Deciphering the molecular mechanisms involved in HIV-associated lipoatrophy by transcriptomics: a pilot study

HIV-associated lipoatrophy (LA) has considerable implications for risk of metabolic diseases, quality of life, and adherence to treatments. Although it has decreased in high-income countries, it is still very common in resource-limited countries. Understanding the pathophysiological mechanisms of LA can open the possibility to explore new ways to treat or prevent this condition. To identify new markers for an accurate and quick diagnosis will be also of interest. Thus, we aimed to examine functional classes of genes implicated in LA and to identify potential new markers for an accurate/quick diagnosis of LA and future complications. Eighteen participants were recruited: seven healthy volunteers, five non-LA-HIV patients, and six LA-HIV subjects. Clinical lipoatrophy was considered when changes in fat volume in the cheeks next to the nose, lateral aspect of the face, legs, arms, and buttocks were observed by the physicians. mRNA was isolated from peripheral blood mononuclear cells (PBMCs) to perform a transcriptomic and Gene Ontology analysis. To confirm RNA sequencing results, qPCRs were developed. A total of 55 genes were differentially expressed between LA and non-LA patients. Thirty-seven genes were overexpressed, whereas 18 genes were repressed. Functional analysis showed that overexpressed genes were involved in lymphocyte/neutrophil activation, inflammation, and atherogenesis. Several lymphoma markers and members of the lipocalin and aquaporin families were also found more expressed in LA patients. In contrast, most of the genes found less expressed in LA subjects were involved in angiogenesis and protection against myocardial infarction. Our results demonstrated a distinct transcriptomic signature in PBMCs of LA patients in comparison with non-LA-HIV subjects and, therefore, provided novel insights to the pathogenesis of HIV-associated lipoatrophy. Our study also highlights the potential usage of some of these genes as early markers of future complications

Deciphering the molecular mechanisms involved in HIV-associated lipoatrophy by transcriptomics: a pilot study.

HIV-associated lipoatrophy (LA) has considerable implications for risk of metabolic diseases, quality of life, and adherence to treatments. Although it has decreased in high-income countries, it is still very common in resource-limited countries. Understanding the pathophysiological mechanisms of LA can open the possibility to explore new ways to treat or prevent this condition. To identify new markers for an accurate and quick diagnosis will be also of interest. Thus, we aimed to examine functional classes of genes implicated in LA and to identify potential new markers for an accurate/quick diagnosis of LA and future complications. Eighteen participants were recruited: seven healthy volunteers, five non-LA-HIV patients, and six LA-HIV subjects. Clinical lipoatrophy was considered when changes in fat volume in the cheeks next to the nose, lateral aspect of the face, legs, arms, and buttocks were observed by the physicians. mRNA was isolated from peripheral blood mononuclear cells (PBMCs) to perform a transcriptomic and Gene Ontology analysis. To confirm RNA sequencing results, qPCRs were developed. A total of 55 genes were differentially expressed between LA and non-LA patients. Thirty-seven genes were overexpressed, whereas 18 genes were repressed. Functional analysis showed that overexpressed genes were involved in lymphocyte/neutrophil activation, inflammation, and atherogenesis. Several lymphoma markers and members of the lipocalin and aquaporin families were also found more expressed in LA patients. In contrast, most of the genes found less expressed in LA subjects were involved in angiogenesis and protection against myocardial infarction. Our results demonstrated a distinct transcriptomic signature in PBMCs of LA patients in comparison with non-LA-HIV subjects and, therefore, provided novel insights to the pathogenesis of HIV-associated lipoatrophy. Our study also highlights the potential usage of some of these genes as early markers of future complications.

Current Efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r) use correlates with elevate markers of atherosclerosis in HIV-infected subjects in Addis Ababa, Ethiopia.

BACKGROUND: HIV patients on antiretroviral therapy have shown elevated incidence of dyslipidemia, lipodystrophy, and cardiovascular disease (CVD). Most studies, however, focus on cohorts from developed countries, with less data available for these co-morbidities in Ethiopia and sub-Saharan Africa. METHODS: Adult HIV-negative (n = 36), treatment naïve (n = 51), efavirenz (EFV)-treated (n = 91), nevirapine (NVP)-treated (n = 95), or ritonavir-boosted lopinavir (LPV/r)-treated (n=44) subjects were recruited from Black Lion Hospital in Addis Ababa, Ethiopia. Aortic pressure, augmentation pressure, and pulse wave velocity (PWV) were measured via applanation tonometry and carotid intima-media thickness (cIMT) and carotid arterial stiffness, and brachial artery flow-mediated dilation (FMD) were measured via non-invasive ultrasound. Body mass index, waist-to-hip circumference ratio (WHR), skinfold thickness, and self-reported fat redistribution were used to quantify lipodystrophy. CD4+ cell count, plasma HIV RNA levels, fasting glucose, total-, HDL-, and LDL-cholesterol, triglycerides, hsCRP, sVCAM-1, sICAM-1, leptin and complete blood count were measured. RESULTS: PWV and normalized cIMT were elevate and FMD impaired in EFV- and LPV/r-treated subjects compared to NVP-treated subjects; normalized cIMT was also elevated and FMD impaired in the EFV- and LPV/r-treated subjects compared to treatment-naïve subjects. cIMT was not statistically different across groups. Treated subjects exhibited elevated markers of dyslipidemia, inflammation, and lipodystrophy. PWV was associated with age, current EFV and LPV/r used, heart rate, blood pressure, triglycerides, LDL, and hsCRP, FMD with age, HIV duration, WHR, and glucose, and cIMT with age, current EFV use, skinfold thickness, and blood pressure. CONCLUSIONS: Current EFV- or LPV/r-treatment, but not NVP-treatment, correlated with elevated markers of atherosclerosis, which may involve mechanisms distinct from traditional risk factors.

Body fat abnormality in HIV-infected children and adolescents living in Europe: prevalence and risk factors.

OBJECTIVES: To estimate the prevalence of and identify risk factors for lipodystrophy syndrome (LS) and body fat abnormality in a population of HIV-infected children and adolescents. DESIGN: Cross-sectional observational study. METHODS: HIV-infected subjects aged 2-18 years were recruited from 15 HIV centers in Belgium, Italy, and Poland between January 2007 and December 2008. Standardized assessments by the patient's long-term clinician were performed to establish the presence of abnormality. Risk factors were explored in logistic regression models for fat abnormality outcomes and LS (abnormality plus dyslipidemia). RESULTS: Among 426 subjects (70% white), median age was 12.2 years (interquartile range: 9.0-15.0 years) and median duration of antiretroviral therapy was 5.2 years (interquartile range: 2.2-8.8 years). Prevalence was 57% (n = 235) for LS and 42% (n = 176) for fat abnormality; 90 subjects with abnormality were affected in ≥3 locations. Lipoatrophy occurred in 28% (n = 117) of subjects and lipohypertrophy in 27% (n = 115), most commonly in the face and trunk, respectively. In multivariable analysis, white ethnicity, body mass index, ritonavir/lopinavir, and nonnucleoside reverse transcriptase inhibitors were each associated with an increased risk of LS (P < 0.05). White ethnicity, history of Centers for Disease Control and Prevention-defined disease, and stavudine were associated with risk of lipoatrophy (P < 0.05). Increased risk of lipohypertrophy was associated with body mass index and prior HIV disease. CONCLUSIONS: Fat abnormality was prevalent in close to half of children and adolescents, who had accumulated long treatment durations. Risk of fat abnormality was associated with specific drugs, including stavudine and ritonavir, and other variables. Our results underline the importance of continued surveillance of children treated with antiretroviral therapy.

Lipodystrophy and insulin resistance in combination antiretroviral treated HIV-1-infected patients: implication of resistin.

BACKGROUND: Little information is available with respect to the involvement of resistin in lipodystrophy and metabolic disturbances in HIV-1-infected patients treated with combination antiretroviral therapy (cART). We determined whether the resistin (rest) -420C>G single-nucleotide polymorphism and plasma resistin are associated with the development of lipodystrophy and metabolic disturbances in HIV-1-infected patients treated with cART. METHODS: The study group comprised 299 HIV-1-infected patients treated with a stable cART for at least 1 year (143 with lipodystrophy and 156 without) and 175 uninfected controls. Anthropometric, clinical, and metabolic variables were determined. Homeostasis model assessment for insulin resistance was used to evaluate insulin resistance. Plasma resistin levels were determined by enzyme-linked immunosorbent assay. The rest -420C>G was assessed using restriction fragment length polymorphism. Student t test, 1-way and 2-way analysis of variance, χ2 test, and Pearson and Spearman correlations were performed for statistical analysis. RESULTS: Genotypes containing the rest -420G variant allele were significantly more common in HIV-1-infected patients without lipodystrophy compared with those with lipodystrophy (P = 0.037). Infected patients had significantly greater plasma resistin levels than uninfected controls (P < 0.001). Among infected patients, plasma resistin levels were significantly lower in patients with lipodystrophy with respect to those without (P = 0.034). In infected patients, plasma resistin levels had a significant positive correlation with insulin and homeostasis model assessment for insulin resistance: P < 0.001 and P = 0.002 in the lipodystrophy subset and P = 0.002 and P = 0.03 in the nonlipodystrophy subset, respectively. CONCLUSIONS: In our cohort of white Spaniards, the rest -420C>G single-nucleotide polymorphism may be associated with cART-related lipodystrophy. Plasma resistin correlates with insulin resistance in infected patients with and without lipodystrophy.

A meta-analysis of six placebo-controlled trials of thiazolidinedione therapy for HIV lipoatrophy.

OBJECTIVE: To determine the impact of thiazolidinediones (TZD) on changes in limb fat mass in HIV-infected individuals, particularly in those not receiving a thymidine analogue. METHODS: Individual patient data from placebo-controlled, randomized trials of rosiglitazone (n = 5) or pioglitazone (n = 1) were combined. Generalized estimating equation (GEE) models were used to estimate the treatment effect on changes in limb fat mass. RESULTS: In the combined dataset of 427 patients, the baseline median age was 45 years, 86% were male, 80% were Caucasian, 63% were receiving stavudine (d4T) or zidovudine (AZT), 66% were on protease inhibitors, and median body mass index was 23 kg/m(2). In a univariate GEE model, TZD was associated with an increase in limb fat mass (coeff = 0.14 kg vs placebo, P = .04). In a multivariable GEE model, patients receiving pioglitazone had significantly higher limb fat mass gains (coeff = 0.35 kg, P < or = .01) compared to patients receiving placebo, while patients on rosiglitazone did not (coeff = 0.05 kg, P = .48). Interactions between thymidine analogue use and rosiglitazone and pioglitazone were not significant. CONCLUSIONS: In this meta-analysis, pioglitazone therapy was more effective than placebo to increase limb fat mass whereas rosiglitazone was not significantly better than placebo. The effectiveness of these drugs did not vary according to whether the patients were receiving thymidine analogues.

Association between HLA-B*4001 and lipodystrophy among HIV-infected patients from Thailand who received a stavudine-containing antiretroviral regimen.

BACKGROUND: Stavudine-containing antiretroviral regimens are widely used in developing countries. Stavudine-associated lipodystrophy commonly occurs, without a clear predictable pattern owing to the unknown interaction between stavudine and the host, among patients who received this regimen. The aim of this study was to determine the clinical risk factors and human leukocyte antigen (HLA) alleles associated with stavudine-associated lipodystrophy. METHODS: A case-control, cross-sectional study was conducted for HIV-infected patients receiving stavudine-containing antiretroviral regimens. Clinical assessments for lipodystrophy by physical examination, anthropometry, and dual-energy X-ray absorptiometry were obtained. On the basis of their clinical assessment, the patients were classified into 2 groups: the case group (moderated to severe lipodystrophy) and the control group (absent to mild lipodystrophy). The clinical characteristics and allelic distribution of HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 were compared between the case group and the control group, to determine the possible association with stavudine-associated lipodystrophy. RESULTS: There were 103 patients; 55 patients were in the case group, and 48 patients were in the control group. By use of forward stepwise logistic regression, the presence of HLA-B*4001 (odds ratio [OR], 14.05; 95% confidence interval [CI], 2.57-76.59; P=.002) and a longer duration of stavudine treatment (OR, 1.02; 95% CI, 1.00-1.04; P=.02) were significantly associated with stavudine-associated lipodystrophy, whereas a higher body mass index during treatment (OR, 0.73; 95% CI, 0.61-0.86; P<.001) was associated with a lower risk for lipodystrophy. HLA-B*4001 has a high specificity (95.8%) and a positive predictive value (88.9%) for lipodystrophy. CONCLUSIONS: HLA-B*4001 is a strong genetic risk factor for stavudine-associated lipodystrophy in HIV-infected patients in Thailand. HLA-B*4001 may be used as a genetic marker to predict which patients will develop stavudine-associated lipodystrophy, to avoid or shorten the duration of stavudine use. This finding needs to be confirmed in further replication studies.

Zidovudine/lamivudine for HIV-1 infection contributes to limb fat loss.

BACKGROUND: Lipoatrophy is known to be associated with stavudine as part of the treatment for HIV infection, but it is less clear if this serious side effect is also related to other nucleoside reverse transcriptase inhibitors like zidovudine. We aimed to determine whether zidovudine-sparing first-line antiretroviral therapy would lead to less lipoatrophy and other metabolic changes than zidovudine-containing therapy. METHODOLOGY/PRINCIPAL FINDINGS: Fifty antiretroviral therapy-naïve HIV-1 infected men with an indication to start antiretroviral therapy were included in a randomized single blinded clinical trial. Randomisation was between zidovudine-containing therapy (zidovudine/lamivudine+lopinavir/ritonavir) and zidovudine-sparing therapy (nevirapine+lopinavir/ritonavir). Main outcome measures were body composition assessed by computed tomography and dual-energy X-ray absorptiometry scan and lipid profile before and after 3, 12, 24 months of antiretroviral therapy. In the zidovudine/lamivudine+lopinavir/ritonavir group, from 3 months onward limb fat decreased progressively by 684+/-293 grams (estimated mean+/-standard error of the mean)(p = 0.02) up to 24 months whereas abdominal fat increased, but exclusively in the visceral compartment (+21.9+/-8.1 cm(2), p = 0.008)). In contrast, in the nevirapine+lopinavir/ritonavir group, a generalized increase in fat mass was observed. After 24 months no significant differences in high density lipoprotein and total/high density lipoprotein cholesterol ratio were found between both treatment groups, but total and low density lipoprotein cholesterol levels were higher in the nevirapine+lopinavir/ritonavir group (6.1+/-0.2 versus 5.3+/-0.2 and 3.6+/-0.1 versus 2.8+/-0.1 mmol/l respectively, p<0.05). Virologic response and safety were comparable in both groups. CONCLUSIONS/SIGNIFICANCE: Zidovudine/lamivudine+lopinavir/ritonavir, but not nevirapine+lopinavir/ritonavir in antiretroviral therapy-naïve patients, is associated with lipoatrophy and greater relative intraabdominal lipohypertrophy, suggesting that zidovudine/lamivudine contributes to both these features of lipodystrophy. These findings support to no longer consider zidovudine/lamivudine as one of the preferred possible components of first-line antiretroviral therapy where alternative treatments are available. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00122226.

The fatty acid binding protein-4 (FABP4) is a strong biomarker of metabolic syndrome and lipodystrophy in HIV-infected patients.

BACKGROUND: The incidence of metabolic abnormalities in HIV-infected patients is increasing. Fatty acid binding protein-4 (FABP4) is an emerging biomarker for metabolic-related disturbances. We aimed to study FABP4 as a marker of metabolic syndrome (MS) or lipodystrophy (LD) in HIV patients. METHODS: FABP4 plasma concentrations were measured by enzyme-linked immunoassays in 183 HIV-infected patients, enrolled as part of a study aimed at identifying predictors of atherosclerosis. The presence of MS or LD was diagnosed according to standard clinical methods. Univariate and multivariate statistical analyses were performed. RESULTS: FABP4 concentration was significantly higher in those patients with either MS or LD criteria than those without any metabolic disturbance. Similarly, FABP4 concentration significantly increased with an increasing of MS features and was strongly correlated with body-mass index, triglycerides, HDL-cholesterol concentrations, insulin and blood pressure. Patients in the highest quartile of FABP4 presented a six-fold increased odds ratio for MS and a three-fold increased odds for LD, adjusted by age, sex, body-mass index and the antiretroviral therapy. CONCLUSIONS: FABP4 is a strong plasma marker of metabolic disturbances in HIV-infected patients, and therefore, could serve to guide therapeutic intervention in this group of patients.

Human immunodeficiency virus (HIV)-1 viral protein R suppresses transcriptional activity of peroxisome proliferator-activated receptor {gamma} and inhibits adipocyte differentiation: implications for HIV-associated lipodystrophy.

HIV-1-infected patients may develop lipodystrophy and insulin resistance. We investigated the effect of the HIV-1 accessory protein viral protein R (Vpr) on the activity of the peroxisome proliferator-activating receptor-gamma (PPARgamma), a key regulator of adipocyte differentiation and tissue insulin sensitivity. We studied expression of PPARgamma-responsive reporter genes in 3T3-L1 mouse adipocytes. We investigated Vpr interaction with the PPAR/retinoid X receptor (RXR)-binding site of the c-Cbl-associating protein (CAP) gene using the chromatin immunoprecipitation assay as well as the interaction of Vpr and PPARgamma using coimmunoprecipitation. Finally, we studied the ability of exogenous Vpr protein to enter cultured adipocytes and retard differentiation. We found that Vpr suppressed PPARgamma-induced transactivation in both undifferentiated and differentiated 3T3-L1 cells. Transcriptional suppression by Vpr required an intact LXXLL coactivator motif. Vpr suppressed mRNA expression of PPARgamma-responsive genes in undifferentiated 3T3-L1 cells and associated with the PPAR/RXR-binding site located in the promoter region of the CAP gene. Vpr interacted with the ligand-binding domain of PPARgamma in an agonist-dependent fashion in vitro. Vpr delivered either by an expression plasmid or as protein added to media suppressed PPARgamma agonist-induced adipocyte differentiation, assessed as lipid accumulation and mRNA expression of the adipocyte differentiation marker adipocyte P2 in 3T3-L1 cells. In conclusion, circulating Vpr or, alternatively, Vpr produced as a consequence of direct infection of adipocytes could suppress in vivo differentiation of preadipocytes by acting as a corepressor of PPARgamma-mediated gene transcription. Vpr may alter sensitivity to insulin and thereby contribute to the development of lipodystrophy and insulin resistance observed in HIV-1-infected patients.

Tumour necrosis factor alpha in fat redistribution syndromes associated with combination antiretroviral therapy in HIV-1-infected patients: potential role in subcutaneous adipocyte apoptosis.

BACKGROUND: The pathogenesis of fat redistribution syndromes (FRS) observed in the setting of highly active antiretroviral therapy (HAART) for the treatment of HIV-1-infection remains elusive. A dysregulation of the tumour necrosis factor alpha (TNF-alpha) system occurs in HIV-infected patients with FRS. MATERIALS AND METHODS: The study looked at both the in vivo and in vitro relationship between TNF-alpha and the degree of subcutaneous adipocyte apoptosis in 60 HIV-1-infected patients on HAART with FRS, another 60 HIV-1-infected patients on HAART without FRS and 60 uninfected control patients. Apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP (deoxyuridine 5'-triphosphate)-digoxigenin Nick End Labelling (TUNEL) method. Soluble receptors of TNF-alpha were determined by the sandwich enzyme immunoassay technique. The in vitro viability was assessed by staining with 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) and apoptosis by TUNEL. RESULTS: HIV-1-infected patients with FRS had significantly higher degrees of subcutaneous adipocyte apoptosis than those without FRS (P = 0.0001) and uninfected controls (P < 0.0001). There was a statistically significant association between serum levels of soluble TNF-alpha receptors #1 and #2 and the degree of subcutaneous adipocyte apoptosis in patients with and without FRS (P < 0.0001 for both receptors). In vitro, the addition of TNF-alpha (10 ng mL(-1)) to an adipocyte culture embedded with indinavir, either alone or in clinically relevant combinations with stavudine (d4T) and lamivudine (3TC), significantly decreased adipocyte viability (P = 0.0001) and increased adipocyte apoptosis (P < 0.0001) with respect to that observed with the addition of antiretrovirals alone. CONCLUSIONS: TNF-alpha plays a significant role in subcutaneous adipocyte apoptosis, which occurs in the setting of FRS in HIV-1-infected patients on highly active antiretroviral therapy.

Insulin-like growth factors, insulin-like growth factor-binding proteins, insulin-like growth factor-binding protein-3 protease, and growth hormone-binding protein in lipodystrophic human immunodeficiency virus-infected patients.

Human immunodeficiency virus (HIV)-lipodystrophy is associated with impaired growth hormone (GH) secretion. It remains to be elucidated whether insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), IGFBP-3 protease, and GH-binding protein (GHBP) are abnormal in HIV-lipodystrophy. These parameters were measured in overnight fasting serum samples from 16 Caucasian males with HIV-lipodystrophy (LIPO) and 15 Caucasian HIV-infected males without lipodystrophy (NONLIPO) matched for age, weight, duration of HIV infection, and antiretroviral therapy. In LIPO, abdominal fat mass and insulin concentration were increased (>90%, P < .01) and insulin sensitivity (Log10ISI(composite)) was decreased (-50%, P < .001). Total and free IGF-I, IGF-II, IGFBP-3, and IGFBP-3 protease were similar between groups (all P > .5), whereas, in LIPO, IGFBP-1 and IGFBP-2 were reduced (-36%, P < .05 and -50%, P < .01). In pooled groups, total IGF-I, free IGF-I, total IGF-II, and IGFBP-3, respectively, correlated inversely with age (all P < .01). In pooled groups, IGFBP-1 and IGFBP-2 correlated positively with insulin sensitivity (age-adjusted all P < .05). IGFBP-3 protease correlated with free IGF-I in pooled groups (r(p) = 0.47, P < .02), and in LIPO (r(p) = 0.71, P < .007) controlling for age, total IGF-I, and IGFBP-3. GHBP was increased, whereas GH was decreased in LIPO (all P < .05). GH correlated inversely with GHBP in pooled groups (P < .05). Taken together the similar IGFs and IGFBP-3 concentrations between study groups, including suppressed GH, and increased GHBP in LIPO, argue against GH resistance of GH-sensitive tissues in LIPO compared with NONLIPO; however, this notion awaits examination in dose-response studies. Furthermore, our data suggest that IGFBP-3 protease is a significant regulator of bioactive IGF-I in HIV-lipodystrophy.

Exogenous cushing syndrome mimicking human immunodeficiency virus lipodystrophy.

A 45-year-old man infected with human immunodeficiency virus (HIV) developed abnormal fat accumulations that initially were believed to be caused by HIV lipodystrophy. Further clinical evaluation revealed, however, that the patient had developed exogenous Cushing syndrome, which presumably was caused by the inhibition of CYP3A4's metabolism of inhaled fluticasone by the protease inhibitor ritonavir. Clinicians should be aware that clinical clues may indicate conditions other than lipodystrophy that may cause abnormal fat accumulation and that fluticasone should be cautiously administered to patients who are receiving ritonavir.

Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy.

Human immunodeficiency virus (HIV) lipodystrophy is associated with fat redistribution, dyslipidemia, and insulin resistance; however, the mechanism of insulin resistance remains unknown. We hypothesized that HIV-infected subjects with fat redistribution have increased rates of lipolysis and increased circulating free fatty acid (FFA) levels that contribute to insulin resistance. Anthrompometric and body composition data were obtained and a standard 75-g oral glucose tolerance test (OGTT) was performed on day 1 of the study. Stable isotope infusions of glycerol and palmitate were completed following an overnight fast to assess rates of lipolysis and FFA flux in HIV-infected men (n = 19) with and without fat redistribution and healthy controls (n = 8) on day 2. Total FFA levels after standard glucose challenge were increased among HIV-infected subjects and positively associated with abdominal visceral adipose tissue area. In contrast, fasting total FFA levels were inversely associated with subcutaneous fat area. Rates of basal lipolysis were significantly increased among HIV-infected subjects (rate of appearance [Ra] glycerol, 4.1 +/- 0.2 v 3.3 +/- 0.2 micromol/kg/min in controls; P =.02). Among HIV-infected subjects, use of stavudine (P =.006) and the rate of lipolysis (ie, Ra glycerol, P =.02) were strong positive predictors of insulin resistance as measured by insulin response to glucose challenge, controlling for effects of age, body mass index (BMI), waist-to-hip ratio (WHR), and protease inhibitor (PI) exposure. These data demonstrate increased rates of lipolysis and increased total FFA levels in HIV-infected subjects and suggest that increased lipolysis may contribute to insulin resistance in this patient population.

Metabolic basis of HIV-lipodystrophy syndrome.

Human immunodeficiency virus (HIV)-lipodystrophy syndrome (HLS) is characterized by hypertriglyceridemia, low high-density lipoprotein-cholesterol, lipoatrophy, and central adiposity. We investigated fasting lipid metabolism in six men with HLS and six non-HIV-infected controls. Compared with controls, HLS patients had lower fat mass (15.9 +/- 1.3 vs. 22.3 +/- 1.7 kg, P < 0.05) but higher plasma glycerol rate of appearance (R(a)), an index of total lipolysis (964.71 +/- 103.33 vs. 611.08 +/- 63.38 micromol x kg fat(-1) x h(-1), P < 0.05), R(a) palmitate, an index of net lipolysis (731.49 +/- 72.36 vs. 419.72 +/- 33.78 micromol x kg fat(-1) x h(-1), P < 0.01), R(a) free fatty acids (2,094.74 +/- 182.18 vs. 1,470.87 +/- 202.80 micromol x kg fat(-1) x h(-1), P < 0.05), and rates of intra-adipocyte (799.40 +/- 157.69 vs. 362.36 +/- 74.87 micromol x kg fat(-1) x h(-1), P < 0.01) and intrahepatic fatty acid reesterification (1,352.08 +/- 123.90 vs. 955.56 +/- 124.09 micromol x kg fat(-1) x h(-1), P < 0.05). Resting energy expenditure was increased in HLS patients (30.51 +/- 2.53 vs. 25.34 +/- 1.04 kcal x kg lean body mass(-1) x day(-1), P < 0.05), associated with increased non-plasma-derived fatty acid oxidation (139.04 +/- 24.17 vs. 47.87 +/- 18.81 micromol x kg lean body mass(-1) x min(-1), P < 0.02). The lipoatrophy observed in HIV lipodystrophy is associated with accelerated lipolysis. Increased hepatic reesterification promotes the hypertriglyceridemia observed in this syndrome.

Increased serum interferon alpha in HIV-1 associated lipodystrophy syndrome.

BACKGROUND: A syndrome of lipodystrophy (LD) associated with peripheral lipoatrophy and central/visceral adiposity has been reported in HIV-1-infected patients treated by combined antiretroviral therapy (ART). Lipid metabolism is partly regulated by both steroid hormones and cytokines and we have previously reported that dyslipidaemia in LD-positive men is correlated to an increase in cortisol : DHEA ratio (Christeff et al., AIDS 1999;13:2251). In this study we questioned whether it is also related to cytokine perturbations. MATERIALS AND METHODS: A cross-sectional study was performed on 42 HIV-1-positive men on ART, 27 of whom had symptoms of LD, defined by computed tomography scan. Serum cytokines (IFN-alpha, TNF-alpha, sTNF-RI, sTNF-RII, IL-6, IL-1beta and IL-2) and lipids [cholesterol, triglycerides (TG) and their subclasses], and apolipoproteins (Apo), were determined. RESULTS: Serum IFN-alpha was markedly increased in LD-positive compared with LD-negative men and controls. IL-6 and TNF-alpha concentrations were also significantly elevated in HIV-positive men compared to controls but the levels of these cytokines did not differ between the two groups of patients. A significant positive correlation was found between accumulation of IFN-alpha and increased levels of cholesterol, TG, VLDL cholesterol, VLDL TG, ApoB and ApoB-ApoA1 ratio. A multivariate forward-performed analysis revealed that IFN-alpha is the best marker for lipid perturbations associated to LD, followed by insulin and cortisol : DHEA ratio. CONCLUSIONS: This study demonstrates an association between serum IFN-alpha and lipid alterations in LD-positive men. The concomittant action of IFN-alpha and cortisol : DHEA ratio is probably one of the mechanisms responsible for hyperlipidaemia in LD syndrome.

HIV-associated lipodystrophy.

The HIV associated lipodystrophy syndrome is characterized by fat loss from the periphery, fat accumulation in the abdominal, dorsocervical regions and breasts, and hyperlipidaemia, insulin resistance and lactic acidaemia. Although several mechanisms have been proposed to explain these abnormalities, the exact aetiology of the condition remains unclear and will likely prove to be complex. The principal clinical concerns that arise from this disorder are possible increased risks of premature atherosclerosis and cardiovascular disease. A variety of therapeutic interventions, designed to limit these risks, are under evaluation.

The prevalence of lipodystrophy in an ambulant HIV-infected population: it all depends on the definition.

OBJECTIVES: This study's objective was to determine the prevalence of body shape changes and metabolic abnormalities in an ambulant population with HIV infection. Three different definitions of lipodystrophy were used to assess these changes. Patients' anthropometric measures and dual-energy X-ray absorptiometry (DEXA) scans were compared in order to estimate fat distribution in this population. We sought to evaluate potential predictors for lipodystrophy according to each of the three definitions. METHODS: We performed a cross-sectional study in the outpatient clinic of a tertiary referral hospital in Melbourne, Australia. We enrolled a total of 167 HIV-infected ambulatory patients over 3 months in mid-1998. Data on 159 males, 149 of whom were receiving triple combination antiretroviral therapy, were evaluated. Anthropometric measures, clinical examination, self-report of body shape changes, biochemical measures and DEXA scan were used to assess lipodystrophy and risk factors for cardiovascular disease. Patients described body shape changes in the face, trunk, arms and legs. Laboratory parameters measured included fasting triglyceride (TG), cholesterol, high-density lipoproteins (HDL), glucose, insulin, CD4 cell count and plasma HIV RNA. Current and past antiretroviral therapies were ascertained. RESULTS: According to one proposed Australian national definition of lipodystrophy (LDNC), the prevalence of lipodystrophy in this population was 65%. This definition included an objective assessment with major and minor criteria. Patient-defined lipodystrophy (LDP), which involved a subjective assessment of thinning arms and legs and central adiposity, occurred in 19%. Patient-defined lipoatrophy (LAP), which involved a subjective assessment of thinning arms and legs without central adiposity, occurred in 21.3%. No change in body habitus was noted by 37% of the cohort. Hypercholesterolaemia was recorded in 44%, hypertriglyceridaemia in 52% and elevated insulin levels in 23%. Anthropometry was predictive of the per cent total body fat recorded by DEXA scan, but produced consistently lower values. In multivariate analysis, LDP and LAP were significantly associated with stavudine (d4T) use, while LAP was also associated with zidovudine (ZDV) treatment. There were no treatment associations with LDNC. Protease inhibitor (PI) exposure was associated with metabolic changes but not patient perceived body shape changes, while d4T and ZDV exposure was associated with increased triglycerides and reduced peripheral fat stores. CONCLUSIONS: The prevalence of body shape changes in a single population varied depending on the definition applied. The LDNC definition overestimated body shape abnormalities in comparison with patient perception. LAP was associated with significantly lower fat stores measured by anthropometry and DEXA scan than those identified under the LDNC definition. In contrast to LDNC, LAP was associated with d4T exposure, nucleoside reverse transcriptase inhibitor (NRTI) and ZDV duration of use, but not PI use. Until a consensus definition for lipodystrophy is developed, including agreement on objective measurement and thresholds for abnormality, careful description of the individual components of the syndrome is required to enable cohort comparisons so that predictors of the syndrome can be assessed more accurately and outcome studies made feasible.