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The aim of this study was to perform a systematic review to identify data reported in the literature concerning the association of APOC3 (rs2854116), ESR2 (rs3020450), HFE (rs1799945), MMP1 (rs1799750) and PPARG (rs1801282) polymorphisms with lipodystrophy in people living with HIV (PLWHIV) on antirretroviral therapy. The research was conducted in six databases and the studies were selected in two steps. First, a search was undertaken in the following electronic databases: PubMed, Science Direct, Medline, World Wide Science, Directory of Open Access Journals, Scielo, Lilacs and Medcarib. The titles and abstracts of 24,859 articles were read to select those that match the elegibilty criteria. Five papers that addressed the association of HAART, lipodystrophy and polymorphisms were selected for the review. There was no association between the polymorphisms of the genes APOC3 and PPARG and lipodystrophy. Another study described an association between the variant allele (G) of HFE and protection concerning the development of lipoatrophy (0.02) when compared with the reference allele (C). On the other hand, the variant allele (T) of the ESR2 gene was associated with the development of lipoatrophy (p = 0.007) when compared with the reference allele (C). In addition, the genotype and the variant allele of the gene MMP1 (2G) were associated with lipodystrophy in PLWHIV on HAART (p = 0.0002 and p = 0.0008, respectively). Therefore, further studies with other populations, involving PLWHIV on HAART are necessary to better understand the role of genetic markers, which may be involved in a predisposition to lipodystrophy.

Lipoatrophy, or fat wasting, remains a syndrome plaguing HIV + patients receiving antiretroviral (ARV) therapy. Both HIV infection per se and certain ARV are associated with lowered adipose tissue mitochondrial deoxyribonucleic acid (mtDNA) and mitochondrial ribonucleic acid (mtRNA) levels, but effects on adenosine triphosphate (ATP) production are unclear. We hypothesized that such alterations would accompany lowering of ATP levels in fat of HIV + patients and would be worse in those displaying lipoatrophy. Gluteal-fold, subcutaneous adipose tissue was obtained from HIV seronegative control patients, from HIV + ARV-naive patients, and those on ARV with or without lipoatrophy. Cellular ATP was measured in isolated adipocytes and preadipocyte fraction cells by bioluminescence. mtDNA copies/cell and oxidative phosphorylation (OXPHOS) mtRNA transcripts were evaluated by quantitative polymerase chain reactions. ATP levels were consistently higher in preadipocyte fraction cells than adipocytes, but values strongly correlated with each other ( r  = 0.66, p  < .001). ATP levels in adipocytes were higher in both ARV-naive and nonlipoatrophic HIV + patients compared to seronegative controls, but significantly lower in adipocytes and preadipocytes of lipoatrophic versus other HIV + patients. Fat mtDNA copies/cell and OXPHOS mtRNA transcripts were lower in lipoatrophic patient samples compared to HIV seronegative. The ratio of specific OXPHOS transcripts to each other was significantly higher in nonlipoatrophic patients versus all groups, and this ratio correlated significantly with ATP levels in adipocytes. Thus, HIV infection is associated with an increase in adipose tissue ATP stores. Decreases in adipose mtDNA and OXPHOS mtRNA are found in those with HIV on ARV; however, ATP level is effected only in patients displaying lipoatrophy.

Context: Microscopic measurement of adipocyte size is the gold standard for determining adipose tissue (AT) quality. AT density on CT may also reflect adipocyte quality (lower density = poorer quality)., Objective: We used abdominal subcutaneous AT (SAT) specimens and CT scans to validate CT SAT density as a marker of SAT quality in adults living with HIV., Setting and Design: Secondary data analysis from completed trial of antiretroviral therapy (ART) initiation (ACTG A5224s). CT abdominal SAT density was measured in HU. SAT specimens were digitally scanned for calculation of mean adipocyte area., Participants: Participants had SAT biopsy and CT data at baseline (n = 54) and HIV-1 RNA <50 copies per milliliter on ART and biopsy or CT data at week 96 (n = 30)., Outcome Measures: Spearman correlations and linear regression models adjusting for participant characteristics examined associations between SAT density and adipocyte area., Results: Baseline median age was 40 years, CD4+ T lymphocyte count 219 cells per cubic millimeter, and body mass index 26.0 kg/m2; 89% were male and 67% white. Median SAT area and density were 199 cm2 and -100 HU. Over 96 weeks, SAT area increased (+18%) and SAT density decreased (-3%). Mean SAT adipocyte area correlated with SAT density (P < 0.01) off and on ART after adjustment for SAT area, age, race, sex, CD4+ T lymphocyte count, and HIV-1 RNA., Conclusions: CT SAT density correlates with biopsy-quantified SAT adipocyte size in adults with HIV on and off ART, suggesting that CT is a useful tool for noninvasive assessment of SAT quality., (Copyright © 2019 Endocrine Society.)

Background: Chronic HIV infection is associated with low-level inflammation and increased risk of chronic diseases and mortality. The objective was to assess the effects of moderate intensity exercise on metabolic and inflammatory markers in HIV-infected treated persons., Methods: This was a pilot study enrolling cART-treated, sedentary persons with metabolic complications in a 12-week protocol, consisting of three sessions per week of 60 min brisk walking with (strength-walk group) or without (walk group) 30 min circuit-training. Assessments at baseline and week 12 (W12) included body morphometrics and total body dual-energy X-ray absorptiometry; lipid and glucose blood profile; plasma level of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), D-dimer, interleukin-18 (IL-18), soluble CD14, and CD38 and HLA-DR expression on CD4+ and CD8+ T-cells., Results: Forty-nine patients were included and 35 (71%) completed the program: 21 in the walk and 14 in the strength-walk group. At W12, significant improvements were observed of body mass index, waist and hip circumference, and total cholesterol both overall and in the walk group, and of LDL cholesterol in both training groups. In the whole group, significant reductions were observed in hsCRP, IL-6, D-dimer, IL-18, and of CD8+/CD38+/HLA-DR+ cell frequencies. HsCRP and CD8+/CD38+/HLA-DR+ frequency decreased significantly in both training groups when examined separately whereas IL-6 and D-dimer in the walk group only., Conclusions: Brisk walking, with or without strength exercise, could improve lipid profile and inflammatory markers in chronic HIV infection., Trial Registration: ACTRN12615001258549, registered 17 November 2015, "retrospectively registered" Web address of trial: http://www.ANZCTR.org.au/ACTRN12615001258549.aspx.

Background: Several studies have reported increased resting energy expenditure (REE) in human immunodeficiency virus (HIV)-infected patients with HIV-associated lipodystrophy syndrome (HALS). However, limited data exist on the total energy expenditure (TEE). This study was aimed at evaluating the REE and TEE of HIV-infected patients with and without HALS by using the doubly labeled water (DLW) technique and the activity monitor based on accelerometry system (AM), and comparing the results obtained using both methods., Methods: Evaluated total of 45 HIV+ men undergoing antiretroviral therapy, including 18 LIPO- (without lipodystrophy) and 27 LIPO+ (with lipodystrophy) individuals were evaluated. Habitual physical activity patterns were measured by using the ActivPAL™ AM system, REE by indirect calorimetry, and TEE by DLW and AM., Results: No significant differences were found between LIPO- and LIPO+ in REE (1,433 ± 196 vs. 1,510 ± 203 kcal), TEE-DLW (2,691 ± 856 vs. 2,618 ± 415 kcal) and TEE-AM (2,560 ± 458 vs. 2,594 ± 456 kcal), respectively. RQ was a predictor of REE in LIPO+. TEE estimated by the AM had a moderate correlation with DLW, but there was a wide variance in the intra-subject results., Conclusions: TEE is not increased in HIV-infected patients with HALS. AM should be used with caution for TEE evaluation during clinical practice., (© 2017 S. Karger AG, Basel.)

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.

Leptin is a hormone secreted by adipocytes that regulates energy metabolism via peripheral action on glucose synthesis and utilization as well as through central regulation of food intake. Patients with decreased amounts of fat in their adipose tissue (lipoatrophy) will have low leptin levels, and hypoleptinemic states have been associated with a variety of metabolic dysfunctions. Pronounced complications of insulin resistance, dyslipidemia and fatty liver are observed in patients suffering from congenital or acquired generalized lipodystrophy while somewhat less pronounced abnormalities are associated with human immunodeficiency virus (HIV) and the use of highly active antiretroviral therapy, the so-called HIV-associated lipodystrophy. Previous uncontrolled open-label studies have demonstrated that physiological doses of leptin repletion have corrected many of the metabolic derangements observed in subjects with rare fat maldistribution syndromes such as generalized lipodystrophy. In the much more commonly encountered HIV-associated lipodystrophy, leptin replacement has been shown to decrease central fat mass and to improve insulin sensitivity, dyslipidemia, and glucose levels. The United States Food and Drug Administration has recently granted approval for recombinant leptin therapy for congenital and acquired generalized lipodystrophy, however large, well-designed, placebo-controlled studies are needed to assess long-term efficacy, safety and adverse effects of leptin replacement. In this review, we present the role of leptin in the metabolic complications of congenital and acquired lipodystrophy and discuss current and emerging clinical therapeutic uses of leptin in humans with lipodystrophy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Dyslipidemia and lipodystrophy represent significant healthcare concerns in HIV-infected patients due to their association with diabetes mellitus and increased cardiovascular disease risk. Since the lipid effects of the nonnucleoside reverse transcriptase inhibitors are not well characterized, we systematically summarized the effects of nonnucleoside reverse transcriptase inhibitor treatment on dyslipidemia and lipodystrophy in HIV-1 infection. As with other classes of antiretroviral agents, the nonnucleoside reverse transcriptase inhibitors are associated with lipid changes, although individual agents exhibit differing effects on lipid profiles. Comparative trials have shown that the risk for hypertriglyceridemia is lower with efavirenz than with the use of ritonavir-boosted lopinavir, but there is a greater likelihood of hypercholesterolemia compared to ritonavir-boosted atazanavir. Data also suggest that efavirenz results in greater increases in plasma lipid levels than integrase inhibitors and CC-chemokine-receptor-5 antagonists. Lipid disturbances are less frequent with the newer nonnucleoside reverse transcriptase inhibitors than with efavirenz. However, in most cases, no change in the total:high-density lipoprotein-cholesterol ratio was seen between the efavirenz and comparator groups. Switching from efavirenz to etravirine or rilpivirine, or the integrase inhibitors raltegravir or elvitegravir, resulted in significant reductions in lipid levels. There appears to be minimal potential for efavirenz or rilpivirine to result in development of lipodystrophy. Overall, nonnucleoside reverse transcriptase inhibitors have a smaller impact on plasma lipids than ritonavir-boosted protease inhibitors, with the newer agents exhibiting more favorable lipid profiles than efavirenz. When considering antiretroviral regimens, awareness of the different lipid effect profiles of the third agent is important, without forgetting the critical contribution of the background antiretrovirals.

Background: Normal lipid metabolism and functioning of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) in the sebaceous gland is critical to maintaining a normal hair follicle. Human immunodeficiency virus (HIV) infection affects lipid metabolism; some have hypothesized a link between PPAR-gamma function and lipodystrophy in HIV infection. Our objective was to determine whether lipodystrophy is associated with altered hair characteristics in HIV-infected women from the Women's Interagency HIV Study., Methods: Hair characteristics and scalp inflammation were assessed by an interviewer-administered questionnaire. Central lipohypertrophy and peripheral lipoatrophy were defined by self-report of moderate to severe fat gain in central body sites and fat loss in peripheral body sites, respectively confirmed by clinical examination. Additional covariates considered in the analyses included demographics, behavioral characteristics, medical history, and HIV-related factors., Results: There were 1037 women with data on all study variables; 76 women reported central lipohypertrophy, while only four women reported lipoatrophy. Women with central lipohypertrophy were more likely to be older, had a self-reported history of injection drug use, statin medication use, diabetes, elevated cholesterol, and have self-reported less hair and shorter eyelashes. After adjustment for age, central lipohypertrophy was associated with shorter eyelashes (OR 2.3; 95% CI 1.4-3.8)., Conclusions: Central lipohypertrophy was not associated with change in scalp hair texture or scalp inflammation in this cohort. Rather, we found an association between central lipohypertrophy and shorter eyelash length. This finding may be explained by an influence of prostaglandin E2 mediators on eyelash follicles., (© 2013 The International Society of Dermatology.)

Background: Conflicting reports on the effects of efavirenz (EFV) and lopinavir/ritonavir (LPV/r) on subcutaneous adipose tissue (SAT) have been described., Objective: The aim was to assess the 48-week molecular and clinical effects of LPV/r and EFV, combined with tenofovir/emtricitabine (TDF/FTC), on SAT of HIV-infected, antiretroviral-naive patients., Methods: Forty-four adults were started on LPV/r or EFV combined with TDF/FTC. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by dual x-ray absorptiometry scans were obtained at study entry and week 48. Mitochondrial DNA (mtDNA) and transcripts for mtDNA-encoded proteins and genes involved in inflammation, adipocyte differentiation, and metabolism were assessed in paired SAT biopsies., Results: Whole-body fat and limb fat mass increased in the LPV/r and EFV groups. MtDNA and cytochrome oxidase subunit II did not change, and cytochrome b increased significantly in EFV-treated patients. Tumor necrosis factor alpha and monocyte chemotactic protein-1 gene expression did not change in the LPV/r group, but these significantly increased in the EFV group. Interleukin 18 decreased in the LPV/r group, whereas it increased in the EFV group., Conclusions: Starting TDF/FTC plus EFV was associated with an increased expression of genes encoding for inflammatory cytokines in SAT in naive patients. Therapy with TDF/FTC plus LPV/r or EFV was associated with an increase in subcutaneous fat mass.

miRNAs are important regulators of biological processes in many tissues, including the differentiation and function of brown and white adipocytes. The endoribonuclease dicer is a major component of the miRNA-processing pathway, and in adipose tissue, levels of dicer have been shown to decrease with age, increase with caloric restriction, and influence stress resistance. Here, we demonstrated that mice with a fat-specific KO of dicer develop a form of lipodystrophy that is characterized by loss of intra-abdominal and subcutaneous white fat, severe insulin resistance, and enlargement and "whitening" of interscapular brown fat. Additionally, KO of dicer in cultured brown preadipocytes promoted a white adipocyte-like phenotype and reduced expression of several miRNAs. Brown preadipocyte whitening was partially reversed by expression of miR-365, a miRNA known to promote brown fat differentiation; however, introduction of other miRNAs, including miR-346 and miR-362, also contributed to reversal of the loss of the dicer phenotype. Interestingly, fat samples from patients with HIV-related lipodystrophy exhibited a substantial downregulation of dicer mRNA expression. Together, these findings indicate the importance of miRNA processing in white and brown adipose tissue determination and provide a potential link between this process and HIV-related lipodystrophy.

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.

Objectives: A relationship between obesity and intestinal bacterial translocation has been reported. Very little information is available with respect to the involvement of the bacterial translocation mechanistic pathway in HIV-1/highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS). We determined whether lipopolysaccharide (LPS)-binding protein (LBP), cluster of differentiation 14 (CD14), myeloid differentiation protein 2 (MD2) and toll-like receptor 4 (TLR4) single-nucleotide polymorphisms and LPS, LBP and soluble CD14 (sCD14) plasma levels are involved in HALS., Patients and Methods: This cross-sectional multicentre study involved 558 treated HIV-1-infected patients, 240 with overt HALS and 318 without HALS. Anthropometric, clinical, immunovirological and metabolic variables were determined. Polymorphisms were assessed by genotyping. Plasma levels were determined by ELISA in 163 patients (81 with HALS and 82 without HALS) whose stored plasma samples were available. Student's t-test, one-way ANOVA, two-way repeated measures ANOVA, the χ(2) test and Pearson and Spearman correlation analyses were carried out for statistical analysis., Results: LBP rs2232582 T→C polymorphism was significantly associated with HALS (P = 0.01 and P = 0.048 for genotype and allele analyses, respectively). Plasma levels of LPS (P = 0.009) and LBP (P < 0.001) were significantly higher and sCD14 significantly lower (P < 0.001) in patients with HALS compared with subjects without HALS. LPS levels were independently predicted by triglycerides (P < 0.001) and hepatitis C virus (P = 0.038), LBP levels by HALS (P < 0.001) and sCD14 levels by age (P = 0.008), current HIV-1 viral load (P = 0.001) and protease inhibitor use (P = 0.018)., Conclusions: HALS is associated with LBP polymorphism and with higher bacterial translocation., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Introduction: HIV Lipodystrophy Syndrome (HIVLS) is a multifactorial clinical expression that presents alterations in the metabolism and distribution pattern of body fat via immunological changes capable of disrupting homeostasis. This study aimed to analyze the degree of inflammatory, anti-inflammatory, and apoptosis activity in the subcutaneous tissue of patients, based on the expression of Tumor Necrosis Factor-α (TNF-α), Transforming Growth Factor-β (TGF-β), and caspase-3, respectively, and correlate them with clinical data and with each other., Methods: This is a cross-analytical study. The biopsy of subcutaneous cellular tissue was performed on the right thigh of 19 patients with HIVLS who were attended to at a university hospital, and four people without HIV and lipodystrophy, for comparison. The type of lipodystrophy and the estimation of body fat were obtained during the consultation or obtained from medical charts. The cytokine expression was observed in the adipose tissue through the streptavidin-biotin peroxidase method, and analyzed by optical microscopy., Results: Despite the mixed clinical form having been prevalent in both genders, men were more lipoatrophic and women were more lipohypertrophic. Men showed higher expression of TNF-α and caspase-3 than women. Patients with lipodystrophy had higher expression of TNF-α and caspase-3 and lower TGF-β, compared to the control group. The percentage of body fat was negatively correlated with the expression of TNF-α and caspase-3. Longer durations of infection and use of antiretroviral therapy (ARVT) were positively associated with the levels of TNF-α. The expression of caspase-3 and TGF-β was associated with higher levels of TNF-α., Conclusion: Regardless of the clinical form, HIVLS is characterized by a chronic inflammatory process associated with the male gender, the percentage of body fat, and lipoatrophy manifestations. There is increased apoptotic activity in more inflamed tissues and there is correlation between TNF-α and TGF-β, which suggests a possible negative feedback mechanism between the inflammatory and anti-inflammatory activity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: HIV-infected patients receiving antiretroviral treatment frequently accumulate fat at the abdominal level. It is unknown whether T-cell activation and immune phenotypes are associated with fat accumulation. Thus, the aim of the study was to search for an association between the presence of clinical lipodystrophy (LD), visceral and subcutaneous abdominal adipose tissue amount (VAT and SAT), and peripheral T-cell immune phenotypes., Design: Cross-sectional study including 87 HIV-infected antiretroviral therapy-treated virologically suppressed and immune-reconstituted patients., Methods: The patients were evaluated for clinical LD, VAT, SAT, homeostasis model of insulin resistance, and coronary artery calcium score (>10). T-cell activation (CD8/CD38), differentiation (CD4/CD8/CCR7/CD45RA), and expression/activation of the interleukin-7 (IL-7)/IL-7R system (CD4/CD8/CD127, IL-7, and CD4/CD8/pStat-5) were assessed by cytometry., Results: In multivariable analyses, CD8 T-cell activation (CD38) was associated with lipoatrophy and central fat accumulation (respectively, β = 5.63, P = 0.005, and β = 4.19, P = 0.020). This was also the case for IL-7R expressing CD8⁺ T cells (CD127⁺) for lipoatrophy β = 12.8, P = 0.003, and for central fat accumulation β = 9.45, P = 0.016. CD8⁺ T-cell activation was also associated with VAT/total adipose tissue (β = 0.01, P = 0.002) and SAT/VAT ratios (β = -0.014, P = 0.015). As expected, VAT/total adipose tissue was an independent risk factor for homeostasis model of insulin resistance (r = 0.364, P = 0.028) and cardiovascular risk (coronary artery calcium, r = 0.406, P = 0.002)., Conclusions: CD8⁺ T-cell activation was associated with LD and the relative amount of VAT in antiretroviral therapy-controlled, virologically suppressed, HIV-infected patients. We propose that CD8 activation may be involved in the accumulation of central fat frequently observed in these patients, with resulting increased cardiometabolic risk.

In the late 1990s, reports of unusual changes in body fat distribution named 'lipodystrophy' (LD) began to appear in HIV patients mitigating the enormous enthusiasm about improvement of survival and quality of life provided by the combinations of antiretroviral (ARV) drug classes, the so-called highly active antiretroviral therapy (HAART), which had just become available at that time. The objective of this paper is to critically review the literature on LD and to discuss the impact of newer ARV agents, namely atazanavir, darunavir and raltegravir, as well as strategies of the late HAART era, including single-tablet regimens and nucleoside-sparing regimens. Studies in which LD was measured by dual-energy x-ray absorptiometry or by abdominal computed tomography or magnetic resonance imaging scan only, were included. We were unable to identify studies depicting a negative impact of drugs or ARV regimens on limb fat loss. On the contrary, a few studies identified a negative impact of atazanavir/ritonavir or darunavir/ritonavir on trunk fat increase. It should be noted that this anthropometric measure is a poor instrument since it cannot distinguish between subcutaneous and visceral fat. We conclude that presumably the body fat changes currently observed in HIV-infected patients is the net result of competing phenomena: on one side the natural history of lipohypertrophy as a result of HIV and HAART impact, and on the other side the physiological body fat changes observed in the aging population.

The treatment of HIV-1 infected patients with HAART has resulted in long-term suppression of viral replication and reduced progression to AIDS. However, the use of HAART has been associated with adverse effects, including metabolic dysregulation and changes in body fat deposition. This syndrome, known as HIV/HAART-associated lipodystrophy syndrome, is characterized by insulin resistance, dyslipidemia, lipodystrophy, and increased visceral adiposity, which contribute to an increased risk of cardiovascular disease amongst these patients. The thiazolidinediones are a class of agonists for the nuclear receptors, the peroxisome proliferator-activated receptor. Since peroxisome proliferator-activated receptor is critically involved in the regulation of insulin sensitivity and lipid metabolism, a number of clinical trials have analyzed whether thiazolidinediones could ameliorate the signs of HIV/HAART-associated lipodystrophy syndrome. Based on these trials, thiazolidinediones appear to up-regulate peroxisome proliferator-activated receptor-dependent genes such as adiponectin, an effect that could have important physiological benefits in the long-term for HIV/HAART-associated lipodystrophy syndrome patients. Critically, many of the studies were of short duration and thus the beneficial effects of thiazolidinediones might have been missed. In addition, the few studies on the thiazolidinedione pioglitazone showed a beneficial effect on limb fat mass that was not associated with a pro-atherogenic lipid profile. Based on these studies, a large-scale clinical trial of pioglitazone use in HIV/HAART-associated lipodystrophy syndrome patients is warranted.

Background and Aims: We tested the effects of recombinant insulin-like growth factor-I (IGF-I) in an adipocyte model of HIV lipodystrophy and in an open label study on body composition and metabolism in patients with HIV lipodystrophy., Methods: The effects of IGF-I on ritonavir-induced adipocyte cell death were studied in vitro. We assessed lipid accumulation, IGF signaling, apoptosis, and gene expression. We conducted a 24-week open label trial of recombinant IGF-I in ten adults with HIV associated lipoatrophy. Laboratory assessments included glucose, insulin, lipids, and IGF-I. At weeks 0 and 24, body composition studies were performed including skinfold measurement, dual-energy x-ray absorptiometry, and computed tomography of the abdomen and thigh., Results: In vitro, ritonavir increased delipidation and apoptosis of adipocytes, whereas co-treatment with IGF-I attenuated the effect. In the clinical study, subcutaneous adipose tissue did not increase in patients after treatment with IGF-I; however, there was a decrease in the proportion of abdominal fat (39.8 ± 7% vs. 34.6 ± 7%, p = 0.007). IGF-I levels increased with treatment (143 ± 28 μg/L at week 0 vs. 453 ± 212 μg/L at week 24, p = 0.002), whereas IGFBP-3 levels declined (3.554 ± 1.146 mg/L vs. 3.235 ± 1.151 mg/L, p = 0.02). Insulin at week 12 decreased significantly (90.1 ± 39.8 pmol/L vs. 33.2 ± 19.6 pmol/L, p = 0.002). There was a nonsignificant decrease in visceral adipose tissue (155.2 ± 68 cm² at week 0 vs. 140.6 ± 70 cm² at week 24, p = 0.08)., Conclusions: Use of recombinant IGF-I may lower fasting insulin and abdominal fat in patients with lipoatrophy associated with HIV infection. Further evaluation of this agent for treatment of HIV-associated lipodystrophy may be warranted., (Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.)

Leptin is an adipocyte-secreted hormone that has been proposed to regulate energy homeostasis as well as metabolic, reproductive, neuroendocrine, and immune functions. In the context of open-label uncontrolled studies, leptin administration has demonstrated insulin-sensitizing effects in patients with congenital lipodystrophy associated with relative leptin deficiency. Leptin administration has also been shown to decrease central fat mass and improve insulin sensitivity and fasting insulin and glucose levels in HIV-infected patients with highly active antiretroviral therapy (HAART)-induced lipodystrophy, insulin resistance, and leptin deficiency. On the contrary, the effects of leptin treatment in leptin-replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. Similarly, experimental evidence suggests a null or a possibly adverse role of leptin treatment in nonlipodystrophic patients with nonalcoholic fatty liver disease. In this review, we present a description of leptin biology and signaling; we summarize leptin's contribution to glucose metabolism in animals and humans in vitro, ex vivo, and in vivo; and we provide insights into the emerging clinical applications and therapeutic uses of leptin in humans with lipodystrophy and/or diabetes.

Highly active antiretroviral therapy (HAART) has considerably improved the prognosis of HIV-infected patients. However, prolonged use of HAART has been related to long-term adverse events that can compromise patient health such as HIV-associated lipodystrophy syndrome (HALS) and nonalcoholic fatty liver disease (NAFLD). There is consistent evidence for a central role of mitochondrial dysfunction in these pathologies. Nucleotide reverse transcriptase inhibitors (NRTIs) have been described to be mainly responsible for mitochondrial dysfunction in adipose tissue and liver although nonnucleoside transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) have also showed mitochondrial toxicity, which is a major concern for the selection and the long-term adherence to a particular therapy. Several mechanisms explain these deleterious effects of HAART on mitochondria, and evidence points to other mechanisms beyond the "Pol- γ hypothesis." HIV infection has also direct effects on mitochondria. In addition to the negative effects described for HIV itself and/or HAART on mitochondria, HIV-infected patients are more prone to develop a premature aging and, therefore, to present an increased oxidative state that could lead to the development of these metabolic disturbances observed in HIV-infected patients.

Background: HIV lipodystrophy - characterized by peripheral lipoatrophy, with or without central fat accumulation - confers increased metabolic risk. However, the functional activity of HIV lipodystrophic tissue in relation to metabolic risk has yet to be fully explored in vivo through the use of non-invasive imaging techniques. This study assesses the relationship between FDG uptake in various fat depots and metabolic/immune parameters among subjects with HIV lipodystrophy., Methods: Lipodystrophic men on antiretroviral therapy underwent whole-body (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography scans and detailed metabolic/immune phenotyping., Results: FDG uptake in the subcutaneous adipose tissue (SAT) of the extremities (mean standardized uptake value [SUV] of the arm and leg SAT) was found to correlate with the degree of peripheral lipoatrophy (r=0.7; P=0.01). Extremity SAT FDG uptake was positively associated with homeostasis model assessment of insulin resistance (HOMA-IR; r=0.6; P=0.02) and fasting hyperinsulinaemia (r=0.7; P=0.01), while fat percentage of extremities was not. Furthermore, extremity SAT FDG uptake was significantly associated with CD4(+) T-cell count (r=0.6; P=0.05). In multivariate modelling for HOMA-IR, extremity SAT FDG uptake remained significant after controlling for body mass index and tumour necrosis factor-α (R(2) for model =0.71, P=0.02; SUV in the extremity SAT β-estimate 12.3, P=0.009)., Conclusions: In HIV lipodystrophic patients, extremity SAT FDG uptake is increased in association with reduced extremity fat and may contribute to insulin resistance. Non-invasive assessments of in situ inflammation using FDG-PET may usefully complement histological and gene expression analyses of metabolic dysregulation in peripheral fat among HIV-positive 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 β-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 β-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.

Objectives: To examine the relationship between human leukocyte antigen (HLA) genotype and body composition changes induced by thymidine analogue nucleoside reverse transcriptase inhibitor (NtRTI) use in HIV-positive individuals., Design: Data collected during the Simplification with Tenofovir-Emtricitabine (TDF-FTC) or Abacavir-Lamivudine (ABC-3TC) (STEAL) study were analysed to examine the potential association of HLA genotypes with changes in body composition in treatment-experienced HIV-positive individuals., Methods: Demographic, HIV-related, body composition and HLA genotyping data from the STEAL study were used in this analysis. The mean percentage peripheral fat at study baseline was compared in participants with and without prior NtRTI use. Analyses were also carried out for each HLA supertype strata, for five HLA genes, within the thymidine-exposed group. These comparisons were made using Mann-Whitney rank-sum tests., Results: Participants with prior NtRTI use had a significantly lower baseline mean peripheral fat percentage compared to those without NtRTI use (31.9 vs. 34.7%; P = 0.0045). However, participants carrying one or more of the three particular HLA supertype alleles, A01, B08 and DQ2, showed no significant difference in mean peripheral fat percentage at baseline by NtRTI use. Among participants with prior NtRTI exposure, there were significant differences in mean peripheral fat by HLA A01, B08 and DQ2 allele expression compared to those without expression of these alleles (A01: 34.91% vs. no A01: 30.3%; P = 0.0087; B08: 36.2% vs. no B08: 31.1%; P = 0.0317; DQ2: 35.16% vs. no DQ2: 30.06%; P = 0.0081)., Conclusion: This analysis suggests that HIV-infected individuals carrying HLA A01, B08 or DQ2 supertype alleles may be resistant to NtRTI-induced peripheral fat loss.

The highly active antiretroviral therapy (HAART) can cause a metabolic syndrome consisting of lipodystropy/lipoatrophy, dyslipidemia, and type 2 diabetes mellitus with an increased cardiovascular risk. The pathogenetic bases of HAART-associated lipodystrophy are poorly known. A genetic screen was used to evaluate proteins that are modulated in HIV-1-infected patients with or without lipodystrophy syndrome, that are routinely treated with HAART regimens. The most significant modulation was represented by FAP48 expression. Stable over-expression of FAP48 was able to alter, in vitro, adipogenesis, acting both on calcineurin and glucocorticoid pathways. Finally, we demonstrated that FAP48 over-expression was able to influence the capacity of some HIV drugs, Saquinavir and Efavirenz, but not Stavudine, Amprenavir, and Indinavir to inhibit adipocyte formation. In conclusion, this molecule could be a potential target for novel therapeutic approaches to the HAART related lipodystrophy in HIV patients., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: The association between HAART and lipodystrophy is well established, but lipodystrophy pathogenesis is still poorly understood. Drugs, and in particular protease inhibitors, accumulate in adipose tissue affecting adipocyte physiology and gene expression by several mechanisms. Recent studies have identified autophagy as another process affected by these classes of drugs, but no studies have been performed in adipose cells., Methods: SW872 preadipocytic human cell line was used to evaluate changes induced by amprenavir (APV), ritonavir (RTV), or atazanavir (ATV), all used at 10-200 μmol/l. A subline was stably transfected with murine stem cell virus (pMSCV)-enhanced green fluorescent protein (EGFP)-LC3 plasmid (to obtain a fluorescent LC3 protein) and treated with ATV at different doses. The distribution of LC3 and the colocalization of mitochondria, lysosome, and autophagosome were assessed by confocal microscopy. Transmission electron microscopy of ATV-treated cells was also performed. The cellular content of lysosomes was assessed using Lysotracker Green; apoptosis was evaluated by annexin V/propidium iodide staining, and mitochondrial superoxide anion (mtO2) was analyzed by mitoSOX red. Lysosomes, apoptosis, and mtO2 were studied by flow cytometry and multispectral imaging flow cytometry., Results: In SW872 cells, RTV caused massive apoptosis, more than autophagy, whereas APV was almost ineffective. ATV induced both apoptosis (high doses) and autophagy (low doses). ATV-treated cells displayed LC3-specific punctae, suggesting the formation of autophagosomes that enclosed mitochondria, as revealed by electron microscopy. At low doses, ATV promoted mitochondrial superoxide generation, whereas at high doses, it induced mitochondrial membrane depolarization., Conclusion: Autophagy/mitophagy can be considered a mechanism triggered by ATV in SW872 preadipocytes.

Patients with HIV-associated dyslipidemic lipodystrophy (HADL) have characteristic lipid kinetic defects: accelerated lipolysis, blunted fat oxidation and increased hepatic fatty acid reesterification. HADL patients with lipoatrophy also have leptin deficiency. Small or non-randomized studies have suggested that leptin replacement improves glucose metabolism in HADL, with very limited data regarding its effects on the lipid kinetic abnormalities. We performed a randomized, double-blind, placebo-controlled, dose-escalating (0.02 mg/kg/d for two months; 0.04 mg/kg/d for a further two months) study of the effects of metreleptin on lipid kinetics in 17 adults with HADL, hypertriglyceridemia and hypoleptinemia. Rates of lipolysis, intra-adipocyte and intrahepatic reesterification and fatty acid oxidation were measured using infusions of (13)C(1)-palmitate and (2)H(5)-glycerol, and indirect calorimetry. Fasting lipid profiles and glucose and insulin responses to oral glucose challenge were also measured. Metreleptin treatment induced significant, dose-dependent increases in fasting plasma leptin levels. There was no significant change in total lipolysis, net lipolysis, adipocyte or hepatic re-esterification or fatty acid oxidation, or in fasting triglyceride or HDL-C concentrations, with metreleptin treatment. Metreleptin decreased fasting non-HDL-C levels (P<.01) and area-under-the-curve for glucose (P<.05). In hypoleptinemic HADL patients, treatment with metreleptin at 0.02 or 0.04 mg/kg/d does not improve abnormal fasting lipid kinetics, or triglyceride or HDL-C levels. Metreleptin does, however, improve glycemia and non-HDL-C in these patients. These results suggest a dissociation between leptin's effects on glucose metabolism compared to those on lipid kinetics in HADL., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Context: The pathogenesis and function of dorsocervical sc adipose tissue (DSAT) accumulation in HIV-infected patients is not known. Previous investigations using either UCP-1 expression or positron emission tomography have been inconclusive as to whether this depot represents brown adipose tissue (BAT). We investigated DSAT gene expression, including DIO2, a deiodinase that contributes to increased thermogenesis in brown fat, and simultaneously determined [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) uptake in lipodystrophic HIV and healthy control subjects., Design: Thirteen HIV-infected and three non-HIV-infected men were recruited. HIV-infected subjects had evidence of significant lipodystrophy, including fat atrophy of the face, arms, and legs, and/or fat accumulation of the neck and abdomen. Subjects were cooled, followed by [¹⁸F]FDG positron emission tomography/computed tomography, fat biopsy of DSAT, and measurement of resting energy expenditure (REE). HIV-infected subjects were characterized as lipohypertrophic and lipoatrophic and compared., Results: Mean standardized uptake value of [¹⁸F]FDG and UCP-1 expression were not significantly different in DSAT among the groups. However, lipohypertrophic subjects demonstrated increased expression of DIO2 in DSAT compared with lipoatrophic subjects (P = 0.03). Among HIV-infected patients, DIO2 expression was strongly related to REE (r = 0.78, P = 0.002) and was a predictor of REE in multivariate modeling controlling for age, TSH, and lean body mass (r² = 0.79, P = 0.008). One control subject demonstrated typical BAT in the supraclavicular area., Conclusions: Adipose tissue accumulating in the dorsocervical area in HIV lipodystrophy does not appear to be classical BAT. However, DIO2 expression is increased in DSAT among patients with HIV lipodystrophy, particularly those with increased visceral adiposity, and is positively associated with energy expenditure.

Highly active antiretroviral therapy (HAART therapy) for HIV-1 infection has significantly increased the survival and quality of life of patients with this disease. However, in several epidemiological studies the onset of metabolic syndrome is a phenomenon reported to be extremely frequent. In the present study, genes involved in the molecular cascade responsible for the alteration of fat tissue and of lipid and glucose metabolism in patients with HIV-1 infection treated with antiretroviral therapy were identified. Towards this goal, hybridization using Atlas cDNA Expression Arrays allowed simultaneous monitoring of the expression levels of approximately 250 genes and identification of a panel of changes in relation to different therapeutic groups and in the presence of metabolic syndrome, with some genes being up-regulated, while others are down-regulated in the different subgroups of patients. The results of this analysis have shown a panel of transcriptional changes associated with oxidative stress mechanisms that provide a basis for further studies on understanding of mechanisms that, in vivo, are the foundation the metabolic disorders in patients with HIV infection.

Soluble urokinase plasminogen activator receptor (suPAR) is associated with inflammation and may predict lipodystrophy and dysmetabolism in human immunodeficiency virus (HIV)-infected individuals on antiretroviral therapy. We aimed to assess firstly, whether suPAR levels are elevated in treated and untreated HIV-1-infected Africans compared to uninfected controls at baseline and at a 3-year follow-up, and secondly whether suPAR levels are correlated with cardiovascular and/or metabolic changes. SuPAR, cardiovascular, and metabolic variables were assessed and the percentage change was determined. HIV-1-infected black South Africans had significantly higher suPAR levels than uninfected controls at baseline and at follow-up 3 years later. However, only the treated HIV-1-infected participants showed an increase in suPAR levels at follow-up. The treated group also showed signs of lipodystrophy and their baseline suPAR levels correlated positively with an increased waist circumference. This study indicates that suPAR levels increase and that baseline suPAR is associated with an increase in abdominal fat distribution in HIV-infected black Africans on antiretroviral therapy.

Obesity, type 2 diabetes, and HIV-associated lipodystrophy are associated with abnormalities in adipocyte growth and differentiation. In persons with these conditions, adipose depots contain increased numbers of macrophages, but the origins of these cells and their specific effects are uncertain. Peripheral blood mononuclear cells (PBMC)-derived monocytes, but not T cells, cocultured via transwells with primary subcutaneous preadipocytes, increased proliferation (approximately twofold) and reduced differentiation (~50%) of preadipocytes. Gene expression analyses in proliferating preadipocytes (i.e., prior to hormonal induction of terminal differentiation) revealed that monocytes down-regulated mRNA levels of CCAAT/enhancer binding protein, alpha (C/EBPα) and up-regulated mRNA levels of G0/G1 switch 2 (G0S2) message, genes important for the regulation of adipogenesis and the cell cycle. These data indicate that circulating peripheral blood monocytes can disrupt adipogenesis by interfering with a critical step in C/EBPα and G0S2 transcription required for preadipocytes to make the transition from proliferation to differentiation. Interactions between preadipocytes and monocytes also increased the inflammatory cytokines IL-6 and IL-8, as well as a novel chemotactic cytokine, CXCL1. Additionally, the levels of both IL-6 and CXCL1 were highest when preadipocytes and monocytes were cultured together, compared to each cell in culture alone. Such cross-talk amplifies the production of mediators of tissue inflammation.

Background: HIV-1 Tat protein has been shown to play multiple roles in the pathogenesis of AIDS; however, there is no information currently available on its effects on adipose tissue alterations. We have studied the effects of Tat on SGBS adipocytes to gain insight on its role on the development of lipodystrophy., Methods: SGBS preadipocytes were exposed to Tat during and after differentiation. Acquisition of adipocyte morphology, expression of gene markers of adipogenesis and inflammation, release of adipokines and cytokines to the medium, and glucose uptake were measured. The action of Tat on tumour necrosis factor (TNF)-α-regulated messenger RNA expression was determined in differentiated adipocytes. The capacity of rosiglitazone, resveratrol and parthenolide to influence the action of Tat was also assessed., Results: Tat treatment reduced the number of SGBS preadipocytes that acquired adipocyte morphology. It also led to repression of adipogenic gene expression and induced the coordinate expression and release of proinflammatory cytokines in human adipose cells. Moreover, combined treatment with Tat and TNF-α produced an additive effect on the repression of adipocyte genes. The observed effects of Tat on gene transcription in adipocytes were due, in part, to TNF-α that was secreted as a consequence of intracellular exposure to Tat., Conclusions: Tat impairs adipogenesis in human SGBS preadipocytes and increases the expression and release of proinflammatory cytokines. Positive crosstalk between Tat and TNF-α contributes to the anti-adipogenic and proinflammatory effects. HIV-1 Tat protein may play a role in the adipose tissue alterations that ultimately lead to lipoatrophy and systemic metabolic disturbances observed in HIV-1-infected patients.

The use of antiretroviral therapies has improved survival in people living with HIV to nearly normal rates. However, ongoing low-level HIV replication and incomplete immune recovery are associated with a chronic inflammatory stimulus. This increases several non-typically AIDS-related complications, including fat mass changes and metabolic conditions. Abdominal adiposity occurs as a result of complex interactions involving HIV itself, antiretroviral drug-associated factors, and several intermediary metabolic alterations and abnormal hormone levels. Abdominal adiposity in turn can further the metabolic derangements, and increase the risk of diabetes and cardiovascular disease. Abnormal growth hormone secretion plays a role in development of the fat depot changes. Effective long-term interventions to decrease central adiposity are limited but studies using growth hormone and especially growth hormone-releasing factor have shown encouraging results. Other emerging therapeutic options have been variably successful in the short term and the continuing clinical and therapeutic challenges will require ongoing investigation.

This cross-sectional study aimed to compare growth, nutritional status and body composition outcomes between a group of 94 HIV-infected children and adolescents on antiretroviral therapy (ART) and 364 healthy controls, and to evaluate their association with clinical and lifestyle variables within the HIV-infected group. When compared with the control group, HIV patients had higher risk of stunting (odds ratio [OR] 5.33, 95% confidence interval [CI]: 2.83-10.04) and thinness (OR 4.7, 95% CI: 2.44-9.06), higher waist-to-hip ratios (medians 0.89 versus 0.82 for boys and 0.90 versus 0.77 for girls, P < 0.001), and lower prevalence of overweight or obesity (OR 0.33, 95% CI: 0.14-0.78). Protease inhibitor usage was associated with thinness (OR 3.51, 95% CI 1.07-11.44) and lipoatrophy (OR 3.5, 95% CI 1.37-8.95). HIV-infected children on ART showed significant nutritional status and body composition abnormalities, consistent with the severity of vertical HIV infection and the consequences of prolonged ART.

Objective: The aim of the study was to determine circulating levels of fatty acid binding protein 4 (FABP-4) in a cohort of HIV-1-infected patients treated with combination antiretroviral therapy (cART) and to investigate the relationships between FABP-4 levels and insulin resistance, dyslipidaemia, lipodystrophy and levels of proinflammatory adipocytokines in these patients., Methods: A total of 282 HIV-1-infected patients treated with stable cART for at least 1 year (132 with lipodystrophy and 150 without) and 185 uninfected controls (UCs) were included in the study. Anthropometric parameters were determined. Plasma levels of FABP-4, soluble tumour necrosis factor receptors 1 and 2 (sTNF-R1 and sTNF-R2), interleukin-18 (IL-18), IL-6, adiponectin and leptin were also analysed. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). Subcutaneous adipose tissue mRNA expression of proinflammatory cytokines was assessed in 38 patients (25 with lipodystrophy and 13 without) by real-time polymerase chain reaction (PCR)., Results: The plasma FABP-4 concentration was significantly higher in patients with lipodystrophy than in those without (P=0.012). FABP-4 concentration was positively correlated with body mass index (BMI), HOMA-IR, and the concentrations of insulin, total cholesterol, triglycerides, sTNF-R1, leptin and IL-18, but showed a negative correlation with high-density lipoprotein (HDL) cholesterol and adiponectin concentrations. After adjusting for age, sex and BMI, the odds ratio (OR) for risk of lipodystrophy was found to be significantly increased for those with the highest levels of FABP-4 [OR 0.838, 95% confidence interval (CI) 0.435-1.616 for medium FABP-4 vs. OR 2.281, 95% CI 1.163-4.475 for high FABP-4]. In a stepwise regression model, FABP-4 was independently associated with HOMA-IR after controlling for clinical and inflammatory parameters (P=0.004). Moreover, a positive relationship was observed in patients with lipodystrophy between subcutaneous adipose tissue CD68 expression and FABP-4 plasma levels (r=0.525; P=0.031)., Conclusions: cART-treated HIV-1-infected patients with lipodystrophy have a systemic overproduction of FABP-4, which is closely linked to insulin resistance and inflammatory markers in subcutaneous adipose tissue., (© 2011 British HIV Association.)

Objective: To study the changes of body composition in females patients with human immunodeficiency virus (HIV)-related lipodystrophy (LD) syndrome (HIV-LD)., Methods: Totally 25 female patients who were treated in our hospital from January 2002 to December 2009 were divided into LD group and non-LD group based on the existence of LD. All these patients were receiving highly active antiretroviral therapy (HAART). In addition, 12 healthy women were set as the controls. Total and regional body composition were measured by dual X-ray absorptiometry in all three groups., Results: The fat mass (FM) was correlated negatively with the duration of HAART (r=-0.431, P=0.029). Multiple linear regression analysis showed that FM had positive correlation with weight and negative correlation with lean mass (LM) (r = - 0. 973, P =0. 000). Total, trunk and leg FM were significantly lower in LD patients than that in controls (P <0.05).Meanwhile, total, trunk and leg bone mineral contents were statistically lower in LD patients than that in controls (P <0. 05). Lumbar bone mineral density of LD patients was lower than that of non-LD patients and controls, and there was significant difference between LD patients and controls (P = 0. 001). LM of LD patients was higher than that of non-LD patients but without statistical difference (P > 0. 05)., Conclusions: The peripheral and central FM and bone mineral contents remarkably decrease in female patients with HIV-LD. How-ever, HIV-LD patients tend to have higher LM than non-LD patients. .

Alterations of fat distribution and insulin resistance are associated with increased risk of metabolic derangements and cardiovascular disease. HIV-infected adult patients on antiretroviral treatment often show lipodystrophy, insulin resistance and hypoadiponectinemia, but data in children are controversial. We investigated serum adiponectin concentration in a cohort of HIV-infected youths, and we assessed the relationships with lipodystrophy and insulin resistance. We studied 36 HIV-infected patients (aged 5.0 - 19.4 years), and 171 healthy subjects (aged 4.9 - 17.9 years) for adiponectin measurements. All patients underwent body composition assessment by dual-energy x-ray absorptiometry, and an oral glucose tolerance test to determine the fasting insulin concentration, the insulin area under the curve (AUC), and the HOMA index. Adiponectin serum concentration was measured by an immunoenzymatic assay. Sixteen patients had central fat accumulation, 6 had peripheral lipoatrophy, 5 had a mixed phenotype, and the remaining 9 were non-lipodystrophic. Fasting insulin, insulin AUC, and HOMA index were significantly higher in patients with central fat adiposity and mixed phenotype than in the other two groups. The patients of the former two groups had adiponectin concentration much lower than healthy controls, and patients with peripheral lipoatrophy or normal phenotype had normal concentration. Low adiponectin concentration is associated to central fat and mixed lipohypertrophy, and to signs of insulin resistance in HIV-infected youths. Strict monitoring of metabolic and cardiovascular evolution should be performed in these patients.

HIV-1/highly active antiretroviral therapy-associated lipodystrophy syndrome (HALS) is an adipose tissue redistribution disorder characterized by subcutaneous adipose tissue lipoatrophy, sometimes including visceral adipose tissue hypertrophy and accumulation of dorsocervical fat ('buffalo hump'). The pathophysiology of HALS appears to be multifactorial and several key pathophysiological factors associated with HALS have been identified. These include mitochondrial dysfunction, adipocyte differentiation disturbances, high adipocyte lipolysis, and adipocyte apoptosis. These alterations in adipose tissue biology expand to involve systemic metabolism through alterations in endocrine functions of adipose tissue (via disturbed adipokine release), enhanced production of pro-inflammatory cytokines and excessive free fatty-acid release due to lipolysis. The deleterious action of some antiretroviral drugs is an important factor in eliciting these alterations in adipose tissue. However, HIV-1 infection-related events and HIV-1-encoded proteins also contribute directly to the complex development of HALS through effects on adipocyte biology, or indirectly through the promotion of local inflammation in adipose tissue., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Introduction: Human immunodeficiency vírus (HIV)-associated lipodystrophy syndrome (LS) includes body composition and metabolic alterations. Lack of validated criteria and tools make difficult to evaluate body composition in this group., Objective: The aim of the study was to compare different methods to evaluate body composition between Brazilians HIV subjects with (HIV+LIPO+) or without LS (HIV+LIPO-) and healthy subjects (Control)., Methods: in a cross-sectional analyses, body composition was measured by bioelectrical impedance analysis (BIA), skinfold thickness (SF) and dual-energy x-ray absorptiometry (DXA) in 10 subjects from HIV+LIPO+ group; 22 subjects from HIV+LIPO- group and 12 from Control group., Results: There were no differences in age and body mass index (BMI) between groups. The fat mass (FM) (%) estimated by SF did not correlate with DXA in HIV+LIPO+ group (r = 0,46/ p > 0,05) and had fair agreement in both HIV groups (HIV+LIPO+ =0,35/ HIV+ LIPO- = 0,40). BIA had significant correlation in all groups (p < 0,05) and strong agreement, meanly in HIV groups, for FM (HIV+LIPO+ = 0,79/ HIV+LIPO- = 0,85 / Control = 0,60) and for fat free mass (FFM) (HIV+LIPO+ = 0,93 / HIV+LIPO- = 0,92 / Control = 0,73)., Discussion: Total fat mass can be measured by BIA with good precision, but not by SF in HIV-infected patients with LS. Segmental BIA, triciptal SF, circumferences of arms, waist and legs maybe alternatives that need more studies.

Objective: antiretrovirals, especially thymidine-analogue nucleoside reverse transcriptase inhibitors (tNRTIs), may cause the mitochondrial damage in adipose tissue that has been associated with lipodystrophy development. HIV itself may damage blood cell mitochondria. However, the viral capacity to induce adipose tissue mitochondrial lesion is still a matter of doubt. We aimed to assess whether untreated HIV infection was associated with adipose tissue mitochondrial abnormalities., Design: : Single-site, cross-sectional, controlled observational and exploratory study without intervention., Methods: we included 24 uninfected controls and 18 HIV-infected patients with undetectable viral load and no clinical signs of lipodystrophy stratified as antiretroviral naive (n = 11) or at least 6-month antiviral-treated with a double NRTI combination, including lamivudine plus one tNRTI (n = 7). Subcutaneous adipose tissue was homogenated to determine mtDNA content by rtPCR and mitochondrial function per mitochondria through the spectrophotometric measurement of cytochrome c oxidase activity normalized by citrate synthase amount (COX/citrate synthase). Differences in mitochondrial parameters among groups were sought to determine the contribution of HIV and antiretrovirals to mitochondrial alterations., Results: compared with uninfected controls (arbitrarily assigned 100%), naive individuals presented a marked decrease in adipose tissue mtDNA content and COX/citrate synthase function (62 and 75% remaining content/activity, P < 0.001 and P < 0.05). Antiretrovirals did not increase this impairment (69 and 70% remaining content/activity, P < 0.05 compared to controls and P = not significant compared to naives). Additionally, molecular and functional mitochondrial parameters were positively correlated (P < 0.05)., Conclusion: in nonlipodystrophic HIV-infected naive patients, viral infection is associated with adipose tissue mtDNA decrease and mitochondrial dysfunction independently of antiretroviral treatment., (2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.)

Background: Mitochondrial DNA (mtDNA) influences metabolic diseases and perhaps antiretroviral therapy (ART) complications. We explored associations between European mtDNA haplogroups and metabolic changes among A5142 participants., Methods: Seven hundred and fifty-seven ART-naive patients were randomized to one of three class-sparing ART regimens including efavirenz and/or lopinavir/ritonavir with or without nucleoside reverse transcriptase inhibitors (NRTIs). Nonrandomized NRTIs included stavudine, tenofovir, or zidovudine, each with lamivudine. Fasting lipid profiles and whole-body dual-energy X-ray absorptiometry (DEXA) were performed. Nine European mtDNA haplogroups were determined for 231 self-identified non-Hispanic white individuals. Metabolic changes from baseline to 96 weeks were analyzed by haplogroup., Results: Median age was 39 years, 9% were women, and 37, 32, and 30 were randomized to NRTI-containing regimens with either efavirenz or lopinavir/ritonavir, and an NRTI-sparing regimen, respectively. Among NRTI-containing regimens, 51% included zidovudine, 28% tenofovir, and 21% stavudine. Compared with other haplogroups, mtDNA haplogroup I (N = 10) had higher baseline non-HDL cholesterol [160 mg/dl (interquartile range 137-171) vs. 120 mg/dl (104-136); P = 0.005], a decrease in non-HDL cholesterol over 96 weeks [-14% (-20 to 6) vs. +25% (8 to 51); P < 0.001], tended to have more baseline extremity fat, and had more extremity fat loss by DEXA [-13% (-13 to 12) vs. +9% (-13 to 26); P = 0.08] and lipoatrophy (50 vs. 20%; P = 0.04). Haplogroup W (N = 5; all randomized to NRTI-sparing regimens) had the greatest increase in extremity fat [+35.5% (26.8 to 54.9); P = 0.02]., Conclusions: Lipids and extremity fat were associated with European mtDNA haplogroups in this HIV-infected population. These preliminary results suggest that mitochondrial genomics may influence metabolic parameters before and during ART.

The aim of this study was to evaluate human immunodeficiency virus (HIV)-infected patient's body composition changes by dual-energy X-ray absorptiometry (DXA) and to analyze factors associated with lipodystrophy (LD). Total-body composition was measured by DXA in HIV-infected men and healthy men. HIV-infected men were divided into LD patients and non-LD patients according to whether they were complicated with LD. Healthy men were selected as controls. Fat mass (FM) of HIV-infected patients correlated negatively with the duration of HIV infection and with the duration of highly active antiretroviral therapy regimen (r(s)=-0.448 and -0.563; p=0.032 and 0.000, respectively). Multiple linear regression results showed that FM had positive correlation with weight and bone mineral content (BMC) and had negative correlation with lean mass (LM). Total body and regional FMs were found to be significantly different among LD patients, non-LD patients, and controls-the lowest in LD patients and the highest in controls (p<0.05). Total body, trunk, and leg BMCs of LD patients were lower than those of controls (p<0.05). Lumbar bone mineral density of LD patients was lower than that of non-LD patients and controls (p=0.04 and 0.007). LM of LD patients was higher than that of non-LD patients, and trunk LM had statistical difference between the 2 groups (p=0.003). Applying DXA to assess HIV-infected patient's body composition changes could provide objective information for physicians to prevent LD and osteoporosis., (Copyright © 2011 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this prospective study was to compare changes in lipid metabolism and nutritional status after either 6 and 12 months of follow-up in subjects with lipodystrophy syndrome after traditional lifestyle therapy with or without fibric acid analogue intervention (bezafibrate and clofibrate)., Methods: Food intake, alterations in body composition and metabolic abnormalities were assessed in subjects with lipodystrophy syndrome at the beginning of the study. The nutritional status and metabolic alterations of the subjects were monitored, and the subjects received nutritional counseling each time they were seen. The subjects were monitored either two times over a period no longer than six months (Group A; n = 18) or three times over a period of at least 12 months (Group B; n = 35). All of the subjects underwent nutrition counseling that was based on behavior modification. The fibric acid analogue was only given to patients with serum triglyceride levels above 400 mg/dL., Results: After six months of follow-up, Group A showed no alterations in the experimental parameters. After twelve months, there was a decrease in serum triglyceride levels (410.4 ± 235.5 vs. 307.7 ± 150.5 mg/dL, p < 0.05) and an increase in both HDLc levels (37.9 ± 36.6 vs. 44.9 ± 27.9 mg/dL, p,0.05) and lean mass (79.9 ± 7.8 vs. 80.3 ± 9.9 %, p < 0.05) in Group B., Conclusion: After one year of follow-up (three sessions of nutritional and medical counseling), the metabolic parameters of the subjects with lipodystrophy improved after traditional lifestyle therapy with or without fibric acid analogue intervention.

Background: Uridine has been advocated for the treatment of HIV-1/HAART-associated lipodystrophy (HALS), although its metabolism in HIV-1-infected patients is poorly understood., Methods: Plasma uridine concentrations were measured in 35 controls and 221 HIV-1-infected patients and fat uridine in 15 controls and 19 patients. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Uridine was measured by a binary gradient-elution HPLC method. Analysis of genes encoding uridine metabolizing enzymes in fat was performed with TaqMan RT-PCR., Results: Median plasma uridine concentrations for HIV-1-infected patients were 3.80 µmol/l (interquartile range: 1.60), and for controls 4.60 µmol/l (IQR: 1.8) (P = 0.0009). In fat, they were of 6.0 (3.67), and 2.8 (4.65) nmol/mg of protein, respectively (P = 0.0118). Patients with a mixed HALS form had a median plasma uridine level of 4.0 (IC95%: 3.40-4.80) whereas in those with isolated lipoatrophy it was 3.25 (2.55-4.15) µmol/l/l (P = 0.0066). The expression of uridine cytidine kinase and uridine phosphorylase genes was significantly decreased in all groups of patients with respect to controls. A higher expression of the mRNAs for concentrative nucleoside transporters was found in HIV-1-infected patients with respect to healthy controls., Conclusions: HIV-1 infection is associated with a decrease in plasma uridine and a shift of uridine to the adipose tissue compartment. Antiretroviral therapy was not associated with plasma uridine concentrations, but pure lipoatrophic HALS was associated with significantly lower plasma uridine concentrations.

Objective: HIV-1-infected patients with lipodystrophy show insulin resistance, dyslipidemia and other signs of metabolic syndrome. Fibroblast growth factor-21 (FGF21) is a novel metabolic regulator that has been suggested to exert beneficial effects on metabolic homeostasis and insulin sensitivity. Our goal was to determine the relationship between FGF21 levels and metabolic alterations in these patients., Research Design and Methods: Serum FGF21 levels were analyzed in 179 individuals belonging to four groups: HIV-1-infected, antiretroviral-treated patients that have developed lipodystrophy (n = 59); HIV-1-infected, antiretroviral-treated patients without lipodystrophy (n = 45); untreated (naive) HIV-1-infected patients (n = 41); and healthy control individuals (n = 34). Serum FGF21 levels were correlated with parameters indicative of altered fat distribution, metabolic and cardiovascular risk, and in relation to HIV-1 infection and antiretroviral treatment regimens., Results: Serum FGF21 levels were increased in all HIV-1-infected patients, but the increases were most marked in those with lipodystrophy. FGF21 levels showed a strong positive correlation with indicators of lipodystrophy (trunk/apendicular fat ratio, waist-to-hip ratio), insulin resistance (fasting glucose, HOMA-R), dyslipidemia (low-density lipoprotein cholesterol), and liver injury (γ-glutamyltransferase)., Conclusions: FGF21 levels are increased in HIV-1-infected patients, especially in those with lipodystrophy, and this increase is closely associated with insulin resistance, metabolic syndrome and makers of liver damage. Further research will be required to determine whether the increase in FGF21 levels is caused by a compensatory response or resistance to FGF21, and to establish the potential of FGF21 as a biomarker of altered metabolism in HIV-1-infected, antiretroviral-treated patients.

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

Highly active antiretroviral therapy improves survival and growth in children with HIV infection. However, its use can be associated with adverse changes in body composition and metabolism. Bone mineral density can be adversely affected in HIV-positive children due to nutritional compromise or certain antiretrovirals. HIV-associated lipodystrophy, consisting of redistribution of adipose tissue, insulin resistance, and dyslipidemia, has also been described in children. Pediatric HIV patients may be at greater risk for these problems because of their longer potential lifetime exposure to these agents and because childhood is normally a period of rapid growth and tissue accretion. Healthcare providers for children with HIV infection must be aware of the potential complications associated with HIV antiretrovirals so that their antiviral efficacy can be balanced against their risk for side effects. In this review, we discuss the alterations in childhood growth and body composition that occur in HIV-infected children, and describe the impact of antiretroviral therapy on these outcomes. The problem of HIV-associated lipodystrophy syndrome in children is also discussed. Children with HIV should have their growth and body composition systematically monitored. Antiretroviral regimens should be tailored to optimize adherence and viral suppression while minimizing the potential for adverse side effects.

Objective: Thymidine reverse transcriptase inhibitors (tNRTI) are strong inhibitors of PPAR-gamma and clearly implicated as a cause of lipoatrophy. Thiazolidenediaones (TZD), potent PPAR-gamma agonists, would be expected to be beneficial in HIV lipoatrophy, but prior studies have been conflicting. None specifically excluded the use of tNRTIs. We report the first study in individuals treated with tNRTI-sparing regimens using a TZD for treatment of HIV lipoatrophy., Design: This double-blind, placebo-controlled study evaluated limb fat in HIV-infected individuals with lipoatrophy who discontinued tNRTI at least 24 weeks prior to enrollment., Methods: Individuals were randomized to rosiglitazone vs. placebo for 48 weeks. Dual energy X-ray absorptiometry (DEXA)-scans and fasting metabolic assessments were serially performed., Results: We enrolled 71 individuals, 17% were female and 51% white. Baseline characteristics were similar between groups except for higher total cholesterol in the placebo group (P = 0.04). At 48 weeks, limb fat (grams) increased significantly (P = 0.02) more in the rosiglitazone than in the placebo group: median (IQR) 448 (138, 1670) vs. 153 (-100, 682), respectively. Of lipids parameters, only total cholesterol increased significantly more in the rosiglitazone group (P = 0.008). Prevalence of metabolic syndrome and total bone mineral density did not change between or within groups., Conclusion: In the absence of tNRTI, rosiglitazone significantly improves lipoatrophy without deleterious effect on bone mineral density. Total cholesterol, but not triglycerides, significantly increased in the rosiglitazone arm. The glitazones may be a promising addition for accelerating fat recovery in individuals who had switched off tNRTI and remain with significant lipoatrophy.

The aim of this study was to define evolution profiles of body composition among human immunodeficiency virus (HIV)-infected men with lipodystrophy. The design is a retrospective analysis using observational data collected longitudinally. We included 101 HIV-infected men with lipodystrophy managed in routine practice and who had 2 dual energy X-ray absorptiometry scans within a minimum interval of 18 mo. Lipodystrophy was defined as a fat mass ratio (FMR, defined as the ratio of the percentage of the trunk fat mass over the percentage of the lower limbs fat mass) equal or superior to 1.5. Patients were classified in "improved" group (IG: increase of lower limbs fat mass >/= 10%) or "nonimproved" group (NIG). Body composition, immunovirological and epidemiological data were collected and compared between the 2 groups. In the whole population, over a 4-yr period, a significant increase was observed for total fat mass, trunk fat mass, and lower limbs fat mass, whereas total lean mass was stable. Total body mineral density decreased. Fifty-nine patients (IG), less exposed to zidovudine than the NIG, had an increase of lower limbs fat mass higher than 10%. But only 13 (22%) regained a normal distribution of fat mass (FMR < 1.5), showing that lipodystrophy was slowly reversible. Among the NIG, 5 patients (11.9%), less exposed to zidovudine and with a higher mean of viral load, reached an FMR below 1.5. It was mainly because of a loss of trunk fat mass, which could be the sign of a lipodystrophy worsening. Lipodystrophy improved for 58.4% of men. The improvement was very slow. Recovery was observed only in patients with an earlier intervention. No correlation was observed between lipodystrophy and total body bone mineral density. The loss of trunk fat mass without gain of lower limbs fat mass may indicate a worsening of HIV disease., (The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)