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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.

Introduction: With the introduction of combination antiretroviral therapy (ART) for HIV infection in the mid-1990s, descriptions of morphological changes and metabolic disturbances in treated patients began to emerge. HIV-1/highly active ART-associated lipodystrophy syndrome (HALS) involves metabolic abnormalities and diverse forms of anomalous fat distribution. The current review focuses on the pathophysiological basis and the clinical evidence for the use of several medical strategies in the management of HALS., Areas Covered: We have covered the most relevant studies related to the pharmacological strategies in the treatment of HALS, with attention to the current and novel antiretroviral agents., Expert Opinion: The most commonly used strategies for HALS reversion have included modification of host-dependent factors, including those related to HIV-1 infection and those associated with ART. Preventive and medical strategies have been associated with moderate success. The only intervention that offers an immediate aesthetical improvement for patients with HALS so far has been plastic surgery.

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.)

Objective: Lipodystrophy in HIV-1-infected antiretroviral-treated patients is often associated with opposite alterations in adipose tissue depots as follows: lipoatrophy of subcutaneous adipose tissue (SAT) versus lipohypertrophy of visceral adipose tissue (VAT). We determined the specific molecular alterations in VAT relative to SAT in patients., Design: We analyzed the expression of marker genes of mitochondrial function, adipogenesis, and inflammation in a unique collection of 8 biopsies of omental VAT from HIV-1-infected antiretroviral-treated patients with lipodystrophy. For comparison, we analyzed SAT from 10 patients, and SAT and VAT from 10 noninfected individuals., Methods: Quantitative real-time polymerase chain reaction of mitochondrial DNA and gene transcripts; immunoblot and multiplex for quantification of specific proteins., Results: Similar mitochondrial DNA depletion and abnormal increases in mitochondrial protein levels were found in VAT and SAT from patients. Transcript levels of adipogenesis and metabolism marker genes were unaltered in VAT but were decreased in SAT. Tumor necrosis factor α and CD68 were similarly induced in both adipose depots from patients, but other markers of inflammation-related pathways showed distinct alterations as follows: interleukin 18 and interleukin 1 receptor antagonist were induced only in SAT, whereas interleukin 6, interleukin 8, and monocyte chemoattractant protein 1 expression was reduced in VAT but not in SAT., Conclusions: Mitochondrial alterations are similar in VAT and SAT from patients, whereas adipogenic gene expression is decreased in SAT but unaltered in VAT, highlighting the relevance of adipogenic processes in the differential alterations of fat depots. Specific disturbances in inflammatory status in VAT relative to SAT are present. Milder induction of proinflammatory signaling in VAT could be involved in preventing fat wasting in this depot.

Objective: To study whether patients with HIV-1 associated lipodystrophy (LD) on highly active antiretroviral treatment (HAART) have more psychopathology and worse psychosocial adjustment than a similar group without this syndrome., Methods: In a cross-sectional, observational study we compared 47 HIV-1 infected patients with LD (LD group) with 39 HIV-1 infected patients without LD (non-LD group). All participants were on HAART. The Beck Depression Inventory (BDI), the State and Trait Anxiety Inventory (STAI) and the Goldberg Health Questionnaire (GHQ-60) were administered. Levels of familial, work and social adjustment and adjustment to stressful events were evaluated in a semi-structured interview. Clinical information was extracted from the clinical records., Results: In the univariate analysis patients with LD showed higher state anxiety scores (p=0.009) and worse work adjustment (p=0.019) than those without LD. A total of 45.3% of LD patients scored above the cut-off point on the trait anxiety scale, and over 33.3% scored above the cut-off point on the BDI, GHQ and state anxiety scales. However, in multivariate analyses LD was not independently associated with psychopathology or with worse adjustment in the studied areas., Conclusions: The finding that LD was not a predictor of greater psychopathology or worse psychosocial adjustment in HIV-1 infected patients, despite the high scores found, suggests that factors not taken into account in this study, such as LD severity and self-perception should have been included in the analysis. Further studies including a greater number of variables and a larger sample size will advance our understanding of this complex condition., (Copyright © 2013 Elsevier Editora Ltda. All rights reserved.)

More than 15 years after the introduction of highly active antiretroviral therapy, HIV/HAART-associated lipodystrophy syndrome still shadows the indisputable efficacy of antiretroviral therapy. Several issues related to this complication (prevalence, diagnosis, pathogenesis, prevention, or clinical management) have not been completely clarified. However, in the last years, substantial progress has been made in elucidating some of these basic aspects. This includes a better knowledge of the pathogenic mechanisms underlying HIV/HAART-associated lipodystrophy syndrome such as genetic host determinants, the impact of HIV infection per se, as well as the contribution of antiretroviral therapy. In regard to treatment, we have learned that certain drugs are especially prone to cause HIV/HAART-associated lipodystrophy syndrome (i.e. thymidine analogues). Pharmacological interventions to treat this condition have yielded mostly disappointing results, and the only intervention which offers an immediate aesthetical improvement for patients with HIV/HAART-associated lipodystrophy syndrome is plastic surgery. Even under the most favorable conditions (ideal host genetic make-up, and the timely initiation of HIV therapy with less toxic drugs), current data show that HIV/HAART-associated lipodystrophy syndrome is a complication of HIV infection and/or antiretroviral treatment that we are unable to avoid. In the context of HIV-1-infected patients under long-term antiretroviral therapy, fat toxicity is still the dark side of the rainbow.

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.)

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.

The development of efficacious antiretroviral drugs that minimize adverse effects is a current challenge in HIV-1 therapy. Metabolic alterations reminiscent of the metabolic syndrome and overt lipodystrophy appear often in HIV-1-infected patients undergoing antiretroviral treatment. The etiopathogenesis of these alterations is complex, but lipotoxicity has recently emerged as a key concept for explaining the metabolic syndrome in HIV-1-infected patients, similarly to what has been observed in diseases such as obesity and genetic lipodystrophies. Antiretroviral drugs from distinct drug families may directly elicit such lipotoxic phenomena, via increased lipolysis, enhanced adipocyte apoptosis and impaired adipogenesis, which collectively lead to a reduced capacity of subcutaneous adipose tissue to enlarge to meet fat storage requirements. Thus, fatty acids that cannot be properly stored as triglycerides in subcutaneous adipose tissue are expected to accumulate in visceral fat as well as in organs and tissues, such as the pancreas, muscle and liver, leading to the pattern of metabolic alterations associated with abnormal ectopic fat accumulation, mainly insulin resistance. Inflammatory responses, evoked by the combined effects of antiretroviral drugs and the underlying HIV-1 infection, also contribute to lipotoxicity, reflecting the action of pro-inflammatory cytokines that enhance lipolytic activity in adipose tissue and impair adipogenesis. Minimizing the lipotoxic action of antiretroviral drugs is ultimately essential in reducing metabolic alterations in treated patients. Moreover, pharmacological strategies that reduce lipotoxicity and promote adipose tissue expandability can be expected to ameliorate the overall metabolic abnormalities in HIV-1-infected, antiretroviral-treated patients.

Background: The link between human immunodeficiency virus/highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS) and the use of thymidine analogues has been well established. However, to our knowledge, no relationship has been proven between intracellular levels of stavudine (d4T) and HALS., Methods: We measured peripheral blood mononuclear cell intracellular levels of d4T-triphosphate (TP) in patients who were receiving d4T as part of their antiretroviral regimens. d4T-TP levels were determined by a validated liquid chromatography-tandem mass spectrometry assay method. The diagnosis of HALS was made in accordance with the criteria of a lipodystrophy severity grading scale. The Student t test, Pearson correlations, 1-way analysis of variance with Bonferroni correction, and stepwise logistic regression were used for statistic analyses., Results: This was a cross-sectional study. There were 33 patients: 17 with HALS and 16 without HALS. The median concentration of d4T-TP for patients with HALS was 20.60 femtomoles (fmol)/1 x 10(6) cells (interquartile range [IQR], 14.90-26.92 fmol/1 x 10(6) cells) and for patients without HALS was 13.85 fmol/1 x 10(6) cells (IQR, 8.65-20.15 fmol/1 x 10(6) cells) (P=.013). The median d4T-TP intracellular level in patients who had developed an AIDS-defining condition was 22.50 fmol/1 x 10(6) cells (IQR, 15.80-27.37 fmol/1 x 10(6) cells) and in those who had not was 14.40 fmol/1 x 10(6) cells (IQR, 10.80-20.40 fmol/1 x 10(6) cells) (P=.037). There were no statistically significant differences in d4T-TP intracellular levels with respect to the presence of metabolic syndrome, the clinical form of HALS (pure lipoatrophic vs mixed), the degree of facial lipoatrophy, the presence of hepatitis C virus infection, and the pair of nucleosides in HAART. d4T-TP levels correlated only with cumulative d4T exposure in time and dose. d4T-TP intracellular levels were independently associated with HALS (odds ratio, 1.58; 95% confidence interval, 1.08-2.32; P=.019)., Conclusions: Intracellular levels of d4T-TP are strongly associated with the development of HALS.

A subset of HIV-1-infected patients undergoing antiretroviral treatment develops a lipodystrophy syndrome. It is characterized by loss of peripheral subcutaneous adipose tissue (face, limbs, buttocks), visceral fat accumulation, and, in some cases, lipomatosis, especially in the dorsocervical area. In addition, these patients show metabolic alterations reminiscent of the metabolic syndrome, particularly dyslipidemia and insulin resistance. These alterations lead to enhanced cardiovascular risk in patients and favor the development of diabetes. Although a complex combination of HIV-1 infection and drug treatment-related events triggers the syndrome, lipotoxicity appears to contribute to the development of the syndrome. Active lipolysis in subcutaneous fat, combined with impaired fat storage capacity in the subcutaneous depot, drive ectopic deposition of lipids, either in the visceral depot or in nonadipose sites. Both hepatic steatosis and increased lipid content in skeletal muscle take place and surely contribute to systemic metabolic alterations, especially insulin resistance. Pancreatic function may also be affected by the exposure to high levels of fatty acids; together with direct effects of antiretroviral drugs, this may contribute to impaired insulin release and a prodiabetic state in the patients. Addressing lipotoxicity as a pathogenic actor in the lipodystrophy syndrome should be considered in strategies for treating and/or preventing the morphological alterations and systemic metabolic disturbances associated with lipodystrophy., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

Metabolic and morphologic abnormalities in persons with HIV remain common contributors to stigma and morbidity. Increased abdominal circumference and visceral adiposity were first recognized in the late 1990s, soon after the advent of effective combination antiretroviral therapy. Visceral adiposity is commonly associated with metabolic abnormalities including low HDL-cholesterol, raised triglycerides, insulin resistance, and hypertension, a constellation of risk factors for cardiovascular disease and diabetes mellitus known as "the metabolic syndrome". Medline and conference abstracts were searched to identify clinical research on factors associated with visceral adiposity and randomized studies of management approaches. Data were critically reviewed by physicians familiar with the field. A range of host and lifestyle factors as well as antiretroviral drug choice were associated with increased visceral adiposity. Management approaches included treatment switching and metformin, both of which have shown benefit for insulin-resistant individuals with isolated fat accumulation. Testosterone supplements may also have benefits in a subset of individuals. Supra-physiological doses of recombinant human growth hormone and the growth hormone releasing hormone analog tesamorelin both significantly and selectively reduce visceral fat over 12-24 weeks; however, the benefits are only maintained if doping is continued. In summary, the prevention and management of visceral adiposity remains a substantial challenge in clinical practice.

Background: Lipodystrophy in HIV type-1 (HIV-1)-infected patients is the consequence of effects originating from antiretroviral treatment and HIV-1 infection. We have studied adipose tissues and circulating parameters in mice bearing the HIV-1 transgene as a model to provide insight into the role of HIV-1-infection-related events in fat alterations., Methods: Heterozygous transgenic mice expressing a 7.7 kb HIV-1 construct (Tg26+/-) were used. Cytokine and adipokine levels were quantified using multiplex procedures. Gene expression and mitochondrial DNA abundance in visceral and subcutaneous white adipose tissues and in brown fat were determined using quantitative real-time PCR., Results: The amount of visceral, but not subcutaneous, adipose depot was lower in Tg26+/- mice. Serum proinflammatory cytokine levels were increased in Tg26+/- mice, whereas adiponectin and leptin levels were reduced. Gene expression of monocyte chemoattractant protein-1 was induced in visceral and subcutaneous fat, whereas tumour necrosis factor-α and interleukin-6 were induced in visceral and subcutaneous white adipose tissues, respectively. Adiponectin and leptin gene expression was repressed in all white fat depots, in concert with reduced expression of peroxisome proliferator-activated receptor γ, a master controller of adipogenesis. In brown fat, a coordinate induction in the expression of thermogenesis marker genes was observed., Conclusions: HIV-1 transgene expression in mice causes changes in adipose tissue reminiscent of those in patients with HIV-1 lipodystrophy, particularly early pretreatment changes. These data support a role for HIV-1-infection-related events in eliciting adipose tissue dysfunction. The Tg26+/- mouse appears as a promising model to assess the effects of HIV-1 infection on adipose tissue and for determining the effects of antiretroviral drugs on an HIV-1-infected background.

Background: Nucleoside reverse-transcriptase inhibitor (NRTI)-related mitochondrial toxicity has been suggested as a key factor in the induction of antiretroviral-related lipoatrophy. This study aimed to evaluate in vivo the effects of NRTI withdrawal on mitochondrial parameters and body fat distribution., Methods: A multicenter, prospective, randomized trial assessed the efficacy and tolerability of switching to lopinavir-ritonavir plus nevirapine (nevirapine group; n = 34), compared with lopinavir-ritonavir plus 2 NRTIs (control group; n = 33) in a group of human immunodeficiency virus-infected adults with virological suppression. A subset of 35 individuals (20 from the nevirapine group and 15 from the control group) were evaluated for changes in the mitochondrial DNA (mtDNA) to nuclear DNA ratio and cytochrome c oxidase (COX) activity after NRTI withdrawal. Dual-energy X-ray absorptiometry (DEXA) scans were used to objectively quantify fat redistribution over time., Results: The nevirapine group experienced a progressive increase in mtDNA content (a 40% increase at week 48; P = .039 for comparison between groups) and in the COX activity (26% and 32% at weeks 24 and 48, respectively; P = .01 and P = .09 for comparison between groups, respectively). There were no statistically significant between-group differences in DEXA scans at week 48, although a higher fat increase in extremities was observed in the nevirapine group. No virologic failures occurred in either treatment arm., Conclusions: Switching to a nucleoside-sparing regimen of nevirapine and lopinavir-ritonavir maintained full antiviral efficacy and led to an improvement in mitochondrial parameters, which suggests a reversion of nucleoside-associated mitochondrial toxicity. Although DEXA scans performed during the study only revealed slight changes in fat redistribution, a longer follow-up period may show a positive correlation between reduced mitochondrial toxicity and a clinical improvement of lipodystrophy.

Body fat disorders are a common and relevant problem in HIV-1-infected patients that can be associated with metabolic alterations. Many controversies in their definition, pathogenesis, measurement, and management remain unclear. Several factors including HIV-1 infection itself and antiretroviral therapy have been associated with the development of these alterations. Most studies show that the action of drugs on the pathogenesis of lipoatrophy is undeniable. However, they also show that there are considerable differences not only between the different families of antiretroviral drugs, but also between the individual members of these families. The diagnosis of lipodystrophy is limited by the absence of an agreed definition and a reference for normality. Accurate diagnosis, especially in mild-moderate cases, is difficult, almost always subjective, not standardized, and cannot be carried out by a single method. In general, subjective evaluation by the physician and patient, together with simple techniques such as anthropometry, can provide highly valuable information, especially when used over time. Although there is no known therapy to completely reverse lipodystrophy once it becomes established, there is evidence that lipoatrophy can be partially improved by replacing thymidine analogs in certain cases. In addition, reparative surgery may prove useful in moderate or severe cases. Neither the interruption of antiretroviral therapy nor the use of metformin, glitazones or growth hormone analogs can be recommended due to their limited efficacy or associated complications.

Highly active antiretroviral therapy plays a central role in the development of lipodystrophy syndrome, which may affect up to 50% of patients depending on the diagnostic criteria used. Most protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs) are involved in body fat changes and associated metabolic disturbances. In contrast, non-NRTIs have not been directly related to the onset of this syndrome. One of the most widely used methods to evaluate body fat changes is dual-energy X-ray absorptiometry (DEXA), which can detect differences in the distribution of body fat in patients with and without lipodystrophy. New information from a randomized open-label clinical trial suggests that efavirenz could have greater potential for causing lipoatrophy than lopinavir+ritonavir. This paper examines the impact of efavirenz on adipose tissue and body fat composition in order to evaluate whether this drug plays a role in the development of lipodystrophy. We have focused on the evidence obtained from comparative randomized clinical trials that use an objective measurement of fat distribution, such as DEXA. We analysed available in vitro data and evidence from non-comparative clinical trials.

We determined the IL-6 -174 G>C single nucleotide polymorphism, IL-6 mRNA expression in subcutaneous adipose tissue (SAT) and IL-6 plasma levels in HIV-1-infected patients with and without lipodystrophy and uninfected controls. HIV-1-infected patients had a greater prevalence of the IL-6 -174 C/C genotype and the C allele, higher SAT IL-6 mRNA expression and plasma IL-6 levels than controls. The IL-6 -174 G>C genotype distribution and allele frequencies, SAT IL-6 mRNA expression and IL-6 plasma levels were non-significantly different between HIV-1-infected patients with and without lipodystrophy.

Objective: To elucidate the molecular basis of the progressive enlargement of dorso-cervical adipose tissue, the so-called 'buffalo hump', that appears in a sub-set of patients with HIV-1/HAART-associated lipodystrophy., Design: Analysis of the expression of marker genes of mitochondrial function, adipogenesis, inflammation and cell proliferation in ten 'buffalo hump' samples and ten subcutaneous fat samples from HIV-1-infected/HAART-treated patients, and in ten healthy controls., Methods: Quantitative real-time polymerase chain reaction analysis of mitochondrial DNA and gene transcripts, and immunoblot for specific proteins., Results: 'Buffalo hump' patients had lower levels of mitochondrial DNA and mitochondrial DNA-encoded transcripts with respect to healthy controls. The uncoupling protein (UCP)-1 gene was expressed only in 'buffalo hump' fat. There were no significant changes in the expression of UCP2, UCP3 or of marker genes of adipogenesis in 'buffalo hump' patients relative to healthy controls. 'Buffalo hump' fat did not show the high expression of tumor necrosis factor-alpha and beta2-microglobulin identified in lipoatrophic subcutaneous fat from patients. The expression of the macrophage marker CD68 was also lower in 'buffalo hump' than in subcutaneous fat from patients. In contrast, 'buffalo hump' showed a higher expression of the cell proliferation marker PCNA., Conclusions: 'Buffalo hump' adipose tissue shows specific disturbances in gene expression with respect to subcutaneous fat from HIV-1-infected/HAART-treated patients. Mitochondrial alterations cannot explain the differential behavior of 'buffalo hump' with respect to adipose depots prone to lipoatrophy. The absence of a local inflammatory status in 'buffalo hump' may explain in part the differential behavior of this adipose tissue.

HIV-1/highly active antiretroviral therapy-associated lipodystrophy syndrome (HALS) is presently the most common long-term adverse effect limiting the doubtless efficacy of antiretroviral therapy. It has a great impact on the quality of life of patients, it is stigmatising and its psychologically devastating consequences may ultimately impact on the adherence to treatment of patients, eventually leading to treatment failure. Despite considerable advances in recent times, the pathogenesis of HALS remains elusive. Factors involved belong to three categories: those intrinsic to the host, some of them modifiable and some not, those associated with antiretroviral therapy, that are sometimes modifiable as well, and finally those related to HIV-1 infection and its consequences, most often not modifiable. The most commonly used strategies for HALS reversion have included host-dependent factors such as lifestyle and dietary modifications and antiretroviral-dependent factors such as switching or avoiding the use of drugs more prone to promote HALS. Lifestyle modifications and switching thymidine analogues have been associated with moderate success. Pharmacological interventions have included the use of insulin-sensitising agents and hormone therapy with disappointing results, whereas treatment with pravastatin or pioglitazone, and uridine supplementation seem to be associated with fat gain in preliminary studies. The only interventions with almost immediate results that may render a patient's appearance similar to his past one have included filling techniques for facial lipoatrophy and ultrasound-assisted liposuction for cervical fat pad hypertrophy. Among the filling options, semipermanent reabsorbable materials and autologous fat transfer have been associated with acceptable outcomes. As of now, the best hope should rely on the use of drugs friendly for fat, on defining the appropriate timing for starting antiretroviral and on continuing the research effort to understand the basic mechanisms underlying HALS pathogenesis. Only through this effort can the best chances for preventing or reverting established HALS be recognised.

Background: Nucleoside transporter proteins (NTs) encoded by members of the SLC28 and SLC29 gene families contribute to nucleoside and nucleobase recycling but also modulate extracellular adenosine levels and thus adenosine-regulated metabolic targets., Methods: We have examined the expression pattern of NT-encoding genes in human adipose tissue and we have further analysed whether the mRNA related to these genes show changes in their amounts associated with either HIV-1 infection, highly active antiretroviral therapy (HAART) or development of HIV-1-associated lipodystrophy syndrome (HALS)., Results: Human adipocytes express SLC28A1, SLC28A2 and SLC28A3 (encoding hCNT1, hCNT2 and hCNT3, respectively) and SLC29A1 and SLC29A2 (encoding hENT1 and hENT2, respectively). HIV-1 infection, prior to HAART and HALS development, is associated with the upregulation of the mRNA levels of the genes encoding hCNT1, hCNT3 and hENT2. The increase in the mRNA amounts for the former two genes may be due to the action of tumour necrosis factor-alpha (TNF-alpha), a cytokine with enhanced expression in adipose tissue following HIV-1 infection, as the effect is also observed in human adipocytes in culture after treatment with TNF-alpha. HAART and HALS development are associated with the upregulation of the mRNA levels encoding hCNT2 and hENT1, and further enhancement of hCNT1, hCNT3 and hENT2 gene expression., Conclusions: These data suggest that selected genes of the SLC28 and SLC29 families are not only targets of HIV-1 infection, but might also contribute to the development of adipose tissue alterations leading to lipodystrophy.

Lipodystrophy, and the metabolic alterations (dislipemia, insulin-resistance) associated with human immunodeficiency virus (HIV) infection, is a multifactorial syndrome due to the interaction of host related factors (cellular immune status, diet, gene mutations), viral factors (cytokine synthesis, polyunsaturated fatty acid or PUFA depletion), and pharmacological effects (mitochondrial DNA-polymerase inhibition, lipolysis inhibition, adiponectin synthesis reduction). HIV probably modifies the adipocyte differentiation and the lipid metabolism. This retroviral effect is mediated by proinflammatory cytokines (tumor necrosis factor) and the participation of other factors (drugs, diet), all in the context of a particular host genetic setting. The adipocyte (and several cellular receptors, fatty acids, membrane proteins, and cytokines) plays a central role in the pathogenesis of HIV-associated lipodystrophy.

Background: The aetiopathogenic bases of HIV-l-/highly active antiretroviral treatment (HAART)-associated lipodystrophy (HALS) are poorly known, but this syndrome indicates that adipose tissue is highly sensitive to either HIV-1 infection, antiretroviral drugs or their combination., Methods: To assess the relative contribution of infection and drugs, we compared the expression of marker genes corresponding to mitochondrial function, adipocyte differentiation and metabolism, and adipokines in subcutaneous adipose tissue from healthy controls, untreated HIV-1-infected patients, and HIV-1-infected patients treated with HAART with or without HALS., Results: Subcutaneous adipose tissue from HIV-1-infected patients contained lower concentrations of the mRNA of the mitochondrial DNA-encoded cytochrome c oxidase subunit II than that of controls. These concentrations decreased further in association with HAART. The expression of nuclear genes coding for mitochondrial proteins, peroxisome proliferator-activated receptor-y, and adipocyte-specific markers was reduced in HIV-1-infected patients, treated or not, with respect to the controls. In contrast, the mRNA concentrations of uncoupling protein-3 and preadipocyte factor-1 increased in lipody-strophic HAART-treated patients. The genes coding for adipokines were strongly affected: tumour necrosis factor-alpha was upregulated, whereas adiponectin and leptin were downregulated in HIV-1-infected patients, treated or not. Thus, substantial alterations of gene expression were already present when naive patients were compared with controls. Further changes were associated with HAART and with the diagnosis of HALS., Conclusions: Disturbances in adipose tissue gene expression are already present in untreated HIV-1-infected patients, thus indicating a role of HIV-1 infection itself in eliciting adipose tissue alterations that are worsened by HAART, which ultimately leads to HALS.

The lipodystrophy syndrome and associated metabolic alterations are the most prevalent adverse effects in HIV-infected patients taking highly active anti-retroviral therapy (HAART). This syndrome involves profound disturbances in adipose tissue. The toxic effect of nucleoside reverse transcriptase inhibitors on mitochondrial function is a major contributor to the lipodystrophy syndrome. Although adipocytes were not expected to be preferential targets of mitochondrial toxicity, recent re-evaluation of the role of mitochondria in white adipocytes helps to explain the molecular basis of HAART-associated lipodystrophy. Adipocytes are a source of paracrine and endocrine signals that influence adipocyte biology and systemic metabolism. Mitochondrial disturbances elicited by HAART result in an abnormal perception of the bioenergetic status by adipocytes, thus leading to enhancement of catalytic pathways and apoptosis in peripheral adipose tissue, alterations in the differentiation of brown versus white adipocytes, and the release of hormonal signals that lead to systemic metabolic disturbances.

Background: Hypertriglyceridaemia and insulin resistance are common in HIV-infected patients treated with protease inhibitors, particularly in those with lipodystrophy. Whether a therapeutic approach addressed to those metabolic abnormalities may have any impact on body fat is not clear., Methods: Patients on stable antiretroviral therapy containing protease inhibitors, with abdominal obesity defined by increased waist-to-hip ratio, and plasma triglycerides >200 mg/dl, were randomized to receive blind medication consisting of metformin 850 mg, gemfibrozil 600 mg or placebo every 12 h for 1 year. Weight, height, waist and hip were measured, and fasting blood analyses, including at least CD4 cell count, plasma HIV-1 RNA, lactate, glucose, insulin, triglycerides, total, HDL and LDL cholesterol were performed at baseline and every 3 months. An oral glucose tolerance test, and assessments of total and regional fat by bioimpedance analysis and sonography, respectively, were also done at baseline, 6 and 12 months., Results: One-hundred-and-eight patients were randomized to placebo (n=36), gemfibrozil (n=37) or metformin (n=35). There was absolute loss of total and regional fat in the three arms without significant changes in the waist-to-hip ratio. However, the loss of fat in patients on gemfibrozil was significantly lower than in patients on placebo. No patient discontinued study drugs due to adverse effects., Conclusion: In this population of HIV-infected patients, there was a loss of fat along time. The finding of relative preservation of fat associated with gemfibrozil therapy deserves further investigation in the search of potential effective therapies for lipodystrophy in HIV-infected subjects.

Objective: To compare body composition, serum lipid profile, parameters of insulin secretion and endocrine measurements in HIV-1-infected patients whose first combination antiretroviral regimen differed only in a nucleoside reverse transcriptase inhibitor (NRTI)., Design and Setting: Cross-sectional study in an AIDS clinic of a university hospital., Patients: One-hundred-and-fifty HIV-infected patients on long-term first highly active antiretroviral therapy including stavudine (n=75) or zidovudine (n=75)., Main Outcome Measure: Fat wasting was assessed by physical examination. Regional fat distribution was estimated using calliper measurements of skinfold thickness at four sites. Central adiposity was assessed by measurement of waist-hip ratio. Fasting glucose, insulin, triglyceride, cholesterol and its fractions, testosterone, follicle stimulating hormone, luteinizing hormone levels, CD4 cell count and HIV viral load were determined. Daily caloric intake and physical activity level were also calculated., Results: Total body fat was significantly lower in patients taking stavudine, whereas the lean body mass was not statistically different amongst both groups. Ninety-four patients (62.7%; 95% CI: 54.9-70.4%) had fat redistribution, being isolated lipoatrophy in 20 (13.3%; 95% CI: 7.9-18.8%), isolated lipohypertrophy in 33 (22.0%; 95% CI: 15.4-28.6%) and mixed syndrome in 41 (27.3%; 95% CI: 20.2-34.5%). There were not statistically significant differences between stavudine- and zidovudine-treated patients with respect to the overall prevalence of fat redistribution syndromes (P=0.34). The prevalence of lipoatrophy (OR=1.86; 95% CI: 0.58-6.33, P=0.37), lipohypertrophy (OR=0.65; 95% CI: 0.25-1.69, P=0.45) and mixed syndromes (OR=1.05; 95% CI: 0.43-2.54, P=0.93) was not statistically different in both groups of patients. The only independent predictor for the appearance of mixed syndrome and lipoatrophy was sedentarism (OR=4.418; 95% CI: 1.565-12.472, P=0.005) and (OR=4.515; 95% CI: 1.148-17.761, P=0.03), respectively. Independent predictors of lipohypertrophy were age (OR=1.138; 95% CI: 1.061-1.220, P<0.0001) and prior AIDS (OR=0.305; 95% CI: 0.100-0.931, P=0.04). There were no statistically significant differences between stavudine and zidovudine-based groups with respect to metabolic and hormonal parameters., Conclusion: The use of stavudine or zidovudine in the context of the first combination antiretroviral therapy is not associated either with an increased likelihood of lipid or gonadal hormones abnormalities, and although there was a trend to a lesser body fat content in the stavudine group, there was no increase in the overall likelihood of fat redistribution syndromes with respect to zidovudine group. Physical activity is a protective factor for the development of fat redistribution syndromes.

Objectives: Dyslipidaemia, insulin resistance, metabolic syndrome and HIV/HAART-associated lipodystrophy syndrome (HALS) are common comorbidities in HIV-1-infected patients, which may increase cardiovascular risk. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone with effects on metabolism and phosphate homeostasis. The aim of this study was to determine the relationship between FGF23 levels, metabolic alterations, fat distribution and cardiovascular risk. Methods: This was a cross-sectional study. Serum FGF23 levels were analysed in 152 patients and 34 healthy control individuals. Patients belonged to three groups: HIV-1-infected, antiretroviral-treated patients who have developed HALS (n=60); HIV-1-infected, antiretroviral-treated patients without HALS (n=43); and untreated (naive) HIV-1-infected patients (n=49). Serum FGF23 levels were compared with lipid and glucose homeostasis parameters, fat distribution and cardiovascular risk. Results: Serum FGF23 levels were increased in HIV-1-infected patients, but the increase was most marked in those with HALS. FGF23 levels showed a strong positive correlation with age, indicators of dyslipidaemia (LDL cholesterol, polyunsaturated fatty acids and monounsaturated fatty acids), HALS parameters (trunk/appendicular fat ratio), insulin resistance (fasting insulin and homeostasis model assessment of insulin resistance) and C-reactive protein. FGF23 levels correlated with cardiovascular risk but correlation was lost after age adjustment. Conclusions: FGF23 levels are increased in HIV-1-infected patients, especially in those with HALS, and this increase is associated with dyslipidaemia, insulin resistance, metabolic syndrome, fat distribution and parameters of inflammation. FGF23 is not associated with cardiovascular risk when age is taken into account. [ABSTRACT FROM AUTHOR]

Purpose: To assess in a cohort of Caucasian patients exposed to stavudine (d4T) the association of polymorphisms in pyrimidine pathway enzymes and HLA-B*40∶01 carriage with HIV/Highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS). Methods: Three-hundred and thirty-six patients, 187 with HALS and 149 without HALS, and 72 uninfected subjects were recruited. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Polymorphisms in the thymidylate synthase (TS) and methylene-tetrahydrofolate reductase (MTHFR) genes were determined by direct sequencing, HLA-B genotyping by PCR-SSOr Luminex Technology, and intracellular levels of stavudine triphosphate (d4T-TP) by a LC-MS/MS assay method. Results: HALS was associated with the presence of a low expression TS genotype polymorphism (64.7% vs. 42.9%, OR = 2.43; 95%CI: 1.53–3.88, P<0.0001). MTHFR gene polymorphisms and HLA-B*40∶01 carriage were not associated with HALS or d4T-TP intracellular levels. Low and high expression TS polymorphisms had different d4T-TP intracellular levels (25.60 vs. 13.60 fmol/106 cells, P<0.0001). Independent factors associated with HALS were(OR [95%CI]: (a) Combined TS and MTHFR genotypes (p = 0.006, reference category (ref.): ‘A+A’; OR for ‘A+B’ vs. ref.: 1.39 [0.69–2.80]; OR for ‘B+A’ vs. ref.: 2.16 [1.22–3.83]; OR for ‘B+B’ vs. ref.: 3.13, 95%CI: 1.54–6.35), (b) maximum viral load ≥5 log10 (OR: 2.55, 95%CI: 1.56–4.14, P = 0.001), (c) use of EFV (1.10 [1.00–1.21], P = 0.008, per year of use). Conclusion: HALS is associated with combined low-expression TS and MTHFR associated with high activity polymorphisms but not with HLA-B*40∶01 carriage in Caucasian patients with long-term exposure to stavudine. [ABSTRACT FROM AUTHOR]

Morphologic and metabolic abnormalities remain a common problem in patients with HIV-1 infection, which contributes to poor self image and may negatively impact on patient's adherence to medication and success of therapy. In addition, these physiological and metabolic changes can lead to increased cardiovascular risk. In such patients, excess central fat could be associated with loss of subcutaneous fat. Several strategies to decrease the excess of visceral fat have been assessed. Tesamorelin, an injectable growth hormone-releasing factor analogue, has been shown to improve visceral fat adiposity with relatively little effect on subcutaneous fat with improvement in triglycerides and belly appearance distress. It is well tolerated overall without clinically significant changes in mean glucose or insulin levels. However, these benefits cease if treatment is discontinued. INSET: Key issues. [ABSTRACT FROM AUTHOR]

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 mmol/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. [ABSTRACT FROM AUTHOR]