Colleen Hadigan

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.

State of the Science Conference Initiative to Decrease Cardiovascular Risk and Increase Quality of Care for Patients Living With HIV/AIDS: Executive Summary

With successful antiretroviral therapy, patients infected with the human immunodeficiency virus (HIV) are living longer; however, recent reports suggest increased rates of coronary heart disease (CHD) among HIV-infected patients,1 and cardiovascular disease has become an important cause of morbidity and mortality in this population.2 Increased CHD rates in the HIV population may relate to traditional risk factors, including advancing age, higher smoking rates, dyslipidemia, insulin resistance, and impaired glucose tolerance. Cardiovascular disease may also be due to nontraditional factors, including changes in body composition with loss of subcutaneous fat and/or accumulation of visceral fat in some patients, inflammation, and direct effects of the virus on the vasculature, as well as to direct effects of specific antiretroviral drugs. Important questions remain as to the pathogenesis, detection, and treatment of cardiovascular disease and related risk factors in HIV-infected patients. These questions concern, among other things, the design of adequate trials to determine CHD incidence and the utility of existing CHD guidelines for screening, prevention, treatment, and risk stratification. To ascertain the state of the science with respect to these and related questions, a multidisciplinary conference with interested HIV specialists, cardiologists, endocrinologists, primary care physicians, National Institutes of Health representatives, and patient advocates was convened June 28–30, 2007, in Chicago, Ill, and chaired by Drs Steven Grinspoon and Robert Eckel. The discussions focused on 6 areas of interest, each with its own working group, including the following: (1) the contribution of metabolic and anthropometric abnormalities to cardiovascular disease risk factors (chaired by Drs Carl Grunfeld and Donald Kotler); (2) the epidemiological evidence for cardiovascular disease and its relationship to highly active antiretroviral therapy (HAART; chaired by Drs Judy Currier and Jens Lundgren); (3) the effects of HIV infection and antiretroviral therapy on the heart and vasculature (chaired by Drs Michael Dube …

Traditional risk factors and D-dimer predict incident cardiovascular disease events in chronic HIV infection

Objective:Cardiovascular disease (CVD) contributes significantly to HIV-related morbidity and mortality. Chronic immune activation and inflammation are thought to augment the progression of atherosclerotic disease. In this retrospective, case–control study of HIV-infected individuals, we investigated the association of traditional cardiac risk factors, HIV-related disease, and inflammation with CVD events. Methods:HIV-infected individuals who experienced an incident CVD event while enrolled in National Institutes of Health clinical protocols from 1995 to 2009 were matched 2: 1 to HIV-infected individuals without known CVD. Markers of inflammation and cell activation were measured in serum or plasma using ELISA-based assays and peripheral mononuclear cells by four-color flow cytometry. Results:Fifty-two patients experienced an incident CVD event. Events were related to smoking, dyslipidemia, hyperglycemia, and family history as well as elevated D-dimer, soluble vascular cell adhesion molecule-1, tissue inhibitor of metalloproteinase-1, and soluble tissue factor, but not high-sensitivity C-reactive protein. No significant differences in antiviral therapy, CD4+ T-cell count, or CD38 and human leukocyte antigen-DR expression were identified between patients and controls. In multivariable analysis, smoking, family history, D-dimer, and glucose were independently related to CVD risk. Conclusion:In this cohort, CVD risk was related to traditional CVD risk factors and markers of thrombosis and endothelial damage, but not to high-sensitivity C-reactive protein or markers of T-cell activation such as CD38/human leukocyte antigen-DR coexpression. D-dimer may help identify HIV-infected patients at elevated CVD risk.

Increased cardiovascular disease risk indices in HIV-infected women.

Little is known regarding cardiovascular disease risk indices in HIV-infected women. This study investigated cardiovascular disease risk indices in 100 consecutively recruited HIV-infected women and 75 healthy female control subjects. Subjects were recruited from hospital- and community-based health care providers. C-reactive protein (CRP), interleukin-6 (IL-6), adiponectin, lipid, and glucose levels were the main outcome measures. CT scan, dual-energy x-ray absorptiometry (DXA), and anthropometry were used to assess body composition. Although similar in age, weight, and racial composition, HIV-infected women demonstrated higher CRP (4.6 ± 0.7 vs. 2.3 ± 0.4 mg/L, P = 0.007), IL-6 (2.7 ± 0.2 vs. 1.8 ± 0.1 pg/mL, P = 0.02), triglyceride (1.84 ± 0.21 vs. 0.85 ± 0.05 mM, P = 0.0002), 2-hour glucose after oral glucose challenge (6.88 ± 0.22 vs. 5.72 ± 0.17 mM, P = 0.0003), and fasting insulin (81 ± 8 vs. 45 ± 2 pM, P = 0.0002) and lower high-density lipoprotein cholesterol (1.17 ± 0.03 vs. 1.45 ± 0.05 mM, P < 0.0001) and adiponectin (5.4 ± 0.3 vs. 7.6 ± 0.5 mg/L, P = 0.0001) levels compared with the control population. HIV-infected women had more abdominal visceral fat and less extremity fat by CT and DXA scan and demonstrated a higher waist-to-hip ratio (WHR) than the control population. Within the HIV group, CRP and other indices were significantly related to body composition in stepwise regression models. Among all subjects, WHR, but not HIV status, was significantly related to CRP and other cardiovascular disease risk indices. HIV-infected women demonstrate significantly increased risk factors for cardiovascular disease in association with abnormal fat distribution.

Prediction of Coronary Heart Disease Risk in HIV-Infected Patients with Fat Redistribution

A metabolic syndrome has been described among human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy; the syndrome is characterized by fat redistribution, insulin resistance, and dyslipidemia. We compared the 10-year coronary heart disease (CHD) risk estimates for 91 HIV-infected men and women with fat redistribution with the risk estimates for 273 age-, sex-, and body mass index (BMI)-matched subjects enrolled in the Framingham Offspring Study. Thirty HIV-infected patients without fat redistribution were also compared with 90 age- and BMI-matched control subjects. The 10-year CHD risk estimate was significantly elevated among HIV-infected patients with fat redistribution, particularly among men; however, when they were matched with control subjects by waist-to-hip ratio, the 10-year CHD risk estimate did not significantly differ between groups. HIV-infected patients without fat redistribution did not have a greater CHD risk estimate than did control subjects. In addition, the CHD risk estimate was greatest in HIV-infected patients who had primary lipoatrophy, compared with those who had either lipohypertrophy or mixed fat redistribution. Therefore, although CHD risk is increased in HIV-infected patients with fat redistribution, the pattern of fat distribution and sex are potential important components in determining the risk in this population.

Effects of exercise training and metformin on body composition and cardiovascular indices in HIV-infected patients.

Objective: To determine whether exercise training in combination with metformin improves cardiovascular risk indices and insulin in comparison to metformin alone among HIV-infected patients. Methods and design: We conducted a prospective, randomized, 3-month study of HIV patients on stable antiretroviral therapy with hyperinsulinemia and fat redistribution. Subjects received metformin alone or metformin and exercise training consisting of 1 h of aerobic and resistance training three times a week. Cardiovascular parameters, including blood pressure and endurance during sub-maximal stress testing, body composition, strength, insulin and other biochemical parameters were determined. Results: Thirty-seven patients were randomized and 25 subjects completed the study. Subjects receiving exercise training and metformin demonstrated significant decreases in median waist-to-hip ratio [−0.02 (−0.06, −0.01) (median (interquartile range) versus −0.01 (0.03, 0.02), P = 0.026], resting systolic [−12 (−20, −4) versus 0 (−11, 11), P = 0.012] and diastolic blood pressures [−10 (−14, −8) versus 0 (−7, 8), P = 0.001], increased thigh muscle cross-sectional area [3 (−3, 12) versus −7 (−11, 0), P = 0.015], and improved exercise time [3 (0, 4) versus 0 (−1, 1), P = 0.045] compared with subjects receiving metformin alone. Fasting insulin and insulin area under the curve decreased significantly more in the exercise and metformin group (P < 0.05). Lipids and resting lactate did not change significantly between treatment groups. Conclusions: These data demonstrate that exercise training in combination with metformin significantly improves cardiovascular and biochemical parameters more than metformin alone in HIV-infected patients with fat redistribution and hyperinsulinemia. Combined treatment was safe, well tolerated and may be a useful strategy to decrease cardiovascular risk in this population.

Increased abdominal visceral fat is associated with reduced bone density in Hiv-infected men with lipodystrophy

ObjectiveTo examine the relationship between bone density and changes in regional and whole body composition in HIV-infected men with and without lipodystrophy. DesignCross-sectional, observational study of HIV-infected men with and without lipodystrophy and matched HIV-negative controls. SettingTertiary care academic medical institution. PatientsA total of 59 men, belonging to three different groups: HIV-positive men with lipodystrophy (n = 21), HIV-positive men without lipodystrophy (n = 20), and age-matched and body mass index-matched HIV-negative controls (n = 18). MethodsBone density, markers of bone turnover and indices of calcium metabolism were measured in all subjects. Quantitative computed tomography was used both to determine volumetric bone density of the spine and to quantify abdominal visceral fat. Dual energy X-ray absorptiometry was used to determine whole body composition and bone density. Statistical comparisons were performed according to lipodystrophy categorization and protease inhibitor exposure. ResultsMen with HIV-associated lipodystrophy had reduced lumbar spine bone density compared with both HIV-infected non-lipodystrophic men [mean ± SD, 132 ± 29 versus 154 ± 30 mg/cm3;P = 0.02] and HIV-negative controls [mean ± SD 132 ± 29 versus 148 ± 18) mg/cm3;P = 0.04]. Lumbar spine bone density was reduced significantly in HIV lipodystrophy patients independently of protease inhibitor use. In an analysis among all HIV-infected subjects, increased visceral abdominal fat area was associated with decreased lumbar spine bone density (r, −0.47;P = 0.002). The association between visceral fat and bone density remained significant (P = 0.007) after controlling for age, body mass index, lowest body weight, protease inhibitor use, and extremity fat in a multivariate regression model. Markers of bone turnover were not related to bone density or lipodystrophy status. ConclusionsLumbar spine bone density is reduced in association with increased visceral fat in HIV-infected men with lipodystrophy. Further studies are needed to determine the mechanisms of osteopenia in HIV lipodystrophy and whether increased marrow fat occurs in such patients and affects bone density.

Assessment of macronutrient and micronutrient intake in women with anorexia nervosa

OBJECTIVE The purpose of this study is to evaluate the accuracy of diet history compared to observed food intake in the nutritional assessment of women with anorexia nervosa (AN) and healthy age-matched controls. METHOD One-month diet history was compared to 1-day observed food intake in 30 women with AN and 28 control subjects. RESULTS Reported intake by diet history was similar to observed intake for macronutrient composition and fat intake for patients with AN. Reported energy intake was higher than observed intake (1,602 +/- 200 kcal vs. 1,289 +/- 150 kcal, p <.05), but was in agreement with predicted energy expenditure by the Harris-Benedict equation (1,594 +/- 18 kcal, p =.97) in patients with AN. Micronutrient intake by diet history was highly correlated with observed intake in patients with AN. More than one half of the patients with AN failed to meet the recommended dietary allowance (RDA) for vitamin D, calcium, folate, vitamin B12, zinc, magnesium, and copper when assessed by diet history. In contrast to patients with AN, diet history did not correlate with observed intake of energy, macronutrients, or most micronutrients among the controls. DISCUSSION Diet history is an accurate tool to assess fat intake and macronutrient composition in patients with AN and demonstrates significant micronutrient deficiencies in this population. The agreement between total energy intake and predicted energy expenditure supports the overall utility of the diet history in the nutritional assessment of patients with AN.

Modifiable Dietary Habits and Their Relation to Metabolic Abnormalities in Men and Women with Human Immunodeficiency Virus Infection and Fat Redistribution

We assessed the relationship between dietary intake, body composition, and metabolic parameters in 85 consecutive human immunodeficiency virus (HIV)-infected patients with fat redistribution. Dietary history and values for fasting glucose, insulin, lipids, and oral glucose tolerance were obtained for 62 men and 23 women with HIV infection and fat redistribution (mean age +/- standard error of the mean [SEM], 43.5+/-0.9 years; mean body mass index [BMI] +/- SEM, 26.3+/-0.5 kg/m2). A multivariate regression analysis was used to predict insulin area under the curve (AUC) following the oral glucose tolerance test; this included age, sex, BMI, waist-to-hip ratio, kilocalories, duration of protease inhibitor (PI) use, fat redistribution pattern, alcohol intake, dietary fiber intake, and polyunsaturated-to-saturated (P:S) fat ratio. Only age (P=.004), PI use duration (P=.02), and P:S fat ratio (P=.003) were positively associated with insulin AUC. Dietary fiber intake was inversely associated with the insulin AUC (P=.001). In a similar analysis, alcohol consumption was a significant positive predictor of low-density lipoprotein cholesterol. Polyunsaturated fats, fiber, and alcohol are strongly associated with insulin resistance and hyperlipidemia in this population and may be important targets for dietary modification.

A1C Underestimates Glycemia in HIV Infection

OBJECTIVE The objective of this study was to determine the relationship between A1C and glycemia in HIV infection. RESEARCH DESIGN AND METHODS We completed a prospective cross-sectional study of 100 HIV-infected adults with type 2 diabetes (77%) or fasting hyperglycemia (23%) with measured glucose, A1C, mean corpuscular volume (MCV), and fructosamine. A total of 200 HIV-uninfected type 2 diabetic subjects matched for key demographic characteristics served as control subjects. RESULTS Relative to the control subjects, A1C underestimated glucose by 29 ± 4 mg/dl in the HIV-infected subjects. Current nucleoside reverse transcriptase inhibitors (NRTIs), higher MCV and hemoglobin, and lower HIV RNA and haptoglobin were associated with greater A1C-glucose discordance. However, only MCV and current NTRI use, in particular abacavir, remained significant predictors in multivariate analyses. Fructosamine more closely reflected glycemia in the HIV-infected subjects. CONCLUSIONS A1C underestimates glycemia in HIV-infected patients and is related to NRTI use. Use of abacavir and increased MCV were key correlates in multivariate analyses. Fructosamine may be more appropriate in this setting.