–releasing hormone analogue, decreases visceral adipose tissue (VAT) by 15%–20% over 6–12 months in individuals with human immunodeficiency virus (HIV)–associated abdominal adiposity, but it is unknown whether VAT reduction is directly associated with endocrine and metabolic changes.
Methods. In 2 phase III, randomized, double-blind studies, men and women with HIV-associated abdominal fat accumulation were randomly assigned (ratio, 2:1) to receive tesamorelin or placebo for 26 weeks. At week 26, patients initially receiving tesamorelin were randomly assigned to continue receiving tesamorelin or to receive placebo for an additional 26 weeks. In per-protocol analysis of 402 subjects initially randomly assigned to receive tesamorelin, those with ≥8% reduction in VAT were defined a priori as responders per the statistical analysis plan. Post hoc analyses were performed to assess differences between responders and nonresponders.
Results. Compared with tesamorelin nonresponders, responders experienced greater mean (±SD) reduction in triglyceride levels (26 weeks: −0.6 ± 1.7 mmol/L vs −0.1 ± 1.2 mmol/L [P = .005]; 52 weeks: −0.8 ± 1.8 mmol/L vs 0.0 ± 1.1 mmol/L [P = .003]) and attenuated changes in fasting glucose levels (26 weeks: 1 ± 16 mg/dL vs 5 ± 14 mg/dL [P = .01]; 52 weeks: −1 ± 14 mg/dL vs 8 ± 17 mg/dL [P < .001]), hemoglobin A1c levels (26 weeks: 0.1 ± 0.3% vs 0.3 ± 0.4% [P < .001]; 52 weeks: 0.0 ± 0.3% vs 0.2 ± 0.5% [P = .003]), and other parameters of glucose homeostasis. Similar patterns were seen for adiponectin levels, with significant improvement in responders vs nonresponders. Changes in lipid levels and glucose homeostasis were significantly associated with percentage change in VAT.
Conclusions. In contrast to nonresponders, HIV-infected patients receiving tesamorelin with ≥8% reduction in VAT have significantly improved triglyceride levels, adiponectin levels, and preservation of glucose homeostasis over 52 weeks of treatment. Registration. NCT00123253, NCT00435136, NCT00608023.
PMCID: PMC3348954  PMID: 22495074
7.  Body Composition and Metabolic Changes in HIV-Infected Patients 
The Journal of Infectious Diseases  2012;205(Suppl 3):S383-S390.
As antiretroviral therapy has decreased human immunodeficiency virus (HIV)–associated mortality, cardiometabolic abnormalities have become increasingly apparent in HIV-infected individuals. Many patients treated for HIV infection exhibit body composition changes, including peripheral fat atrophy and visceral lipohypertrophy. In addition, HIV-infected individuals demonstrate a higher prevalence of dyslipidemia, insulin resistance and diabetes, and cardiovascular risk, compared with the general population. Although antiretroviral therapy appears to contribute to some of the cardiometabolic abnormalities in HIV infection, HIV itself, immunologic factors, and lifestyle factors are also important mediators of cardiovascular risk. Treatment strategies for body composition changes and cardiometabolic abnormalities in HIV infection include lifestyle modification, lipid-lowering agents, insulin sensitizers, and treatments to reverse endocrine abnormalities in HIV, including growth hormone–releasing hormone. None of these strategies has comprehensively addressed the abnormalities experienced by this population, however, and further research is needed into combined strategies to improve body composition and ameliorate cardiovascular risk.
PMCID: PMC3349298  PMID: 22577212
8.  2013 ACC/AHA and 2004 ATP III Cholesterol Guidelines Applied to HIV-Infected Patients with/without Subclinical High Risk Coronary Plaque 
AIDS (London, England)  2014;28(14):2061-2070.
The 2013 ACC/AHA cholesterol guidelines are being applied to HIV-infected patients but have not been validated in this at-risk population, known to have a high prevalence of subclinical high-risk morphology (HRM) coronary atherosclerotic plaque.
To compare recommendations for statins among HIV-infected subjects with/without HRM coronary plaque according to 2013 ACC/AHA versus 2004 ATP III guidelines.
Data from 108 HIV-infected subjects without known CVD or lipid-lowering treatment who underwent contrast-enhanced computed-tomography angiography were analyzed. Recommendations for statin therapy according to 2013 versus 2004 guidelines were assessed among those with/without HRM coronary plaque.
Among all subjects, 10-year ASCVD risk score was 3.3% (1.6, 6.6), yet 36% of subjects had HRM coronary plaque. Among those with HRM coronary plaque, statins would be recommended for 26% by 2013 guidelines versus 10% by 2004 guidelines (p=0.04). Conversely, among those without HRM coronary plaque, statins would be recommended for 19% by 2013 guidelines versus 7% by 2004 guidelines (p=0.005). In multivariate modeling, while 10-year ASCVD risk score related to HRM coronary plaque burden (p=0.02), so too did other factors not incorporated into 2013 guidelines.
2013 ACC/AHA cholesterol guidelines recommend statin therapy for a higher percentage of subjects with and without HRM coronary plaque relative to 2004 guidelines. However, even by 2013 guidelines, statin therapy would not be recommended for the majority (74%) of HIV-infected subjects with subclinical HRM coronary plaque. Outcome studies are needed to determine the utility of new statin recommendations and the contribution of HRM coronary plaque to CVD events among HIV-infected subjects.
PMCID: PMC4405159  PMID: 25265074
HIV; cholesterol guidelines; atherosclerosis; computed tomography angiography
9.  Effects of Exercise and Lifestyle Modification on Fitness, Insulin Resistance, Skeletal Muscle Oxidative Phosphorylation, and Intramyocellular Lipid Content in Obese Children and Adolescents 
Pediatric obesity  2013;9(4):281-291.
Obesity is associated with poor fitness and adverse metabolic consequences in children.
To investigate how exercise and lifestyle modification may improve fitness and insulin sensitivity in this population.
Design and Subjects
RCT, 21 obese (BMI ≥ 95%ile) subjects, ages 10 to 17 years.
Subjects were given standardized healthful lifestyle advice for 8 weeks. In addition, they were randomized to an in-home supervised exercise intervention (n = 10) or control group (n=11).
Fasting laboratory studies (insulin, glucose, lipid profile) and assessments of fitness, body composition, skeletal muscle oxidative phosphorylation and intramyocellular lipid content (IMCL), were performed at baseline and study completion.
Subjects were 13.0 ± 1.9 (SD) years old, 72% female, and 44% non-white. Exercise improved fitness (p = 0.03) and power (p = 0.01), and increased IMCL (p = 0.02). HOMA-IR decreased among all subjects in response to lifestyle modification advice (p = 0.01), regardless of exercise training assignment. In univariate analysis over all subjects, change in cardiovascular fitness was associated with change in HOMA-IR. In exploratory analyses, increased IMCL was associated with greater resting energy expenditure (r = 0.78, p = 0.005) and a decrease in fasting RQ (r = −0.70, p = 0.02) (n=11).
Change in fitness was found to be related to change in insulin resistance in response to lifestyle modification and exercise in obese children. IMCL increased with exercise in these obese children, which may reflect greater muscle lipid oxidative capacity.
PMCID: PMC3808470  PMID: 23801526
fitness; insulin resistance; pediatric obesity; mitochondrial function; IMCL
10.  Associations of Cardiovascular Risk Factors with Two Surrogate Markers of Subclinical Atherosclerosis: Endothelial Function and Carotid Intima Media Thickness 
Atherosclerosis  2011;217(2):437-440.
Endothelial function and carotid intima media thickness (cIMT) were investigated in a cohort of 54 healthy adults without known cardiovascular disease.
Pulse wave amplitude was determined with peripheral arterial tonometry (PAT) to obtain the reactive hyperemia (RH)-PAT ratio. Ultrasound was used to determine cIMT.
cIMT and RH-PAT were significantly associated (rho = −0.35, P = 0.02) in univariate analysis. RH-PAT was significantly associated with age, triglycerides, fasting glucose, HDL, WHR, waist circumference and VAT. cIMT was associated with age, smoking history, fasting glucose, systolic blood pressure, diastolic blood pressure and LDL. In multivariate regression analyses, triglyceride level (P = 0.04) remained a significant determinant of RH-PAT whereas systolic blood pressure (P = 0.02) and smoking pack-year history (P = 0.046) were significant determinants of cIMT.
Determinants of cIMT and RH-PAT were different, dominated by triglyceride and abdominal adiposity measures for RH-PAT but traditional risk factors including blood pressure, glucose, smoking and LDL for cIMT.
PMCID: PMC3146552  PMID: 21570076
Endothelial function; carotid intima media thickness; atherosclerosis
11.  Effect of Tesamorelin on Liver Fat and Visceral Fat in HIV-Infected Patients With Abdominal Fat Accumulation: A Randomized Clinical Trial 
JAMA  2014;312(4):380-389.
Among HIV-infected patients, visceral adiposity is associated with metabolic dysregulation and ectopic fat accumulation. Tesamorelin, a growth hormone-releasing hormone analogue, specifically targets visceral fat reduction, but its effects on liver fat are unknown.
To investigate the effect of tesamorelin on visceral and liver fat.
Design, Setting, and Participants
Fifty antiretroviral-treated HIV-infected men and women with abdominal fat accumulation were recruited for this double-blind, randomized, placebo-controlled trial at Massachusetts General Hospital. The first patient was enrolled on 1/10/2011; the final patient completed his 6 month study visit on 9/6/2013.
Tesamorelin 2mg vs. placebo SC daily for 6 months
Main Outcomes
Primary endpoints were changes in visceral adipose tissue (VAT) and liver fat. Secondary endpoints included glucose and other metabolic endpoints.
76 patients were screened and 54 randomized. 50 presented for baseline assessment and 48 received treatment with study drug. Tesamorelin significantly reduced VAT (Δ −34 [−53, −15] vs. 8 [−14, 30] cm2, mean [95% CI], tesamorelin vs. placebo, treatment effect −42cm2 [95% CI −71, −14], P = 0.005) and liver fat (Δ −2.0 [−6.4, 0.1] vs. 0.9 [−0.6, 3.7] lipid-to-water %, median [IQR], tesamorelin vs. placebo, P=0.003) over 6 months, for a net treatment effect of −2.9 lipid-to-water %. Fasting glucose increased in the tesamorelin group at 2 weeks (Δ 9 [5, 13] vs. 2 [−3, 8] mg/dL, mean [95% CI], treatment effect 7mg/dL [95% CI 1, 14], P=0.03), but overall changes over 6 months in fasting glucose (Δ 4 [−2, 10] vs. 2 [−4, 7] mg/dL, mean [95% CI], treatment effect 2mg/dL [95% CI −6, 10], P=0.72) and 2 hour glucose (Δ −1 [−18, 15] vs. −8 [−24, 8] mg/dL, mean [95% CI], treatment effect 7mg/dL [95% CI −16, 29], P=0.53) were not significant.
Conclusions and Relevance
In this preliminary study of HIV-infected patients with abdominal fat accumulation, tesamorelin administered for 6 months was associated with reductions in visceral fat and, additionally, with modest reductions in liver fat. Further studies are needed to determine the clinical importance and long-term consequences of these findings.
Trial Registration NCT01263717
PMCID: PMC4363137  PMID: 25038357
liver fat; visceral fat; growth hormone releasing hormone; HIV
12.  Relationship Between Neck Circumference and Cardiometabolic Parameters in HIV-Infected and non–HIV-Infected Adults 
Diabetes Care  2011;34(4):1026-1031.
Upper body fat is associated with increased cardiometabolic risk. More recently, neck circumference (NC) and/or neck fat have been associated with hyperlipidemia, impaired glucose homeostasis, and hypertension. The objective of this study was to determine whether this relationship is evident in HIV-infected individuals, who often exhibit changes in relative fat distribution, and to determine whether NC is independently associated with carotid intima-media thickness (cIMT) in HIV and non–HIV-infected patients.
Body composition, including anthropometrics, visceral adipose tissue assessment by CT, and metabolic parameters, including lipids, cIMT, and oral glucose tolerance test, were measured in 174 men and women with HIV infection and 154 non–HIV-infected subjects. NC was measured in triplicate inferior to the laryngeal prominence.
In univariate analysis, NC was significantly and positively related to blood pressure, hemoglobin A1c, glucose, and insulin and significantly and negatively related to HDL cholesterol in HIV-infected individuals and HIV-negative control subjects. NC was significantly associated with cIMT in univariate regression analysis among HIV-infected (r = 0.21, P = 0.006) and non–HIV-infected (r = 0.31, P = 0.0001) patients. This relationship remained significant among non–HIV-infected patients (R2 = 0.45, P < 0.001) but not HIV-infected patients in multivariate modeling controlling for age, sex, race, smoking hypertension, glucose, and lipids.
Among both HIV and non–HIV-infected patients, increased NC is strongly associated with decreased HDL and impaired glucose homeostasis. Among non–HIV-infected subjects, NC also predicts increased cIMT when controlling for traditional risk factors.
PMCID: PMC3064017  PMID: 21378212
14.  Effects of Obesity, Body Composition, and Adiponectin on Carotid Intima-Media Thickness in Healthy Women 
Increased common carotid intima-media thickness (IMT) is predictive of coronary artery disease and stroke.
In this study, we investigated common carotid IMT by obesity category in a cohort of healthy women without previously known cardiovascular disease.
Design, Setting, Participants, and Main Outcome Measures
One hundred healthy women (aged 24-59 yr) from the general community enrolled in an observational study conducted at an academic medical center participated in the study. B-mode ultrasound imaging of the common carotid arteries was used to measure common carotid IMT in 99 subjects. Fat distribution was determined by computed tomography. Hormonal and inflammatory parameters related to cardiovascular disease and obesity were measured.
IMT was higher in obese [body mass index (BMI) ≥ 30 kg/m2], compared with overweight women (BMI ≥ 25 and < 30 kg/m2) [0.69 mm, interquartile range (IQR) 0.60-0.75 mm] vs. 0.62 mm [IQR 0.56-0.68 mm), P = 0.044] and in comparison with lean women (BMI < 25 kg/m2) [0.69 mm (IQR 0.60-0.75 mm) vs. 0.59 mm (IQR 0.54-0.67 mm), P = 0.016]. In multivariate modeling, age (beta = 0.0050 mm change in IMT per year of age, P = 0.003), smoking (beta = 0.0044 mm change in IMT per pack-year, P = 0.046), and sc abdominal adiposity (beta = 0.00026 mm change in IMT per square centimeter, P = 0.010) were positively associated with IMT, whereas adiponectin (beta =–0.0042 mm change in IMT per milligram per liter, P = 0.045) was negatively associated with IMT. Visceral adiposity (beta = 0.00048 mm change in IMT per square centimeter, P = 0.092) was not significantly associated with IMT after adjusting for age, race, smoking, sc abdominal adiposity, and adiponectin.
Obesity is associated with increased common carotid IMT in young and middle-aged women. Adiponectin and sc abdominal adiposity are associated with carotid IMT in this population.
PMCID: PMC3210448  PMID: 16522690
15.  Effects of Etanercept in Patients With the Metabolic Syndrome 
Archives of internal medicine  2006;166(8):902-908.
Adipose-derived cytokines, including tumor necrosis factor α, may contribute to the inflammation that occurs in the metabolic syndrome. We investigated the effects of inhibition of tumor necrosis factor α with etanercept in patients with the metabolic syndrome.
Fifty-six subjects with the metabolic syndrome were randomized to administration of either etanercept or identical placebo, 50 mg subcutaneously once a week for 4 weeks. The C-reactive protein level was the primary end point. Effects on other inflammatory markers (including fibrinogen, interleukin 6, and adiponectin), insulin sensitivity, lipid levels, and body composition were also determined.
Baseline characteristics were similar between the groups. Two subjects dropped out of each group, and etanercept was well tolerated throughout the study. The C-reactive protein levels decreased significantly in the treated compared with the placebo group (−2.4 ± 0.4 vs 0.5 ± 0.7 mg/L; P<.001). Adiponectin levels rose significantly in the etanercept group compared with the placebo group (0.8 ± 0.4 vs −0.3 ± 0.3 µg/mL; P=.03). Fibrinogen levels decreased (−68 ± 16 vs −2 ± 31 mg/dL [−2.0 ± 0.47 vs −0.06 ± 0.91 µmol/L]; P=.04) and interleukin 6 levels tended to decrease (−1.2 ± 0.8 vs 0.5 ± 0.5 ng/L; P=.07) in the etanercept-treated subjects compared with placebo, respectively. No changes occurred in body composition parameters or insulin sensitivity, but high-density lipoprotein levels tended to decrease in the etanercept group (−1 ± 1 vs 2 ± 1 mg/dL [−0.03 ± 0.03 vs 0.05 ± 0.03 mmol/L]; P=.06) compared with the placebo group.
Etanercept reduces C-reactive protein levels and tends to improve other inflammatory cardiovascular risk indexes in patients with the metabolic syndrome. Etanercept may interrupt the inflammatory cascade that occurs with abdominal obesity. Further, longer-term studies are needed to determine the effects of tumor necrosis factor α inhibition on cardiovascular disease in patients with the metabolic syndrome.
PMCID: PMC3196549  PMID: 16636217
16.  “HDL Redox Activity is Increased in HIV-Infected Men in Association with Macrophage Activation and Noncalcified Coronary Atherosclerotic Plaque” 
Antiviral therapy  2014;19(8):805-811.
HIV is associated with atherosclerosis and low HDL. With inflammation, HDL becomes dysfunctional. We previously showed that pro-inflammatory HDL has high HDL redox activity (HRA). In this study, we: 1) compare HRA in HIV-infected versus non-HIV-infected subjects and 2) relate HRA to indices of macrophage activation and cardiovascular disease risk.
102 HIV-infected subjects and 41 matched non-HIV controls without clinical cardiovascular disease underwent coronary CT angiography (CTA) and testing for immune/inflammatory biomarkers. The effect of purified HDL from each study subject on the oxidation rate of dihydrorhodamine-123(DOR) was normalized to the DOR of pooled HDL from healthy subjects. The normalized ratio DORsubject/DORpooled (nHRA) was used as a measure of HRA, with higher HRA suggesting dysfunctional HDL.
HRA was higher in HIV-infected versus non-HIV subjects (1.4±0.01 versus 1.3±0.01, p=0.03). In multivariate modeling for HRA among all subjects, HIV status remained positively related to HRA (p=0.02), even after controlling for traditional cardiovascular risk factors, comorbid conditions, and immune activation. Among HIV-infected subjects, HRA correlated inversely with HDL (rho=−0.32, p=0.002) and log adiponectin (r=−0.28, p=0.006) and correlated positively with log sCD163 (r=0.24, p=0.02) - a monocyte/macrophage activation marker - and with percent non-calcified coronary atherosclerotic plaque (r=0.29, p=0.03). sCD163 remained significantly associated with HRA in multivariate modeling among HIV-infected subjects (p=0.03).
These data demonstrate increased HRA among HIV-infected subjects versus matched non-HIV subjects with comparable HDL levels. In HIV-infected subjects, HRA relates to macrophage activation and to non-calcified coronary atherosclerotic plaque, which may be rupture prone. Further studies are needed in HIV-infected patients to elucidate the interplay between immune activation, HDL function, and CVD risk.
PMCID: PMC4423391  PMID: 24535655
HIV; HDL; atherosclerosis; HDL oxidative potential
17.  Genetic Analysis Implicates Resistin in HIV Lipodystrophy 
AIDS (London, England)  2008;22(13):1561-1568.
To investigate the role of genetic variation in influencing the risk of metabolic complications associated with highly active anti-retroviral therapy (HAART).
Cluster analysis of metabolic traits of 189 patients enrolled in ACTG5005s, the metabolic sub-study of ACTG384, a clinical trial of HAART, was performed to identify a sub-group of subjects with increased risk of developing a cluster of metabolic abnormalities after exposure to HAART. Almost 300 single nucleotide polymorphisms (SNPs) in 135 candidate genes were evaluated for their association with this sub-group.
A sub-group of patients was identified that had a normal metabolic profile at baseline but developed significantly elevated lipids and insulin resistance on HAART. This high-risk sub-group of patients also experienced significant body composition changes, particularly limb fat loss. Candidate gene analysis revealed that a single nucleotide polymorphism in resistin, a gene previously implicated in obesity and insulin resistance, was associated with this high-risk group (P = 0.0003).
Genetic variation in resistin is associated with metabolic complications caused by highly active anti-retroviral therapy.
PMCID: PMC4410015  PMID: 18670214
highly active antiretroviral therapy; HAART; dyslipidemia; lipoatrophy; pharmacogenetics; single nucleotide polymorphism; resistin
18.  Effects of TNF-alpha antagonism on E-selectin in obese subjects with metabolic dysregulation 
Clinical endocrinology  2010;73(1):48-54.
Endothelial adhesion molecules like E-selectin play an important role in leukocyte recruitment and development of atherosclerotic plaque. E-selectin is increased in obesity, yet little is known regarding the specific factors contributing to elevated E-selectin in obesity and whether tumor necrosis factor alpha (TNF-alpha) increases E-selectin in vivo in this population. The objectives of this study were to: 1) determine the body composition, metabolic and inflammatory factors associated with increased E-selectin, and 2) determine the role of TNF-alpha in the physiological regulation of E-selectin by antagonism of TNF-alpha with etanercept among obese subjects.
E-selectin levels, body composition, metabolic parameters and inflammatory cytokines were assessed in 51 obese subjects and 37 non-obese healthy controls. Obese subjects were randomized to etanercept 50 mg weekly or placebo for four weeks. Changes in E-selectin were compared between treatment groups.
Obese subjects had higher E-selectin than non-obese controls (47.4 [32.7 – 58.8] vs. 27.2 [20.3 – 42.1] ng/mL, obese vs. non-obese, p<0.0001). E-selectin was significantly associated with multiple body composition measures and metabolic parameters, along with specific measures of TNF-alpha activation, including soluble tumor necrosis factor receptors 1 (p=0.03) and 2 (p=0.02). In multivariate modeling, visceral adipose tissue, but not other measures of body composition, remained significantly associated with E-selectin. Among obese subjects, treatment with etanercept significantly decreased E-selectin (−5.7 ± 8.7 vs. 0.5 ± 6.0 ng/mL, etanercept vs. placebo, p=0.005).
E-selectin is increased in obesity, in relationship to increased visceral adiposity and markers of TNF-alpha activation. TNF-alpha antagonism with etanercept reduces E-selectin in obese subjects, providing evidence that the systemic circulatory release of E-selectin is regulated at least in part by TNF-alpha in obesity.
PMCID: PMC2891313  PMID: 19878508
obesity; inflammation; tumor necrosis factor-alpha; E-selectin
19.  Effects of Switching from Lopinavir/ritonavir to Atazanavir/ritonavir on Muscle Glucose Uptake and Visceral Fat in HIV Infected Patients 
AIDS (London, England)  2009;23(11):1349-1357.
To determine the effects of switching from lopinavir/ritonavir (LPV/r) to atazanavir/ritonavir (ATV/r) on muscle glucose uptake, glucose homeostasis, lipids, and body composition.
Fifteen HIV-infected men and women on a regimen containing LPV/r and with evidence of hyperinsulinemia and/or dyslipidemia were randomized to continue LPV/r or to switch to ATV/r (ATV 300mg and ritonavir 100mg daily) for six months. The primary endpoint was change in thigh muscle glucose uptake as measured by positron emission tomography (PET). Secondary endpoints included abdominal visceral adipose tissue, fasting lipids and safety parameters. The difference over time between treatment groups (treatment effect of ATV/r relative to LPV/r) was determined by repeated measures ANCOVA.
After six months, anterior thigh muscle glucose uptake increased significantly (treatment effect +18.2 ± 5.9 μmol/kg/min, ATV/r vs. LPV/r, p=0.035), and visceral adipose tissue (VAT) area decreased significantly in subjects who switched to ATV/r (treatment effect -31 ± 11cm2, ATV/r vs. LPV/r, p=0.047). Switching to ATV/r significantly decreased triglyceride (treatment effect -182 ± 64 mg/dL, ATV/r vs. LPV/r, p=0.02) and total cholesterol (treatment effect -23 ± 8 mg/dL, ATV/r vs. LPV/r, p=0.01), whereas HDL and LDL did not change significantly. Fasting glucose also decreased significantly following switch to ATV/r (treatment effect -15 ± 4 mg/dL, ATV/r vs. LPV/r, p=0.002).
Switching from LPV/r to ATV/r significantly increases glucose uptake by muscle, decreases abdominal visceral adipose tissue, improves lipid parameters and decreases fasting glucose over 6 months.
PMCID: PMC2886977  PMID: 19474651
HIV; lipodystrophy; atazanavir; lopinavir; glucose; intra-abdominal fat; lipids
20.  Decreased respiratory quotient in relation to resting energy expenditure in HIV-infected and non-infected subjects 
The purpose of this study was to evaluate the relationship of respiratory quotient (RQ), a surrogate marker of substrate oxidation, as well as body composition and dietary intake to resting energy expenditure (REE) among HIV-infected patients in the current era of HAART and among non HIV-infected control subjects. Resting energy expenditure (REE) is increased in HIV-infected patients, but little is known regarding the potential contribution of altered substrate metabolism, body composition and dietary intake to increased energy expenditure in this population. RQ, REE, body composition and dietary intake parameters were assessed in 283 HIV-infected patients and 146 community-derived HIV-negative controls that were evaluated for metabolic studies between 1998 and 2005. RQ was lower (0.83±0.00 vs. 0.85±0.01, P=0.005) whereas REE adjusted for fat free mass (FFM) was higher (31.8±0.3 vs. 29.8±0.3 kcal/d/kg, P=<0.0001) in HIV-infected compared to control subjects. In multivariate modeling among HIV-infected patients, including age, gender and parameters of immune function, FFM (beta=24.811334, P <0.0001), visceral adiposity (beta=0.7182746, P=0.008), and total body fat (beta=8.0506839, P=0.041) were positively associated with REE, whereas RQ was negatively associated with REE (beta= −528.4808, P=0.024). Overall r2=0.705, P<0.0001 for the model. In control subjects, by contrast, only visceral adiposity (beta = 1.0612073, P=0.004), total body fat (beta = 15.805547, P=0.010), and FFM (beta = 22.613005, P <0.0001) were significant predictors of REE, and there was no relationship with RQ. Overall r2=0.825, P<0.0001 for the model. These data suggest that alterations in substrate metabolism may contribute to increased REE in HIV-infected patients compared to control subjects.
PMCID: PMC2691476  PMID: 19375582
HIV; resting energy expenditure; lipid oxidation; substrate metabolism; RQ
21.  Increased Acute Myocardial Infarction Rates and Cardiovascular Risk Factors among Patients with Human Immunodeficiency Virus Disease 
Metabolic changes and smoking are common among HIV patients and may confer increased cardiovascular risk.
The aim of the study was to determine acute myocardial infarction (AMI) rates and cardiovascular risk factors in HIV compared with non-HIV patients in two tertiary care hospitals.
Design, Setting, and Participants
We conducted a health care system-based cohort study using a large data registry with 3,851 HIV and 1,044,589 non-HIV patients. AMI rates were determined among patients receiving longitudinal care between October 1, 1996, and June 30, 2004.
Main Outcome Measures
The primary outcome was myocardial infarction, identified by International Classification of Diseases coding criteria.
AMI was identified in 189 HIV and 26,142 non-HIV patients. AMI rates per 1000 person-years were increased in HIV vs. non-HIV patients [11.13 (95% confidence interval [CI] 9.58–12.68) vs. 6.98 (95% CI 6.89–7.06)]. The HIV cohort had significantly higher proportions of hypertension (21.2 vs. 15.9%), diabetes (11.5 vs. 6.6%), and dyslipidemia (23.3 vs. 17.6%) than the non-HIV cohort (P < 0.0001 for each comparison). The difference in AMI rates between HIV and non-HIV patients was significant, with a relative risk (RR) of 1.75 (95% CI 1.51–2.02; P < 0.0001), adjusting for age, gender, race, hypertension, diabetes, and dyslipidemia. In gender-stratified models, the unadjusted AMI rates per 1000 person-years were higher for HIV patients among women (12.71 vs. 4.88 for HIV compared with non-HIV women), but not among men (10.48 vs. 11.44 for HIV compared with non-HIV men). The RRs (for HIV vs. non-HIV) were 2.98 (95% CI 2.33–3.75; P < 0.0001) for women and 1.40 (95% CI 1.16–1.67; P = 0.0003) for men, adjusting for age, gender, race, hypertension, diabetes, and dyslipidemia. A limitation of this database is that it contains incomplete data on smoking. Smoking could not be included in the overall regression model, and some of the increased risk may be accounted for by differences in smoking rates.
AMI rates and cardiovascular risk factors were increased in HIV compared with non-HIV patients, particularly among women. Cardiac risk modification strategies are important for the long-term care of HIV patients.
PMCID: PMC2763385  PMID: 17456578
22.  Association of C-Reactive Protein and HIV Infection With Acute Myocardial Infarction 
To investigate whether elevated C-reactive protein (CRP) levels and HIV infection are independently associated with acute myocardial infarction (AMI) among patients receiving care in a large US health care system.
Analyses included patients receiving care in the Partners HealthCare System between January 1997 and December 2006, with a most recent CRP less than 3 years and more than 1 week before AMI. Over this period, 70,357 (487 HIV and 69,870 non-HIV) patients met these criteria, from the background population of 1,648,687 patients followed in the system. We included both CRP and high-sensitivity CRP and defined elevated CRP based on the normal range of the assay used. We used multivariate logistic regression analysis to test the association of elevated CRP and HIV with AMI after adjustment for demographic and other cardiovascular covariates, including hypertension, diabetes, and dyslipidemia.
In univariate analyses, elevated CRP and HIV were each significantly associated with AMI [odds ratio (OR) 2.51; 95% confidence interval (CI) 2.27 to 2.78; P < 0.0001 for elevated CRP and OR 2.07; 95% CI 1.31 to 3.10; P = 0.001 for HIV]. In a combined model including CRP category and HIV status, elevated CRP (OR 2.50; 95% CI 2.26 to 2.77; P < 0.0001) and HIV (OR 1.74; 95% CI 1.10 to 2.61; P = 0.01) were both independently associated with AMI. In a fully adjusted model controlling for age, sex, race, hypertension, diabetes, and dyslipidemia, both elevated CRP (OR 2.13; 95% CI 1.92 to 2.37; P < 0.0001) and HIV (OR 1.93; 95% CI 1.21 to 2.93; P = 0.004) remained independently associated with AMI. Compared with patients with normal CRP and without HIV, the OR for AMI was increased more than 4-fold among patients with HIV and elevated CRP.
Elevated CRP and HIV are independently associated with increased AMI risk, and patients with HIV with increased CRP have a markedly increased relative risk of AMI. Measurement of CRP may be useful in the cardiovascular risk assessment of patients with HIV.
PMCID: PMC2763381  PMID: 19387353
C-reactive protein; coronary disease; HIV; myocardial infarction; risk factors
23.  High-Density Lipoprotein-Mediated Cholesterol Efflux Capacity Is Improved by Treatment With Antiretroviral Therapy in Acute Human Immunodeficiency Virus Infection 
Open Forum Infectious Diseases  2014;1(3):ofu108.
 Individuals infected with human immunodeficiency virus (HIV) have decreased high-density lipoprotein (HDL)-cholesterol and increased cardiovascular disease (CVD). Reverse cholesterol transport from macrophages may be inhibited by HIV and contribute to increased CVD. Human studies have not investigated longitudinal effects of HIV and antiretroviral therapy (ART) on cholesterol efflux.
 Subjects with acute HIV infection were randomized to ART or not. Cholesterol efflux capacity was determined ex vivo after exposure of murine macrophages to apolipoprotein B-depleted patient sera obtained at baseline and after 12 weeks.
 After 12 weeks, HIV RNA decreased most in subjects randomized to ART. Available data on cholesterol demonstrated that efflux capacity from Abca1+/+ macrophages was increased most by sera obtained from ART-treated subjects (20.5% ± 5.0% to 24.3 % ± 6.9%, baseline to 12 weeks, P = .007; ART group [n = 6] vs 18.0 % ± 3.9% to 19.1 % ± 2.9%, baseline to 12 weeks, P = .30; untreated group [n = 6] [P = .04 ART vs untreated group]). Change in HIV RNA was negatively associated with change in Abca1+/+ macrophage cholesterol efflux (r = − 0.62, P = .03), and this finding remained significant (P = .03) after controlling for changes in HDL-cholesterol, CD4+ cells, and markers of monocyte or macrophage activation.
 In subjects acutely infected with HIV, ATP-binding cassette transporter A1-mediated cholesterol efflux was stimulated to a greater degree over time by apolipoprotein B-depleted serum from subjects randomized to ART. The improvement in cholesterol efflux capacity is independently related to reduction in viral load.
PMCID: PMC4324225  PMID: 25734176
acute HIV infection; antiretroviral therapy; atherosclerosis; cholesterol efflux; inflammation
24.  Aspirin Use for Primary and Secondary Prevention in Human Immunodeficiency Virus (HIV)-Infected and HIV-Uninfected Patients 
Open Forum Infectious Diseases  2014;1(3):ofu076.
Aspirin use is lower among HIV-infected patients compared to HIV-uninfected patients with a pronounced difference among those patients at highest cardiovascular risk. Aspirin use is also lower among HIV-infected patients when used for secondary prevention.
 Human immunodeficiency virus (HIV) infection is associated with increased risk of myocardial infarction (MI). The use of aspirin for primary and secondary MI prevention in HIV infection has not been extensively studied.
 We performed a cross-sectional study of 4037 patients infected with HIV and 36 338 demographics-matched control patients in the Partners HealthCare System HIV cohort. We developed an algorithm to ascertain rates of nonepisodic acetylsalicylic acid (ASA) use using medication and electronic health record free text data. We assessed rates of ASA use among HIV-infected and HIV-uninfected (negative) patients with and without coronary heart disease (CHD).
 Rates of ASA use were lower among HIV-infected compared with HIV-uninfected patients (12.4% vs 15.3%, P < .001), with a relatively greater difference among patients with ≥2 CHD risk factors (22.1% vs 42.4%, P < .001). This finding was present among men and among patients in the 30–39 and 40–49 age groups. Among patients with prevalent CHD using ASA for secondary prevention, rates of ASA use were also lower among HIV-infected patients compared with HIV-uninfected patients (51.6% vs 65.4%, P < .001).
 Rates of ASA use were lower among HIV-infected patients compared with controls, with a greater relative difference among those with elevated CHD risk and those with known CHD. Further studies are needed to investigate the optimal strategies for ASA use among patients infected with HIV.
PMCID: PMC4324233  PMID: 25734156
aspirin; coronary disease; HIV; prevention; primary care
25.  Cost-Effectiveness Analysis of Coronary Artery Disease Screening in HIV-infected Patients 
HIV-infected patients are at increased risk of coronary artery disease (CAD). We evaluated the cost-effectiveness of cardiac screenings for HIV-positive men at intermediate or greater CAD risk.
We developed a lifetime microsimulation model of CAD incidence and progression in HIV-infected men.
Input parameters were derived from two HIV cohort studies and the literature. We compared no CAD screening with stress testing and coronary computed tomography angiography (CCTA)-based strategies. Patients with test results indicating 3-vessel/left main CAD underwent invasive coronary angiography (ICA) and received coronary artery bypass graft surgery. In the “Stress-testing+Medication”/“CCTA+Medication” strategies, patients with 1-/2-vessel CAD results received lifetime medical treatment without further diagnostics whereas in the “Stress-testing+Intervention”/“CCTA+Intervention” strategies, patients with these results underwent ICA and received percutaneous coronary intervention.
Compared to no screening, the “Stress-testing+Medication”, “Stress-testing+Intervention”, “CCTA+Medication” and “CCTA+Intervention” strategies resulted in 14, 11, 19, and 14 quality-adjusted life days per patient and incremental cost effectiveness ratios of 49,261, 57,817, 34,887 and 56,518 € per quality-adjusted life year (QALY), respectively. Screening only at higher CAD risk thresholds was more cost-effective. Repeated screening was clinically beneficial compared to one-time screening but only “Stress-testing+Medication” every five years remained cost-effective. At a willingness-to-pay threshold of 83,000 €/QALY (~100,000 US$/QALY), implementing any CAD screening was cost-effective with a probability of 75-95%.
Screening HIV-positive men for CAD would be clinically beneficial and comes at a cost-effectiveness ratio comparable to other accepted interventions in HIV care.
PMCID: PMC3841232  PMID: 23539717
HIV; coronary heart disease; prevention; cost-effectiveness; Markov model

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