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Cytokines affect lipid and glucose metabolism and also alter the body's habitus. They play a role in the development of lipodystrophy syndrome. Adipocytes secrete the pro-inflammatory cytokines IL-1, TNF-α and IL-6. The plasma cytokine concentration is associated with the percentage and distribution of fat tissue in the body. The metabolic disturbances are strongly associated with increased levels of pro-inflammatory cytokines (IL-1, IL-6 and TNF-α). Plasma levels of cytokines such as TNF-α, IL-6 and leptin were found to be increased while plasma resistin levels were found to be variable in patients suffering from obesity and type II diabetes mellitus. Until now, limited information has been available on the polymorphism of cytokine and adipokine genes in patients of HIV-associated lipodystrophy (HIVLD), which can contribute to individual variations in susceptibility to metabolic diseases, especially to HIVLD. Hence, we studied the association of cytokine and adipokine gene polymorphisms in various diseases and their impact on HIVLD. We carry out an extensive search using several databases, including PubMed, EMBASE and Google Scholar. The distribution of cytokine and adipokine gene polymorphisms and their expression levels varied among various populations. We examined the variants of cytokine and adipokine genes, which can contribute to individual variations in susceptibility to metabolic diseases, especially to HIVLD. In the current review, we present a brief account of the risk factors of HIVLD, the pathogenesis of HIVLD and the polymorphism of cytokine and adipokine genes in various diseases with special reference to their impact on HIVLD., (© 2023 John Wiley & Sons Ltd.)

Introduction: Human immunodeficiency virus-related lipodystrophy is characterized by a variety of phenotypes and metabolic changes; however, consensus has not yet been reached on its diagnostic criteria. Different cutoff values for fat mass ratio have been proposed for this specific population as an objective diagnostic criterion for lipodystrophy. This study aimed to establish sex-specific reference values for fat mass ratio and to correlate them with anthropometric measurements for the diagnosis of human immunodeficiency virus-related lipodystrophy., Methodology: A cross-sectional study was performed on 189 human immunodeficiency virus-infected patients under antiretroviral therapy. Anthropometric measurements were evaluated, and body composition was determined using dual-energy X-ray absorptiometry. Fat mass ratio was calculated as the ratio of the percentage of the trunk fat mass and the percentage of the lower limb fat mass., Results: One hundred and thirty-two patients (69%) presented lipodystrophy by objective criteria. In men, the cutoff for the fat mass ratio was 1.55 (area under the receiver operating characteristic curve: 0.73 [95% confidence interval: 0.62-0.83], p = 0.000008), with a sensitivity of 62.5%, a specificity of 70.5%, a positive predictive value of 77.8%, and a negative predictive value of 53.4%. In women, the cutoff for the fat mass ratio was 0.959 (area under the receiver operating characteristic curve: 0.70 [95% confidence interval: 0.56-0.85], p = 0.03), with a sensitivity of 83.60%, a specificity of 61.5%, a positive predictive value of 90.2%, and a negative predictive value of 47.1%. Fat mass ratio was positively correlated with waist circumference (men: r = 0.246, p = 0.019; women: r = 0.302, p = 0.014) and neck circumference (men: r = 0.304, p = 0.004; women: r = 0.366, p = 0.003) in both sexes; and body mass index (r = 0.288, p = 0.006) and waist-hip ratio (r = 0.288, p = 0.006) in men., Conclusion: The fat mass ratio evaluated using dual-energy X-ray absorptiometry with the sex-specific cutoffs is an objective tool to define human immunodeficiency virus-related lipodystrophy., (Copyright © 2018. Published by Elsevier Inc.)

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.)

Despite achieving human immunodeficiency virus type 1 (HIV-1) RNA suppression below levels of detection and, for most, improved CD4+ T-cell counts, those aging with HIV experience excess low-level inflammation, hypercoagulability, and immune dysfunction (chronic inflammation), compared with demographically and behaviorally similar uninfected individuals. A host of biomarkers that are linked to chronic inflammation are also associated with HIV-associated non-AIDS-defining events, including cardiovascular disease, many forms of cancer, liver disease, renal disease, neurocognitive decline, and osteoporosis. Furthermore, chronic HIV infection may interact with long-term treatment toxicity and weight gain after ART initiation. These observations suggest that future biomarker-guided discovery and treatment may require attention to multiple biomarkers and, possibly, weighted indices. We are clinical trialists, epidemiologists, pragmatic trialists, and translational scientists. Together, we offer an operational definition of a biomarker and consider how biomarkers might facilitate progress along the translational pathway from therapeutic discovery to intervention trials and clinical management among people aging with or without HIV infection., (© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Noncommunicable conditions such as cardiovascular disease, hypertension, renal and bone diseases, and malignancies as well as infectious complications are an ongoing concern during the course of treated HIV disease. Research in this area continues to focus on the epidemiology and risk factors for these conditions, on identifying the contributions of HIV-related immunopathology to specific and collective end-organ diseases, and on evaluating interventions to prevent or reduce the morbidity associated with these conditions. Data presented at the 2016 Conference on Retroviruses and Opportunistic Infections provided new insights into all of these areas.

Context: HIV patients are at an increased risk for cardiometabolic disease secondary to depot-specific alterations in adipose function, but mechanisms remain poorly understood., Objective: The endoribonuclease Dicer has been linked to the modulation of brown and white adipocyte differentiation. We previously demonstrated that Dicer knockout mice undergo transformation of brown adipose tissue to white adipose tissue and develop a lipodystrophic phenotype. We hypothesized reduced Dicer and brown adipose tissue gene expression from nonlipomatous sc fat among HIV patients with a lipodystrophic phenotype., Design: Eighteen HIV (nine with and without lipodystrophic changes in fat distribution, characterized by excess dorsocervical adipose tissue [DCAT]) and nine non-HIV subjects underwent punch biopsy of abdominal sc fat to determine expression of Dicer and other adipose-related genes., Results: HIV subjects with long-duration antiretroviral use demonstrated excess DCAT vs non-HIV subjects (9.8 ± 1.0 vs 6.6 ± 0.8 cm(2), P = .02) with similar body mass index. Dicer expression was decreased in abdominal sc fat of HIV vs non-HIV (4.88 [1.91, 11.93] vs 17.69 [10.72, 47.91], P = .01), as were PPARα, ZIC1, PRDM16, DIO2, and HSP60 (all P ≤ .03). Moreover, the expression of Dicer (2.49 [0.02, 4.88] vs 11.20 [4.83, 21.45], P = .006), brown fat (PPARα [P = .002], ZIC1 [P = .004], LHX8 [P = .03], PRDM16 [P = .0008], PAT2 [P = .008], P2RX5 [P = .02]), beige fat (TMEM26 [P = .004], CD137 [P = .008]), and other genes (DIO2 [P = .002], leptin [P = .003], HSP60 [P = .0004]) was further decreased in abdominal sc fat comparing HIV subjects with vs without excess DCAT. Down-regulation of Dicer in the abdominal sc fat correlated with the down-regulation of all brown and beige fat genes (all P ≤ .01)., Conclusion: Our results demonstrate dysfunctional sc adipose tissue marked by reduced Dicer in relationship to the down-regulation of brown and beige fat-related genes in lipodystrophic HIV patients and may provide a novel mechanism for metabolic dysregulation. A strategy to increase browning of white adipose tissue may improve cardiometabolic health in HIV.

In the current study we explored the occurrence of adverse drug reactions (ADRs) to antiretroviral therapy among human immune-deficiency virus (HIV)/AIDS patients. We concluded an observational retrospective study in all patients who were diagnosed with HIV infection and were receiving highly active antiviral therapy from Jan. 2007 to Dec. 2012 at Hospital Pulau Pinang, Malaysia. Patient socio-demographic details along with clinical features and susceptible ADRs were observed during the study period. Out of 743 patients, 571 (76.9%) were men, and 172 (23.1%) were women. Overall 314 (42.2%) patients experienced ADRs. A total of 425 ADRs were reported, with 311 (73.1%) occurring in men and 114 (26.8%) in women, with a significant statistical relationship (P value (P) = 0.02, OR = 1.21). Overall 239 (56.2%) ADRs were recorded among Chinese, 94 (22.1%) in Malay, and 71 (16.7%) in Indian patients, which had a statistically significant association with ADRs (P = 0.05, OR = 1.50). Out of a total 425 among ADRs, lipodystrophy was recorded in 151 (35.5%) followed by skin rashes in 80 (18.8%), anemia in 74 (17.4%), and peripheral neuropathy in 27 (6.3%) patients. These findings suggest a need of intensive monitoring of ADRs in HIV treatment centres across Malaysia.

We evaluated retrospectively an automated method for the separate detection of subcutaneous and visceral fat in the abdominal region by magnetic resonance studies in HIV-positive patients on highly active antiretroviral therapy. The patients were divided into four different groups: lipoatrophy, lipohypertrophy, mixed and the control group. The use of software for the automated detection of abdominal compartment visceral adipose tissue (VAT), total adipose tissue (TAT) and subcutaneous adipose tissue (SAT) was compared to manual evaluation methods (fuzzy C-mean). The results of ROC analysis showed that the parameters, particularly the VAT, are better than the VAT/TAT and at identifying patients with the symptoms of abdominal fat accumulation. A sensitivity of 80.3% and a specificity of 79.5% resulted from a threshold VAT value of >87 cm(2). Moreover, the manual evaluation method was shown to provide greater values for VAT and the VAT/TAT ratio than those given by the automated method. In the present study, a rapid MRI protocol for the detection and assessment of the course of lipodystrophy was presented and tested on a group of patients with signs of HALS, as well as on an antiretroviral naïve control group., (© The Author(s) 2014.)

Very little information is available on the involvement of newly characterized adipokines in human immunodeficiency virus (HIV)/antiretroviral therapy (ART)-associated lipodystrophy syndrome (HALS). Our aim was to determine whether apelin, apelin receptor, omentin, RBP4, vaspin and visfatin genetic variants and plasma levels are associated with HALS. We performed a cross-sectional multicentre study that involved 558 HIV type 1-infected patients treated with a stable highly active ART regimen, 240 of which had overt HALS and 318 who did not have HALS. Epidemiologic and clinical variables were determined. Polymorphisms in the apelin, omentin, RBP4, vaspin and visfatin genes were assessed by genotyping. Plasma apelin, apelin receptor, omentin, RBP4, vaspin and visfatin levels were determined by enzyme-linked immunosorbent assay in 163 patients (81 with HALS and 82 without HALS) from whom stored plasma samples were available. Student's t test, one-way ANOVA, chi-square test, Pearson and Spearman correlations and linear regression analysis were used for statistical analyses. There were no associations between the different polymorphisms assessed and the HALS phenotype. Circulating RBP4 was significantly higher (p < 0.001) and plasma omentin was significantly lower (p 0.001) in patients with HALS compared to those without HALS; differences in plasma levels of the remaining adipokines were nonsignificant between groups. Circulating RBP4 concentration was predicted independently by the presence of HALS. Apelin and apelin receptor levels were independently predicted by body mass index. Visfatin concentration was predicted independently by the presence of acquired immunodeficiency syndrome. HALS is associated with higher RBP4 and lower omentin in plasma. These two adipokines, particularly RBP4, may be a link between HIV/ART and fat redistribution syndromes., (Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: This prospective observational study evaluated magnetic resonance imaging (MRI) findings of hyaluronic acid (HA) injections used for the correction of HIV-associated facial lipoatrophy., Methods: Ten consecutive males underwent subdermal HA injection (mean 1.3 ± 0.6 ml per side) and MRI examinations prior to and then 1, 6 and 12 months after injection. Two radiologists blinded to the clinical data assessed morphologic and quantitative changes., Results: MRI revealed HA deposition in the subdermal and deep fat compartments. A significant HA volume increase was observed 1 month after injection (mean increase 331%, p < 0.0001) as compared to the injected amount. No volume reduction occurred at 12 months (p = 0.9961). The measured bound water content did not change (p > 0.9991), whereas skin thickness and tissue vascularization increased during the first 6 months (p = 0.01)., Conclusion: Our data show that the cosmetic results of HA injections are caused by water binding in the deep facial fat and by a transient increase in vascularization and skin thickness.

Buffalo hump is a manifestation of HIV related lipodistrophy, it is characterized by an enlargment of dorsocervical fat pad and is distressing for patients. Surgical correction until a few years ago was the only option for treatment, however in last years non surgical corrections was carried out with minimally invasive techniques. Authors report this case that describe a longer follow up of an already published study were this deformity was treated with the injection of an adipocitolitic aqueous micro-gelatinous solution and during all the follow up no relapse was observed.

Objective: To describe magnetic resonance imaging (MRI) features of Kager's fat pad inflammation in HIV-positive patients with lipodystrophy due to protease inhibitor treatment and posterior ankle pain., Methods: A case-control, cross-sectional study; group 1 included 14 HIV-positive patients using protease inhibitors, presenting lipodystrophy syndrome and having posterior ankle pain; group 2 (CGHIV-) included 112 HIV-negative patients without lipodystrophy syndrome who were being evaluated for posterior ankle pain; group 3 (CGHIV + 1) included 23 HIV-positive patients not using a protease inhibitor, without lipodystrophy syndrome and with posterior ankle pain; group 4 (CGHIV + 2) comprised 18 HIV-positive patients who were being treated with a protease inhibitor and had lipodystrophy syndrome but did not have posterior ankle pain. Images were evaluated for the presence of edema by two radiologists who were blinded to clinical features. Fisher's exact test was used to evaluate differences among the groups. Interobserver variation was tested using Cohen's kappa (κ) statistic., Results: The presence of edema within Kager's fat pad was strongly associated with symptoms in HIV-positive patients who had lipodystrophy (p ≤ 0.0001). Concordance between observers was excellent (κ > 0.9)., Conclusion: MRI findings of Kager's fat pad inflammation related to HIV/AIDS is a source of symptoms in HIV patients with posterior ankle pain using protease inhibitors and having lipodystrophy syndrome.

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: HIV-infected patients may be at increased risk of cardiovascular (CV) events, and lipodystrophy is generally associated with proatherogenic metabolic disturbances. Carotid intima-media thickness (cIMT) has been used as a surrogate marker for atherosclerosis and it has been shown to be an independent risk factor for CV disease. Our objective was to evaluate cIMT in HIV-infected patients on combined anti-retroviral therapy (cART) with and without lipodystrophy defined by fat mass ratio (L-FMR), and to determine the association of lipodystrophy and visceral obesity [(visceral (VAT), subcutaneous adipose tissue (SAT) volume and VAT/SAT ratio, objectively evaluated by CT scan] with cIMT., Methods: Cross-sectional study of 199 HIV-infected patients. Body composition by DXA and abdominal CT, lipids, blood pressure, inflammatory markers, and cIMT by ultrasonography were performed. L-FMR was defined as the ratio of the percentage of trunk fat mass to the percentage of lower limb fat mass by DXA. Categorical variables were compared using the chi-square or Fisher's exact test. Spearman correlation coefficients were estimated to study the association between cIMT and clinical and metabolic characteristics. Means of cIMT, adjusted for age, were calculated, using generalized linear models., Results: L-FMR was present in 41.2% of patients and cIMT was higher in these patients [0.81 (0.24) vs. 0.76 (0.25); p=0.037)]. Lipodystrophic patients had higher VAT and VAT/SAT ratio and lower SAT. cIMT was associated with lipodystrophy evaluated by FMR, trunk fat, total abdominal fat, VAT and VAT/SAT ratio. No association was observed between cIMT and leg fat mass. Using generalized linear models, cIMT means were adjusted for age and no significant differences remained after this adjustment. The adjusted mean of cIMT was 0.787 (95%CI: 0.751-0.823) in patients without lipodystrophy, and 0.775 (95%CI: 0.732-0.817) in those with lipodystrophy (p=0.671)., Conclusions: HIV-infected patients on cART with lipodystrophy defined by FMR, had a significantly higher cIMT. Carotid IMT was also associated with classical cardiovascular risk factors. In these patients, visceral adipose tissue had a significant impact on cIMT, although age was the strongest associated factor.

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

Injectable poly-L-lactic acid (PLLA) is a biodegradable, biocompatible, synthetic polymer that acts as a scaffold to promote collagen formation and is FDA-approved for the correction of facial lipoatrophy in patients with human immunodeficiency virus (HIV) infection. The safety and efficacy of injectable PLLA for the treatment of HIV-associated facial lipoatrophy has been demonstrated in clinical studies and is accompanied by improvement in patient quality of life. Volumization of the mid-face is regarded as complex. The importance of respecting patient mid-face differences at rest and in motion was highlighted in a study that demonstrated effectiveness of silicone microdroplets (0.01 mL) in a depot manner to treat HIV patients with facial lipoatrophy. One of the challenges of facial volume rejuvenation with these techniques is preserving and enhancing dynamic facial movements after treatment. To address this challenge, we developed an injection technique termed "smile-and-fill." In this case series, we describe three patients treated by this technique to restore the malar aspect of the mid-face with improvement several months post-treatment.

Alcohol abuse is the most common and costly form of drug abuse in the United States. It is well known that alcohol abuse contributes to risky behaviors associated with greater incidence of human immunodeficiency virus (HIV) infections. As HIV has become a more chronic disease since the introduction of antiretroviral therapy, it is expected that alcohol use disorders will have an adverse effect on the health of HIV-infected patients. The biomedical consequences of acute and chronic alcohol abuse are multisystemic. Based on what is currently known of the comorbid and pathophysiological conditions resulting from HIV infection in people with alcohol use disorders, chronic alcohol abuse appears to alter the virus infectivity, the immune response of the host, and the progression of disease and tissue injury, with specific impact on disease progression. The combined insult of alcohol abuse and HIV affects organ systems, including the central nervous system, the immune system, the liver, heart, and lungs, and the musculoskeletal system. Here we outline the major pathological consequences of alcohol abuse in the HIV-infected individual, emphasizing its impact on immunomodulation, erosion of lean body mass associated with AIDS wasting, and lipodystrophy. We conclude that interventions focused on reducing or avoiding alcohol abuse are likely to be important in decreasing morbidity and improving outcomes in people living with HIV/AIDS.

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.

Objectives: Lipoatrophy is a long-term adverse effect of some antiretrovirals that affects quality of life, compromises adherence and may limit the clinical impact of HIV treatments. This paper explores the effect of tenofovir/emtricitabine (TDF/FTC) on the amount of limb fat in patients with virological suppression., Methods: A randomized, prospective clinical trial was performed to compare continuation on a zidovudine/lamivudine (ZDV/3TC)-based regimen with switching to a TDF/FTC-based regimen in terms of the effect on limb fat mass as assessed by DEXA over a 72-week period., Results: Eighty patients were included (39 in the TDF/FTC arm and 41 in the ZDV/3TC arm) and 73 completed the study (37 and 36, respectively). In the switch arm, limb fat increased by a median of 540 g from baseline (P = 0.022), while in the ZDV/3TC arm it decreased by a median of 379 g (P = 0.112; p between groups = 0.007). Subjects with baseline limb fat ≤ 7200 g, previous time on ZDV > 5 years or a body mass index > 25 kg/m(2) experienced higher limb fat gains than other subjects, and these differences were statistically significant. Haemoglobin increased by a median of 1.0 g/dL in the TDF/FTC arm (P < 0.001) and remained unchanged in the ZDV/3TC arm (p between groups = 0.0002). There were no significant differences between groups in other secondary endpoints (body weight, total body and trunk fat content, total body bone mineral density, laboratory parameters, CD4 cell count and viral load)., Conclusions: Switching from a ZDV/3TC-based to a TDF/FTC-based regimen led to a statistically significant improvement in limb fat, in contrast to the progressive loss of limb fat in subjects continuing ZDV/3TC., (© 2013 British HIV Association.)

Background: The prevalence of potentially stigmatizing lipoatrophy in children receiving antiretroviral therapy in Southern Africa is high, affecting around a third of children. Early diagnosis of lipoatrophy is essential for effective intervention to arrest progression., Methods: Prepubertal children receiving antiretroviral therapy were recruited from a hospital-based family HIV clinic in Cape Town and followed up prospectively. Lipoatrophy was identified and graded by consensus between 2 HIV pediatricians. A dietician performed anthropometric measurements of trunk and limb fat. Anthropometric measurements in children with and without lipoatrophy were compared using multivariable linear regression adjusting for age and gender. The most discerning anthropometric indicators of lipoatrophy underwent receiver operating characteristic curve analysis. The precision of anthropometric measurements performed by an inexperienced healthcare worker was compared with that of a research dietician., Results: Of 100 recruits, 36 had lipoatrophy at baseline and a further 9 developed lipoatrophy by 15-month follow-up. Annual incidence of lipoatrophy was 12% (confidence interval [CI]: 5-20%) per person-year of follow-up. A biceps skin-fold thickness <5 mm at baseline had a sensitivity of 89% (CI: 67-100%) and a specificity of 60% (CI: 46-75%) for predicting development of lipoatrophy by 15-month follow-up. Negative and positive predictive values were 97% (CI: 91-100%) and 32% (CI: 14-50%)., Conclusion: Biceps skin-fold thickness <5 mm in prepubertal children exposed to thymidine analogue-based antiretroviral therapy may be a useful screening tool to identify children who are likely to develop lipoatrophy. The variation in precision of measurements performed by an inexperienced healthcare worker only marginally impacted performance.

Background: Hepatitis B reactivation has been observed in HIV-infected patients with isolated anti-HBc. However, the impact of isolated anti-HBc on liver fibrosis is not known in this population., Methods: We investigated liver stiffness values (LSV) in a population of HIV-infected patients with isolated anti-HBc, and attempted to identify risk factors for high values., Results: Fifty-one out of 69 patients (74%) had low LSV (≤7.1 kPa). In univariate analysis, high LSV (>7.1 kPa) were associated with HCV coinfection, the duration of HIV infection, the duration of antiretroviral therapy and lipodystrophy. In age-adjusted multivariate analysis, HCV coinfection (OR 11.5; 95% CI, 3.0-62.9; P=0.001) and lipodystrophy (OR 4.6; 95% CI, 1.1-20.7; P=0.031) remained associated with high liver stiffness values., Conclusions: Lipodystrophy was the only factor associated with high liver stiffness values in our population of HIV-infected patients with isolated anti-Hbc and extensive exposure to antiretroviral drugs active on HBV, apart from HCV coinfection Our study correlates to recent studies the results of which have shown that lipodystrophy, and more generally mitochondrial toxicity, was associated with advanced liver fibrosis in HIV/HCV co-infected patients., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background: Many HIV patients receiving antiretroviral treatment develop lipodystrophy. NEW-FILL® is a polylactic acid injected to treat facial lipoatrophy. The objectives of this study were to describe (1) change in quality of life (QoL) of HIV patients treated with NEW-FILL® in the management of facial lipoatrophy; (2) efficacy of NEW-FILL® using facial photographs and (3) a patient-reported "Overall Treatment Effect" (OTE) scale; and (4) safety of NEW-FILL®., Methods: Doctors from 13 treatment centres recruited 230 HIV patients to receive up to 5 sessions of NEW-FILL® injections. Patients self-reported QoL with the ABCD questionnaire before the first set of injections, at 2 months and at 12 to 18 months after the last session of injections. Efficacy was evaluated at each interval through photographs and OTE scale. Safety was evaluated via Case Report Form (CRF) data., Results: 64.4% of patients reported QoL improvements of >10% at 2 months, and 58.8% at 12-18 months. Lipoatrophy grades improved at each visit ("no lipoatrophy" or "limited lipoatrophy": 20.3% at inclusion, 77.4% at 2 months, 58.4% at 12-18 months). Average OTE scores of 5.3 and 5.0 at 2 and 12-18 months indicated "moderate improvement". Minimum Important Difference (MID) in QoL score was 7.1 points at 2 months; 7.4 points at 12-18 months. For 911 injection sessions performed, 3.4% resulted in "immediate" adverse events, 7% in "non-immediate" events, and 1.7% in "other" events., Conclusions: Improvements to quality of life and diminished lipoatrophy visibility were observed in the months immediately following NEW-FILL® treatment and were maintained 12-18 months post-treatment. Most adverse events were mild and transient. ABCD MID thresholds provide clinicians with means to assess the impact of lipoatrophy therapies on QoL.

Background and Objective: To study the association between hypertriglyceridemic waist phenotype and the presence of subclinical atherosclerosis in human immunodeficiency virus (HIV) infected patients., Patients and Methods: Cross sectional study. Hypertriglyceridemic waist phenotype was considered if the waist was ≥90cm and triglycerides ≥2.0mmol/l (178mg/dl) in men and ≥85cm and ≥1.5mmol/L (133mg/dl) in women, respectively. We used the intima-media thickness (IMT) to detect carotid subclinical atherosclerosis., Results: We analyzed 152 patients, of whom 128 (84.2%) were receiving antiretroviral therapy, 40.7% were receiving protease inhibitors and 38.1% were treated with non-nucleoside reverse transcriptase inhibitors. The prevalence of hypertriglyceridemic waist phenotype was 23.6% (95% confidence interval [CI] 16.8-30.3%). Patients with hypertriglyceridemic waist phenotype had higher cardiovascular risk according to the Framingham score (11.09 [7.6] vs 3.88 [4], P=0.001) and lipodystrophy (33.3 vs. 13.7%, P=0.032) and metabolic syndrome (69.4 vs. 1.9%, P<0.001) were more frequent. The IMT was elevated in 21 (13.8%) patients. Hypertriglyceridemic waist phenotype (odds ratio [OR] 4.66 [95%CI 1.05-20.6; P = 0.043]) and metabolic syndrome (OR 3.74 [95%CI 1.25-11.23; P = 0.018]) were independently associated with higher IMT., Conclusions: The hypertriglyceridemic waist phenotype is a risk factor for subclinical atherosclerosis in HIV infected patients and it is useful to detect patients with lipodystrophy, metabolic syndrome and high cardiovascular risk., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

Objective: No randomized study has prospectively followed subcutaneous adipose tissue mitochondrial DNA (mtDNA) changes when starting thymidine nucleoside reverse transcriptase inhibitors (tNRTIs)., Design: The Metabolic Effects of DIfferent CLasses of AntiretroviralS study randomized HIV-positive, treatment-naive male participants to start lopinavir/ritonavir (LPVr) with either zidovudine/lamivudine (ZDV/3TC) or nevirapine (NVP)., Methods: Regional body fat was assessed by dual energy x-ray absorptiometry and abdominal computed tomography at months 0, 3, 12, 24 and 36. In a molecular substudy, subcutaneous adipose tissue (SAT) biopsies were taken, with mtDNA quantified by quantitative PCR. Data were analyzed using repeated measures linear regression analyses., Results: Of 50 participants recruited (23 to LPVr/ZDV/3TC), 48 started therapy, and 37 participants (19 on LPVr/ZDV/3TC) enrolled in the substudy. At 36 months, the LPVr/ZDV/3TC group had significantly lower limb fat [6.4 kg (0.26) versus 7.3 kg (0.31), P = 0.017] and a trend toward lower abdominal SAT compared to the LPVr/NVP group [131 cm (6.86) versus 146 cm (6.33), P = 0.097]. Over 36 months, mtDNA declined in the LPVr/ZDV/3TC group [mtDNA region 1: -190 (95) copies/cell, P = 0.053, region 2: -269 (106) copies/cell, P = 0.016] but not within the LPVr/NVP group [region 1: +28 (99) copies/cell, P = 0.78, region 2: +51 (111) copies/cell, P = 0.65, between-group difference P < 0.01 for both measurements]. mtDNA was significantly lower in the LPVr/ZDV/3TC group at 36 months., Conclusion: This is the first randomized study to prospectively demonstrate reductions in SAT mtDNA in patients initiating ZDV/3TC-containing antiretroviral therapy (ART) but not in those initiating nucleoside reverse transcriptase inhibitor-sparing ART containing NVP and protease inhibitor. That reductions in SAT mtDNA were also accompanied by lower limb fat suggests that use of ART not containing ZDV/3TC may help prevent development of peripheral lipoatrophy.

Lipodystrophy (LD) was evaluated in 205 children receiving antiretroviral therapy by a single investigator: 51 (24.9%) had LD; 46 peripheral lipoatrophy, three central lipohypertrophy and two combined type. All cases of peripheral and combined LD also had facial lipoatrophy. Serial photographs were provided by the families to confirm the severity of facial lipoatrophy. Forty-six (95.8%) children with peripheral or combined LD, and 75 (48.7%) without LD were exposed to stavudine (d4T) for a median duration of 45.9 versus 26.4 months (P = 0.005). In multivariate analysis, exposure to d4T for more than three months was the only factor associated with peripheral or combined LD (P < 0.001). Noticeable improvement of facial lipoatrophy was found in 11/48 (22.9%) children after a mean duration of 45.6 months following d4T discontinuation, mostly occurring during early adolescence.

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.

In the present study, we investigated the ability of anti-HIV drugs to interfere with normal cell cycle progression and to induce oxidative stress by perturbing the redox environment. Our results provide evidence that anti-HIV drugs have a differential effect on adipocyte cell cycle and differentiation, being able to modify the response to oxidative stress through an increase of reactive oxygen species (ROS) that compromises the induction of phase-2 and antioxidant enzymes. In detail, saquinavir, efavirenz, and stavudine exert antiadipogenic influences on the model 3T3-L1 cell line, perturbing the oxidative response and inducing of apoptosis. When considered together, the effects of anti-HIV drugs on 3T3-L1 pre adipocytes are distinct but commonly antiadipogenic, thus suggesting another additional possible mechanism by which antiretroviral therapies could contribute to lipoatrophy.

Objective: To develop an objective definition of human immunodeficiency virus (HIV)-associated lipodystrophy by using regional fat mass ratios and to assess the utility of anthropometric and skinfold measurements in the initial screening for lipodystrophy., Methods: Male patients between 25 and 50 years old with proven HIV infection (highly active antiretroviral therapy [HAART]-naïve subjects and those receiving successful HAART) were studied and compared with body mass index (BMI)-matched HIV-negative control subjects. Anthropometric variables, body composition, dual-energy x-ray absorptiometry findings, and metabolic variables were compared among the 3 study groups and between those patients with and those without lipodystrophy., Results: Trunk fat/lower limb fat mass ratio >2.28 identified 54.3% of patients with HIV receiving HAART as having lipodystrophy and had the highest odds ratio for predicting metabolic syndrome. The "clinical diagnosis of lipodystrophy" and the "clinical scoring system" had too many false-positive and false-negative results. Triceps skinfold thickness (SFT)/BMI ratio ≤0.49 and abdominal SFT/triceps SFT ratio >1.385 have good sensitivity but poor specificity in identifying lipodystrophy. In comparison with HAART-naïve patients with HIV, those receiving HAART had significantly higher insulin resistance, and a significantly greater proportion had impaired glucose tolerance and dyslipidemia. Among patients receiving HAART, those with lipodystrophy had a greater degree of insulin resistance, higher triglyceride levels, and lower levels of high-density lipoprotein cholesterol., Conclusion: The trunk fat/lower limb fat mass ratio in BMI-matched normal subjects can be used to derive cutoff values to define lipodystrophy objectively in HIV-infected patients. Defining lipodystrophy in this way is better than other methods of identifying those patients with increased cardiovascular risk. Triceps SFT/BMI and abdominal SFT/triceps SFT ratios may be useful as screening tools in resource-poor settings.

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.

HIV-lipodystrophy syndrome is characterized by different patterns of body fat distribution (BFD) which are identified by clinical and body composition (BC) assessment, including bioimpedance analysis (BIA). Our aim was to compare BC in HIV-infected patients on combination antiretroviral therapy (cART) according to 4 distinct phenotypes of BFD (G1-no lipodystrophy, G2-isolated central fat accumulation, G3-lipoatrophy, G4-mixed forms of lipodystrophy) and assessed factors associated with them. Anthropometry and BIA were performed in 344 HIV-1 patients. G2 and G4 phenotype patients had significantly higher fat mass (FM) but no differences were observed in fat-free mass (FFM) and total body water among the 4 phenotypes. Significant negative associations were found between the presence of lipoatrophy and female gender, body mass index (BMI), waist (WC), hip (HC) and thigh circumferences, and total body FM estimated by BIA. After adjustment for gender, cART duration and BMI, G3 had significant lower WC [odds ratio (OR)=0.84; 0.78- 0.90] and HC (OR=0.88; 0.81-0.96) mean. Independently of gender, cART duration and BMI, G2 remained significantly associated with higher WC (OR=1.11; 1.05-1.18) and HC (OR=1.15; 1.07-1.23) mean, and with FM estimated by BIA [FM as %, OR=1.17 (1.09-1.26); and FM as kg, OR=1.15 (1.06- 1.25)]. There was a significant positive association between G4 and female gender (OR=1.66; 1.01-2.75), BMI (OR=1.10; 1.04-1.17) and WC (OR=1.15; 1.09-1.21). The similar FFM along the BFD spectrum describes the actual BC of these patients without sarcopenia. In a clinical setting, BIA is an easy and useful tool to evaluate fat mass and FFM and gives us a picture of BC that was not possible with anthropometry.

Objective: To assess the prevalence, imaging appearance, and clinical significance, of bone marrow MR signal changes in a group of human immunodeficiency virus (HIV)-infected patients with lipodystrophy syndrome., Materials and Methods: Twenty-eight HIV-infected patients with lipodystrophy syndrome treated with highly active antiretroviral therapy, and 12 HIV-negative controls underwent MRI of the legs. Whole-body MRI, SPECT/CT, and a complete radiographic skeletal survey were obtained in subjects with signal changes in bone marrow. MRI and clinical evaluations were reviewed 6 months after baseline to determine changes after switching from thymidine analogs (TA) to tenofovir-DF (TDF). MRI results correlated with clinical parameters., Results: We observed foci of a serous-like pattern (low signal and no enhancement on T1-weighted, high signal on T2-weighted images) in 4 out of 28 patients (14.3%) and an intermediate signal on T1-weighted images in 4 out of 28 patients (14.3%). Serous-like lesions were located in the lower limbs and scattered in the talus, calcaneus, femurs, and humeral bones; they showed slight uptake on SPECT bone scans and were normal on CT and radiographs. Patients with serous-like lesions had significantly lower peripheral and total fat at baseline than other groups (P < 0.05). No changes at 6 months were observed on MRI, and the serous-like lesion group showed good peripheral fat recovery after changing drug treatment., Conclusion: A serous-like MRI pattern is observed in the peripheral skeletons of HIV-infected patients with lipodystrophy, which correlates with peripheral lipoatrophy, and should not be misdiagnosed as malignant or infectious diseases. Although the MR lesions did not improve after switching the treatment, there was evidence of lipoatrophy recovery.

HIV-infected individuals are at increased risk for cardiovascular disease (CVD) and lipodystrophy, but the relationship between regional adipose tissue (AT) depots and CVD risk is not well described. We determined regional AT volumes and CVD risk in an analysis of 586 HIV-infected and 280 control FRAM study subjects using whole-body magnetic resonance imaging (MRI) and the Framingham Risk Score (FRS). Median FRS and FRS >10% were higher in HIV than control men (4.7% vs. 3.7%, p=0.0002; 16% vs. 4%, p<0.0001). HIV and control women had similarly low FRS (1.1% vs. 1.2%, p=0.91). In controls, total AT and all regional AT depots showed strong positive correlations with FRS (p<0.001) in men and weaker positive correlations in women. Greater visceral AT (VAT) and lower leg subcutaneous AT (SAT) volumes were associated with elevated FRS in HIV subjects with a trend for upper trunk SAT. Controls in the lowest quartile of leg SAT had the lowest FRS (1.5%), whereas HIV with similarly low leg SAT had the highest FRS (4.0%, p<0.001 vs. controls). Increased VAT is associated with CVD risk, but the risk is higher in HIV-infected individuals relative to controls at every level of VAT. Peripheral lipoatrophy (as measured by leg SAT) is associated with striking increased CVD risk in HIV-infected patients even after controlling for VAT, whereas low leg SAT is associated with low CVD risk in controls.

Objective: Combination antiretroviral therapy (cART) is associated with lipodystrophy, i.e., loss of subcutaneous adipose tissue in the abdomen, limbs, and face and its accumulation intra-abdominally. No fat is lost dorsocervically and it can even accumulate in this region (buffalo hump). It is unknown how preserved dorsocervical fat differs from abdominal subcutaneous fat in HIV-1-infected cART-treated patients with (cART+LD+) and without (cART+LD-) lipodystrophy., Research Design and Methods: We used histology, microarray, PCR, and magnetic resonance imaging to compare dorsocervical and abdominal subcutaneous adipose tissue in cART+LD+ (n=21) and cART+LD- (n=11)., Results: Albeit dorsocervical adipose tissue in cART+LD+ seems spared from lipoatrophy, its mitochondrial DNA (mtDNA; copies/cell) content was significantly lower (by 62%) than that of the corresponding tissue in cART+LD-. Expression of CD68 mRNA, a marker of macrophages, and numerous inflammatory genes in microarray were significantly lower in dorsocervical versus abdominal subcutaneous adipose tissue. Genes with the greatest difference in expression between the two depots were those involved in regulation of transcription and regionalization (homeobox genes), irrespective of lipodystrophy status. There was negligible mRNA expression of uncoupling protein 1, a gene characteristic of brown adipose tissue, in either depot., Conclusions: Because mtDNA is depleted even in the nonatrophic dorsocervical adipose tissue, it is unlikely that the cause of lipoatrophy is loss of mtDNA. Dorsocervical adipose tissue is less inflamed than lipoatrophic adipose tissue. It does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal subcutaneous adipose tissue is in expression of homeobox genes., (© 2011 by the American Diabetes Association.)

HIV-associated lipodystrophy is clinically characterized by body fat changes including subcutaneous fat loss (lipoatrophy) with or without truncal fat accumulation (lipohypertrophy). Thymidine nucleoside reverse transcriptase inhibitors, stavudine and to a lesser extent zidovudine, are major contributors for lipoatrophy. Drug factors are not clear for lipohypertrophy. Restoration to health with effective viral suppression and weight gain may be factors playing significant roles in lipohypertrophy. Mitochondrial dysfunction and inflammation in subcutaneous adipose tissue are key factors in the pathogenesis of HIV-associated lipoatrophy. The pathogenesis of lipohypertrophy is less well understood. Switching from thymidine nucleoside reverse transcriptase inhibitors restores subcutaneous fat in patients with HIV-associated lipoatrophy, but improvement is slow and limited. Surgical filling cosmetically improves facial lipoatrophy. Exercise and diet may reduce increased visceral adipose tissue. Liposuction may be useful to remove superficial, localized fat accumuli., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Human immunodeficiency virus (HIV)-associated lipodystrophy is a syndrome that occurs primarily in individuals who are being treated with highly active antiretroviral therapy (HAART)., Observations: We describe 3 patients with an 8- to 15-year history of HIV disease and HAART who presented a unique feature of HIV lipodystrophy, the "bullfrog neck." In addition to their features of facial lipoatrophy and "buffalo hump," patients had the unique feature of circumferential enlargement of the neck. All patients were undergoing treatment with the same non-nucleoside reverse-transcriptase inhibitor (NRTI) medication, efavirenz., Conclusions: We present a novel finding of the bullfrog neck in 3 patients with classic features of HIV lipodystrophy. The dysmorphic features of HIV lipodystrophy present a significant therapeutic challenge because the current repertoire of treatments is only modestly effective, and the disease in patients who continue HAART regimens over the long term will progress. Review of the recent literature suggests that the individual protease inhibitors and NRTIs used may play a role in the development and progression of HIV lipodystrophy.

The availability of highly active antiretroviral therapy has markedly improved the survival rate and quality of life in patients infected with HIV. At present, however, there is still no cure for HIV and those undergoing treatment have to do so for life. The use of antiretroviral drugs has been associated with several toxicities that limit their success. Some acute and chronic toxicities associated with these drugs include hypersensitivity reactions, neurotoxicity, nephropathy, liver damage, the appearance of body fat redistribution syndrome and the different metabolic alterations that accompany it. Some of these toxicities are family- or even drug-specific. Since not all patients that take a particular antiretroviral medication develop the adverse effect that has been attributed to that drug, it has therefore been postulated that there must be a genetically-conditioned individual predisposition to developing the adverse effect. Pharmacogenetics is the science that studies interindividual variations in the response to and toxicity of drugs due to variations in the genetic composition of individuals. Sufficient advances have been made in this discipline to allow this fertile field of research to move out of the basic science laboratory and into clinical applications. The present article reviews the investigations that have been published regarding the association between the genetic determinants of persons infected with HIV and the metabolic toxicity and chronic vascular consequences resulting from antiretroviral drugs. The influence of host genetic variants on dyslipidemia, hyperglycemia and insulin resistance, lipodystrophy and atherosclerosis are presented and discussed.

Antiretroviral therapy (ART) has significantly reduced the morbidity and mortality of patients infected with the human immunodeficiency virus 1 (HIV-1). In a significant number of patients, ART is associated with fat redistribution and metabolic alterations such as dyslipidemia, insulin resistance (IR) and type 2 diabetes, summarized under the term HIV-associated lipodystrophy syndrome (HIV-LS). The pathogenesis of HIV-LS is complex and involves a number of factors including ART, HIV-1, abnormal fat redistribution, metabolic abnormalities and chronic inflammation. In view of a novel understanding on how chronic inflammation contributes to the pathogenesis of HIV-1 infection, this review focuses on the interaction of the immune system and metabolic pathways and the potential consequences for the HIV-LS. Based on the current literature, we suggest a central role of systemic inflammation in triggering and deteriorating various components of the HIV-LS.

Objective: Peripheral fat loss and visceral fat gain have been reported in HIV infection. There are limited data on long-term change in adipose tissue in HIV-infected patients vs. controls. Therefore, we determined change in regional adipose tissue from baseline examination to 5 years later among participants in the study of Fat Redistribution and Metabolic Change in HIV Infection., Methods: Regional adipose tissue volume was measured using MRI at both examinations in 477 HIV-infected and 214 control men and women. Lipoatrophy was defined as leg subcutaneous adipose tissue (SAT) below the cutoff point marking the lowest decile (10%) of controls at each examination., Results: HIV-infected and control participants showed similar adipose tissue gains. In men, all SAT depots and visceral adipose tissue started lower and remained lower on average in HIV-infected vs. controls. In women, leg and arm SAT also started lower and remained lower in HIV-infected vs. controls. Mean leg SAT of HIV-infected men was 67% of control men at baseline and 65% at follow-up; for women 83% and 77%. At baseline, 48% of HIV-infected participants had lipoatrophy; on average those with baseline lipoatrophy gained 0.96L of leg SAT compared with 1.23L gain for controls in the lowest decile (P = 0.16). At follow-up, 53% of HIV-infected participants had lipoatrophy. In multivariable models, discontinuation of stavudine appeared to produce little gain in leg SAT ( approximately 1.1%/year)., Conclusion: HIV-infected participants did not substantially recover SAT compared with controls, although both showed average gains. HIV-associated lipoatrophy persisted after 5 years of follow-up.

The aim of this study was to describe the status of oxidative stress and antioxidant biomarkers and their association with metabolic and body composition components of HIV-lipodystrophy syndrome. In a cross-sectional study of blood samples from HIV-infected men with lipodystrophy syndrome (HIV+LIPO+ = 10), HIV-infected men without lipodystrophy syndrome (HIV+LIPO- = 22), and healthy subjects (control = 12), the following oxidative stress biomarkers were analyzed: total hydroperoxide, thiobarbituric acid reactive substances (TBARS), and advanced oxidation protein products (AOPP). In addition, antioxidant biomarkers, including total glutathione, uric acid, alpha-tocopherol, and metabolic components were tested. Dual-energy x-ray absorciometry (DXA) was used to measure the fat mass. The duration of HIV infection and the duration and type of highly active antiretroviral therapy were similar between the two HIV-infected groups. Higher levels of total hydroperoxide were observed in the HIV+LIPO+ (50 +/- 33 H(2)O(2)/L) group compared to the HIV+LIPO- (19 +/- 13 H(2)O(2)/L) and control (5 +/- 5 H(2)O(2)/L) groups (p < 0.05). Similarly, higher levels of AOPP were observed in the HIV+LIPO+ (326 +/- 173 micromol/L) group compared to the HIV+LIPO- (105 +/- 92 micromol/L) and control groups (80 +/- 20 micromol/L) (p < 0.05). Total hydroperoxide significantly correlated with insulin serum levels in the HIV+LIPO+ (r = 0.47, p < 0.05) and HIV+LIPO- groups (r = 0.29, p < 0.05), while AOPP significantly correlated with insulin serum levels in the HIV+LIPO+ (r = 0.73, p < 0.05) and HIV+LIPO- (r = 0.54, p < 0.05) groups. Therefore, higher lipid and protein oxidation were found in HIV-infected patients with lipodystrophy syndrome, and both were associated with insulin levels.

Objectives: To assess whether mitochondrial dysfunction in skeletal muscle characterizes antiretroviral therapy (ART)-associated lipoatrophy (LA)., Methods: A cross-sectional study comparing HIV-infected, antiretroviral-treated patients with LA (n = 5; LA+) and without LA (n = 5; non-LA) was conducted. Positron emission tomography was used to measure blood flow, oxygen extraction and oxygen consumption in quadriceps femoris muscle during rest and aerobic exercise. Mitochondrial DNA (mtDNA) was quantified by PCR. Body composition was measured by dual-energy X-ray absorptiometry and magnetic resonance imaging. All data are given as means +/- SEM., Results: Compared with the non-LA group, the LA+ group had significantly less limb fat and more intra-abdominal fat, but similar leg muscle mass. The LA+ group versus the non-LA group had reduced mtDNA content per nucleus in adipose tissue (173 +/- 38 versus 328 +/- 62; P = 0.067), but not in skeletal muscle (2606 +/- 375 versus 2842 +/- 309; P = 0.64). Perfusion in resting muscle (34 +/- 7 versus 28 +/- 6 mL/kg/min in the LA+ group versus the non-LA group; P = 0.5), and the mean absolute (277 +/- 30 versus 274 +/- 43 mL/kg/min, respectively; P = 0.95) and relative (10.6 +/- 2.5- versus 11.9 +/- 1.5-fold change, respectively; P = 0.67) increases in perfusion during exercise were similar between the groups. Oxygen consumption at rest (2.2 +/- 0.7 versus 2.1 +/- 0.3 mL/kg/min in the LA+ group versus the non-LA group; P = 0.9), and the mean absolute (14.6 +/- 1.7 versus 24.3 +/- 8.8 mL/kg/min, respectively; P = 0.3) and relative (10.3 +/- 2.8- versus 11.7 +/- 2.4-fold change, respectively; P = 0.73) exercise-induced increases in oxygen consumption were similar between the groups. The oxygen extraction fraction was comparable between the groups, both at rest and during exercise. Plasma lactate concentrations remained unchanged in both groups during exercise., Conclusions: HIV-infected patients with ART-associated LA have similar mtDNA content in skeletal muscle and comparable skeletal muscle aerobic exercise metabolism to antiretroviral-treated non-lipoatrophic patients.

The advent of highly active antiretroviral therapy (HAART) has dramatically improved the life expectancy of people infected with human immunodeficiency virus (HIV). Although patients often have excellent disease control with these combinations of antiretrovirals, they are at risk for the multiple toxicities associated with these drugs. Facial lipoatrophy is a particularly distressing complication of some HAART regimes. This disfigurement can lead to significant psychosocial stress, resulting in decreased treatment compliance. Polylactic acid (PLA) facial implants provide a potential method of restoring a normal appearance. One hundred consecutive patients had a course of PLA facial implants. All patients were assessed clinically and had photographs, facial surface laser scans and completed psychological questionnaires throughout the course of treatment. After a mean of 4.85 treatments per patient, there were improvements in all measures. The mean clinical scores improved from a moderate-severe grade to none-mild grade after treatment. Three-dimensional (3D) laser surface scans showed a volume increase of 2.81 cc over the treated area of the cheek. There were significant improvements in all of the psychological measures. This study shows clear objective evidence of the psychological and physical benefit of PLA implants in HIV-associated facial lipodystrophy.

Poly-L-lactic acid (PLLA) has been available to the European medical community as a treatment for Human Immunodeficiency Virus (HIV)-associated facial lipoatrophy for nearly a decade, gaining U.S. Food and Drug Administration (FDA) approval for this indication in 2004. PLLA has been utilized in an off-label manner in the U.S. to treat lipoatrophy of aging in the non-HIV population. The literature regarding safety and efficacy of PLLA is well-documented, while studies regarding patient satisfaction and duration are more limited. The following review article discusses the currently available literature pertaining to the durability and patient satisfaction after PLLA treatment. Patients treated for HIV-related facial lipoatrophy and cosmetic use of PLLA for lipoatrophy of aging are discussed separately.

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.

This article will provide insight into the evolving perspectives on HIV-related lipodystrophy syndrome: recent changes in epidemiology, a shifting focus from individual component assessment towards a more comprehensive risk evaluation for organ dysfunction and disease, the impact of patient-related outcomes in heath-related quality of life and the integration of this syndrome into a wider scenario of a premature ageing process in HIV-infected people will be discussed. The time has come to proceed beyond lipodystrophy studies based on blood concentrations of lipids and glucose and body fat evaluation. Surrogate markers of organ disease associated with lipodystrophy better identify patients vulnerable to non-infectious co-morbidities (NICMs) rather than statistical risk algorithms. In this evolving perspective NICMs take the place of lipodystrophy in the description of the clinical spectrum of HIV disease and allow integration of this syndrome into the wider scenario of a premature ageing process in HIV-infected people. Management of NICMs needs to be considered as part of a multi-disciplinary holistic approach that accommodates the increasing number of factors influencing non-infectious HIV-related outcomes.

Background: Long-term antiretroviral therapy dramatically reduces HIV-related morbidity and mortality but is also associated with metabolic and morphological changes and requires high levels of adherence., Methods: A randomized, 48-week, open-label, comparative study of continuation of twice-daily zidovudine/lamivudine or replacement with once-daily tenofovir disoproxil fumarate/emtricitabine in individuals on successful efavirenz-based antiretroviral therapy. Limb fat mass was assessed by dual x-ray absorptiometry in a subset of participants through week 48., Results: Two hundred thirty-four individuals were randomized and treated (117 each to continue or switch) with 206 subjects completing 48 weeks of study. Five percent subjects in the continue group and 3% subjects in the switch group discontinued due to adverse events. By intent-to-treat, missing = failure analysis, no differences in virological efficacy were observed at any time point (week 48 <50 copies/mL continue 85%, switch 88%). At week 24, switching was associated with significant increases in hemoglobin (mean difference 0.37 g/dL, 95% confidence interval: 0.15 to 0.58 g/dL, P < 0.001) and significant declines in total cholesterol and triglycerides. In the dual x-ray absorptiometry substudy (n = 100), fat was preserved or increased in the switch group but declined in the continue group (mean difference 448 g, 95% confidence interval: 57 to 839 g, P = 0.025). Individuals with longer exposure to zidovudine and lower baseline limb fat experienced less limb fat increase after switching. No differences in renal adverse events were observed between groups., Conclusions: Switching from zidovudine/lamivudine to tenofovir disoproxil fumarate/emtricitabine in persons on efavirenz therapy maintains virological control, establishes a once-daily regimen, results in improvements in hemoglobin and key lipid parameters, and preserves and restores limb fat relative to continuation of zidovudine/lamivudine.

Background: Alterations in regional fat are often reported in HIV infection. Prior studies have not distinguished between normal changes in regional fat related to sexual maturation and those due to HIV. The study aim was to compare changes in regional fat distribution in HIV-infected (HIV+) and healthy (HIV-) children and adolescents living in the United States., Methods: Serial dual energy X-ray absorptiometry was performed at baseline and two annual follow-up visits in 64 HIV+ and 147 HIV--participants aged 6-16 years. Total, leg, arm, and trunk fat masses (kg) and regional fat distribution as the percentage of total body fat (%) were compared., Results: HIV+ and HIV--participants did not differ in total fat mass, but the HIV+ group had significantly lower leg and greater arm fat and trunk fat percentage at all time points. Over time, decreases in leg fat percentage and increases in arm fat percentage were more marked among the HIV+ group. Differences between HIV+ and HIV--groups in arm and leg fat percentage remained significant when age, sex, race, height, and pubertal stage were accounted for by mixed effect modeling. Apart from prior treatment with stavudine, no differences in fat distribution were observed according to treatment or degree of immunodeficiency or viremia., Conclusion: Although no single pattern of change in regional fat distribution was uniquely associated with HIV, perinatally HIV-infected youth manifest significantly decreased leg fat and increased arm and trunk fat. These differences increase over time and may contribute to cardiovascular disease risk.

Highly active antiretroviral therapy (HAART) for HIV-infection is associated with lipodystrophy, insulin resistance, increased prevalence of disturbances in glucose tolerance and diabetes, hyperlipidemia and increased cardiovascular risk. Whether dietary intake influences total body fat, visceral fat, insulin resistance, glucose metabolism, lipid metabolism and circulating inflammatory markers in HIV-infected subjects with lipodystrophy is unclear and the focus of this report. We examined the dietary intake of 106 male HIV-infected HAART-recipients with lipodystrophy, enrolled in a study of the effects of rosiglitazone. All subjects had normal glucose tolerance. Dietary intakes were determined at study entry using Food Frequency Questionnaires and examined cross-sectionally against body composition by dual-energy Xray absorptiometry, visceral obesity by computed tomography, fasting glucose, insulin, lipids, adiponectin, leptin, insulin resistance (by HOMA). Energy underreporters were identified and excluded. After exclusion of underreporters (n = 22) we found no relationships between diet composition (% dietary fat, %carbohydrate) and BMI, %body fat and visceral adiposity (p>0.3). Only modest relationships were found between BMI and fat subtypes: polyunsaturated fats (g/day) (r = 0.14, p = 0.007), monounsaturated fat (g/d) (r = 0.06, p = 0.001), saturated fat (g/d) (r = 0.02, p<0.0001). Only saturated fat related to % total body fat (g/d: r = 0.08, p<0.0001, %energy intake: r = 0.16, p<0.0001). No nutrient related to visceral adiposity by CT. Dietary fat intake (expressed as a % of energy intake) was not related to total cholesterol, HDL cholesterol, triglycerides, fasting insulin, glucose, leptin, adiponectin or HOMA-IR (p>0.4). Fat subtype did not relate to fasting insulin, insulin resistance, total cholesterol, HDL, triglycerides, glucose, adiponectin. In conclusion, there are weak relationships between saturated fat intake and adiposity in HIV-infected subjects with lipodystrophy, using gold standard measures of body fat. There were no relationships between nutrient intake and visceral adiposity, any measure of glucose metabolism, insulin resistance or adipokines. Only interventional, prospective studies will determine whether any nutritional strategy can assist in ameliorating the metabolic complications associated with HIV lipodystrophy.