Adipocytokine dysregulation, abnormal glucose metabolism, and lipodystrophy in HIV-infected adolescents receiving protease inhibitors.

BACKGROUND: Lipodystrophy is common in HIV-infected patients receiving protease inhibitors (PIs), stavudine, and zidovudine. Adipocytokines may be altered in lipodystrophy. We evaluated risk factors, adipocytokine levels, insulin resistance, and lipid profiles in HIV-infected adolescents with different lipodystrophy types. METHODS: A cross-sectional study was conducted in 80 perinatally HIV-infected adolescents receiving PI-based highly active antiretroviral therapy for ≥ 6 months. Patients underwent oral glucose tolerance tests and measurements of high-molecular-weight (HMW) adiponectin, leptin, resistin, insulin, and lipids. They were classified into 3 groups based on the clinical findings: no lipodystrophy, isolated lipoatrophy, and any lipohypertrophy (isolated lipohypertrophy or combined type). RESULTS: Of the 80 patients (median age, 16.7 years), 18 (22.5%) had isolated lipoatrophy, while 8 (10%) had any lipohypertrophy (four with isolated lipohypertrophy, and four with the combined type). In a multivariate analysis, longer exposure to stavudine (OR: 1.03; 95% CI, 1.01-1.06; p = 0.005) and indinavir (OR: 1.03; 95% CI, 1.01-1.06; p = 0.012) were associated with lipoatrophy, while longer exposure to didanosine (OR: 1.04; 95% CI, 1.01-1.08; p = 0.017) and indinavir (OR: 1.10; 95% CI, 1.00-1.21; p = 0.045) were associated with any lipohypertrophy. Leptin levels were highest in the any-lipohypertrophy group and lowest in the isolated-lipoatrophy group (p = 0.013). HMW adiponectin levels were significantly lowest in the any-lipohypertrophy group and highest in the no-lipodystrophy group (p = 0.001). There were no significant differences in the levels of resistin among the three groups (p = 0.234). The prevalence of insulin resistance (p = 0.002) and prediabetes/diabetes (p < 0.001) were significantly highest in the any-lipohypertrophy group. Patients with lipoatrophy and those without lipodystrophy had comparable degrees of insulin resistance (p = 0.292). In multiple linear regression analysis, adjusted for age, sex, and waist-height ratio, HMW adiponectin levels were associated with Matsuda index (ß = 0.5; p = 0.003) and quantitative insulin sensitivity check index (QUICKI) (ß = 40.1; p = 0.010) and almost significantly associated with homeostatic model assessment of insulin resistance (HOMA-IR) (p = 0.054). Leptin and resistin levels were not associated with HOMA-IR, Matsuda index, or QUICKI (all p > 0.05). CONCLUSIONS: Abnormal glucose metabolism and dysregulation of adipocytokines were common in the HIV-infected adolescents with lipohypertrophy and the combined type. Preventive screening for cardiovascular diseases caused by metabolic alterations should be routinely performed.

Improvement of lipid profile after switching from efavirenz or ritonavir-boosted protease inhibitors to rilpivirine or once-daily integrase inhibitors: results from a large observational cohort study (SCOLTA).

BACKGROUND: Dyslipidemia represents a significant non-infectious comorbidity among people living with HIV. The aim of this study is to evaluate the impact on lipid profile of switches from an efavirenz (EFV) or protease inhibitor/ritonavir (PI/r)-based regimen to a rilpivirine (RPV) or a once-daily integrase inhibitor-based regimen. METHODS: We analyzed data from SCOLTA prospective database. All patients with HIV-RNA < 50 copies/ml in therapy with two NRTI + EFV or PI/r were included if they switched from EFV to dolutegravir (group EFV-DTG), elvitegravir (EFV-EVG), or RPV (EFV-RPV) and from PI/r to DTG (PI/r-DTG), PI/r to EVG (PI/r-EVG), or PI/r to RPV (PI/r-RPV). Total cholesterol (TC), TC/HDL ratio, LDL-cholesterol (LDL) and triglycerides (TG) were compared at baseline, six months and one year. Comparisons among groups were performed by a general linear model. RESULTS: Four hundred and ninety patients were enrolled, 24.9% female, mean age 47.3 years (±10.1). According to ART switch, 11.4% were classified in group EFV-DTG, 3.9% in EFV-EVG, 23.9% in EFV-RPV, 17.6% in PI/r-DTG, 17.8% in PI/r-EVG, and 25.5% in PI/r-RPV. After adjusted analysis, TC significantly decreased in all groups but EFV-EVG, TC/HDL in all but EFV-DTG and EFV-EVG, while the reduction of TG was significant only in switches to RPV (EFV-RPV and PI/r-RPV). The one year decrease of TC, TC/HDL, LDL and TG was higher in patients with higher baseline levels of the same variable (p < .0001 for all). CONCLUSIONS: In SCOLTA, all switches from PI/r regimens gave advantages on lipid profile, while stopping EFV had consistently favorable lipid effects only if replaced by RPV.

Polymorphisms in adiponectin receptor genes are associated with lipodystrophy-related phenotypes in HIV-infected patients receiving antiretroviral therapy.

OBJECTIVES: Adiponectin is a circulating peptide secreted by mature adipocytes that may act as a regulator of glucose and lipid metabolism. This study aimed to investigate the association between genetic variability in the adiponectin receptor genes ADIPOR1 (adiponectin receptor 1) and ADIPOR2 and lipodystrophy and its related anthropometric and metabolic phenotypes in HIV-infected patients on highly active antiretroviral therapy (HAART). METHODS: We studied six single nucleotide polymorphisms (SNPs) in the adiponectin receptor genes ADIPOR1 (rs1342387 and rs10920533) and ADIPOR2 (rs11061925, rs10773983, rs929434 and rs767870) and their association with adiponectin plasma levels, lipodystrophy subtypes and other parameters linked to glucose and lipid metabolism involved in the lipodystrophic syndrome. The genotypes of 407 HIV-infected patients receiving HAART were investigated using real-time polymerase chain reaction. Mean biochemical and anthropometrical parameters were compared between the different genotypes using analysis of variance. RESULTS: Two ADIPOR2 SNPs (rs11061925 and rs929434) were associated with fasting plasma triglyceride concentrations in the entire sample. Stronger significant associations were found between these SNPs and biochemical parameters (levels of triglycerides, total cholesterol, adiponectin and glucose) in men. We did not find any significant associations with ADIPOR1 gene variants. CONCLUSIONS: SNPs in the ADIPOR2 gene appear to be involved in the metabolic alterations in HIV-infected men receiving HAART.

IL-4 and IL-6 levels and adipose tissue distribution in HIV-1 patients under antiretroviral therapy.

PURPOSE: Combined antiretroviral therapy (cART) for the treatment of HIV-1 infection has been associated with complications, including lipodystrophy. Several interleukins have been implicated in the pathology and physiology of lipodystrophy. The present study aimed to compare the levels of IL-4 and IL-6 in HIV-1 patients under cART with and without, clinically and fat mass ratio defined, lipodystrophy and in four different groups of fat distribution: (1) no lipodystrophy; (2) isolated central fat accumulation; (3) isolated lipoatrophy and (4) mixed forms of lipodystrophy. METHODS: In the present cross-sectional study we evaluated IL-4 and IL-6 levels, insulin resistance and insulin sensitivity indexes in 86 HIV-infected adults under cART. RESULTS: No significant differences in IL-4 and IL-6 levels between the four groups of body composition were observed. Patients with HOMA-IR >4 presented higher levels of IL-6 and lower levels of IL-4, although without statistical significance. No correlation between IL-6, or IL-4, HOMA-IR and quantitative body fat mass distribution was found. CONCLUSION: Although there was a tendency for patients with isolated lipoatrophy and isolated fat accumulation to present higher IL-6 levels, these differences were not statistically significant. No differences were found relating IL-4 levels.

Adipokines, hormones related to body composition, and insulin resistance in HIV fat redistribution syndrome.

BACKGROUND: Lipodystrophies are characterized by adipose tissue redistribution, insulin resistance (IR) and metabolic complications. Adipokines and hormones related to body composition may play an important role linking these alterations. Our aim was to evaluate adipocyte-derived hormones (adiponectin, leptin, resistin, TNF-α, PAI-1) and ghrelin plasma levels and their relationship with IR in HIV-infected patients according to the presence of lipodystrophy and fat redistribution. METHODS: Anthropometric and metabolic parameters, HOMA-IR, body composition by DXA and CT, and adipokines were evaluated in 217 HIV-infected patients on cART and 74 controls. Fat mass ratio defined lipodystrophy (L-FMR) was defined as the ratio of the percentage of the trunk fat mass to the percentage of the lower limb fat mass by DXA. Patient's fat redistribution was classified into 4 different groups according the presence or absence of either clinical lipoatrophy or abdominal prominence: no lipodystrophy, isolated central fat accumulation (ICFA), isolated lipoatrophy and mixed forms (MXF). The associations between adipokines levels and anthropometric, metabolic and body composition were estimated by Spearman correlation. RESULTS: Leptin levels were lower in patients with FMR-L and isolated lipoatrophy, and higher in those with ICFA and MXF. Positive correlations were found between leptin and body fat (total, trunk, leg, arm fat evaluated by DXA, and total, visceral (VAT), subcutaneous adipose tissue (SAT), and VAT/SAT ratio evaluated by CT) regardless of FMR-L, and with HOMA-IR only in patients with FMR-L. Adiponectin correlated negatively with VAT, and its mean levels were lower in patients with ICFA and higher in those with no lipodystrophy. Resistin was not correlated with adipose tissue but positively correlated with HOMA-IR in FMR-L patients. PAI-1 levels were higher in MXF-patients and their levels were positively correlated with VAT in those with FMR-L. Ghrelin was higher in HIV-infected patients than controls despite BMI-matching. CONCLUSION: The overall body fat reduction in HIV lipoatrophy was associated with low leptin plasma levels, and visceral fat accumulation was mainly associated with decreased plasma levels of adiponectin.

Lipodystrophy syndrome in HIV treatment-multiexperienced patients: implication of resistin.

BACKGROUND: Impaired production of adipocytokines is a major factor incriminated in the occurrence of lipodystrophy (LD). OBJECTIVE: To evaluate LD prevalence and subtypes in HIV treatment-multiexperienced patients, and to determine the correlations between adipocytokines and LD subtypes. METHODS: Cross-sectional study in a Romanian tertiary care hospital, between 2008 and 2010, in HIV-positive patients, undergoing cART for ≥6 months. LD diagnosis, based on clinical and anthropometric data, was classified into lipoatrophy (LA), lipohypertrophy (LH) and mixed fat redistribution (MFR). Blood samples were collected for leptin, adiponectin and resistin assessments. RESULTS: We included 100 patients, 44 % with LD, among which LA had 63 %. LA patients had sex ratio, median age, treatment duration and median number of ARV regimens of 1, 20, 93 and 3.5 compared to non-LD patients: 1.65, 31, 44 and 1. LH and MFR patients were older and had higher total and LDL cholesterol versus non-LD patients. For both overall group and female group, LA was associated in univariate and multivariate analysis with increased resistin (p = 0.02 and 0.04) and number of ARV regimens (p < 0.001). Determination coefficient (Nagelkerke R (2)) of increased resistin and the number of ARV combinations in the presence of LA was 33 % in overall group and 47 % in female patients. CONCLUSIONS: In our young HIV-positive population, LD had high prevalence with predominance of LA subtype. LA was associated with high resistin levels and greater number of ARV regimens in overall group and female subgroup. Resistin could be used as a marker of peripheral adipose tissue loss and might be used as a target for new anti-LD therapeutic strategies.

Early loss of bone mineral density is correlated with a gain of fat mass in patients starting a protease inhibitor containing regimen: the prospective Lipotrip study.

BACKGROUND: HIV-infected patients starting antiretroviral treatment (ART) experience deep and early disorders in fat and bone metabolism, leading to concomitant changes in fat mass and bone mineral density. METHODS: We conducted a prospective study in treatment-naive HIV-infected patients randomized to receive two nucleoside reverse transcriptase inhibitors in combination with either a protease inhibitor (PI) or a non-nucleosidic reverse transcriptase inhibitor (NNRTI), to evaluate early changes in body composition, bone mineral density and metabolic markers as differentially induced by antiretroviral therapies. We measured changes in markers of carbohydrate, of fat and bone metabolism, and, using dual-emission X-ray absorptiometry (DXA), body composition and bone mineral density (BMD). Complete data on changes between baseline and after 21 months treatment were available for 35 patients (16 in the PI group and 19 in the NNRTI group). RESULTS: A significant gain in BMI and in total and lower limb fat mass was recorded only in patients receiving PI. A loss of lumbar BMD was observed in both groups, being higher with PI. Plasma markers of bone metabolism (alkaline phosphatase, osteocalcin, collagen crosslaps) and levels of parathormone and of 1,25diOH-vitamin D3 significantly increased in both groups, concomitant with a decline in 25OH-vitamin D3. Lipids and glucose levels increased in both groups but rise in triglyceride was more pronounced with PI. A correlation between loss of BMD and gain of fat mass is observed in patients starting PI. CONCLUSIONS: We evidenced an early effect of ART on lipid and bone metabolisms. PI lead to a significant gain in fat mass correlated with a sharp drop in BMD but active bone remodelling is evident with all antiretroviral treatments, associated with low vitamin D levels and hyperparathyroidism. In parallel, signs of metabolic restoration are evident. However, early increases in lean and fat mass, triglycerides, waist circumference and leptin are much more pronounced with PI.

Zinc alpha-2 glycoprotein is implicated in dyslipidaemia in HIV-1-infected patients treated with antiretroviral drugs.

OBJECTIVES: Treated HIV-1-infected patients with lipodystrophy often develop insulin resistance and proatherogenic dyslipidaemia. Zinc alpha-2 glycoprotein (ZAG) is a recently characterized adipokine which has been shown to be involved in the development of obesity and metabolic syndrome in uninfected subjects. We assessed the relationship between circulating ZAG levels and metabolic derangements in HIV-1-infected patients receiving antiretroviral drugs. METHODS: Plasma ZAG levels were assessed in 222 individuals: 166 HIV-1-infected patients treated with antiretroviral drugs (77 with lipodystrophy and 89 without lipodystrophy) and 56 uninfected controls. Plasma ZAG levels were assessed by enzyme-linked immunosorbent assay (ELISA) and were correlated with fat distribution abnormalities and metabolic parameters. RESULTS: HIV-1-infected patients had lower plasma ZAG levels compared with uninfected controls (P < 0.001). No differences were found in ZAG plasma levels according to the presence of lipodystrophy, components of the metabolic syndrome or type of antiretroviral treatment regimen. Circulating ZAG levels were strongly determined by high-density lipoprotein cholesterol (HDLc) in men (B = 0.644; P < 0.001) and showed a positive correlation with total cholesterol (r = 0.312; P < 0.001) and HDLc (r = 0.216; P = 0.005). CONCLUSIONS: HIV-1-infected patients have lower plasma ZAG levels than uninfected controls. In infected patients, plasma ZAG levels are in close relationship with total cholesterol and HDLc.

Differential effects of rosiglitazone and metformin on postprandial lipemia in patients with HIV-lipodystrophy.

OBJECTIVE: To compare the effects of rosiglitazone (8 mg/d, n=19) and metformin (2 g/d, n=18) on postprandial lipemia in patients with HIV-lipodystrophy. METHODS AND RESULTS: Lipodystrophy in HIV is associated with insulin resistance and disturbed postprandial triglyceride and free fatty acid (FFA) metabolism. We conducted an open randomized 6-month study with standardized 10-h oral fat-loading tests at baseline and after treatment. Rosiglitazone (-34%) and metformin (-37%) reduced homeostasis model assessment similarly (P<0.05). Rosiglitazone did not change the area under the curve for FFA and triglyceride; however, it did reduce the area under the curve for hydroxybutyric acid (a marker of hepatic FFA oxidation) by 25% (P<0.05). Rosiglitazone increased the area under the curve for remnantlike particle cholesterol by 40% (P<0.01) compared with baseline. Metformin did not change any of the postprandial measurements. CONCLUSIONS: Rosiglitazone improved insulin sensitivity and decreased postprandial hydroxybutyric acid levels in patients with HIV-lipodystrophy, suggesting improved FFA handling. Despite metabolic improvements, rosiglitazone caused a marked increase in postprandial remnantlike particle cholesterol, which may adversely affect cardiovascular risk. Metformin did not affect postprandial lipemia and could be used to treat insulin resistance in this population.

Altered pattern of circulating miRNAs in HIV lipodystrophy perturbs key adipose differentiation and inflammation pathways.

We identified a microRNA (miRNA) profile characterizing HIV lipodystrophy and explored the downstream mechanistic implications with respect to adipocyte biology and the associated clinical phenotype. miRNA profiles were extracted from small extracellular vesicles (sEVs) of HIV-infected individuals with and without lipodystrophic changes and individuals without HIV, among whom we previously showed significant reductions in adipose Dicer expression related to HIV. miR-20a-3p was increased and miR-324-5p and miR-186 were reduced in sEVs from HIV lipodystrophic individuals. Changes in these miRNAs correlated with adipose Dicer expression and clinical markers of lipodystrophy, including fat redistribution, insulin resistance, and hypertriglyceridemia. Human preadipocytes transfected with mimic miR-20a-3p, anti-miR-324-5p, or anti-miR-186 induced consistent changes in latent transforming growth factor beta binding protein 2 (Ltbp2), Wisp2, and Nebl expression. Knockdown of Ltbp2 downregulated markers of adipocyte differentiation (Fabp4, Pparγ, C/ebpa, Fasn, adiponectin, Glut4, CD36), and Lamin C, and increased expression of genes involved in inflammation (IL1ß, IL6, and Ccl20). Our studies suggest a likely unique sEV miRNA signature related to dysregulation of Dicer in adipose tissue in HIV. Enhanced miR-20a-3p or depletion of miR-186 and miR-324-5p may downregulate Ltbp2 in HIV, leading to dysregulation in adipose differentiation and inflammation, which could contribute to acquired HIV lipodystrophy and associated metabolic and inflammatory perturbations.

Association between changes in body fat distribution, biochemical profile, time of HIV diagnosis, and antiretroviral treatment in adults living with and without virus infection.

OBJECTIVES: Individuals living with HIV seem to be more prone to changes in the redistribution of body fat, characterized as lipodystrophy, which may occur in conjunction with metabolic diseases. In the present study, such impacts were assessed in adults with and without HIV and associated with the time of virus diagnosis and treatment with antiretroviral. METHODS: A cross-sectional study with 123 adults, in which 87 had HIV and 36 without HIV, of both sexes, in outpatient follow-up at the Specialized Care Service (SAE) in Macaé-RJ. The following were made: 1) Alteration in body fat distribution, measured by anthropometric parameters and self-reported lipodystrophy; 2) Biochemical profile; 3) Association between HIV diagnosis time and antiretroviral treatment. RESULTS: 54.47% (n = 67) males, 45.52% (n = 56) females, mean age 37 years. Of these 87 were people living with HIV, 29% (n = 25) had self-reported lipodystrophy, mean time of virus infection, and antiretroviral treatment (5.80 ± 4.56 and 5.14 ± 3.82 years), respectively. Patients with self-reported lipodystrophy had a greater change in body fat distribution between 3-6 years of HIV diagnosis and a negative cholesterol profile. The antiretroviral treatment time influenced total cholesterol and triglycerides, even for patients without self-reported lipodystrophy, with a further nine years under treatment. CONCLUSION: In this study, the negative cholesterol profile was mainly related to antiretroviral treatment time, even for patients without self-reported lipodystrophy, and changes in body fat distribution, measured by anthropometry, was especially associated with time for HIV infection in those with lipodystrophy self-reported.

Effect of L-acetylcarnitine on body composition in HIV-related lipodystrophy.

This study examined the impact of L-acetylcarnitine treatment on metabolic parameters and body composition in patients with lipodystrophy syndrome secondary to antiretroviral treatment in human immunodeficiency virus (HIV) infection. A total of 9 HIV-1 infected patients with lipodystrophy syndrome (4F/5M, age 41+/-5 years, HIV duration 8+/-2 years, BMI 23.7+/-3.4 kg/m(2), on protease inhibitors and nucleoside analogue Reverse Transcriptase inhibitors) were evaluated before and after 8 months of therapy with L-acetylcarnitine (2 g/die) and 9 matched healthy subjects served as control subjects. In all patients fasting plasma glucose, insulin concentrations (for evaluation of surrogate indexes of insulin sensitivity), lipid profile, lipid oxidation (by indirect calorimetry), body composition (by DEXA), and intramyocellular triglyceride (IMCL) content of the calf muscles (by (1)H NMR spectroscopy) were assessed. After this therapy, in HIV-1 patients, the IMCL content of the soleus had significantly decreased (p=0.03). Plasma FFAs (0.79+/-0.31 to 0.64+/-0.25; p<0.05) and Respiratory Quotient (0.83+/-0.18 to 0.72+/-0.16; p<0.03) also decreased. Insulin sensitivity was significantly lower prior (HOMA-IS 0.56+/-0.30) and nonstatistically different than controls after therapy (0.72+/-0.49 vs. 0.78+/-0.42) whilst the percentage of fat in the legs increased (p=0.05). Eight months of L-acetylcarnitine treatment increased lipid oxidation, decreased intramyocellular triglyceride content, and induced a more physiological distribution of fat deposits.

Hypoadiponectinemia in lipodystrophic HIV individuals: a metabolic marker of subclinical cardiac damage.

BACKGROUND AND AIM: To evaluate cardiovascular abnormalities in highly active antiretroviral therapy (HAART) treated HIV patients with no signs or symptoms of cardiovascular impairment, and to assess the relative role of multiple concomitant risk factors. METHODS AND RESULTS: Forty-four consecutive HIV subjects (mean age 41+/-6 yrs) were enrolled. Inclusion criteria were HIV infection, CD4+cell count>150/ml, HAART treatment for at least 4 years. Metabolic serum levels, morphological and functional echocardiographic parameters were assessed in all subjects. Sixteen healthy age and sex matched subjects with no cardiovascular risk factors were recruited as controls. HIV patients showed increased left ventricular mass index with reduced mid-wall fractional shortening (mFS) when compared to controls (50.2+/-10.5 vs. 38.6+/-14.4, p=0.05 and 18.3+/-0.6 vs. 21.9+/-0.7, p<0.05, respectively). Twenty-nine patients were lipodystrophic (LD) and showed a longer HAART period (p=0.0004) and greater use of protease inhibitors (PI) (p=0.001). Coronary flow reserve (CFR) was significantly reduced in HIV patients as compared to controls (p<0.0001), as it was in LD subjects when compared to non-lipodystrophic ones (NLD) (p<0.001). Adiponectin concentrations were found to be significantly lower in LD subjects than in NLD ones (7.8+/-0.8 vs. 13.8+/-1.2 microg/ml, p=0.01), and showed a direct correlation with CFR. In multiple regression analysis, insulin, HDL and adiponectin accounted for 63% of CFR variations. CONCLUSIONS: Left ventricular hypertrophy, depressed mFS and reduced CFR represent the main signs of subclinical cardiac damage in HIV subjects treated with HAART. Hypoadiponectinemia in these subjects seems to be a metabolic risk factor of cardiovascular impairment.

The effect of strength and endurance training on insulin sensitivity and fat distribution in human immunodeficiency virus-infected patients with lipodystrophy.

CONTEXT: Fat redistribution, insulin resistance, and low-grade inflammation characterize HIV-infected patients with lipodystrophy. Currently, no effective therapies exist for the combined treatment of fat redistribution and insulin resistance. OBJECTIVE: Our objective was to evaluate the effects of strength and endurance training on insulin sensitivity and fat distribution in HIV-infected patients with lipodystrophy. SUBJECTS AND METHODS: Twenty sedentary HIV-infected men with lipodystrophy were randomly assigned to supervised strength or endurance training three times a week for 16 wk. The primary endpoints were improved peripheral insulin sensitivity (euglycemic-hyperinsulinemic clamp combined with isotope-tracer infusion) and body fat composition (dual-energy x-ray absorptiometry scan). Secondary endpoints included fasting lipids and inflammatory markers. RESULTS: Insulin-mediated glucose uptake increased with both endurance training (55.7 +/- 11 to 63.0 +/- 11 micromol glucose/kg lean mass.min, P = 0.02) and strength training (49.0 +/- 12 to 57.8 +/- 18 micromol glucose/kg lean mass.min, P = 0.005), irrespective of training modality (P = 0.24). Only strength training increased total lean mass 2.1 kg [95% confidence interval (CI), 0.8-3.3], decreased total fat 3.3 kg (95% CI, -4.6 to -2.0), trunk fat 2.5 kg (95% CI, -3.5 to -1.5), and limb fat 0.75 kg (95% CI, -1.1 to -0.4). Strength training significantly decreased total and limb fat mass to a larger extent than endurance training (P < 0.05). Endurance training reduced total cholesterol, low-density lipoprotein cholesterol, free fatty acids, high-sensitivity C-reactive protein, IL-6, IL-18, and TNF-alpha and increased high-density lipoprotein cholesterol, whereas strength training decreased triglycerides, free fatty acids, and IL-18 and increased high-density lipoprotein cholesterol (P < 0.05 for all measurements). CONCLUSION: This study demonstrates that both strength and endurance training improve peripheral insulin sensitivity, whereas only strength training reduces total body fat in HIV-infected patients with lipodystrophy.

The influence of HIV infection and antiretroviral therapy on the mitochondrial membrane potential of peripheral mononuclear cells.

OBJECTIVES: Clinical disorders occurring in HIV-infected patients on antiretroviral therapy (ART) have been linked to mitochondrial dysfunction, for example, lactic acidosis and lipodystrophy. Mitochondrial membrane potential (delta psi m) is the most direct measure of the state of energization of the mitochondria. We analysed delta psi m, of peripheral blood mononuclear cells (PBMCs) in HIV-negative, healthy subjects (n=8), HIV-infected, treatment-naive patients (n=30), and HIV-infected patients on ART (n=58). The influence of ART was analysed in six patients who started their first regimen. METHODS: The delta psi m of PBMC was measured by flow cytometry using the dye JC-1. RESULTS: The delta psi m was significantly lower in HIV-infected patients than in HIV-negative controls. This difference was detected in both treated (P = 0.0001) and untreated patients (P = 0.001). The delta psi m of PBMCs was highly correlated with CD4+ T-cell count in therapy-naive patients (P = 0.002, r = 0.546) and in treated patients (P = 0.028, r = 0.288). The delta psi m increased significantly in therapy-naive patients after starting ART (P = 0.001). Patients with lipoatrophy had significantly lower delta psi m than patients without lipodystrophy or with lipohypertrophy (P = 0.023). CONCLUSIONS: In HIV-infected persons delta psi m is significantly reduced. Patients with lipoatrophy have significantly reduced delta psi m. This is the first study showing that the delta psi m of PBMCs is highly correlated with CD4+ T-cell count in HIV infection.

Lipodystrophy is an independent predictor of hypertriglyceridemia during pregnancy in HIV-infected women.

Lipid values were measured during pregnancy in HIV-infected, treatment-experienced women. A previous history of lipodystrophy was associated with significantly higher triglyceride values at all pregnancy trimesters. In multivariate analyses lipodystrophy independently increased the risk of hypertriglyceridemia by threefold at the first trimester, and by eightfold at the second and third trimesters. Protease inhibitor treatment was also independently associated with hypertriglyceridemia.

Ezetimibe effectively decreases LDL-cholesterol in HIV-infected patients.

We tested the security and efficacy of ezetimibe in the treatment of HIV-associated dyslipemia. Twenty HIV-infected patients were randomly assigned to receive ezetimibe 10 mg/day or fluvastatin 80 mg/day. Patients receiving ezetimibe experienced a statistically significant (P = 0.003) 20% reduction in the concentration of LDL-cholesterol, similar to that observed with fluvastatin (24%, P between groups 0.70). We concluded that ezetimibe monotherapy effectively decreases LDL-cholesterol in HIV-infected patients.

A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy.

BACKGROUND: Long-term antiretroviral therapy, while dramatically reducing HIV-related morbidity and mortality, is associated with metabolic and morphological changes. Peripheral fat loss, lipoatrophy, appears most associated with prolonged therapy with thymidine nucleoside analogues. METHODS: A randomized, open-label, comparative study of switching from a thymidine nucleoside analogue to either tenofovir disoproxil fumarate (DF) or abacavir in 105 individuals on successful antiretroviral therapy with clinically evident moderate to severe lipoatrophy. RESULTS: Individuals were randomized to tenofovir DF (52) or abacavir (53). The switch was well tolerated and the majority of patients completed 48 weeks of study. One individual in the tenofovir DF group and three in the abacavir group discontinued due to drug-related adverse events. Both groups similarly maintained virological control. Limb fat mass increased similarly in both groups: mean increases by week 48 of 329 and 483 g in tenofovir DF and abacavir groups, respectively [mean 95% confidence interval for difference, -154.3 (range -492.8 to 184.3)]. This change from baseline was statistically significant in both groups (tenofovir DF, P = 0.01; abacavir, P = 0.0001). Mean total cholesterol, low density lipoprotein cholesterol and triglycerides improved modestly with switching to tenofovir DF but were unchanged with abacavir. The changes in these parameters were significantly greater in the tenofovir DF arm relative to abacavir. CONCLUSIONS: Switching from a thymidine nucleoside analogue to either tenofovir DF or abacavir leads to significant improvement in limb fat mass over 48 weeks. Tenofovir DF may have modest advantages over abacavir for changes in lipids. Peripheral lipoatrophy, when clinically apparent, resolves slowly following treatment switching.

Skeletal muscle insulin signaling defects downstream of phosphatidylinositol 3-kinase at the level of Akt are associated with impaired nonoxidative glucose disposal in HIV lipodystrophy.

More than 40% of HIV-infected patients on highly active antiretroviral therapy (HAART) experience fat redistribution (lipodystrophy), a syndrome associated with insulin resistance primarily affecting insulin-stimulated nonoxidative glucose metabolism (NOGM(ins)). Skeletal muscle biopsies, obtained from 18 lipodystrophic nondiabetic patients (LIPO) and 18 nondiabetic patients without lipodystrophy (NONLIPO) before and during hyperinsulinemic (40 mU.m(-2).min(-1))-euglycemic clamps, were analyzed for insulin signaling effectors. All patients were on HAART. Both LIPO and NONLIPO patients were normoglycemic (4.9 +/- 0.1 and 4.8 +/- 0.1 mmol/l, respectively); however, NOGM(ins) was reduced by 49% in LIPO patients (P < 0.001). NOGM(ins) correlated positively with insulin-stimulated glycogen synthase activity (I-form, P < 0.001, n = 36). Glycogen synthase activity (I-form) correlated inversely with phosphorylation of glycogen synthase sites 2+2a (P < 0.001, n = 36) and sites 3a+b (P < 0.001, n = 36) during clamp. Incremental glycogen synthase-kinase-3alpha and -3beta phosphorylation was attenuated in LIPO patients (Ps < 0.05). Insulin-stimulated Akt Ser473 and Akt Thr308 phosphorylation was decreased in LIPO patients (P < 0.05), whereas insulin receptor substrate-1-associated phosphatidylinositol (PI) 3-kinase activity increased significantly (P < 0.001) and similarly (NS) in both groups during clamp. Thus, low glycogen synthase activity explained impaired NOGM(ins) in HIV lipodystrophy, and insulin signaling defects were downstream of PI 3-kinase at the level of Akt. These results suggest mechanisms for the insulin resistance greatly enhancing the risk of type 2 diabetes in HIV lipodystrophy.

Mitochondrial (mt)DNA changes in tissue may not be reflected by depletion of mtDNA in peripheral blood mononuclear cells in HIV-infected patients.

OBJECTIVES: Most data on mitochondrial toxicity have been derived from peripheral blood mononuclear cells (PBMCs). However, whether mitochondrial DNA (mtDNA) content in PBMCs reflects the mitochondrial state in tissues remains elusive. We report herein on mitochondrial toxicity in skeletal muscle in HIV-infected patients naive to antiretroviral treatment (ART [HIV+ART-naive]; n = 10) patients exposed to nucleoside reverse transcriptase inhibitors (NRTIs [HIV+NRTI+]; n = 24) and healthy controls (n = 11), and compare these tissue data with mtDNA in PBMCs. METHODS: Muscle biopsies were examined for (i) mtDNA and nuclear DNA (nDNA) content using TaqMan real-time PCR system, (ii) mtDNA deletions using long expand PCR with subsequent gel electrophoresis, and (iii) mitochondrial myopathy expressed as cytochrome c oxidase (COX)-deficient muscle fibres. RESULTS: The mt/n DNA ratio in muscle from HIV+NRTI+ patients was reduced compared with HIV-negative controls (P = 0.028). Moreover, mtDNA deletions were more frequent in HIV+NRTI+ patients than in both HIV-negative controls (P = 0.009) and HIV+ART-naive patients (P = 0.005). HIV+NRTI+ also tended to have more COX-deficient fibres than HIV-negative controls (P = 0.076). COX-deficient fibres were positively correlated with mtDNA deletions in HIV+NRTI+ patients (r = 0.83, P < 0.001). Patients with current use of didanosine (ddl) had more frequent mtDNA deletions and COX-deficient fibres than HIV+NRTI+ not on current treatment with ddl. It should be noted that mitochondrial alterations were not correlated with mtDNA/cell in PBMCs in any group. CONCLUSIONS: In skeletal muscle, HIV+NRTI+ had a reduced mt/n DNA ratio, more frequent mtDNA deletions and possibly more COX-deficient muscle fibres than HIV-negative controls. However, the mtDNA/cell in peripheral blood was decreased in both HIV+NRTI+ and HIV+ART-naive patients. Thus, mtDNA in peripheral blood may not be a relevant marker of mitochondrial toxicity in organ-specific tissue.