HIV-associated lipodystrophy is a term used to describe a constellation of body composition (lipoatrophy and lipohypertrophy) and metabolic (dyslipidemia and insulin resistance) alterations that accompany highly active antiretroviral therapy. These changes, which resemble metabolic syndrome, have been associated with a variety of adverse outcomes including accelerated cardiovascular disease. The body composition and metabolic changes appear to cluster in HIV infection, although they are distinct alterations and do not necessarily coexist. Epidemiological studies have demonstrated multiple pathogenic influences associated with host, disease, and treatment-related factors. The adverse treatment effects were more prominent in early regimens; continued drug development has led to the application of metabolically safer regimens with equal or greater potency than the regimens being replaced. Disease-related factors include HIV infection as well as inflammation, immune activation, and immune depletion. The body composition changes promote anxiety and depression in patients and may affect treatment adherence. Treatment of dyslipidemia and alterations in glucose metabolism is the same as in non-HIV-infected individuals. Lipoatrophy is managed by strategic choice of antivirals or by antiviral switching, and in some cases by plastic/reconstructive surgery. Lipohypertrophy has been managed mainly by lifestyle modification, ie, a hypocaloric diet and increased exercise. A growth hormone releasing factor, which reduces central fat, has recently become available for clinical use.
lipoatrophy; lipohypertrophy; body composition; dyslipidemia; insulin resistance
A large proportion of HIV-infected subjects on antiretroviral medication develop insulin resistance, especially in the context of fat redistribution. This study investigates the interrelationships among fat distribution, hepatic lipid content, and insulin resistance in HIV-infected men.
Design and methods
We performed a cross-sectional analysis of baseline data from twenty-three HIV-infected participants in 3 prospective clinical studies. Magnetic resonance spectroscopy was applied to quantify hepatic lipid concentrations. Magnetic resonance imaging was used to quantify whole body adipose tissue compartments, i.e., subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes as well as inter-muscular adipose tissue (IMAT) subcompartment, and omental-mesenteric adipose tissue (OMAT) and retroperitoneal adipose tissue (RPAT) subcompartments of VAT. Homeostasis model for assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin concentrations.
Hepatic lipid content correlated significantly with total VAT (r=0.62, p=0.0014) but not with SAT (r=0.053, p=0.81). In univariate analysis, hepatic lipid content was associated with the OMAT (r=0.67, p=0.0004) and RPAT (r=0.53, p=0.009) subcompartments; HOMA-IR correlated with both VAT and hepatic lipid contents (r=0.61, p=0.057 and 0.68, p=0.0012, respectively). In stepwise linear regression models, hepatic lipid had the strongest associations with OMAT and with HOMA-IR.
Hepatic lipid content is associated with VAT volume, especially the omental-mesenteric subcompartment, in HIV-infected men. Hepatic lipid content is associated with insulin resistance in HIV-infected men. Hepatic lipid content might mediate the relationship between VAT and insulin resistance among treated, HIV-infected men.
liver fat; visceral adipose tissue; subcutaneous adipose tissue; inter-muscular adipose tissue; omental-mesenteric adipose tissue; retroperitoneal adipose tissue; HOMA; insulin resistance; HIV
Intermuscular adipose tissue (IMAT) is associated with metabolic abnormalities similar to those associated with visceral adipose tissue (VAT). Increased IMAT has been found in obese human immunodeficiency virus (HIV)-infected women. We hypothesized that IMAT, like VAT, would be similar or increased in HIV-infected persons compared with healthy controls, despite decreases in subcutaneous adipose tissue (SAT) found in HIV infection. In the second FRAM (Study of Fat Redistribution and Metabolic Change in HIV infection) exam, we studied 425 HIV-infected subjects and 211 controls (from the Coronary Artery Risk Development in Young Adults study) who had regional AT and skeletal muscle (SM) measured by magnetic resonance imaging (MRI). Multivariable linear regression identified factors associated with IMAT and its association with metabolites. Total IMAT was 51% lower in HIV-infected participants compared with controls (P = 0.003). The HIV effect was attenuated after multivariable adjustment (to −28%, P < 0.0001 in men and −3.6%, P = 0.70 in women). Higher quantities of leg SAT, upper-trunk SAT, and VAT were associated with higher IMAT in HIV-infected participants, with weaker associations in controls. Stavudine use was associated with lower IMAT and SAT, but showed little relationship with VAT. In multivariable analyses, regional IMAT was associated with insulin resistance and triglycerides (TGs). Contrary to expectation, IMAT is not increased in HIV infection; after controlling for demographics, lifestyle, VAT, SAT, and SM, HIV+ men have lower IMAT compared with controls, whereas values for women are similar. Stavudine exposure is associated with both decreased IMAT and SAT, suggesting that IMAT shares cellular origins with SAT.
Following gastric bypass surgery (GBP), there is a post-prandial rise of incretin and satiety gut peptides. The mechanisms of enhanced incretin release in response to nutrients after GBP is not elucidated and may be in relation to altered nutrient transit time and/or malabsorption.
Seven morbidly obese subjects (BMI=44.5±2.8 kg/m2) were studied before and 1 year after GBP with a d-xylose test. After ingestion of 25 g of d-xylose in 200 mL of non-carbonated water, blood samples were collected at frequent time intervals to determine gastric emptying (time to appearance of d-xylose) and carbohydrate absorption using standard criteria.
One year after GBP, subjects lost 45.0±9.7 kg and had a BMI of 27.1±4.7 kg/m2. Gastric emptying was more rapid after GBP. The mean time to appearance of d-xylose in serum decreased from 18.6±6.9 min prior to GBP to 7.9±2.7 min after GBP (p=0.006). There was no significant difference in absorption before (serum d-xylose concentrations=35.6±12.6 mg/dL at 60 min and 33.9±9.1 mg/dL at 180 min) or 1 year after GBP (serum d-xylose=31.5± 18.1 mg/dL at 60 min and 27.2±11.9 mg/dL at 180 min).
These data confirm the acceleration of gastric emptying for liquid and the absence of carbohydrate malabsorption 1 year after GBP. Rapid gastric emptying may play a role in incretin response after GBP and the resulting improved glucose homeostasis.
Bariatric surgery; Gastric bypass; Gastric emptying; Carbohydrate absorption; d-xylose
Recombinant human growth hormone (rhGH) reduces visceral adipose tissue (VAT) volume in HIV-infected patients but can worsen glucose homeostasis and lipoatrophy. We aimed to determine if adding rosiglitazone to rhGH would abrogate the adverse effects of rhGH on insulin sensitivity (SI) and subcutaneous adipose tissue (SAT) volume.
Randomized, double-blind, placebo-controlled, multicenter trial using a 2×2 factorial design in which HIV-infected subjects with abdominal obesity and insulin resistance were randomized to rhGH 3 mg daily, rosiglitazone 4 mg twice daily, combination rhGH + rosiglitazone, or double placebo (control) for 12 weeks. The primary endpoint was change in SI by frequently sampled intravenous glucose tolerance test from entry to week 12. Body composition was assessed by whole body magnetic resonance imaging (MRI) and dual Xray absorptiometry (DEXA).
Seventy-seven subjects were randomized of whom 72 initiated study drugs. Change in SI from entry to week 12 differed across the 4 arms by 1-way ANCOVA (P = 0.02); by pair-wise comparisons, only rhGH (decreasing SI; P = 0.03) differed significantly from control. Changes from entry to week 12 in fasting glucose and glucose area under the curve on 2-hour oral glucose tolerance test differed across arms (1-way ANCOVA P = 0.004), increasing in the rhGH arm relative to control. VAT decreased significantly in the rhGH arms (−17.5% in rhGH/rosiglitazone and −22.7% in rhGH) but not in the rosiglitazone alone (−2.5%) or control arms (−1.9%). SAT did not change significantly in any arm. DEXA results were consistent with the MRI data. There was no significant rhGH x rosiglitazone interaction for any body composition parameter.
The addition of rosiglitazone abrogated the adverse effects of rhGH on insulin sensitivity and glucose tolerance while not significantly modifying the lowering effect of rhGH on VAT.
Exercise interventions often aim to affect abdominal obesity and glucose tolerance, two significant risk factors for type 2 diabetes. Because of limited financial and clinical resources in community and university-based environments, intervention effects are often measured with interviews or questionnaires and correlated with weight loss or body fat indicated by body bioimpedence analysis (BIA). However, self-reported assessments are subject to high levels of bias and low levels of reliability. Because obesity and body fat are correlated with diabetes at different levels in various ethnic groups, data reflecting changes in weight or fat do not necessarily indicate changes in diabetes risk. To determine how exercise interventions affect diabetes risk in community and university-based settings, improved evaluation methods are warranted.
We compared a noninvasive, objective measurement technique—regional BIA—with whole-body BIA for its ability to assess abdominal obesity and predict glucose tolerance in 39 women. To determine regional BIA's utility in predicting glucose, we tested the association between the regional BIA method and blood glucose levels.
Regional BIA estimates of abdominal fat area were significantly correlated (r = 0.554, P < 0.003) with fasting glucose. When waist circumference and family history of diabetes were added to abdominal fat in multiple regression models, the association with glucose increased further (r = 0.701, P < 0.001).
Regional BIA estimates of abdominal fat may predict fasting glucose better than whole-body BIA as well as provide an objective assessment of changes in diabetes risk achieved through physical activity interventions in community settings.
Skeletal muscle (SM) mass decreases with advanced age and with disease in HIV infection. It is unknown whether age-related muscle loss is accelerated in the current era of antiretroviral therapy and which factors might contribute to muscle loss among HIV-infected adults. We hypothesized that muscle mass would be lower and decline faster in HIV-infected adults than in similar-aged controls.
Whole-body 1H-magnetic resonance imaging was used to quantify regional and total SM in 399 HIV-infected and 204 control men and women at baseline and 5 years later. Multivariable regression identified associated factors.
At baseline and Year 5, total SM was lower in HIV-infected than control men. HIV-infected women were similar to control women at both time points. After adjusting for demographics, lifestyle factors, and total adipose tissue, HIV infection was associated with lower Year 5 SM in men and higher SM in women compared with controls. Average overall 5-year change in total SM was small and age related, but rate of change was similar in HIV-infected and control men and women. CD4 count and efavirenz use in HIV-infected participants were associated with increasing SM, whereas age and stavudine use were associated with decreasing SM.
Muscle mass was lower in HIV-infected men compared with controls, whereas HIV-infected women had slightly higher SM than control women after multivariable adjustment. We found evidence against substantially faster SM decline in HIV infected versus similar-aged controls. SM gain was associated with increasing CD4 count, whereas stavudine use may contribute to SM loss.
Sarcopenia; Lipoatrophy; Fat redistribution; Body composition
Metabolic complications associated with HIV infection and treatment frequently present as a relative lack of peripheral adipose tissue associated with dyslipidemia and insulin resistance. In this review we explain the connection between abnormalities of intermediary metabolism, observed either in vitro or in vivo, and this group of metabolic effects. We review molecular mechanisms by which the HIV protease inhibitor (PI) class of drugs may affect the normal stimulatory effect of insulin on glucose and fat storage. We then propose that both chronic inflammation from HIV infection and treatment with some drugs in this class trigger cellular homeostatic stress responses with adverse effects on intermediary metabolism. The physiologic outcome is such that total adipocyte storage capacity is decreased, and the remaining adipocytes resist further fat storage. The excess circulating and dietary lipid metabolites, normally “absorbed” by adipose tissue, are deposited ectopically in lean (muscle and liver) tissue, where they impair insulin action. This process leads to a pathologic cycle of lipotoxicity and lipoatrophy and a clinical phenotype of body fat distribution with elevated waist-to-hip ratio similar to the metabolic syndrome.
protease inhibitors; lipodystrophy; dyslipidemia; insulin resistance; cardiovascular disease; mechanisms of toxicity; molecular pathology; clinical pathology; in vitro toxicology; endocrine system; pharmaceutical development/products
AHA Conference Proceedings; cardiovascular diseases; morbidity; mortality; risk factors
fibrinogen; HIV; protease inhibitors; non-nucleoside reverse transcriptase inhibitors
The association of fat distribution with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations is not well-defined in HIV-infected individuals. Obesity is associated with hepatic steatosis, and ALT is a marker of steatosis in the general population.
Cross-sectional analysis of 1119 HIV-infected and 284 control subjects. Hepatitis C virus (HCV) RNA testing determined HCV infection. Magnetic resonance imaging measured regional adipose tissue volume.
After adjustment for demographic and lifestyle factors, visceral adipose tissue (VAT) was positively associated with ALT in HIV/HCV-coinfected subjects (+9.8%, 95% confidence interval [CI]: 2.8 to 17.6), HIV-monoinfected subjects (+8.0%, 95% CI: 4.2 to 12.1), and controls (+5.9%, 95% CI: 2.0 to 10.1). In contrast, lower trunk subcutaneous adipose tissue (SAT) was negatively associated with ALT in HIV/HCV-coinfected subjects (−14.3%, 95% CI: −24.7 to −4.2) and HIV-monoinfected subjects (−11.9%, 95% CI: −18.4 to −5.3); there was a trend toward an association in controls (−7.1%, 95% CI: −22.7 to 5.9). Estimated associations between regional adipose tissue and AST were small and did not reach statistical significance.
More VAT and less lower trunk SAT are associated with elevated ALT, which likely reflects the presence of steatosis. There was little association with AST. HCV infection and having more VAT or less lower trunk SAT are independently associated with elevated ALT in HIV infection. Study regarding the association between VAT, trunk SAT, HCV, and progression of steatosis and fibrosis is needed in HIV-infected individuals.
adipose tissue; aminotransferase levels; hepatitis C virus; HIV; lipodystrophy
Inflammation is a potential mechanism to explain the accelerated atherosclerosis observed in HIV- and hepatitis C virus (HCV)–infected persons. We evaluated C-reactive protein (CRP) in HIV-infected and HIV/HCV-coinfected individuals in the era of effective antiretroviral (ARV) therapy.
Cross-sectional study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) cohort and controls from the Coronary Artery Risk Development in Young Adults (CARDIA) study.
CRP levels were measured in 1135 HIV-infected participants from the FRAM cohort and 281 controls from the CARDIA study. The associations of HIV and HIV/HCV infection with CRP levels were estimated by multivariable linear regression.
Compared with controls, HIV monoinfection was associated with an 88% higher CRP level in men (P < 0.0001) but with no difference in women (5%; P = 0.80) in multivariate analysis. CRP levels were not associated with ARV therapy, HIV RNA level, or CD4 cell count. Compared with controls, HIV/HCV coinfection was associated with a 41% lower CRP level in women (P = 0.012) but with no difference in men (+4%; P = 0.90). Among HIV-infected participants, HCV coinfection was associated with 50% lower CRP levels after multivariable analysis (P < 0.0001) in men and women. Greater visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were strongly associated with CRP levels. Among HIV- infected participants, CRP levels were 17% (P < 0.001) and 21% (P = 0.002) higher per doubling of VAT and SAT; among controls, CRP levels were 34% (P < 0.001) and 61% (P = 0.009) higher, respectively.
In the absence of HCV coinfection, HIV infection is associated with higher CRP levels in men. HCV coinfection is associated with lower CRP levels in men and women.
cardiovascular disease; C-reactive protein; hepatitis C virus; HIV; inflammation
Obesity and insulin resistance are growing problems in HIV-positive (HIV+) women receiving highly active antiretroviral therapy (HAART).
The objective was to determine the contribution of adipose tissue (AT) enlargement and distribution to the presence of insulin resistance in obese HIV+ women.
Whole-body intermuscular AT (IMAT), visceral AT (VAT), subcutaneous AT (SAT), and SAT distribution (leg versus upper body) were measured by whole-body magnetic resonance imaging. Insulin sensitivity (SI) was measured with an intravenous glucose tolerance test in obese HIV+ women recruited because of their desire to lose weight (n = 17) and in obese healthy controls (n = 32).
The HIV+ women had relatively less whole-body SAT and more VAT and IMAT than did the controls (P < 0.05 for all). A significant interaction by HIV status was observed for the relation of total SAT with SI (P < 0.001 for the regression’s slope interactions after adjustment for age, height, and weight). However, relations of IMAT, VAT, and SAT distribution (leg SAT as a percentage of total SAT; leg SAT%) with SI did not differ significantly between groups. For both groups combined, the best model predicting a low SI included significant contributions by both high IMAT and low leg SAT%, independent of age, height, and weight, and no interaction between groups was observed (overall r2 = 0.44, P = 0.0003).
In obese HIV+ women, high whole-body IMAT and low leg SAT% distribution are independently associated with insulin resistance.
Subcutaneous adipose tissue; intermuscular adipose tissue; adipose tissue distribution; insulin resistance; HIV infection