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Central fat accumulation is increasingly recognized as a problem for patients with HIV infection. The term 'lipodystrophy' has been used to describe collectively a constellation of body habitus changes and metabolic abnormalities commonly observed in HIV-infected patients, particularly since the advent of highly active antiretroviral therapy. Visceral fat accumulation can place patients at increased risk of coronary artery disease. Furthermore, body shape changes are a source of distress to patients that may compromise treatment adherence. Reduction of abdominal obesity can therefore be considered part of therapy in HIV-positive patients with visceral adipose tissue (VAT) accumulation. Currently, there are no drugs approved by the Food and Drug Administration for the treatment of HIV-associated central fat accumulation. Lifestyle modifications such as diet and exercise and switching antiretroviral therapies appear to be of limited value in reducing VAT. Metformin has shown some benefit in reducing VAT but at the expense of accelerating peripheral fat loss, and the thiazolidinediones have no effect on VAT. Similarly, testosterone does not appear to reduce VAT in these patients, and there are no data on anabolic steroids. Two large, randomized controlled trials have demonstrated the efficacy of recombinant human growth hormone (rhGH) in reducing visceral adipose tissue. There are also promising data regarding treatment with growth hormone releasing hormone (GHRH).

People living with HIV (PLWH) who are on protease inhibitor (PI)-containing regimens have been shown to have increases in visceral adipose tissue (VAT) and a greater decrease in spine bone mineral density (BMD) than those receiving non-PI regimens when initiating treatment. This increase in VAT has been hypothesized to falsely lower spine BMD measured via dual-energy X-ray absorptiometry, suggesting that the PI-associated BMD loss is an artefact rather than real. To test this, data collected from two completed 96-week clinical trials, AIDS Clinical Trial Group studies A5224s and A5260s, of antiretroviral therapy-naive PLWH initiating treatment with PI and non-PI-containing regimens were analyzed comparing VAT accumulation and spine BMD loss. Results showed no significant decrease in spine BMD in persons in the highest quartile (Q4) of VAT gain versus the rest of the study population (Q1–3) in either the PI and non-PI arms, suggesting that PI-associated BMD loss is not likely to be an artefact of overlying VAT. [ABSTRACT FROM AUTHOR]

The mechanisms causing HIV-associated immune activation remain incompletely understood. Alteration of intestinal integrity with subsequent translocation of bacterial products appears to play an important role; however, little is known about the impact of fungal translocation. We assessed the effect of fungal translocation and its association with immune activation in people living with HIV (PLWH) compared with uninfected controls. We measured serum levels of β-D-glucan (BDG) and anti-Saccharomyces cerevisiae antibodies (ASCA) immunoglobulin G (IgG) and immunoglobulin A (IgA) and markers of systemic inflammation and immune activation in virally suppressed PLWH on antiretroviral therapy (ART) and uninfected controls. T-test and Mann–Whitney tests were used to compare markers by HIV status and correlation and regression analyses were used to assess associations of fungal translocation markers with markers of inflammation. One hundred seventy-six participants were included (128 HIV+ and 48 HIV−); 72% male, 65% African American, median age was 50 years, and CD4 was 710 cells/cm3. Levels of BDG tended to be lower in HIV+ when compared with controls (p = .05). No significant difference in levels of ASCA IgG and IgA was seen between groups (p > .75). There was a significant correlation between BDG and several markers of inflammation and immune activation in PLWH, not seen in uninfected controls. In contrast, no correlations were seen between levels of ASCA IgG and IgA with inflammatory markers. PLWH on ART do not have higher levels of BDG or ASCA when compared with uninfected controls, however, the association found between BDG and several inflammation markers suggests a potential role of fungal translocation in the heightened immune activation seen in treated HIV. [ABSTRACT FROM AUTHOR]

Background: Obesity is prevalent among HIV-infected individuals on antiretroviral therapy (ART). Cross-sectional studies have suggested that HIV-infected women are more likely to be overweight than men, but observational studies evaluating sex differences in body mass index (BMI) increases following ART initiation are conflicting. Materials and Methods: We pooled data from three randomized clinical trials of ART initiation in persons with HIV in the United States. BMIs were compared between 760 women and 3041 men to test whether BMI changes in the first 96 weeks following initiation of ART differed by sex at birth. Linear regression estimated the relationship between sex and change in BMI from pre-ART initiation to week 96. Results: After 96 weeks, women gained an average of 1.91 kg/m2 (95% confidence interval [CI] 1.64–2.19), men gained an average of 1.39 kg/m2 (95% CI 1.30–1.48); p for sex difference <0.001; the sex difference persisted within each pre-ART initiation BMI subgroup. After adjusting for pre-ART initiation age, CD4+ count, HIV-1 viral load, race/ethnicity, study, and ART regimen, mean BMI change for women was 0.59 kg/m2 (95% CI 0.37–0.81) more than for men (p < 0.001). Statistical interactions were observed between sex and both pre-ART CD4+ count and HIV-1 viral load and suggest that for subgroups with higher viral load and lower CD4+ at baseline, the estimated BMI changes in women are even larger than the average estimated difference. Conclusions: HIV-1-infected women experienced a significantly greater increase in BMI following ART initiation than men. These differences are a problem of clinical significance to women living with HIV. [ABSTRACT FROM AUTHOR]

Smoking is an important contributor to cardiovascular disease risk and is highly prevalent in the HIV population. In the Stopping Atherosclerosis and Treating Unhealthy Bone with Rosuvastatin in HIV trial (SATURNHIV), a 96-week, randomized placebo-controlled study testing the effect of rosuvastatin on subclinical vascular disease and immune activation in HIV-infected adults, rosuvastatin improved immune activation and arrested common carotid artery intima media thickness (CCA IMT) progression. In this exploratory analysis, ANOVA was used to test for effect modification by smoking. One-hundred forty-seven adults were included (72 in rosuvastatin group; 75 in placebo group). Groups were similar at baseline. Overall, mean ± SD age was 45.4 ± 9.9 years, 115 (78%) were men and 100 (68%) were African American. Ninety-three (63%) were current smokers (mean ± SD 0.6 ± 0.44 packs/day) and another 24 (16%) were smokers in the past. There were statistically significant randomization group by smoking status interactions for 0-24 (p = .01) and 0-48 (p < .01) week changes in proportion of activated CD4+ T cells and for 0-48 (p < .01) and 0-96 (trend only; p = .06) week changes in CCA IMT. No effect modification by smoking was detected for changes in markers of inflammation or monocyte activation. The beneficial effect of rosuvastatin on CCA IMT was not apparent in smokers although T cell activation improved to a greater degree in this subgroup. [ABSTRACT FROM AUTHOR]

Amino acids play critical roles in metabolism, cell function, body composition and immunity, but little data on plasma amino acid concentrations in HIV are available. We evaluated plasma amino acid concentrations and associations with CD4 counts and inflammatory biomarkers in HIV-infected youth. HIV-infected subjects with a high (≥500 cells/mm3) and low (<500 cells/mm3) current CD4+ T cell counts were compared to one another and to a matched healthy control group. Plasma concentrations of 19 amino acids were determined with an amino acid analyzer. Plasma levels of interleukin-6, tumor necrosis factor receptor-I, and soluble vascular cellular adhesion molecule-I were also measured. Seventy-nine HIV-infected subjects (40 and 39 with high and low CD4+ T cell counts, respectively) and 40 controls were included. There were no differences in amino acid concentrations between HIV-infected subjects with high or low CD4+ T cell counts. When combined, the HIV-infected group exhibited significantly lower median plasma concentrations compared to controls for total, essential, branched-chain and sulfur amino acids, as well as for 12 individual amino acids. Glutamate was the only amino acid that was higher in the HIV-infected group. There were no significant correlations between amino acid endpoints and inflammatory biomarkers for either HIV-infected group or controls. Plasma amino acid concentrations were lower in HIV-infected youth compared to healthy controls, regardless of immune status, while glutamate concentrations were elevated. These findings can inform future interventional studies designed to improve metabolic and clinical parameters influenced by amino acid nutriture. [ABSTRACT FROM AUTHOR]

Heightened inflammation and immune activation are associated with lower bone mineral density (BMD) and lean body mass (LBM) among HIV-infected persons. We hypothesized that a reduction in inflammation with rosuvastatin would be associated with improvements in BMD and LBM. HIV-infected participants on stable antiretroviral therapy without statin indication and with heightened immune activation (≥19% CD8+CD38+HLA-DR+ T cells) or inflammation (hsCRP ≥2 mg/liter) were randomized to rosuvastatin 10 mg daily or placebo for 96 weeks. Among 72 participants randomized to rosuvastatin and 75 to placebo, there were no significant differences in the relative changes in BMD ( p > 0.29) or in fat ( p ≥ 0.19). A trend toward increased LBM ( p = 0.059) was seen in the rosuvastatin arm without differences in creatinine kinase or self-reported physical activity ( p ≥ 0.10). In a multivariable regression model, rosuvastatin was associated with a significant positive effect on LBM after adjusting for age, sex, race, smoking status, and detectable HIV-1 viral load. Higher baseline sCD163 correlated with increases in LBM from weeks 0 to 96 ( p = 0.023); greater changes in total and leg lean mass were seen among statin users with higher compared to lower baseline IP-10 levels (LBM 1.8 vs. −0.3%; p = 0.028 and leg lean mass 2.9 vs. −1.7%; p = 0.012). Rosuvastatin is associated with an absence of toxicity on BMD and a potential benefit on LBM over 96 weeks of therapy. The preservation of LBM in the rosuvastatin arm over the 2 years of the study is of major clinical relevance in delaying loss of muscle mass with aging. [ABSTRACT FROM AUTHOR]

HIV/hepatitis C virus (HCV) patients have a 3-fold increased fracture incidence compared to uninfected patients. The impact of HCV therapy on bone health is unclear. We evaluated bone turnover markers (BTM) in well-controlled (HIV RNA <50 copies/ml) HIV/HCV-coinfected patients who received pegylated interferon-α and ribavirin (PEG-IFN/RBV) in ACTG trial A5178. Early virologic responders (EVR: ≥2 log HCV RNA drop at week 12) continued PEG-IFN/RBV and non-EVRs were randomized to continuation of PEG-IFN alone or observation. We assessed changes in C-terminal telopeptide of type 1 collagen (CTX; bone resorption marker) and procollagen type I intact N-terminal propeptide (P1NP; bone formation marker), and whether BTM changes were associated with EVR, complete early virologic response (cEVR: HCV RNA <600 IU/ml at week 12), or PEG-IFN treatment. A total of 192 subjects were included. After 12 weeks of PEG-IFN/RBV, CTX and P1NP decreased: −120 pg/ml and −8.48 μg/liter, respectively (both p < 0.0001). CTX declines were greater in cEVR ( N = 91; vs. non-cEVR ( N = 101; p = 0.003). From week 12 to 24, CTX declines were sustained among EVR patients who continued PEG-IFN/RBV ( p = 0.027 vs. non-EVR) and among non-EVR patients who continued PEG-IFN alone ( p = 0.022 vs. Observation). Median decreases of P1NP in EVR vs. non-EVR were similar at weeks 12 and 24. PEG-IFN-based therapy for chronic HCV markedly reduces bone turnover. It is unclear whether this is a direct IFN effect or a result of HCV viral clearance, or whether they will result in improved bone mineral density. Further studies with IFN-free regimens should explore these questions. [ABSTRACT FROM AUTHOR]

Sclerostin is linked to bone physiology and cardiovascular disease through the Wnt/β-catenin signaling pathway. The goal of this study was to determine if sclerostin is related to bone physiology and cardiovascular disease during antiretroviral treatment in HIV-infected persons. This was a cross-sectional analysis from study entry into the Stopping Atherosclerosis and Treating Unhealthy bone with RosuvastatiN in HIV (SATURN) trial, an ongoing randomized trial comparing rosuvastatin to placebo in HIV-infected adults on antiretroviral therapy. Plasma sclerostin was measured at study entry by ELISA from participants with available samples. Spearman correlation and multivariable linear regression were used to test relationships between sclerostin and bone density or bone turnover and cardiovascular disease. Among 139 HIV-infected participants (median age 46 years, CD4 lymphocyte count 614 cells/μl), the median plasma sclerostin level was 444.1 (IQR 330.3, 570.1) pg/ml. Correlations were detected between sclerostin and age ( r=0.26), lumbar spine Z-score ( r=0.31), RANKL ( r=−0.21), carotid intima-media thickness (CIMT, r=0.19), and sVCAM-1 ( r=0.27), p<0.05. No significant correlations were detected between sclerostin and current ( r=0.006) or nadir CD4 count ( r=0.11). While associations between sclerostin, lumbar spine Z-score, and sVCAM-1 were robust to covariate adjustment ( p<0.01), association with CIMT was no longer significant ( p=0.08). Our findings provide preliminary support for a relationship between sclerostin and bone mineral density in HIV-infected persons. The Wnt/β-catenin pathway should be investigated as a potential mechanism for loss of bone mineral density in treated HIV infection. [ABSTRACT FROM AUTHOR]

Few studies have evaluated habitual nutrient intake among HIV-infected youth in the United States, even though diet may influence disease progression and risk of comorbidities. This study determined habitual micronutrient and macronutrient intake in HIV-infected youth. HIV-infected subjects and healthy controls 1-25 years old were prospectively enrolled. Nutrient intake was assessed via 24-h dietary recalls performed every 3 months for 1 year and compared to recommended intake from the U.S. Dietary Reference Intakes (DRIs) and Acceptable Macronutrient Distribution Ranges (AMDRs). Subjects with two or more food recalls were analyzed (175 HIV+ and 43 healthy controls). Groups were similar in age, race, sex, body mass index, and kilocalorie intake. In both groups, intake of several micronutrients was below the DRI. In addition, HIV+ subjects had a lower percentage DRI than controls for vitamins A, D, E, pantothenic acid, magnesium, calcium, folate, and potassium. HIV+ subjects' percentage caloric intake from fat was above the AMDR and was higher than controls. Caloric intake was negatively correlated with current and nadir CD4 count. Zinc, riboflavin, and magnesium percentage DRI were positively associated with current CD4 count. In HIV+ subjects not on antiretroviral therapy, HIV-1 RNA levels were negatively correlated with protein intake. HIV+ youth have an inadequate dietary intake of several essential nutrients and poorer dietary intake compared to controls. Intake of some nutrients was associated with important HIV-related factors. Further investigation is warranted to determine the impact of dietary intake of specific nutrients on HIV progression and chronic complication risk in this population. [ABSTRACT FROM AUTHOR]

Antimicrobial peptide LL-37 is produced in response to active vitamin D to exert immunomodulatory effects and inhibits HIV replication in vitro. To date, no studies have investigated LL-37 in HIV-infected patients. This study sought to investigate LL-37 and the relationship to 25-hydroxyvitamin D [25(OH)D] and HIV-related variables in this population. HIV-infected subjects and healthy controls ages 1-25 years old were prospectively enrolled in this cross-sectional study. Fasting plasma LL-37 and 25(OH)D concentrations were measured in duplicate with ELISA. HIV+ subjects (36 antiretroviral therapy (ART)-experienced subjects; 27 ART-naïve subjects) and 31 healthy controls were enrolled. Overall, 93% were black and the median age was 20 years. There was no difference in median (interquartile range) LL-37 between the HIV-infected group and controls [58.3 (46.4,69.5) vs. 51.3 (40.8,98.2) ng/ml, respectively; p=0.57]; however, the ART-experienced group had higher concentrations than the ART-naive group [66.2 (55.4,77.0) vs. 48.9 (38.9,57.9) ng/ml, respectively; p<0.001]. LL-37 was positively correlated with 25(OH)D in controls, but not in HIV-infected groups, and was positively correlated with current CD4 and ΔCD4 (current-nadir) in the ART-experienced group. After adjustment for age, race, sex, and HIV duration, the association between LL-37 and CD4 remained significant. These findings suggest that HIV and/or HIV-related variables may alter the expected positive relationship between vitamin D and LL-37 and should be further investigated. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency is common in HIV-infected populations. In resource-limited settings, vitamin D deficiency has been shown to affect HIV disease progression and mortality in pregnant women, and also increases mother-to-child HIV transmission and mortality in their infants. This study sought to investigate vitamin D status in HIV-infected women compared to healthy controls in a high-income country setting and determine variables associated with vitamin D deficiency. We prospectively enrolled 40 women/infant pairs (16 HIV-infected women/HIV-exposed infant pairs and 24 uninfected/unexposed pairs). In serum cord blood, 25-hydro-xyvitamin D [25(OH)D] concentrations were suboptimal (<30ng/ml) in 100% of subjects from both groups. White race, non-Hispanic ethnicity was the only variable associated with higher serum 25(OH)D concentrations. This high prevalence of vitamin D deficiency, especially among HIV-infected women and their infants, deserves further investigation, as it may have a negative impact on maternal and infant health. [ABSTRACT FROM AUTHOR]

Abacavir has been associated with myocardial infarction in several studies. This may be related to inflammation and endothelial cell activation. We compared changes in inflammation and endothelial activation markers between antiretroviral-riaive adults initiating zidovudine, lamivudine, abacavir, and nonnucleoside reverse transcriptase inhibitor (NNRTI) or this regimen without abacavir. Changes in soluble tumor necrosis factor receptors-I, -II (sTNFR-I, -II), high sensitivity C-reactive protein, and soluble vascular cell adhesion molecule-1 (sVCAM-1) from baseline (pre-ART) to a second time point about 24 weeks after initiating antiretroviral therapy (ART) were compared between groups using multivariable linear regression. A total of 37 met eligibility criteria; 12 received abacavir. The median (interquartile range) age was 37 years (27-45). Most were men (32/37), African-American (15/37), or white (15/37). The median nadir CD4+ and baseline HIV-1 RNA were 230 cells/ mm³ (180-301) and 82,642 copies/ml (34,400-204,703). In all, 15/30 smoked, 7/37 had hypertension, 1/37 had diabetes, and 1/37 had hyperlipidemia. None had coronary or renal disease. Changes in CD4+ and HTV-l RNA level and timing of stored samples with regard to ART initiation were not different between groups. In univariable analysis, log transformed percent change in sTNFR-I (p = 0.05) and -II (p = 0.04) showed significant between-group differences and trended toward significance for sVCAM-1 (p = 0.08). These markers decreased less in the abacavir group. After adjustment for confounders, significantly less decrease for sTNFR-II and sVCAM-1 was seen for those receiving the abacavir-containing regimen. When taken with an NNRTI, abacavir induced a smaller decrease in inflammation biomarkers in this cohort, suggesting a possible proinflammatory effect of this nucleoside analogue. [ABSTRACT FROM AUTHOR]

Lipohypertrophy in HIV-infected patients is associated with metabolic abnormalities. Raltegravir (RAL) is not known to induce fat changes or severe metabolic perturbations. HIV-infected women with central adiposity and HIV-1 RNA less than 50 copies per milliliter on non-nucleoside reverse transcriptase inhibitor (NNRTI)- or protease inhibitor (PI)-based antiretroviral therapy (ART) continued their nucleoside reverse transcriptase inhibitor (NRTI) backbone and were randomized to switch to open label RAL immediately or after 24 weeks. The primary end point was 24-week between-group change in computed tomography (CT)-quantified visceral adipose tissue (AT) volume. Fasting lipids, glucose, C-reactive protein (CRP), anthropometric measurements, and patient-reported quality of life assessments were also measured. Thirty-six subjects provided 80% power to detect a 10% between-group difference in visceral AT over 24 weeks. Thirty-seven of 39 enrolled subjects completed week 24. At entry, subjects were 75% black or Hispanic, and on 62% PI-based and 38% NNRTI-based regimens. The median age was 43 years, CD4 count 558 cells per microliter, and body mass index (BMI) 32 kg/m2. After 24 weeks, no statistically significant changes in visceral or subcutaneous AT, anthropometrics, BMI, glucose, or CRP were observed. In subjects receiving RAL, significant improvements in total and LDL cholesterol ( p=0.04), self-reported belly size ( p=0.02) and composite body size ( p=0.02) were observed. Body size changes correlated well with percent visceral AT change. No RAL-related adverse events occurred. Compared to continued PI or NNRTI, switch to RAL was associated with statistically significant 24-week improvements in total and LDL cholesterol but not AT volumes. Additional insights into AT and metabolic changes in women on RAL will be provided by 48-week follow-up of the immediate-switch arm. [ABSTRACT FROM AUTHOR]

Central fat accumulation is increasingly recognized as a problem for patients with HIV infection. The term “lipodystrophy” has been used to describe collectively a constellation of body habitus changes and metabolic abnormalities commonly observed in HIV-infected patients, particularly since the advent of highly active antiretroviral therapy. Visceral fat accumulation can place patients at increased risk of coronary artery disease. Furthermore, body shape changes are a source of distress to patients that may compromise treatment adherence. Reduction of abdominal obesity can therefore be considered part of therapy in HIV-positive patients with visceral adipose tissue (VAT) accumulation. Currently, there are no drugs approved by the Food and Drug Administration for the treatment of HIV-associated central fat accumulation. Lifestyle modifications such as diet and exercise and switching antiretroviral therapies appear to be of limited value in reducing VAT. Metformin has shown some benefit in reducing VAT but at the expense of accelerating peripheral fat loss, and the thiazolidinediones have no effect on VAT. Similarly, testosterone does not appear to reduce VAT in these patients, and there are no data on anabolic steroids. Two large, randomized controlled trials have demonstrated the efficacy of recombinant human growth hormone (rhGH) in reducing visceral adipose tissue. There are also promising data regarding treatment with growth hormone releasing hormone (GHRH). [ABSTRACT FROM AUTHOR]

The article focuses on according to a study antiretroviral therapy (ART) with increased fractures in HIV infected are not associated with activation of CD8+ T Cell. It states that Activated CD8+ T cells were measured on peripheral blood mononuclear cell (PBMC) samples and activated CD8 was associated with increased hazard of fracture but continuous activated CD8 was not associated with fracture. It mentions that there is no role of chronic immune activation with HIV infection in bone loss.