Takara L. Stanley

Metabolic Abnormalities and Cardiovascular Disease Risk Factors in Adults with Human Immunodeficiency Virus Infection and Lipodystrophy

We evaluated metabolic and clinical features of 71 HIV-infected patients with lipodystrophy by comparing them with 213 healthy control subjects, matched for age and body mass index, from the Framingham Offspring Study. Thirty HIV-infected patients without fat redistribution were compared separately with 90 matched control subjects from the Framingham Offspring Study. Fasting glucose, insulin, and lipid levels; glucose and insulin response to standard oral glucose challenge; and anthropometric measurements were determined. HIV-infected patients with lipodystrophy demonstrated significantly increased waist-to-hip ratios, fasting insulin levels, and diastolic blood pressure compared with controls. Patients with lipodystrophy were more likely to have impaired glucose tolerance, diabetes, hypertriglyceridemia, and reduced levels of high-density lipoprotein (HDL) cholesterol than were controls. With the exception of HDL cholesterol level, these risk factors for cardiovascular disease (CVD) were markedly attenuated in patients without lipodystrophy and were not significantly different in comparison with controls. These data demonstrate a metabolic syndrome characterized by profound insulin resistance and hyperlipidemia. CVD risk factors are markedly elevated in HIV-infected patients with fat redistribution.

Effects of Testosterone and Progressive Resistance Training in Eugonadal Men with AIDS Wasting: A Randomized, Controlled Trial

Substantial loss of lean body and muscle mass occur among HIV-infected patients with relatively preserved body weight (1); these changes are associated with reduced functional status and strength (2). Protease inhibitor therapy has not been shown to increase muscle mass in patients with AIDS wasting (3), suggesting the need for successful anabolic strategies in these patients. Testosterone therapy and progressive resistance training increase lean body mass in hypogonadal men with AIDS wasting (4-6). However, most men with AIDS wasting have normal testosterone levels (7). We assessed the independent effects of progressive resistance training and testosterone in eugonadal men with AIDS wasting. Baseline (2) and screening data (7) from a subset of participants were previously reported. Methods Patients From 1997 to 1999, 54 HIV-infected men with AIDS-related wasting (weight<90% ideal body weight or self-reported weight loss>10%) and a normal serum level of free testosterone (>42 pmol/L) were recruited through community advertisements and contact with physicians in the multidisciplinary HIV practice at the Massachusetts General Hospital, Boston, Massachusetts, and other community clinics. Exclusion criteria were new opportunistic infection diagnosed within 6 weeks of the study; other contraindication to exercise; use of a new antiretroviral agent within 8 weeks of the study; abnormal prostate-specific antigen level; symptomatic prostatism; prostate malignancy; bipolar disorder; use of parenteral nutrition, megestrol acetate, glucocorticoids, androgen, estrogen, growth hormone or other anabolic agent within 3 months of the study; hemoglobin value less than 90 g/L or greater than 170 g/L; platelet count less than 50 000 cells/mm3; or serum creatinine concentration greater than 177 mol/L (2.0 mg/dL). All patients gave written consent, and the study was approved by the Human Studies Committee of the Massachusetts General Hospital. Protocol Eligible patients were stratified for weight less than 90% of ideal body weight or 90% or greater than ideal body weight. Using a 2 2 factorial design, we randomly assigned patients to receive intramuscular injections of testosterone enanthate (200 mg/wk; Bio-Technology General Corp., Iselin, New Jersey) or placebo and to progressive resistance training (three times per week) or no training for 12 weeks. The study statistician used a permuted-block algorithm with blocks of 8 to perform randomization; the code was available only to the hospital pharmacy that bottled the study drug. Placebo contained sesame oil with chlorobutanol as a preservative and matched testosterone enanthate in color and consistency. Compliance with drug therapy was confirmed by history, outpatient injection records, and vial counts. Patients assigned to training participated in supervised progressive strength training and aerobic conditioning three times per week for 12 weeks. During each session, patients began by performing 20 minutes of aerobic exercise on a stationary bicycle at a target heart rate of 60% to 70% of their age-predicted maximum, in accordance with American College of Sports Medicine recommendations (8). A cool-down period of 15 minutes and normalization of heart rate preceded resistance training. Training was performed isotonically on the following computerized equipment (Life Fitness, Franklin Park, Illinois): leg extension, leg curl, leg press, latissimus dorsi pull-down, arm curl, and triceps extension. A one-repetition maximum weight was established at baseline for each patient on each machine in the best of three efforts. Patients increased resistance as follows: weeks 1 and 2, 2 sets, 8 repetitions/set, 60% one-repetition maximum; weeks 3 through 6, 2 sets, 8 repetitions/set, 70% one-repetition maximum; weeks 7 through 12, 3 sets, 8 repetitions/set, 80% one-repetition maximum. Patients were asked to refrain from exercise for 2 weeks before the baseline visit and to refrain from any exercise or activity beyond normal daily activity during the study. Food intake was ad libitum; caloric intake was determined by using a 4-day food record (Nutrition Data System for Research, version 12A/2.91, Nutrition Coordinating Center, University of Minnesota, Minneapolis, Minnesota). Resting and predicted energy expenditure were calculated (VMAX 29N, SensorMedics, Inc., Loma Linda, California). Clinical End Points Clinical end points were assessed at baseline and 12 weeks. Lean body mass and fat mass were measured by using dual-energy x-ray absorptiometry (QDR-4500 Densitometer, Hologic, Inc., Waltham, Massachusetts) with a precision error of 1.5% for fat-free mass (9). Cross-sectional muscle areas of the leg and arm were assessed by performing computed tomography of the midfemur and humerus (General Electric High Speed Helical CAT Scanner, Milwaukee, Wisconsin; SE 3% for arm muscle area and 1% for leg muscle area). The location of the midfemur and humerus were determined from the scout image. Upper- and lower-extremity muscle strength were measured by using the quantitative muscle function test (10, 11). Peak isometric force of shoulder flexion, shoulder extension, elbow flexion, elbow extension, knee flexion, knee extension, dorsiflexion, and grip were measured on the best of two repetitions (10, 12). Z scores were calculated for upper- and lower-extremity strength (MVCT Computer Analysis Software, Boston, Massachusetts) by standardizing to a group of healthy male controls (11, 12). Serum levels of total and free testosterone were measured by using a radioimmunoassay kit (Diagnostics Products Corp., Los Angeles, California) (4). CD4 cell counts were measured by using flow cytometry (Becton-Dickinson Immunocytochemistry Systems, San Jose, California); viral load was measured by using the Amplicor HIV-1 Monitor (Roche Molecular Systems, Branchburg, New Jersey). Other tests were done according to published methods (13). A digital prostate examination was performed at each visit. Statistical Analysis The effects of training and testosterone were simultaneously assessed in the same factorial model. In the primary analysis, we used analysis of covariance to assess change from baseline at 3 months simultaneously in the testosterone arm (testosterone recipients vs. placebo recipients) and the training arm (trained patients vs. nontrained patients), controlling for baseline values. To test for an interaction between testosterone and training, we used analysis of covariance with an interaction term. Change in lean body mass was the primary clinical end point for the effect of testosterone, and change in cross-sectional muscle area was the primary end point for the effect of resistance training. Change from baseline was also determined within each individual treatment group and was compared with zero change by using analysis of covariance. The t- test was used to compare treatment groups at baseline. All available data are included in the analysis. Results are reported as the mean SD. Results No patient withdrew from the study because of an adverse event or side effect; dropout rates did not differ by group (Appendix Figure). Patients had lost significant weight but were not severely ill or low weight at study entry (Table 1). Seventy-six percent of patients were receiving antiretroviral therapy and 72% were receiving highly active antiretroviral therapy. Seventy-six percent of patients had previously had an opportunistic infection. Appendix Figure. Flow of participants through the study. Table 1. Results of Factorial Analysis Changes in response to testosterone therapy and training are shown in Table 1. Lean body mass and muscle area increased significantly in response to training and testosterone therapy. Muscle strength on elbow flexion and shoulder extension and overall upper-extremity Z score increased in response to testosterone therapy. The change in muscle area correlated with the change in muscle strength (R =0.48; P =0.001 for mid-thigh muscle area and strength on knee extension). No interaction was found between testosterone therapy and training. Levels of high-density lipoprotein (HDL) cholesterol increased in response to training but decreased in response to testosterone therapy. Levels of total and free testosterone increased in response to testosterone therapy, and levels of gonadotropin and sex hormonebinding globulin decreased. Caloric intake did not change significantly between the groups. The CD4 count did not change significantly in response to training or testosterone therapy (P >0.2). Viral load decreased in testosterone-treated patients. Use of antiretroviral therapy did not change in any study group. Levels of aspartate aminotransferase or prostate-specific antigen did not change significantly (P >0.2). No patient developed new prostate nodules. Three patients developed breast tenderness or gynecomastia (two were receiving testosterone and one was receiving placebo). Compliance with the training program was 78% among patients who completed the study; compliance with testosterone therapy was 98%. Discussion Previous studies suggest that testosterone therapy, alone (4, 5) and in combination with resistance training, increases lean body mass in hypogonadal men with AIDS wasting (6). However, recent data indicate that androgen levels are normal in most HIV-infected men (7), and the independent effects of testosterone and supervised exercise in eugonadal men with AIDS wasting are not known. The patients in our study generally had normal body weight and a normal Karnofsky score but had lost substantial weight. Most patients had a history of opportunistic infection, and although they were not cachectic or malnourished, they had reduced muscle mass (2). Previous studies have shown that resistance training in combination with testosterone or anabolic steroid therapy increases lean body mass (6, 14, 15). In contrast, we found that training had a significant effect (increase of 2.3 kg) on lean bod

TNF-α Antagonism with Etanercept Decreases Glucose and Increases the Proportion of High Molecular Weight Adiponectin in Obese Subjects with Features of the Metabolic Syndrome

CONTEXT AND OBJECTIVE Obesity is associated with activation of the TNF-α system, increased inflammatory markers, and insulin resistance. Although studies in rodents suggest that attenuation of TNF activity improves glucose homeostasis, the effect of prolonged inhibition of TNF-α with etanercept on inflammation and glucose homeostasis in a human model of obesity is not known. DESIGN AND PARTICIPANTS Forty obese subjects with features of metabolic syndrome were randomized to etanercept or placebo, 50 mg twice weekly for 3 months, followed by 50 mg once weekly for 3 months. OUTCOME MEASURES Subjects underwent oral glucose tolerance testing and measurement of serum inflammatory biomarkers and adipokines. Subcutaneous fat biopsy was performed in a subset for measurement of adipokine and TNF-α mRNA expression. RESULTS Visceral adiposity was significantly associated with serum concentrations of TNF receptor 1 (TNFR1), TNFR2, and vascular cell adhesion molecule-1 and adipose tissue expression of TNF-α and SOCS-3 (all P < 0.05). Insulin resistance as assessed by homeostasis model assessment was significantly associated with TNFR1, C-reactive protein, IL-6, and soluble intracellular adhesion molecule-1 (sICAM-1) (all P < 0.05). Etanercept significantly improved fasting glucose (treatment effect vs. placebo over 6 months, -10.8 ± 4.4%, P = 0.02). Etanercept also increased the ratio of high molecular weight adiponectin to total adiponectin (+22.1 ± 9.2% vs. placebo, P = 0.02), and decreased levels of sICAM-1 (-11 ± 2% vs. placebo, P < 0.0001). In contrast, body composition, lipids, C-reactive protein, and IL-6 were unchanged after 6 months. CONCLUSIONS Prolonged therapy with etanercept improved fasting glucose, increased the ratio of high molecular weight to total adiponectin, and decreased sICAM-1 in obese subjects with abnormal glucose homeostasis and significant subclinical inflammation.

Prevalence of Hypogonadism among Men with Weight Loss Related to Human Immunodeficiency Virus Infection Who Were Receiving Highly Active Antiretroviral Therapy

Previous studies have indicated that there is a significant prevalence (50%) of hypogonadism among men with acquired immunodeficiency syndrome (AIDS)-associated wasting, and for these patients testosterone administration has been shown to increase lean body mass and improve quality of life. However, the prevalence of hypogonadism is not known among men with weight loss related to human immunodeficiency virus (HIV) infection who are receiving highly active antiretroviral therapy (HAART). From 1997 through 1999, we investigated total and free testosterone levels in 90 men who were <90% of ideal body weight or had weight loss of >10% from preillness weight; 71% of these subjects were receiving HAART. Twenty-one percent of the subjects receiving HAART had low free testosterone levels. No correlation was seen between weight, CD4 cell count, medication status, and other clinical factors. These data suggest that hypogonadism remains relatively common in men with AIDS wasting, despite treatment with HAART. HIV-infected men with wasting syndrome should be screened for hypogonadism and receive physiological androgen replacement therapy if they are hypogonadal.

The Effects of Central Adiposity on Growth Hormone (GH) Response to GH-Releasing Hormone-Arginine Stimulation Testing in Men

CONTEXT The relative contribution of central adiposity vs. weight on GH response to stimulation testing in obesity is not known. OBJECTIVE We aimed to assess the contribution of weight and specific measures of central and peripheral adiposity to GH response to GHRH-arginine testing in lean, overweight, and obese men. DESIGN A total of 75 men [mean age, 44.3+/-1.1 yr; body mass index (BMI), 28.8+/-0.7 kg/m2] were investigated. Subjects were classified as lean (BMI<25 kg/m2; n=23), overweight (BMI>or=25 and <30 kg/m2; n=28), or obese (BMI>or=30 kg/m2; n=24). Subjects were also stratified by waist circumference (WC) (<102 cm, n=47; >or=102 cm, n=28). Body composition and regional adiposity were assessed by anthropometrics, dual-energy x-ray absorptiometry (DEXA), and abdominal computed tomography (CT) scans. RESULTS Peak stimulated GH was 36.4+/-5.4, 16.6+/-2.9, and 7.6+/-0.9 microg/liter among lean, overweight, and obese subjects, respectively (P<0.001 for all comparisons). Peak stimulated GH was 26.9+/-3.4 microg/liter among subjects with WC less than 102 cm compared to 7.9+/-0.9 microg/liter among subjects with WC of 102 cm or greater (P<0.0001). Separate multivariate models using anthropometric, DEXA, and CT-derived measures of central adiposity demonstrated strong associations between peak stimulated GH and measures of central adiposity including WC, trunk fat by DEXA, and visceral adiposity by CT, controlling for age, BMI, and more general measures of adiposity. WC was independently associated with peak GH response to GHRH-arginine in a model including age, BMI, and hip circumference. In this model, BMI was no longer significant, and peak GH was reduced 1.02 microg/liter for each 1 cm increase in WC (P=0.02). CONCLUSIONS GH response to GHRH-arginine testing is reduced in both overweight and obese subjects and negatively associated with indices of central abdominal obesity including WC, trunk fat, and visceral adipose tissue. The use of waist circumference, as a surrogate for central adiposity, adds predictive information to the determination of GH response, independent of BMI.

Body Composition and Metabolic Changes in HIV-Infected Patients

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.

Effect of Body Mass Index on Peak Growth Hormone Response to Provocative Testing in Children with Short Stature

CONTEXT Obesity is associated with decreased spontaneous and stimulated GH secretion, but the effect of body mass index (BMI) on results of GH stimulation testing in children with short stature is not known. OBJECTIVE The aim of the study was to determine the impact of BMI on peak GH to provocative testing in children with short stature. DESIGN, SETTING, AND PARTICIPANTS This was a retrospective review of provocative GH testing performed in 116 children 2-18 yr old in the ambulatory clinic of the Pediatric Endocrinology Unit at the Massachusetts General Hospital from 2004-2008. MAIN OUTCOME MEASURES The main outcome measure was peak stimulated GH. Height, weight, IGF-I, and IGF-binding protein 3 were also measured. RESULTS In univariate regression analysis, BMI sd score (BMI SDS) was inversely associated with natural log (ln) peak GH to provocative testing (P = 0.002), whereas height SDS, ln IGF-I, and IGF-binding protein 3 were not significantly associated with ln peak GH. After controlling for age, gender, BMI, and pubertal status, BMI (P = 0.002) remained independently associated with ln peak GH. BMI SDS significantly influenced the likelihood of diagnosis of GH deficiency using peak GH cutoffs of 10, 7, and 5 microg/liter. CONCLUSION In children with short stature, BMI affects peak stimulated GH and should be considered when interpreting GH testing. Higher BMI SDS, even within the normal range, may lead to overdiagnosis of GH deficiency.

Effects of Switching from Lopinavir/ritonavir to Atazanavir/ritonavir on Muscle Glucose Uptake and Visceral Fat in HIV Infected Patients

Objective: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. Methods: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 300 mg and ritonavir 100 mg daily) for 6 months. The primary endpoint was change in thigh muscle glucose uptake as measured by positron emission tomography. 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. Results:After 6 months, anterior thigh muscle glucose uptake increased significantly (treatment effect +18.2 ± 5.9 μmol/kg per min, ATV/r vs. LPV/r, P = 0.035), and visceral adipose tissue area decreased significantly in individuals who switched to ATV/r (treatment effect −31 ± 11 cm2, 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 high-density lipoprotein and low-density lipoprotein 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). Conclusion: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.

Sustained Anabolic Effects of Long-Term Androgen Administration in Men with AIDS Wasting

Fifty-one human immunodeficiency virus-positive men with hypogonadism and wasting were randomized to receive testosterone enanthate, 300 mg i.m. every 3 weeks, or placebo for 6 months, followed by open-label testosterone administration for 6 months. Subjects initially randomized to placebo gained lean body mass (LBM) only after crossover to testosterone administration (mean change +/- standard error of the mean, -0.6 +/- 0.7 kg [months 0-6] vs. 1.9 +/- 0.7 kg [months 6-12]; P = .03). In contrast, subjects initially randomized to testosterone continued to gain LBM during open-label administration (2.0 +/- 0.7 kg [months 0-6] vs. 1.6 +/- 0.6 kg [months 6-12]; P = .62) and had gained more LBM at 1 year than did subjects receiving testosterone for only the final 6 months of the study (3.7 +/- 0.8 kg vs. 1.0 +/- 1.0 kg; P = .05). Testosterone administration results in sustained increases in LBM during 1 year of therapy in hypogonadal men with AIDS wasting.

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.