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In HIV-infected patients, combined antiretroviral therapy (cART) is associated to adipose tissue redistribution known as lipodystrophy and associated cardiometabolic risk. This study aimed to evaluate the evolution of body composition in HIV-infected patients, with and without lipodystrophy, over 2 yr. We evaluated anthropometric parameters and body composition by whole-body dual-energy X-ray absorptiometry in 144 HIV-infected patients on cART. We defined lipodystrophy by fat mass ratio. Lipodystrophy was present in 45.77% of the patients. These patients presented higher HIV infection duration, cART duration, and CD4+ cell count, with no differences regarding gender, age, body mass index, and viral load. Patients with lipodystrophy showed an increase in total fat mass (9.9%) and upper-limbs fat mass (17.6%), with a decrease in total, trunk, and lower-limbs fat-free mass (2.2%; 2.2%, and 3.9%, respectively), over 2 yr. In patients without lipodystrophy, the trunk fat-free mass decreased 1.9% over time, and no changes were observed in the other studied parameters. In patients with lipodystrophy, there was predominantly a central fat mass gain, with no changes in lower limbs, suggesting that peripheral adipocytes lose their regenerative capacity., (Copyright © 2016 International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

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.

Objective: To assess the role of HIV and monocytes/macrophages in adipose tissue dysregulation., Methods: Cross-sectional study in 5 groups: HIV seronegative, HIV+ antiretroviral therapy (ART)-naive, HIV+ nonlipoatrophic on zidovudine- and/or stavudine-containing ART, HIV+ lipoatrophic on similar ART, and HIV+ on abacavir- or tenofovir-containing ART. HIV DNA in circulating monocyte subsets was quantitated by real-time polymerase chain reaction. Biopsied subcutaneous fat was examined for macrophage content by CD68 staining. Isolated adipocytes and macrophages were cultured and the supernatant assayed for secretory products by Luminex multiplex cytokine technology., Results: Sixty-nine subjects were enrolled. Lipoatrophic subjects had higher median HIV DNA levels (270.5 copies/10 cells) in circulating peripheral CD14CD16 co-expressing monocyte subsets compared with subjects who were ART-naive (25.0 copies), nonlipoatrophic (15.0 copies), or on abacavir/tenofovir (57.5 copies), P < 0.01. Group differences in adipocytes and adipose macrophage content were marginal. Although adipocyte secretory products were similar, HIV-infected subjects had higher adipose macrophage-derived interleukin (IL)-12p40, IL-6, IL-8, and monocyte inflammatory protein 1 alpha and lower eotaxin and interferon gamma levels than HIV seronegative subjects (P < 0.05). Within HIV-infected subjects, adipose macrophage secretory products were comparable between subjects naive with ART versus those on ART., Conclusions: Circulating HIV-infected and proinflammatory CD14CD16 monocyte subsets contribute to the pathogenesis of HIV-associated lipoatrophy. Among HIV-infected individuals, macrophages, rather than adipocytes, are the primary source of low-grade inflammation in subcutaneous adipose tissue. HIV infection modifies these macrophages to a more proinflammatory phenotype, and these changes are not substantially mitigated by the use of ART.

Background: HIV/AIDS-Associated Lipodystrophy Syndrome includes changes in body fat distribution, with or without metabolic changes. The loss of fat from the face, called facial lipoatrophy, is one of the most stigmatizing signs of the syndrome., Objectives: To evaluate the effect of FL treatment using polymethylmethacrylate (PMMA) implants on disease progression, assessed by viral load and CD4 cell count., Methods: This was a prospective study of 44 patients treated from July 2009 to December 2010. Male and female patients, aged over 18 years, with clinically detectable FL and who had never been treated were included in the study. PMMA implantation was done to fill atrophic areas. Laboratory tests were conducted to measure viral load and CD4 count before and after treatment., Results: Of the 44 patients, 72.72% were male and 27.27% female, mean age of 44.38 years. Before treatment, 82% of patients had undetectable viral load, which increased to 88.6% after treatment, but without statistical significance (p = 0.67). CD4 count before treatment ranged from 209 to 1293, averaging 493.97. After treatment, the average increased to 548.61. The increase in CD4 count after treatment was statistically significant with p = 0.02., Conclusion: The treatment of FL with PMMA implants showed a statistically significant increase in CD4 count after treatment, revealing the impact of FL treatment on disease progression. Viral load before and after treatment did not vary significantly.

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.

Objective: The aim of the study was to evaluate the interleukin-17 (IL-17) plasma level in HIV-1-infected patients and its relation to central obesity., Methods: Eighty-four HIV-1-infected patients [42 with visceral obesity (group A) and 42 without visceral obesity (group B)] and 46 HIV-negative subjects [23 with visceral obesity (group C) and 23 without visceral obesity (group D)] were enrolled in the study. Sonographic measurements of perirenal fat diameter/body mass index (PRFD/BMI) were used to assess visceral adipose tissue thickness., Results: HIV-1-infected patients had higher plasma levels of IL-17 than HIV-negative subjects [837.8 ± 260 pg/mL (mean ± standard deviation) vs. 395.3 ± 138.6 pg/mL, respectively; P<0.001]. Furthermore, HIV-1-infected patients with a diagnosis of visceral obesity had lower levels of IL-17 than HIV-infected lean patients (756.9 ± 282.9 pg/mL vs. 918.7 ± 208.4 pg/mL, respectively; P<0.01). IL-17 (r= -0.21; P=0.03) and waist circumference (r=0.48; P<0.001) were significantly associated with visceral adipose tissue thickness. A negative correlation of IL-17 (r= -0.23; P<0.001) with PRFD/BMI was found., Conclusions: This study suggests a linear negative association between IL-17 and visceral adipose tissue thickness., (© 2012 British HIV Association.)

Highly active antiretroviral therapy (HAART) is associated with fat redistribution and metabolic disorders. The present study was undertaken to evaluate the association between peroxisome proliferator activated receptor (PPAR)α and PPARγ polymorphisms, two genes involved in lipid metabolism and adipocyte differentiation, and elements of the metabolic syndrome, lipodystrophy, or carbohydrate metabolism abnormalities in patients receiving HAART. The frequency distribution of rare alleles for PPARα (L162V) and PPARγ (P12A and H449H) was compared using the chi square test in 363 HIV-1-infected patients classified according to the presence or absence of the metabolic syndrome after 48 months of follow-up on their first PI-containing regimen. The P12A rare g allele was present in 12% patients with normal glucose metabolism, 11% patients with impaired glucose tolerance or impaired fasting glucose, and 35% patients with diabetes (p=0.014). The rare g allele for L162V was present in 14% of patients free of hypertriglyceridemia and in 7% patients with hypertriglyceridemia (p=0.04). The rare g allele for L162V was found in 15% of patients free of any sign of lipodystrophy and 8% with at least one sign of lipodystrophy (p=0.04) and the rare t allele for H449H was found in 14% of patients free of any sign of lipodystrophy and 23% of patients with at least one sign of lipodystrophy (p=0.05). There was no convincing association between any polymorphism of PPARα and PPARγ and each individual component of the metabolic syndrome, except for the relationship of the P12A polymorphism with diabetes. Confirmatory studies on a larger number of individuals are needed.

Background: The use of antiretroviral therapy (ART) in AIDS has been associated with lipodystrophic syndrome, which is characterized by metabolic alterations and abnormal corporal fat distribution. Our goal was to describe and evaluate the use of polymethylmethacrylate (PMMA) to treat lipoatrophy in patients with AIDS from Amazonas, Brazil., Methods: Patients with AIDS undergoing ART and presenting with facial lipoatrophy were invited to participate in the study. A face-to-face interview was conducted, and patients were treated with applications of PMMA 30%., Results: A total of 49 cases were included. The mean age was 45 (SD 6.1) years old, and the mean educational level (measured in schooling years) was 10.5 (SD 3.2) years of schooling. The median of CD4 cell count was 482.5 (interquartile range: 338-574.5) cells/mm(3) . Stavudine and zidovudine were the most frequently prescribed ART drugs. The total number of PMMA injections ranged from one to five times, and side effects were not frequent. A total of 42 (85.7%) patients reported satisfaction after a follow-up of more than 12 months, presenting good fullness of the deformity., Conclusions: Our data showed that patients with AIDS with lipoatrophy related to ART could safely benefit from PMMA-based treatment., (© 2011 The International Society of Dermatology.)

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.

Objective: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in extracellular matrix remodelling and adipocyte differentiation and are inhibited by antiretrovirals. MMPs and TIMPs and their single nucleotide polymorphisms (SNPs) might contribute to the HAART-related lipodystrophic syndrome pathogenesis., Design and Setting: Cross-sectional study in a university-based outpatient clinic., Patients and Methods: Two hundred and sixteen HIV-infected patients on extended HAART were studied. Serum MMPs (1, 2, 3, 8, 9, 10, 13) and TIMPs (1, 2, 4) were measured by ELISA microarrays. MMP1 (-16071G/2G) SNP was also genotyped. Lipodystrophic syndrome was diagnosed by a clinical scale validated by fat dual energy X-ray absorptiometry., Results: Eighty-two patients (38.0%) showed lipodystrophic syndrome, mostly lipoatrophy. The 2G/2G MMP1 SNP genotype was more frequent among lipodystrophic syndrome patients (41.3 vs. 20.5%, odds ratio, 2.73; 95% confidence interval, 1.41-5.29; χ² = 9.62, P = 0.002 for HIV-infected patients with and without lipodystrophic syndrome respectively). Carriers of this genotype had higher serum levels of MMP1 compared with those with the 1G/1G (P = 0.02). Higher MMP1 (P = 0.022) and lower TIMP4 (P = 0.038) serum levels were observed while comparing HIV patients with and without lipodystrophic syndrome. MMP1 2G carriage (P = 0.0008), TIMP4 lower serum levels (P = 0.02), treatment with stavudine (P < 0.0001), treatment with zidovudine (P = 0.006) and absence of hepatitis C virus coinfection (P = 0.002) were associated with lipodystrophic syndrome by logistic regression., Conclusion: MMP1 SNP, which induced increased serum levels of this protein, was associated with lipodystrophic syndrome.

Cytokines play important roles in the pathogenesis of lipodystrophy syndrome (LS). Single nucleotide polymorphisms (SNPs) at positions -607(C/A) and -137(C/G) in the promoter region of the interleukin-18 (IL-18) gene and at position +874(T/A) of the interferon-gamma (IFN-gamma) gene are related to the expression of these cytokines. To examine whether IL-18 and IFN-gamma polymorphisms are associated with LS, these SNPs were genotyped in 88 human immunodeficiency virus (HIV)-infected patients presenting LS, 79 HIV-infected without LS, and 133 healthy controls. The -607A allele, -607AA genotype, and -137G/-607A and -137C/-607A haplotypes in the IL-18 gene were over-represented in HIV patients presenting LS. The -137G/-607C haplotype was associated with protection against LS. These results indicate that the -607(C/A) SNP is associated with LS development in HIV-infected patients.

IL-18 is a pleiotropic and multifunctional proinflammatory cytokine that is often produced in response to a viral infection. The biological activities of the cytokine are tightly controlled by its natural antagonist, IL-18 binding protein (IL-18BP), as well as by activation of caspase-1, which cleaves the precursor form of IL-18 into its biologically mature form. The cytokine plays an important role in both innate and adaptive antiviral immune responses. Depending upon the context, it can promote TH1, TH2 and TH17 responses. Increased serum concentrations of IL-18 and concomitantly decreased concentrations of its natural antagonist have been described in HIV-infected persons as compared to HIV-seronegative healthy subjects. We discuss in this review article how increased biological activities of IL-18 contribute towards immunopathogenesis of AIDS, HIV-associated lipodystrophy syndrome and related metabolic disturbances. While the advent of potent anti-HIV drugs has significantly enhanced life span of HIV-infected patients, it has also increased the number of these patients suffering from metabolic disorders. The cytokine may prove to be a useful target for therapeutic intervention in these patients.

Objectives: To evaluate the impact on peripheral fat tissue of a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen in lipoatrophic HIV-1 infected patients., Methods: This 96-week prospective, randomized study compared lipoatrophic patients switched to an NRTI-sparing regimen with patients remaining on an NRTI-containing regimen. The primary endpoint was the change in thigh subcutaneous fat tissue volume between baseline and week 48, as assessed by computerized tomography., Results: One hundred patients were included, 50 in each arm. At baseline, patients had been on highly active antiretroviral therapy (HAART) for a median time of 6.6 years (4.9-9.7); 71% of the patients had received thymidine analogues [stavudine (37%), zidovudine (34%)]. The mean change in fat volume between baseline and week 48 significantly favoured the NRTI-sparing arm over the NRTI-maintaining arm in the intent-to-treat analysis, with a last-observation-carried-forward approach [+34 cm(3); 95% confidence interval (CI) 5-63 cm(3); P=0.002]. This was confirmed in the intent-to-treat analysis of available data, with a mean difference of +109 cm(3) (95% CI 34-185 cm(3)) at week 96 (n=53; P=0.001). This corresponded to increases of 12 and 30% in fat volume at weeks 48 and 96, respectively, in the NRTI-sparing arm., Conclusions: Switching from an effective NRTI-containing regimen to an NRTI-sparing regimen preserves immunovirological status and increases subcutaneous fat volume at weeks 48 and 96.

Before the introduction of successful antiretroviral therapy (ART), cardiovascular complications in HIV-infected patients were largely those resulting from immunosuppression (e.g. myocarditis, pericarditis, tamponade). With the advent of ART, there has been a spectacular decrease in morbidity and mortality in HIV-infected individuals. However, alongside metabolic complications caused by ART such as insulin resistance, dyslipidemia and lipodystrophy syndrome have been observed, which potentially increase the risk of cardiovascular complications, in particular coronary artery disease. Whether HIV infection and ART are independent and individual coronary risk factors is still controversial. More and more data are available demonstrating that increasing the duration of exposure to ART, and in particular protease inhibitors, increases the risk of myocardial infarction. At the same time, chronic infection, inflammation and the disruption of immune balance as a result of HIV infection itself may have the potential to alter vascular structure and function. In this article, we will review cardiovascular complications in HIV-infected patients before and after the advent of ART, focusing on coronary artery disease, its diagnosis, prognosis and therapy.

To assess the comparability of ultrasonographic (US) subcutaneous fat thickness (SFT) measurements in comparison with computed tomography (CT) at reference points (RPs) representative of HIV related adipose redistribution syndrome (HARS) in patients treated with antiretrovirals. US and CT measurements were compared in nine patients with clinical reports of HARS. We obtained the best resolution of facial (at deepest point of Bichat pad), brachial (in the dorsal face of arm) and crural SFT (at mid thigh) by means of minimal transducer pressures avoiding potential biases such as stand off pads pressure on the skin and artefacts due to too abundant quantity of gel. CT scans were obtained in the same RP where US measurements were performed such as identified by means of metallic skin markers. Median US measurement of facial SFT was 8.8 mm (95% CI: 3.1 to 13.4), 3.95 mm (95% CI: 2.62 to 5.84) for brachial SFT and 4 mm (95% CI: 3.4 to 9.4) for crural SFT. Median CT assessments of facial SFT was 8.7 mm (95% CI: 3.5 to 13.5), 4.2 mm (95% CI: 2.6 to 5.88) for brachial SFT and 5 mm (95% CI: 3.9 to 10.3) for crural SFT, with no significant difference at each RP. A linear regression showed good CT/US comparability at each RP, with no significant deviation from linearity (p > 0.10). US shows to be highly comparable with CT, excluding invaliding biases as the transducer pressure on the skin. Given the proven efficacy on the HARS assessments, if well standardized, US could be a reliable method, simpler than CT in the management of body fat changes related to HARS.

In this cross-sectional study, we sought to determine whether gene expression of macrophage markers and inflammatory chemokines in lipoatrophic subcutaneous abdominal adipose tissue and liver fat content are increased and interrelated in human immunodeficiency virus (HIV)-1-positive, highly active antiretroviral therapy (HAART)-treated patients with lipodystrophy (HAART+LD+; n = 27) compared with those without (HAART+LD-; n = 13). The study groups were comparable with respect to age, gender, and body mass index. The HAART+LD+ group had twofold more intra-abdominal (P = 0.01) and 1.5-fold less subcutaneous (P = 0.091) fat than the HAART+LD- group. As we have reported previously, liver fat was 10-fold higher in the HAART+LD+ compared with the HAART+LD- group (P = 0.00003). Inflammatory gene expression was increased in HAART-lipodystrophy: CD68 4.5-fold (P = 0.000013), tumor necrosis factor (TNF)-alpha 2-fold (P = 0.0094), chemokine (C-C motif) ligand (CCL) 2 2.5-fold (P = 0.0024), CCL3 7-fold (P = 0.0000017), integrin alphaM (ITGAM) 3-fold (P = 0.00067), epidermal growth factor-like module containing, mucin-like, hormone receptor-like (EMR)1 2.5-fold (P = 0.0038), and a disintegrin and metalloproteinase domain (ADAM)8 3.5-fold (P = 0.00057) higher in the HAART+LD+ compared with the HAART+LD- group. mRNA concentration of CD68 (r = 0.37, P = 0.019), ITGAM (r = 0.35, P = 0.025), CCL2 (r = 0.39, P = 0.012), and CCL3 (r = 0.54, P = 0.0003) correlated with liver fat content. In conclusion, gene expression of markers of macrophage infiltration and adipose tissue inflammation is increased in lipoatrophic subcutaneous abdominal adipose tissue of patients with HAART-associated lipodystrophy compared with those without. CD68, ITGAM, CCL2, and CCL3 expression is significantly associated with accumulation of liver fat.

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.

In this cross-sectional study, we evaluate potential predictors of Metabolic Syndrome (MS) in a group of 54 Caucasian chronically HIV-infected patients with lipodystrophy. According to ATP-III criteria, 22 patients were affected by MS and 32 were not. The mean age of the sample was 41.2+/-8.6 years, and most patients were males (74.1%); the two groups were homogeneous for gender, age, viro-immunologic status and the duration of antiviral therapy. The independent association between MS and several factors including demographic characteristics, type of highly-active antiviral therapy (HAART), viro-immunologic response, common cardiovascular risk factors (including Framingham scores), and selected cytokines (IFN-gamma, TNF-alpha, IL-2, IL-4, IL-6, IL-10 and IL-18), was investigated using stepwise forward logistic regression. At multivariate analysis, the only independent predictors of the metabolic syndrome were triglycerides and IL-18. A 10 mg/dL increase in triglycerides corresponds to an adjusted risk ratio for MS of 1.11 (95 percent IC: 1.04-1.19); and patients in the top tertile of IL-18 (those with IL-18 >/= 530 pg/L) had more than three times the likelihood of MS, as compared to the bottom and medium tertiles of IL-18 (patients with IL-18< 530 pg/L). This relationship was not attenuated by the inclusion of any other variable in the multivariate model. However, the association between metabolic syndrome and IL-18 is no longer significant when IL-18 is treated as a continuous variable (trend p = 0.087). Our results on HIV patients with lipodystrophy confirm previous findings on a strong independent association between IL-18 and MS in the general population. Further research is needed to clarify the mechanism of this association and its role in the development of cardiovascular disease in HIV patients.

Objective: An antiretroviral regimen based on lamivudine+stavudine+protease inhibitor impairs peripheral fat accrual in HIV-infected children and adolescents. We assess the effect on body composition parameters of replacing stavudine with tenofovir and protease inhibitor with efavirenz in paediatric patients., Methods: A 96-week prospective study on 24 patients, (age range: 5.0-17.9 years) with stable undetectable HIV-1 loads, who were switched from stavudine to tenofovir and from protease inhibitor to efavirenz. Patient assessment included: body composition parameters measured by dual-energy X-ray absorptiometry (DXA), viral load and CD4+ T-count and percentage. As a control group for DXA data, we studied 143 healthy controls (HCs; age range: 4.9-20.0 years)., Results: Virological suppression and unchanged CD4+ T-cell count and percentage were maintained in all patients. At baseline, patients showed decreased total, arm and leg fat masses (P < 0.01) but a similar trunk fat mass to HCs. From baseline to week 96, patient fat mass increases were comparable to those for HCs (total fat: 1.3 vs 1.2 kg; fat in arms: 0.09 vs 0.08 kg; fat in legs: 0.5 vs 0.5 kg; trunk fat: 0.6 vs 0.6 kg). However, at week 96, total and leg fat mass in patients were still significantly lower than those in HCs (P < 0.02). At baseline and at week 96, lean mass in patients was similar to that expected in HCs., Conclusions: Replacing stavudine with tenofovir and protease inhibitor with efavirenz for 96 weeks in lipoatrophic paediatrics patients led to a restoration of physiological fat accrual. Lipoatrophy did not progress but was still present, indicating the need for additional strategies.

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

Objectives: To evaluate the efficacy, overall esthetic effect, and safety of a new permanent, polyalkylimide dermal filler in HIV-infected patients with severe facial lipodystrophy., Methods: Eleven subjects with severe facial lipodystrophy secondary to HIV infection were injected bilaterally with 15 and 30 cm3 of a polyalkylimide gel into the buccal, malar, and temporal areas of the face in an attempt to restore their facial contour. The youngest treated subject was 31 years of age and the oldest 73 years of age., Results: All 11 subjects received an immediately acceptable therapeutic esthetic effect. Injections were generally well tolerated, with only three adverse events (swelling and bruising) recorded. Subjects, assessed at 3 and 18 months after treatment, continued to show improvement., Conclusions: The immediate benefits of a polyalkylimide gel in the correction and restoration of facial contour in subjects having severe HIV-related facial lipodystrophy were demonstrated. This improvement was still noted at 18 months. The efficacy, ease of injection, and safety profile of polyalkylimide gel make this filling material a potentially attractive treatment for lipodystrophy. These data must be tempered with the need for significant further safety studies to determine whether this long-term filler has a safety profile consistent with other currently popular fillers.

Objectives: Adipocytokines, secreted by adipose tissue, may regulate fat metabolism, lipid and glucose homeostasis and insulin sensitivity. We analysed the relations between circulating concentrations of adiponectin, leptin, interleukin-6, tumor necrosis factor alpha and its soluble receptors sTNFR1 and R2, lipodystrophic phenotypes and metabolic alterations in patients under highly active antiretroviral therapy (HAART)., Methods: We studied 131 consecutive HIV-infected males under protease inhibitor (PI)-based HAART, with body mass index < 27 kg/m2 and C-reactive protein (CRP) < 10 mg/l. Patients were classified in four groups according to clinical examination: no lipodystrophy (NL), lipohypertrophy (LH), lipoatrophy (LA) and mixed lipodystrophy (ML). In addition to adipocytokines, we measured plasma fasting levels of triglycerides, cholesterol, cardiovascular risk markers (high-sensitivity CRP and apolipoproteins B/A1 ratio), fasted and 2 h post-glucose loading glycemia and insulinemia and calculated the quantitative insulin sensitivity check index., Results: The patients were HIV-infected and PI-treated for a mean of 8.2 and 1.6 years respectively; 74% presented lipodystrophy, 38% altered glucose tolerance and 42% hypertriglyceridemia. Insulin sensitivity correlated positively with adiponectin and negatively with leptin and interleukin-6. Adiponectin, but not leptin, negatively correlated with all metabolic parameters. Insulin resistance, metabolic defects and cardiovascular risk markers were strongly negatively correlated with the adiponectin/leptin ratio (A/L), and positively with sTNFR1. LA patients had a longer duration of infection but ML patients presented the most severe metabolic alterations, insulin resistance and A/L decrease., Conclusions: These results suggest that adiponectin and the TNFalpha system are related to lipodystrophy, insulin resistance and metabolic alterations in patients under PI-based HAART. A/L and sTNFR1 could predict insulin sensitivity and potential cardiovascular risk in these patients.

The results of epidemiologic investigations have clearly indicated that the development of lipodystrophy is multifactorial. Factors related to HIV infection, hormonal influences, mitochondrial dysfunction, cytokine activation related to immune reconstitution, and individual genetic predisposition all have been hypothesized as etiologic. Recent studies suggest that immune dysregulation rather than HIV infection per se may be the predominant factor in the development of lipodystrophy.

To identify clinical factors associated with the incidence of HIV-1-associated lipoatrophy, HIV-1-infected patients in the HIV Outpatient Study (HOPS) were prospectively evaluated for clinical signs of lipoatrophy at two visits about 21 months apart. Development of lipoatrophy was analyzed in stratified and multivariate analyses for its relationship to immunologic, virologic, clinical, and drug treatment information for each patient. Of 337 patients with no lipoatrophy at Survey 1, 44 (13.1%) developed moderate or severe lipoatrophy between the two surveys. In multivariate analyses, significant risk factors for incident lipoatrophy were white race (OR = 5.2; 95% CI: 1.9-17.1; =.003), CD4 T-lymphocyte count at Survey 2 less than 100 cells/mm3 (OR = 4.2; 95% CI: 1.3-13.1; =.013), and body mass index (BMI) less than 24 kg/m2 (OR = 2.4; 95% CI: 1.1-5.4; =.024). Analyses that controlled for the severity of HIV illness demonstrated no significant association with use of or time on any antiretroviral agent or class of agents and the development of lipoatrophy. Some host factors and factors associated with previous or current severity of HIV infection, especially CD4 T-lymphocyte cell count, appeared to have the strongest association with incidence of lipoatrophy.

This multicentre, randomized, open-label, prospective trial is evaluating the effects of switching treatment from a protease inhibitor (PI)-containing regimen to one containing the non-nucleoside reverse transcriptase (RT) inhibitor nevirapine in human immunodeficiency virus (HIV)-infected patients with durable viral suppression but suffering from lipodystrophy. Objectives of this ongoing study are to evaluate the effects of this switch on changes in body shape and metabolic abnormalities associated with acquired HIV-related lipodystrophy syndrome (AHL), as well as on maintenance of viral suppression and immunological and psychological effects. Preliminary data involving 57 patients with 3 months of follow-up show an initial improvement of AHL in two regions, the face and arms. There is also a tendency toward improved cholesterol and triglyceride levels and improved quality of life among patients receiving the nevirapine-containing regimen. Maintenance of viral suppression was equivalent in both treatment groups. Additional data with longer follow-up are needed to confirm these results.