Kathleen V. Fitch

Increased coronary atherosclerosis and immune activation in HIV-1 elite controllers.

HIV-1 elite controllers spontaneously maintain suppressed levels of viremia, but exhibit significant immune activation. We investigated coronary atherosclerosis by coronary computed tomography angiography (CTA) in elite controllers, nonelite controller, chronically HIV-1 infected, antiretroviral therapy (ART)-treated patients with undetectable viral load (‘chronic HIV’), and HIV-negative controls. Prevalence of atherosclerosis (78 vs. 42%, P < 0.05) and markers of immune activation were increased in elite controllers compared with HIV-negative controls. sCD163, a monocyte activation marker, was increased in elite controllers compared with chronic HIV-1 (P < 0.05) and compared with HIV-negative controls (P < 0.05). These data suggest a significant degree of coronary atherosclerosis and monocyte activation among elite controllers.

Effects of a lifestyle modification program in HIV- infected patients with the metabolic syndrome

Objectives:A large percentage of HIV-infected patients receiving HAART develop the metabolic syndrome. In this study, we sought to determine whether lifestyle modification improves metabolic syndrome criteria, including waist circumference, blood pressure, fasting blood sugar, triglycerides, and HDL-cholesterol among HIV-infected patients with the metabolic syndrome. Design:We conducted a randomized, 6-month study in HIV-infected patients with metabolic syndrome as defined by the National Cholesterol Education Program. Subjects were randomly assigned to an intensive lifestyle modification program, which included weekly one-on-one counseling sessions with a registered dietician, or observation (control group). Methods:Metabolic syndrome criteria and cardiovascular parameters, including blood pressure, body composition, submaximal stress testing, lipids and other biochemical parameters were determined. Results:Thirty-four patients were randomly assigned and 28 subjects completed the study. Compared with the control group, subjects randomly assigned to the lifestyle modification program demonstrated significant decreases in waist circumference (−2.6 ± 1.1 versus 1.2 ± 1.0 cm, P = 0.022), systolic blood pressure (−13 ± 4 versus 4 ± 4 mmHg, P = 0.008), hemaglobin A1C (−0.1 ± 0.1 versus 0.2 ± 0.1%, P = 0.017), lipodystrophy score (−1.2 ± 0.3 versus 0.9 ± 0.6, P = 0.006) and increased activity (17.7 ± 14.3 versus −33.1 ± 12.7 metabolic equivalents, P = 0.014) as measured by the Modifiable Activity Questionnaire, but lipid levels did not improve. Conclusion:These data demonstrate that intensive lifestyle modification significantly improved important cardiovascular risk indices in HIV-infected patients with the metabolic syndrome. Lifestyle modification may be a useful strategy to decrease cardiovascular risk in this population.

Noncalcified Coronary Atherosclerotic Plaque and Immune Activation in HIV-Infected Women

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.

Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial.

BACKGROUND HIV-infected patients have a high risk of myocardial infarction. We aimed to assess the ability of statin treatment to reduce arterial inflammation and achieve regression of coronary atherosclerosis in this population. METHODS In a randomised, double-blind, placebo-controlled trial, 40 HIV-infected participants with subclinical coronary atherosclerosis, evidence of arterial inflammation in the aorta by fluorodeoxyglucose (FDG)-PET, and LDL-cholesterol concentration of less than 3.37 mmol/L (130 mg/dL) were randomly assigned (1:1) to 1 year of treatment with atorvastatin or placebo. Randomisation was by the Massachusetts General Hospital (MGH) Clinical Research Pharmacy with a permuted-block algorithm, stratified by sex with a fixed block size of four. Study codes were available only to the MGH Research Pharmacy and not to study investigators or participants. The prespecified primary endpoint was arterial inflammation as assessed by FDG-PET of the aorta. Additional prespecified endpoints were non-calcified and calcified plaque measures and high risk plaque features assessed with coronary CT angiography and biochemical measures. Analysis was done by intention to treat with all available data and without imputation for missing data. The trial is registered with ClinicalTrials.gov, number NCT00965185. FINDINGS The study was done from Nov 13, 2009, to Jan 13, 2014. 19 patients were assigned to atorvastatin and 21 to placebo. 37 (93%) of 40 participants completed the study, with equivalent discontinuation rates in both groups. Baseline characteristics were similar between groups. After 12 months, change in FDG-PET uptake of the most diseased segment of the aorta was not different between atorvastatin and placebo, but technically adequate results comparing longitudinal changes in identical regions could be assessed in only 21 patients (atorvastatin Δ -0.03, 95% CI -0.17 to 0.12, vs placebo Δ -0.06, -0.25 to 0.13; p=0.77). Change in plaque could be assessed in all 37 people completing the study. Atorvastatin reduced non-calcified coronary plaque volume relative to placebo: median change -19.4% (IQR -39.2 to 9.3) versus 20.4% (-7.1 to 94.4; p=0.009, n=37). The number of high-risk plaques was significantly reduced in the atorvastatin group compared with the placebo group: change in number of low attenuation plaques -0.2 (95% CI -0.6 to 0.2) versus 0.4 (0.0, 0.7; p=0.03; n=37); and change in number of positively remodelled plaques -0.2 (-0.4 to 0.1) versus 0.4 (-0.1 to 0.8; p=0.04; n=37). Direct LDL-cholesterol (-1.00 mmol/L, 95% CI -1.38 to 0.61 vs 0.30 mmol/L, 0.04 to 0.55, p<0.0001) and lipoprotein-associated phospholipase A2 (-52.2 ng/mL, 95% CI -70.4 to -34.0, vs -13.3 ng/mL, -32.8 to 6.2; p=0.005; n=37) decreased significantly with atorvastatin relative to placebo. Statin therapy was well tolerated, with a low incidence of clinical adverse events. INTERPRETATION No significant effects of statin therapy on arterial inflammation of the aorta were seen as measured by FDG-PET. However, statin therapy reduced non-calcified plaque volume and high-risk coronary plaque features in HIV-infected patients. Further studies should assess whether reduction in high-risk coronary artery disease translates into effective prevention of cardiovascular events in this at-risk population. FUNDING National Institutes of Health, Harvard Clinical and Translational Science Center, National Center for Research Resources.

Dietary fat intake and relationship to serum lipid levels in HIV-infected patients with metabolic abnormalities in the HAART era.

Objective:To evaluate dietary intake and its relationship to lipid parameters in HIV-infected patients with metabolic abnormalities. Method:We prospectively determined dietary intake (4-day food records or 24-h recall) in 356 HIV-infected patients and 162 community-derived HIV-negative controls evaluated for metabolic studies between 1998–2005. Differences in dietary intake between HIV-infected patients and non-HIV-infected controls, in relation to the established 2005 USDA (United States Department of Agriculture) Recommended Dietary Guidelines, were determined. The relationship between dietary fat intake and serum lipid levels among HIV-infected individuals was also evaluated. Results:Assessment of dietary intake in this group of HIV-infected patients demonstrated increased intake of total dietary fat (P < 0.05), saturated fat (P = 0.006), and cholesterol (P = 0.006) as well as a greater percentage of calories from saturated fat (P = 0.002) and from trans fat (P = 0.02), despite similar caloric intake to the control individuals. A significantly higher percentage of HIV-infected patients were above the 2005 USDA Recommended Dietary Guidelines for saturated fat (> 10%/day) (76.0% HIV vs. 60.9% controls, P = 0.003), and cholesterol (> 300 mg/day) (49.7% HIV vs. 37.9% controls, P = 0.04). Saturated fat intake was strongly associated with triglyceride level [triglyceride level increased 8.7 mg/dl (parameter estimate) per gram of increased saturated fat intake, P = 0.005] whereas total fat was inversely associated with triglyceride level [triglyceride level decreased 3.0 mg/dl (parameter estimate) per gram of increased total fat intake, P = 0.02] among HIV-infected individuals. Conclusions:Increased intake of saturated fat is seen and contributes to hypertriglyceridemia among HIV-infected patients who have developed metabolic abnormalities. Increased saturated fat intake should be targeted for dietary modification in this population.

Relationship Between Neck Circumference and Cardiometabolic Parameters in HIV-Infected and non–HIV-Infected Adults

OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS 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. CONCLUSIONS 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.

2013 American College of Cardiology/American Heart Association and 2004 Adult Treatment Panel III cholesterol guidelines applied to HIV-infected patients with/without subclinical high-risk coronary plaque

Background:The 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines are being applied to HIV-infected patients but have not been validated in this at-risk population, which is known to have a high prevalence of subclinical high-risk morphology (HRM) coronary atherosclerotic plaque. Objective:To compare recommendations for statins among HIV-infected subjects with/without HRM coronary plaque according to 2013 ACC/AHA versus 2004 Adult Treatment Panel III guidelines. Methods/design:Data from 108 HIV-infected subjects without known cardiovascular disease (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. Results:Among all subjects, 10-year atherosclerotic cardiovascular disease (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. Conclusion:The 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.

Effects of lifestyle modification and metformin on atherosclerotic indices among HIV-infected patients with the metabolic syndrome.

Objective:Metabolic abnormalities including diabetes, dyslipidemia, hypertension, and abdominal obesity occur commonly in HIV patients, are associated with increased coronary artery calcification (CAC), and contribute to increased cardiovascular disease (CVD) in this population. We hypothesized that lifestyle modification (LSM) and metformin would improve CVD indices in HIV patients with metabolic syndrome. Design:A randomized, placebo-controlled trial to investigate LSM and metformin, alone and in combination, over 1 year, among 50 HIV-infected patients with metabolic syndrome. Methods:We assessed CAC, cardiovascular and metabolic indices. Results:Among the participants, duration of HIV-infection was 14 ± 1 year and duration of antiretroviral therapy was 6 ± 1 year. Metformin-treated patients demonstrated significantly less progression of CAC (−1 ± 2 vs. 33 ± 17, P = 0.004, metformin vs. placebo), whereas the effect of LSM on CAC progression was not significant (8 ± 6 vs. 21 ± 14, P = 0.82, LSM vs. no-LSM). Metformin had a significantly greater effect on CAC than LSM (P = 0.01). Metformin-treated patients also demonstrated less progression in calcified plaque volume (−0.4 ± 1.9 vs. 27.6 ± 13.8 &mgr;l, P = 0.008) and improved homeostatic model of assessment-insulin resistance (HOMA-IR) (P = 0.05) compared with placebo. Participants randomized to LSM vs. no-LSM showed significant improvement in HDL (P = 0.03), high-sensitivity C-reactive protein (hsCRP) (P = 0.05), and cardiorespiratory fitness. Changes in CAC among the four groups – no-LSM–placebo (43 ± 30); LSM–placebo (19 ± 7); no-LSM–metformin (1 ± 1) and LSM–metformin (−4 ± 6) – were different (P = 0.03 for ANOVA and linear trend across groups), and the majority of this effect was mediated by metformin. Results are mean ± SEM. Conclusion:Metformin prevents plaque progression in HIV-infected patients with the metabolic syndrome.

Increased coronary artery calcium score and noncalcified plaque among HIV-infected men: relationship to metabolic syndrome and cardiac risk parameters.

Objective:In this study, the effects of traditional cardiac risk factors on coronary artery calcium (CAC) score and presence of plaque, including noncalcified plaque, measured by computed tomography coronary angiography, were compared among HIV-infected and non-HIV-infected subjects, with respect to the presence of the metabolic syndrome (MS). Design and Methods:HIV-infected men recruited for the presence of the MS (HIV + MS, n = 27) were compared with 2 control groups, HIV-infected men recruited without regard to metabolic criteria (HIV, n = 87), and HIV-negative control men (C, n = 40), also recruited without regard to any metabolic criterion. Results:All 3 groups were similar in age, demographic parameters, and smoking. MS was seen in 100% of the HIV + MS group, compared with 28% in the HIV-infected control group and 11% in the HIV-negative controls. HIV + MS subjects had higher mean CAC score than HIV-infected controls (72 ± 25 vs. 30 ± 8, P = 0.04, HIV + MS vs. HIV) and HIV-negative controls (72 ± 25 vs. 18 ± 7; P = 0.02, HIV + MS vs. C). With respect to CAC, only the HIV + MS group had increased CAC compared with non-HIV. In contrast, both HIV groups demonstrated an increased prevalence of plaque [63% vs. 38%, P = 0.04 (HIV + MS vs. C) and 59% vs. 38%, P = 0.02, (HIV vs. C)] and increased number of noncalcified plaque segments compared with the HIV-negative group [1.26 ± 0.31 vs. 0.45 ± 0.16, P = 0.01 (HIV + MS vs. C); 1.02 ± 0.18 vs. 0.45 ± 0.16, P = 0.04 (HIV vs. C)]. Plaque and noncalcified plaque did not differ significantly between the HIV groups. Conclusions:Metabolic abnormalities in HIV patients are specifically associated with increased coronary artery calcification, whereas HIV itself or other factors may be associated with the development of noncalcified lesions.

Relation of body composition to body mass index in HIV-infected patients with metabolic abnormalities.

Objective:To determine visceral adiposity (VAT), subcutaneous adiposity (SAT), and regional body adipose differences between HIV-infected and non-HIV-infected subjects in relation to body mass index (BMI) and World Health Organization BMI categories. Design, Setting, and Participants:Analyses were conducted of 306 HIV-infected and 107 community-derived HIV-negative subjects evaluated for metabolic studies between 1999 and 2006. Analyses were stratified by gender. Additional analyses were performed stratifying subjects by metabolic syndrome status. Results:HIV-infected men and women demonstrated decreased total extremity fat by 1.1 kg and 0.85 kg, respectively, relative to non-HIV-infected control subjects. VAT was increased among HIV-infected men and women in the normal (18.5 to 24.9 kg/m2) and overweight (25.0 to 29.9 kg/m2) categories relative to control subjects but not among those in the obese category (≥30.0 kg/m2). In contrast, abdominal SAT was reduced among HIV-infected men in the normal and overweight categories but was similar among HIV-infected women and control subjects in these categories. Abdominal SAT was increased among HIV-infected women in the obese category relative to control subjects. Similar results were obtained limiting the analysis to HIV-infected (n = 204) and control subjects (n = 89) without the metabolic syndrome. Conclusions:Peripheral lipoatrophy is a consistent finding among HIV-infected men and women with metabolic abnormalities. Relative increases in VAT are most pronounced among male and female HIV-infected subjects in the normal weight and overweight categories. Gender differences in abdominal SAT accumulation are observed, with preservation of SAT among HIV-infected women relative to control subjects.