Viva W. Tai

Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection.

Summary: Although protease inhibitor (PI) therapy has improved the clinical status of patients with HIV infection, concerns have arisen that such treatment may have deleterious effects on glucose control, lipid metabolism, and body fat distribution. To determine whether initiation of PI therapy uniquely affects glucose and lipid metabolism, we analyzed paired data in HIV‐infected patients before and after beginning antiretroviral therapy that included a PI (PI; N = 20) or lamivudine (3TC) but no PI (3TC; N = 9); and a control group on stable regimens that included neither of these agents (CONT; N = 12). Measurements included fasting glucose; insulin; triglycerides; total, high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) cholesterol; HIV RNA; CD4+ lymphocytes; weight; and total and regional body composition. Neither weight nor total or regional fat content changed significantly in any group during the period of observation. Nonetheless, in patients beginning PI therapy, there were significant increases in glucose (+9 ± 3 mg/dl; p = .0136), insulin (+12.2 ± 4.9 U/ml; p = .023), triglycerides (+53 ± 17 mg/dl; p = .0069), and total and LDL cholesterol (+32 ± 11 and +18 ± 5 mg/dl; p = .0082 and .0026, respectively). None of these parameters changed significantly in the 3TC or CONT groups. The PI and 3TC groups experienced comparable increases in CD4+ lymphocytes, suggesting that the observed metabolic effects may be associated with PIs uniquely, rather than improvement in clinical status. However, it is also possible that the metabolic effects of PIs are associated with more effective viral suppression, because a greater proportion of patients in the PI group achieved undetectable levels of virus. We conclude that changes in glucose and lipid metabolism are induced by PI therapy in the absence of significant changes in weight or fat distribution. Longer periods of follow‐up will be required to determine the clinical significance of these changes. However, at the moment, the risks associated with these metabolic effects do not appear to outweigh improvements in survival seen with PI therapy.

Cross-sectional and longitudinal evaluation of body composition in men with HIV infection.

Body wasting is an increasingly prevalent AIDS-defining condition and an independent risk factor for mortality in patients infected with HIV. Largely on the basis of studies conducted early in the epidemic, HIV-associated wasting has been assumed to feature a disproportionate loss of lean tissue. We report the results obtained from cross-sectional and longitudinal studies that differ from these earlier observations. In a cross-sectional analysis, weight and body composition determined by dual-energy x-ray absorptiometry and bioelectrical impedance analysis in 32 HIV-infected men with documented weight loss of > or = 10% were compared to those in 46 HIV-positive men without significant weight loss and 32 HIV-negative controls. Fat, lean body mass (LBM), and body cell mass (BCM) were significantly lower in men with weight loss relative to controls (p < 0.001 for fat and BCM; p = 0.01 for LBM). Two thirds of the difference in weight was fat. For the longitudinal analysis, the composition of weight lost over time was evaluated in paired measurements in men grouped by body fat content (<15% or >15%, n = 10 per group). Weight loss in patients with baseline fat of more than 15% was only 16% LBM, but the composition of weight lost in men with baseline fat of less than 15% was 70% LBM. We conclude that progressive decreases in fat and lean tissue occur in men with HIV infection, with the composition of weight lost depending on baseline fat content. These results argue against the widely held notion that HIV-associated wasting is characterized by preservation of fat at the expense of lean tissue.

The Effects of Recombinant Human Leptin on Visceral Fat, Dyslipidemia, and Insulin Resistance in Patients with Human Immunodeficiency Virus-Associated Lipoatrophy and Hypoleptinemia

CONTEXT Leptin deficiency is associated with dyslipidemia and insulin resistance in animals and humans with lipoatrophy; leptin replacement ameliorates these abnormalities. OBJECTIVE The objective of the study was to evaluate the effects of leptin therapy in lipoatrophic HIV-infected patients with dyslipidemia and hypoleptinemia. DESIGN This was a 6-month, open-label, proof-of-principle pilot study. SETTING Metabolic ward studies were performed before and 3 and 6 months after leptin treatment. PARTICIPANTS Participants included eight HIV-infected men with lipoatrophy, fasting triglycerides greater than 300 mg/dl, and serum leptin less than 3 ng/ml. INTERVENTION Recombinant human leptin was given by sc injection (0.01 mg/kg and 0.03 mg/kg twice daily for successive 3 month periods). OUTCOME MEASURES Measures included fat distribution by magnetic resonance imaging and dual-energy X-ray absorptiometry; fasting lipids; insulin sensitivity by euglycemic hyperinsulinemic clamp; endogenous glucose production, gluconeogenesis, glycogenolysis, and whole-body lipolysis by stable isotope tracer studies; oral glucose tolerance testing; liver fat by proton magnetic resonance spectroscopy; and safety. RESULTS Visceral fat decreased by 32% (P = 0.001) with no changes in peripheral fat. There were significant decreases in fasting total (15%, P = 0.012), direct low-density lipoprotein (20%, P = 0.002), and non-high-density lipoprotein (19%, P = 0.005) cholesterol. High-density lipoprotein cholesterol increased. Triglycerides, whole-body lipolysis, and free fatty acids decreased during fasting and hyperinsulinemia. Fasting insulin decreased. Endogenous glucose production decreased during fasting and hyperinsulinemia, providing evidence of improved hepatic insulin sensitivity. Leptin was well tolerated but decreased lean mass. CONCLUSIONS Leptin treatment was associated with marked improvement in dyslipidemia. Hepatic insulin sensitivity improved and lipolysis decreased. Visceral fat decreased with no exacerbation of peripheral lipoatrophy. Results from this pilot study suggest that leptin warrants further study in patients with HIV-associated lipoatrophy.

Effect of a High-Fructose Weight-Maintaining Diet on Lipogenesis and Liver Fat

CONTEXT Consumption of high-fructose diets promotes hepatic fatty acid synthesis (de novo lipogenesis [DNL]) and an atherogenic lipid profile. It is unclear whether these effects occur independent of positive energy balance and weight gain. OBJECTIVES We compared the effects of a high-fructose, (25% of energy content) weight-maintaining diet to those of an isocaloric diet with the same macronutrient distribution but in which complex carbohydrate (CCHO) was substituted for fructose. DESIGN, SETTING, AND PARTICIPANTS Eight healthy men were studied as inpatients for consecutive 9-day periods. Stable isotope tracers were used to measure fractional hepatic DNL and endogenous glucose production (EGP) and its suppression during a euglycemic-hyperinsulinemic clamp. Liver fat was measured by magnetic resonance spectroscopy. RESULTS Weight remained stable. Regardless of the order in which the diets were fed, the high-fructose diet was associated with both higher DNL (average, 18.6 ± 1.4% vs 11.0 ± 1.4% for CCHO; P = .001) and higher liver fat (median, +137% of CCHO; P = .016) in all participants. Fasting EGP and insulin-mediated glucose disposal did not differ significantly, but EGP during hyperinsulinemia was greater (0.60 ± 0.07 vs 0.46 ± 0.06 mg/kg/min; P = .013) with the high-fructose diet, suggesting blunted suppression of EGP. CONCLUSION Short-term high-fructose intake was associated with increased DNL and liver fat in healthy men fed weight-maintaining diets.

Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome.

Dietary fructose is implicated in metabolic syndrome, but intervention studies are confounded by positive caloric balance, changes in adiposity, or artifactually high amounts. This study determined whether isocaloric substitution of starch for sugar would improve metabolic parameters in Latino (n = 27) and African‐American (n = 16) children with obesity and metabolic syndrome.

Altered fat distribution in HIV-positive men on nucleoside analog reverse transcriptase inhibitor therapy.

Summary: To determine whether HIV infection, the wasting syndrome, or nucleoside analog reverse transcriptase inhibitor (NRTI) or protease inhibitor (PI) therapy uniquely affect fat distribution in men, we performed manual regional analysis of total, appendicular, trunk, and central abdominal fat measured by dual‐energy X‐ray absorp tiometry (DEXA). Five groups of study subjects were identified for this cross‐sectional analysis: HIV‐negative controls (HIV‐; N = 44) and four groups of HIV‐posi tive subjects: antiretroviral (ARV)‐naive or with limited prior use of NRTIs (ARV‐; N = 23); on NRTIs for ≥ months but Pi‐naive (NRTI; N = 30); on an NRTI/PI regimen for ≥6 months but with no complaints of abnormal fat distribution (NRTI/PI; N = 26); and those on NRTIs but Pi‐naive with the wasting syndrome (NRTI/WS; N = 40). Total, appendicular, trunk, and central abdominal fat was sig nificantly lower in NRTI/WS. The ratio of trunk fat to appendicular fat was virtually identical in HIV‐ and ARV‐. This ratio was significantly higher in the NRTI, NRTI/PI, and NRTI/WS groups, and values in these three groups were similar. These cross‐sectional data suggest that HIV‐infected men receiving NRTIs have an altered pattern of fat distribution, compared with HIV‐negative men and HIV‐positive men who are not receiving antiretroviral therapy. This effect was independent of the con comitant use of a PI or a diagnosis of the wasting syndrome. We saw no evidence of a unique effect of HIV infection per se on regional fat distribution. Although the fat ratio is increasingly employed, its physiologic significance is unclear. Our results, which have been obtained retrospectively, are intended to provide the impetus for prospective, controlled studies of the interactions among drug and host factors in the development of fat distribution abnormalities.

Effects of Insulin-Like Growth Factor (IGF)-I/IGF-Binding Protein-3 Treatment on Glucose Metabolism and Fat Distribution in Human Immunodeficiency Virus-Infected Patients with Abdominal Obesity and Insulin Resistance

CONTEXT HIV-infected patients on antiretroviral therapy are at increased risk for excess visceral adiposity and insulin resistance. Treatment with GH decreases visceral adiposity but worsens glucose metabolism. IGF-I, which mediates many of the effects of GH, improves insulin sensitivity in HIV-negative individuals. OBJECTIVE Our objective was to determine whether IGF-I, complexed to its major binding protein, IGF-binding protein-3 (IGFBP-3), improves glucose metabolism and alters body fat distribution in HIV-infected patients with abdominal obesity and insulin resistance. METHODS We conducted a pilot, open-label study in 13 HIV-infected men with excess abdominal adiposity and insulin resistance to assess the effect of 3 months of treatment with IGF-I/IGFBP-3 on glucose metabolism and fat distribution. Glucose metabolism was assessed by oral glucose tolerance test and hyperinsulinemic-euglycemic clamp. Endogenous glucose production (EGP), gluconeogenesis, whole-body lipolysis, and de novo lipogenesis (DNL) were measured with stable isotope infusions. Body composition was assessed by dual-energy x-ray absorptiometry and abdominal computed tomography scan. RESULTS Glucose tolerance improved and insulin-mediated glucose uptake increased significantly during treatment. EGP increased under fasting conditions, and suppression of EGP by insulin was blunted. Fasting triglycerides decreased significantly in association with a decrease in hepatic DNL. Lean body mass increased and total body fat decreased, whereas visceral adipose tissue did not change. CONCLUSIONS Treatment with IGF-I/IGFBP-3 improved whole-body glucose uptake and glucose tolerance, while increasing hepatic glucose production. Fasting triglycerides improved, reflecting decreased DNL, and visceral adiposity was unchanged.

Use of Growth Hormone and Other Anabolic Agents in AIDS Wasting

Body wasting and loss of lean body mass (LBM) have been associated with increased mortality and disease progression, and reduced quality of life, in patients with human immunodeficiency virus (HIV) infection. The failure of nutritional therapies and, more recently, of effective viral suppression, to consistently restore LBM has prompted investigation of the pharmacologic use of a number of specific protein anabolic agents, including recombinant human growth hormone (rhGH), insulin-like growth factor I (rhIGF-I), and synthetic testosterone derivatives, such as nandrolone decanoate, oxandrolone, and oxymetholone. In a placebo-controlled trial, treatment with rhGH resulted in a significant and sustained increase in weight that was accompanied by an even greater increase in LBM and a decrease in fat, and improvement in treadmill work output. Preliminary data suggest that short-term rhGH treatment may be effective in mitigating weight loss in patients with secondary infections. Open-label studies of nandrolone decanoate suggest that this injectable agent also can increase weight and LBM. Two oral agents, oxandrolone and oxymetholone, can increase weight, but their effects on LBM in placebo-controlled trials have not been reported. Taken together, these studies demonstrate that HIV-infected individuals can regain weight and LBM under the proper therapeutic circumstances. The effects of reversal of wasting on survival and disease progression, long-term safety, and the potential value of these therapies in the treatment of fat redistribution remain to be determined.

Dual-energy X-ray absorptiometry–based body volume measurement for 4-compartment body composition

BACKGROUND Total body volume (TBV), with the exclusion of internal air voids, is necessary to quantify body composition in Lohmans 4-compartment (4C) model. OBJECTIVE This investigation sought to derive a novel, TBV measure with the use of only dual-energy X-ray absorptiometry (DXA) attenuation values for use in Lohmans 4C body composition model. DESIGN Pixel-specific masses and volumes were calculated from low- and high-energy attenuation values with the use of first principle conversions of mass attenuation coefficients. Pixel masses and volumes were summed to derive body mass and total body volume. As proof of concept, 11 participants were recruited to have 4C measures taken: DXA, air-displacement plethysmography (ADP), and total body water (TBW). TBV measures with the use of only DXA (DXA-volume) and ADP-volume measures were compared for each participant. To see how body composition estimates were affected by these 2 methods, we used Lohmans 4C model to quantify percentage fat measures for each participant and compared them with conventional DXA measures. RESULTS DXA-volume and ADP-volume measures were highly correlated (R(2) = 0.99) and showed no statistically significant bias. Percentage fat by DXA volume was highly correlated with ADP-volume percentage fat measures and DXA software-reported percentage fat measures (R(2) = 0.96 and R(2) = 0.98, respectively) but were slightly biased. CONCLUSIONS A novel method to calculate TBV with the use of a clinical DXA system was developed, compared against ADP as proof of principle, and used in Lohmans 4C body composition model. The DXA-volume approach eliminates many of the inherent inaccuracies associated with displacement measures for volume and, if validated in larger groups of participants, would simplify the acquisition of 4C body composition to a single DXA scan and TBW measure.

Effects of Recombinant Human Growth Hormone on Fat Distribution in Patients with Human Immunodeficiency Virus-Associated Wasting

In light of current interest in recombinant human growth hormone (GH) as a treatment for fat distribution abnormalities, we retrospectively evaluated regional changes in fat and lean body mass in a subset of subjects who participated in randomized, double-blind, placebo-controlled trials of GH for treatment of wasting. Treatment with a pharmacologic dose of GH (0.1 mg/kg/day) resulted in significant and sustained increases in lean body mass and losses of fat in both the trunk and appendicular regions.