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.

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.

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.

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

SUMMARY 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.

RESUMO OBJETIVOS Indivíduos vivendo com HIV parecem mais propensos às alterações na redistribuição da gordura corporal, caracterizada como lipodistrofia, podendo acontecer em conjunto com as metabólicas. No presente estudo avaliaram-se tais impactos em adultos com e sem HIV e se associou ao tempo de diagnóstico do vírus e tratamento com antirretroviral. MÉTODOS Estudo tipo transversal, com 123 adultos, no qual 87 tinham HIV e 36 sem HIV, de ambos os sexos, em seguimento ambulatorial no Serviço de Atendimento Especializado (SAE) em Macaé - RJ. Foram feitos: 1) Alteração na distribuição da gordura corporal, mensurados por parâmetros antropométricos e lipodistrofia autorreferida; 2) Perfil bioquímico; 3) Associação entre tempo diagnóstico do HIV e tratamento com antirretroviral. RESULTADOS Incluíram-se 54,47% (n=67) do sexo masculino, 45,52% (n=56) do feminino, com média de idade de 37 anos. Destes, 87 eram pessoas vivendo com HIV, 29% (n=25) possuíam lipodistrofia autorreferida; tempo médio de infecção pelo vírus e tratamento antirretroviral (5,80±4,56 e 5,14±3,82 anos), respectivamente. Os pacientes com lipodistrofia autorreferida tiveram maior alteração na distribuição da gordura corporal entre 3-6 anos de diagnóstico do HIV e um perfil colesterolêmico negativo. O tempo de tratamento com antirretroviral influenciou o colesterol total e os triglicerídeos, mesmo para os pacientes sem lipodistrofia autorreferida, com mais de nove anos sob tratamento. CONCLUSÃO Neste estudo, o perfil colesterolêmico negativo se relacionou principalmente ao tempo de tratamento com antirretroviral, mesmo para os pacientes sem lipodistrofia autorreferida e as alterações na distribuição da gordura corporal, mensuradas por antropometria, se associaram especialmente ao tempo de infecção pelo HIV naqueles com lipodistrofia autorreferida.

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.

A Prospective, Multicentre, Open-Label Single-Arm Exploratory Study to Evaluate Efficacy and Safety of Saroglitazar on Hypertriglyceridemia in HIV Associated Lipodystrophy.

OBJECTIVE: This study was designed to explore the efficacy and safety of saroglitazar 4 mg on hypertriglyceridemia in patients with HIV associated lipodystrophy. METHODS: During this 12-week prospective, multi-centric, open-label, single arm exploratory study, 50 patients were enrolled to receive saroglitazar 4 mg orally once daily in the morning before breakfast. The primary efficacy endpoint was the percent change in triglyceride (TG) levels from baseline to Week 6 and Week 12. The secondary efficacy endpoints were assessment of low-density-lipoprotein (LDL), very-low-density-lipoprotein (VLDL), high-density-lipoprotein (HDL), non-HDL cholesterol, total cholesterol, apo-lipoprotein (Apo) A1, Apo B, and C-peptide and fasting insulin for HOMA beta and HOMA IR. Safety assessment was performed during the study. RESULTS: Saroglitazar 4 mg significantly decreased the serum TG levels from baseline at Week 6 (percent change: -40.98; 95% CI: -50.82, -31.15) and Week 12 (percent change -45.11; 95% CI: -52.37, -37.86). Reduction in VLDL cholesterol (percent change: -46.33; 95% CI: -52.89, -39.76) and total cholesterol (percent change: 7.37; 95% CI: 1.96, 12.78) was observed at week 12 from baseline. Saroglitazar increased HDL cholesterol (percent change: 34.56, 95% CI: 22.22, 46.90), Apo A1 (percent change: 33.16; 95% CI: 18.69, 47.63) and Apo B (percent change: 10.55, 95% CI: 2.86, 18.25) levels at week 12 from baseline. Saroglitazar treatment led to increase in the C-peptide (percent change: 59.42, 95% CI: 48.78, 70.06), fasting insulin levels (percent change: 47.10; 95% CI: 38.63, 55.57), HOMA of beta cell function for C-peptide (percent change: 71.67; 95% CI: 39.09, 104.26) and HOMA of insulin resistance for C-peptide (percent change: 58.29, 95% CI: 46.74, 69.83) at week 12 from baseline. Saroglitazar treatment was safe and well tolerated in this study. CONCLUSION: Overall, the observed changes in lipid profile after 12 weeks of saroglitazar treatment were in the direction of improvement in patients with HIV associated lipodystrophy. TRIAL REGISTRATION: Clinical Trial Registry of India Phase II/CTRI/2010/091/000107.

HIV-1/HAART-Related Lipodystrophy Syndrome (HALS) Is Associated with Decreased Circulating sTWEAK Levels.

BACKGROUND AND OBJECTIVES: Obesity and HIV-1/HAART-associated lipodystrophy syndrome (HALS) share clinical, pathological and mechanistic features. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that plays an important role in obesity and related diseases. We sought to explore the relationship between HALS and circulating levels of soluble (s) TWEAK and its scavenger receptor sCD163. METHODS: This was a cross-sectional multicenter study of 120 HIV-1-infected patients treated with a stable HAART regimen; 56 with overt HALS and 64 without HALS. Epidemiological and clinical variables were determined. Serum levels of sTWEAK and sCD163 levels were measured by ELISA. Results were analyzed with Student's t-test, Mann-Whitney U and χ2 test. Pearson and Spearman correlation were used to estimate the strength of association between variables. RESULTS: Circulating sTWEAK was significantly decreased in HALS patients compared with non-HALS patients (2.81±0.2 vs. 2.94±0.28 pg/mL, p = 0.018). No changes were observed in sCD163 levels in the studied cohorts. On multivariate analysis, a lower log sTWEAK concentration was independently associated with the presence of HALS (OR 0.027, 95% CI 0.001-0.521, p = 0.027). CONCLUSIONS: HALS is associated with decreased sTWEAK levels.

Predictors of Treatment Response to Tesamorelin, a Growth Hormone-Releasing Factor Analog, in HIV-Infected Patients with Excess Abdominal Fat.

BACKGROUND: Tesamorelin, a synthetic analog of human growth hormone-releasing factor, decreases visceral adipose tissue (VAT) in human immunodeficiency virus (HIV)-infected patients with lipodystrophy. OBJECTIVES: 1) To evaluate the utility of patient characteristics and validated disease-risk scores, namely indicator variables for the metabolic syndrome defined by the International Diabetes Federation (MetS-IDF) or the National Cholesterol Education Program (MetS-NCEP) and the Framingham Risk Score (FRS), as predictors of VAT reduction during tesamorelin therapy at 3 and 6 months, and 2) To explore the characteristics of patients who reached a threshold of VAT <140 cm2, a level associated with lower risk of adverse health outcomes, after 6 months of treatment with tesamorelin. METHODS: Data were analyzed from two Phase 3 studies in which HIV-infected patients with excess abdominal fat were randomized in a 2:1 ratio to receive tesamorelin 2 mg (n = 543) or placebo (n = 263) subcutaneously daily for 6 months, using ANOVA and ANCOVA models. RESULTS: Metabolic syndrome (MetS-IDF or MetS-NCEP) and FRS were significantly associated with VAT at baseline. Presence of metabolic syndrome ([MetS-NCEP), triglyceride levels >1.7 mmol/L, and white race had a significant impact on likelihood of response to tesamorelin after 6 months of therapy (interaction p-values 0.054, 0.063, and 0.025, respectively). No predictive factors were identified at 3 months. The odds of a VAT reduction to <140 cm2 for subjects treated with tesamorelin was 3.9 times greater than that of subjects randomized to placebo after controlling for study, gender, baseline body mass index (BMI) and baseline VAT (95% confidence interval [CI] 2.03; 7.44). CONCLUSIONS: Individuals with baseline MetS-NCEP, elevated triglyceride levels, or white race were most likely to experience reductions in VAT after 6 months of tesamorelin treatment. The odds of response of VAT <140 cm2 was 3.9 times greater for tesamorelin-treated patients than that of patients receiving placebo.

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.

Gender differences in GH response to GHRH+ARG in lipodystrophic patients with HIV: a key role for body fat distribution.

OBJECTIVE: Gender influence on GH secretion in human immunodeficiency virus (HIV)-infected patients is poorly known. DESIGN AND METHODS: To determine the effect of gender, we compared GH response to GH-releasing hormone plus arginine (GHRH+Arg), and body composition in 103 men and 97 women with HIV and lipodystrophy. The main outcomes were IGF1, basal GH, GH peak and area under the curve (AUC) after GHRH+Arg, body composition, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT). RESULTS: Men had lower GH peak and AUC than women (P<0.001). Of the study population, 21% of women and 37% of men had biochemical GH deficiency (GHD; GH peak <7.5 µg/l). VAT-to-SAT ratio was higher in men than in women with GHD (P<0.05). Unlike women, VAT, SAT, and trunk fat were greater in men with GHD than in men without GHD. IGF1 was significantly lower in women with GHD than in women without GHD, but not in men. At univariate analysis, BMI, trunk fat mass, VAT, and total adipose tissue were associated with GH peak and AUC in both sexes (P<0.05). BMI was the most significant predictive factor of GH peak, and AUC at multiregression analysis. Overall, abdominal fat had a less pronounced effect on GH in females than in males. CONCLUSIONS: These data demonstrate that GH response to GHRH+Arg is significantly lower in HIV-infected males than females, resulting in a higher percentage of GHD in men. Adipose tissue distribution more than fat mass per se seems to account for GH gender differences and for the alteration of GH-IGF1 status in these patients.

Small-dense LDL cholesterol/large-buoyant LDL cholesterol ratio as an excellent marker for indicating lipodystrophy in HIV-infected patients.

OBJECTIVES: To examine whether the lipid parameters are predicting factors for human immunodeficiency virus (HIV)-associated lipodystrophy. METHODS: Whole-body fat compositions of HIV-positive patients receiving stavudine-containing antiretroviral regimens (n = 79) were determined. Lipodystrophy was defined as a ratio of trunk fat mass/lower limb fat mass greater than 2.28. Blood samples were analyzed for total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), small-dense LDL-C (sdLDL-C), apoAI, apoB, lipoprotein(a), and CD4 cell counts. Large-buoyant LDL-C (lbLDL-C) was calculated (LDL-C minus sdLDL-C). RESULTS: Twenty-six patients were classified as having lipodystrophy. The mean values of triglycerides, HDL-C, sdLDL-C, apoB, TC/HDL-C, apolipoprotein (apo) B/apoAI, and sdLDL-C/lbLDL-C showed significant differences between patients with and without lipodystrophy (P < .02). Using logistic regression analysis, sdLDL-C/lbLDL-C was identified as a significant predictor of lipodystrophy (P < .001). At a ratio of 0.554, the odds ratio was 17.8 with a likelihood ratio of 5.5. CONCLUSIONS: The sdLDL-C/lbLDL-C ratio is an excellent marker for indicating lipodystrophy in HIV-infected patients.

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.

Altered relationship of plasma triglycerides to HDL cholesterol in patients with HIV/HAART-associated dyslipidemia: further evidence for a unique form of metabolic syndrome in HIV patients.

INTRODUCTION: Plasma triglycerides (TG) and HDL-C are inversely related in Metabolic Syndrome (MetS), due to exchange of VLDL-TG for HDL-cholesteryl esters catalyzed by cholesteryl ester transfer protein (CETP). We investigated the relationship of TG to HDL-C in highly-active antiretroviral drug (HAART)-treated HIV patients. METHODS: Fasting plasma TG and HDL-C levels were compared in 179 hypertriglyceridemic HIV/HAART patients and 71 HIV-negative persons (31 normotriglyceridemic (NL) and 40 hypertriglyceridemic due to type IV hyperlipidemia (HTG)). CETP mass and activity were compared in 19 NL and 87 HIV/HAART subjects. RESULTS: Among the three groups, a plot of HDL-C vs. TG gave similar slopes but significantly different y-intercepts (9.24±0.45, 8.16±0.54, 6.70±0.65, sqrt(HDL-C) for NL, HIV and HTG respectively; P<0.001); this difference persisted after adjusting HDL-C for TG, age, BMI, gender, glucose, CD4 count, viral load and HAART strata (7.18±0.20, 6.20±0.05 and 4.55±0.15 sqrt(HDL-C) for NL, HIV and HTG, respectively, P<0.001). CETP activity was not different between NL and HIV, but CETP mass was significantly higher in HIV (1.47±0.53 compared to 0.93±0.27µg/mL, P<0.0001), hence CETP specific activity was lower in HIV (22.67±13.46 compared to 28.46±8.24nmol/µg/h, P=0.001). CONCLUSIONS: Dyslipidemic HIV/HAART patients have a distinctive HDL-C plasma concentration adjusted for TG. The weak inverse relationship between HDL-C and TG is not explained by altered total CETP activity; it could result from a non-CETP-dependent mechanism or a decrease in CETP function due to inhibitors of CETP activity in HIV patients' plasma.

Polymorphisms in Fas gene is associated with HIV-related lipoatrophy in Thai patients.

The present study aimed to evaluate the role of genetic polymorphisms in the emergence of lipoatrophy or lipodystrophy in HIV-infected patients with antiretroviral therapy (ART) in Thailand. Position 455 upstream of the Apolipoprotein C3 gene (ApoC3 T-455C, rs2854116), codon 64 of the Beta3 adrenergic receptor gene (ARß3 Tcod64C, rs4994), and position 670 upstream of the Fas gene (Fas A-670G, rs1800682) were genotyped in 829 HIV-infected Thai patients who had started ART. Crude and adjusted incidence rate ratios (IRR) were calculated using Poisson regression. The serum levels of cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were also analyzed. Multivariate analysis revealed an association between the Fas -670AA genotype, but not the ApoC3 -455 or ARß3 cod64 genotypes, with the incidence of lipoatrophy after adjusting for gender and stavudine (d4T)-containing regimens (IRR=1.72, 95% CI=1.20-2.45, p=0.003). However, ApoC3 -455C homozygous patients showed elevated serum levels of triglycerides, while this genotype did not affect serum total cholesterol, HDL, or LDL levels in patients with lipoatrophy or lipodystrophy. In contrast, the ARß3 cod64 genotype did not show any significant association with the serum levels of cholesterol, triglycerides, HDL, or LDL. In conclusion, Fas -670AA affected the incidence of lipoatrophy in HIV-1-infected Thai patients, while the ApoC3 -455C allele affected the serum levels of triglycerides. These results confirmed the role of genetics in the development of ART-related metabolic disorders.

Reduced levels of serum FGF19 and impaired expression of receptors for endocrine FGFs in adipose tissue from HIV-infected patients.

BACKGROUND: To determine the role of fibroblast growth factor (FGF)-19 and FGF21 and the endocrine FGFs receptor system in the metabolic alterations that manifest in HIV-1-infected patients undergoing highly active antiretroviral treatment (HAART). METHODS: Serum FGF19 and FGF21 levels were determined in 4 groups of individuals as follows: (1) HIV-1-infected HAART patients with lipodystrophy (n = 38); or (2) without lipodystrophy (n = 34); (3) untreated (naive) HIV-1-infected patients (n = 34); and (4) healthy controls (n = 31). Serum FGF19 levels were correlated with anthropometric, metabolic, HIV-1 infection-related, and HAART-related parameters and with FGF21 levels. The gene expression of FGF receptor 1 and the coreceptor ß-Klotho was analyzed in adipose tissue from 10 individuals from each group. RESULTS: Serum FGF19 levels were significantly reduced in all groups of HIV-1-infected patients, whereas FGF21 levels were increased. FGF19 levels were negatively correlated with insulin resistance and insulin levels and positively correlated with high-density lipoprotein cholesterol. FGF19 was inversely correlated with cumulative exposure to nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor drugs. The expression of FGF receptor 1 and coreceptor ß-Klotho was reduced in adipose tissue from all groups of HIV-infected patients. CONCLUSIONS: FGF19 levels are reduced in HIV-1-infected patients, in contrast with FGF21 levels. Impaired expression of the corresponding receptor and coreceptor, which mediate the actions of endocrine FGFs in adipose tissue, suggests a resistance to the metabolic effects of FGF19 and FGF21 in HIV-1-infected patients. Considering the beneficial effects of endocrine FGFs on metabolism, the observed reduction in FGF19 levels and decreased sensitivity to endocrine FGFs in adipose tissue may contribute to metabolic alterations in HIV-1-infected patients.