Sara E. Looby

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.

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.

Associations of cardiovascular risk factors with two surrogate markers of subclinical atherosclerosis: Endothelial function and carotid intima media thickness

OBJECTIVE Endothelial function and carotid intima media thickness (cIMT) were investigated in a cohort of 54 healthy adults without known cardiovascular disease. METHODS Pulse wave amplitude was determined with peripheral arterial tonometry (PAT) to obtain the reactive hyperemia (RH)-PAT ratio. Ultrasound was used to determine cIMT. RESULTS 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. CONCLUSION 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.

Effects of long-term testosterone administration in HIV-infected women: a randomized, placebo-controlled trial.

Objective:Androgen deficiency is common in HIV-infected women. We investigated the long-term effects of transdermal testosterone on body composition, bone mineral density, quality of life, and safety. Design:Twenty-five HIV-infected women with free testosterone below the median (≤3 pg/ml) of the female normal range were randomized to receive transdermal testosterone (300 μg twice weekly) or identical placebo over 18 months. Results:Women demonstrated low androgen levels (1.3 ± 0.1 pg/ml) with relatively low weight (22.8 ± 0.6 kg/m2) and low bone mineral density (−0.61 ± 0.17 SD hip T score) at baseline. No statistically significant differences were seen between the groups at baseline. The discontinuation rate was 16% and did not differ between treatment groups (P = 0.24). Free testosterone by equilibrium dialysis increased over 18 months (7.9 ± 1.8 vs. 0.3 ± 0.4 pg/ml; P = 0.002, testosterone vs. placebo). Testosterone was well tolerated and did not affect lipids, liver, or safety indices. Lean mass (1.8 ± 0.5 vs. 0.8 ± 0.9 kg; P = 0.04) and BMI (1.6 ± 0.4 vs. 0.8 ± 0.6 kg/m2; P = 0.03, testosterone vs. placebo) increased in response to testosterone, whereas fat mass remained unchanged. Testosterone increased bone mineral density at the hip (0.01 ± 0.01 vs. −0.01 ± 0.01 g/cm2; P = 0.02) and trochanter (0.01 ± 0.01 vs. −0.02 ± 0.01 g/cm2; P = 0.01, testosterone vs. placebo). Testosterone significantly improved depression indices (−6.8 ± 2.2 vs. −1.9 ± 3.1; P = 0.02) and problems affecting sexual function (−1.8 ± 0.8 vs. 0.5 ± 0.5; P = 0.01, testosterone vs. placebo). Conclusion:Long-term testosterone administration was well tolerated in HIV-infected women and resulted in significant improvements in body composition, bone mineral density, and quality of life indices. Further evaluation of the safety and efficacy of testosterone use among HIV-infected women is warranted.

Serum oxidized low-density lipoprotein decreases in response to statin therapy and relates independently to reductions in coronary plaque in patients with HIV.

Objective:Circulating oxidized low-density lipoprotein (oxLDL) levels are elevated in HIV-infected patients and have been associated with atherosclerosis. Statins have been shown to reduce plaque on coronary computed tomography angiography (cCTA) in HIV-infected individuals. Thus, we investigated the effect of statins on serum oxLDL levels and the relationship between changes in oxLDL and coronary atherosclerosis on cCTA in patients with HIV. Design:We previously conducted a 12-month randomized, placebo-controlled trial with atorvastatin in 40 HIV-infected patients on stable antiretroviral therapy with subclinical coronary atherosclerosis and low-density lipoprotein (LDL)-cholesterol less than 130 mg/dl. Methods:In the current analysis, patients underwent cCTA and measurements of serum oxLDL, sCD14, sCD163, lipoprotein phospholipase-A2, and fasting lipids at baseline and end of the study. Results:Nineteen patients were randomized to atorvastatin and 21 patients to placebo. Serum oxLDL decreased –22.7% (95% CI –28.7 to –16.7) in the atorvastatin group and increased 7.5% (95% CI –3.3 to 18.4) in the placebo group (P < 0.0001). Change in oxLDL significantly correlated with changes in noncalcified plaque volume, total plaque volume, positively remodeled plaque, and low attenuation plaque. The association between changes in oxLDL and noncalcified plaque volume was independent of the baseline 10-year Framingham risk, LDL, CD4+ cell count, and viral load. Conclusion:Statins lower oxLDL levels in HIV-infected patients, and reductions in oxLDL are related to improvements in coronary atherosclerosis, independent of traditional cardiovascular risk factors. Reductions in oxLDL may be one mechanism through which statins exert beneficial effects on reducing atherosclerosis in HIV-infected individuals.

Effects of aging and smoking on carotid intima-media thickness in HIV-infection.

Objectives:To investigate the effects of aging and smoking on carotid intima–media thickness (cIMT) among patients with and without HIV. Methods: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. Results:Data on 166 male 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 sex, 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, sex, CVD risk factors, immunological function, and antiretroviral therapy use. Conclusion: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.

Decreased respiratory quotient in relation to resting energy expenditure in HIV-infected and noninfected 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 highly active antiretroviral therapy and among non-HIV-infected control subjects. Resting energy expenditure 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. Respiratory quotient, REE, body composition, and dietary intake parameters were assessed in 283 HIV-infected patients and 146 community-derived HIV-negative controls who were evaluated for metabolic studies between 1998 and 2005. Respiratory quotient was lower (0.83 +/- 0.00 vs 0.85 +/- 0.01, P = .005), whereas REE adjusted for fat-free mass (FFM) was higher (31.8 +/- 0.3 vs 29.8 +/- 0.3 kcal/[d kg], P < or = .0001), in HIV-infected compared with control subjects. In multivariate modeling among HIV-infected patients, including age, sex, and parameters of immune function, FFM (beta = 24.811334, P < .0001), visceral adiposity (beta = .7182746, P = .008), and total body fat (beta = 8.0506839, P = .041) were positively associated with REE, whereas RQ was negatively associated with REE (beta = -528.4808, P = .024). Overall r(2) was equal to 0.705 and P was less than .0001 for the model. In control subjects, by contrast, only visceral adiposity (beta = 1.0612073, P = .004), total body fat (beta = 15.805547, P = .010), and FFM (beta = 22.613005, P < .0001) were significant predictors of REE; and there was no relationship with RQ. Overall r(2) was equal to 0.825 and P was less than .0001 for the model. These data suggest that alterations in substrate metabolism may contribute to increased REE in HIV-infected patients compared with control subjects.

Increased Aldosterone Among HIV-Infected Women with Visceral Fat Accumulation

Increased aldosterone has been associated with obesity and the metabolic syndrome in non-HIV-infected individuals, but aldosterone has not been investigated among HIV-infected patients with increased visceral adipose tissue (VAT). Twenty-four-hour urine aldosterone was assessed among age and BMI-matched HIV-infected women with increased VAT, HIV-infected women without increased VAT and healthy controls. Twenty-four hour urine aldosterone was higher in HIV-infected women with increased VAT and was associated with SBP, VAT and hemoglobin A1c. Increased aldosterone may contribute to the detrimental effects of excess visceral adiposity on blood pressure and glucose homeostasis among HIV patients.

The Effect of Prevention Messages and Self-Efficacy Skill Building With Inner-City Women at Risk for HIV Infection

&NA; The purpose of this study was to examine the effect of gender‐sensitive and culturally relevant HIV prevention film messages combined with self‐efficacy and skill building exercises on self‐reported safe sex behaviors, intentions, attitudes, and self‐advocacy over time. A sample of 131 women of mixed ethnicity from inner‐city Boston who were living in transitional housing participated in a 4‐week pre/postmeasurement design. Results showed that, despite the short duration of the intervention, participants self‐reported significantly more use of safe sex behaviors and being prepared for sexual intimacy after the intervention. The study validated use of an approach originally intended for African American women with other women at risk for HIV.

Metabolic Effects of Long-Term Reduction in Free Fatty Acids With Acipimox in Obesity: A Randomized Trial

CONTEXT Increased circulating free fatty acids (FFAs) have been proposed to contribute to insulin resistance in obesity. Short-term studies have investigated the effects of acipimox, an inhibitor of hormone-sensitive lipase, on glucose homeostasis, but longer-term studies have not been performed. OBJECTIVE To test the hypothesis that long-term treatment with acipimox would reduce FFA and improve insulin sensitivity among nondiabetic, insulin-resistant, obese subjects. DESIGN, SETTING, PATIENTS, AND INTERVENTION At an academic medical center, 39 obese men and women were randomized to acipimox 250 mg thrice-daily vs identical placebo for 6 months. MAIN OUTCOME MEASURES Plasma lipids, insulin sensitivity, adiponectin, and mitochondrial function via assessment of the rate of post-exercise phosphocreatine recovery on (31)P-magnetic resonance spectroscopy as well as muscle mitochondrial density and relevant muscle gene expression. RESULTS Fasting glucose decreased significantly in acipimox-treated individuals (effect size, -6 mg/dL; P = .02), in parallel with trends for reduced fasting insulin (effect size, -6.8 μU/mL; P = .07) and HOMA-IR (effect size, -1.96; P = .06), and significantly increased adiponectin (effect size, +668 ng/mL; P = .02). Acipimox did not affect insulin-stimulated glucose uptake, as assessed by euglycemic, hyperinsulinemic clamp. Effects on muscle mitochondrial function and density and on relevant gene expression were not seen. CONCLUSION These data shed light on the long-term effects of FFA reduction on insulin sensitivity, other metabolic parameters, and muscle mitochondrial function in obesity. Reduced FFA achieved by acipimox improved fasting measures of glucose homeostasis, lipids, and adiponectin but had no effect on mitochondrial function, mitochondrial density, or muscle insulin sensitivity.