Background

We examined whether waist circumference (WC) and self-reported abdominal size changes can estimate visceral adipose tissue (VAT) changes for those initiating antiretroviral therapy (ART).

Methods

Prospectively collected data from ACTG A5257 and its metabolic substudy, A5260s, were used for this analysis. ART-naive HIV-infected participants were randomized to one of three contemporary ART regimens. Changes in abdominal CT-measured VAT and total adipose tissue (TAT) and DXA-measured trunk fat were tested for association with WC changes (by Pearson correlation) and categories of self-reported abdominal size changes (by ANOVA) between entry and week 96. Linear models compared WC and self-reported changes.

Results

The study population (n=328) was predominantly male (90%) and White non-Hispanic (44%) with a baseline median age of 36 years and body mass index of 25 kg/m². At week 96, median WC change was +2.8 cm. Of those reporting at week 96, 53% indicated 'no change/lost', 39% 'gained some/somewhat larger' and 8% 'gained a lot/much larger' as their self-reported changes. Trunk fat, VAT and TAT changes differed across self-reported groups (ANOVA P<0.0001 for all), and the group ordering was as expected. WC changes were strongly correlated with CT and DXA changes (trunk fat: ρ=0.72, p<0.0001; VAT: ρ=0.52, p<0.0001; TAT: ρ=0.62, p<0.0001). While WC changes explained a greater proportion of VAT, TAT and trunk fat variation, self-reported changes remained a significant predictor after controlling for WC (p<0.05).

Conclusions

WC and self-reported abdominal changes each correlated directly with imaging-derived abdominal fat measures, and can be used as reliable, affordable tools for central adiposity assessment.

Background

This study investigates the association of clinical and demographic predictors with abdominal fat gain, measured using waist circumference (WC) and self-reported abdominal size.

Methods

We analyzed data from ACTG A5257, a clinical trial that randomized treatment-naïve HIV-infected participants to 1 of 3 antiretroviral regimens: raltegravir (RAL) or the protease inhibitors (PIs) atazanavir/ritonavir (ATV/r) or darunavir/ritonavir (DRV/r), each in combination with tenofovir disoproxil fumarate/emtricitabine. Associations of treatment and baseline/demographic characteristics with 96-week WC change were assessed using repeated-measures models. Ordinal logistic regression was used to examine the associations of predictors with week 96 self-reported abdominal changes.

Results

The study population (n = 1809) was 76.0% male and predominantly black non-Hispanic (41.9%) and white non-Hispanic (34.1%). Mean baseline WC was 90.6 cm, with an average 96-week increase of 3.4 cm. WC increases were higher in the RAL arm compared with DRV/r (P = .0130). Females experienced greater increases in WC on RAL vs ATV/r than males (P = .0065). Similarly, a larger difference in WC change was found for RAL vs DRV/r for black vs nonblack individuals (P = .0043). A separate multivariable model found that in addition to the treatment regimen, higher baseline viral load and lower CD4+ were also associated with WC increases.

Conclusions

With antiretroviral therapy initiation, higher WC increases in the RAL arm compared with PIs were more pronounced in female and black participants, and a more advanced baseline HIV disease state was a strong predictor of larger abdominal increases. Understanding factors predisposing individuals to abdominal fat gain could inform health management after therapy initiation.

Background

Inflammation is associated with the downregulation of drug metabolizing enzymes and transporters. Thus, we investigated the chronic inflammatory state associated with HIV infection as a source of pharmacokinetic variability of atazanavir. We also explored the association of total bilirubin concentrations with markers of inflammation and endothelial activation.

Methods

Apparent oral clearance (CL/F) of atazanavir was estimated from plasma samples collected from participants in AIDS Clinical Trials Group Study A5202. Several inflammatory and endothelial activation biomarkers were measured at baseline and weeks 24 and 96 as part of metabolic substudy A5224s: high-sensitivity C-reactive protein (hsCRP), interleukin-6, tumour necrosis factor-α and its soluble receptors, soluble vascular cellular and intracellular adhesion molecules and total bilirubin. Statistical analysis was performed by a matrix of correlation coefficients between atazanavir CL/F and biomarker concentrations measured at week 24. The correlation between atazanavir clearance and percentage change in bilirubin from baseline to weeks 24 and 96, and between biomarkers and bilirubin concentrations at each week were also evaluated.

Results

Among 107 participants, there were no significant correlations observed between atazanavir CL/F and inflammatory and endothelial activation biomarkers measured at week 24 (P≥0.24). As expected, bilirubin increased with increasing exposure to atazanavir (rho=-0.25, P=0.01). Bilirubin concentrations were inversely correlated (P<0.01) with each of the biomarkers except hsCRP.

Conclusions

Atazanavir CL/F did not correlate with the inflammatory biomarkers changes. Inflammatory-mediated inhibition of cytochrome P450 3A may have been attenuated due to atazanavir-associated increases of bilirubin, which has known anti-inflammatory properties.

Human immunodeficiency virus-infected women with central adiposity switched to raltegravir-based antiretroviral therapy immediately or after 24 weeks. No statistically significant changes in computed tomography-quantified visceral adipose tissue (VAT) or subcutaneous fat were observed, although 48 weeks of raltegravir was associated with a 6.4% VAT decline. Raltegravir for 24 weeks was associated with improvements in lipids.

Background.  Antiretroviral therapy (ART) can alter glucose metabolism, but little data exist on the association of raltegravir (RAL) with insulin resistance. Methods.  A5260s was a substudy of A5257, a prospective open-label randomized trial in which human immunodeficiency virus (HIV)-infected treatment-naive participants were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or RAL over 96 weeks. Baseline and changes in insulin resistance as estimated by the homeostatic model assessment of insulin resistance (HOMA-IR) were assessed. Wilcoxon rank-sum tests were used to assess shifts in the distribution of fold increase from baseline between treatment arms, and Spearman correlation was used to assess associations between HOMA-IR and measures of inflammation and body composition. Results.  Three hundred twenty-eight participants were randomized; 90% were male, baseline median age was 36, HIV ribonucleic acid copies were 4.55 log₁₀ copies/mL, and CD4 cell count was 349/mm³. Overall, HOMA-IR increased significantly after 4 weeks (1.9-fold change; 95% confidence interval, 1.73-2.05) then plateaued over the remainder of the study. Changes in HOMA-IR were not different between the arms (P ≥ .23). Changes in HOMA-IR were associated with changes in body mass index at weeks 48 and 96 (r = 0.12-0.22; P ≤ .04). There was a trend with increases in HOMA-IR and increases in visceral abdominal fat at week 96 (r = 0.12; P = .06). At 48 and 96 weeks, HOMA-IR correlated with interleukin-6, high-sensitivity C-reactive protein, and soluble CD163 (r = 0.16-0.27; P ≤ .003). Conclusions.  Insulin resistance increased rapidly and then plateaued in treatment-naive participants initiating ART with TDF/FTC, and no differences were found with RAL when compared with ATV/r or DRV/r.

Background

The adipokines leptin and adiponectin, produced primarily by adipose tissue, have diverse endocrine and immunologic effects, and circulating levels reflect adipocyte lipid content, local inflammation, and tissue composition. We assessed relationships between changes in regional fat depots, leptin and adiponectin levels, and metabolic and inflammatory markers over 96 weeks in the AIDS Clinical Trials Group (ACTG) A5260s metabolic substudy of the A5257 randomized trial of tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir among treatment-naive persons with human immunodeficiency virus (PWH).

Methods

Fat depots were measured using dual-energy absorptiometry and abdominal computed tomographic imaging at treatment initiation and 96 weeks later. Serum leptin and adiponectin, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP) were measured at the same timepoints. Multivariable regression models assessed relationships between fat depots, adipokines, HOMA-IR, and hsCRP at week 96.

Results

Two hundred thirty-four participants maintained viral suppression through 96 weeks (90% male, 29% black, median age 36 years). Serum leptin increased over 96 weeks (mean change 22%) while adiponectin did not (mean change 1%), which did not differ by study arm. Greater trunk, limb, and abdominal subcutaneous and visceral fat were associated with higher HOMA-IR and hsCRP at 96 weeks, but serum leptin level was a stronger determinant of these endpoints using a mediation model approach. A similar mediating effect was not observed for adiponectin.

Conclusions

Higher circulating leptin is associated with greater HOMA-IR and hsCRP independent of fat depot size, suggesting that greater adipocyte lipid content may contribute to impaired glucose tolerance and systemic inflammation among PWH starting antiretroviral therapy.

Background

The contributions of the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) axis to cardiovascular and bone disease in treated HIV-1 infection are not well defined.

Setting

Prospective, observational, longitudinal study.

Methods

In a subset analysis of a prospective randomized clinical trial, 234 HIV-1-infected antiretroviral therapy-naive participants received tenofovir-emtricitabine plus either atazanavir/ritonavir, darunavir/ritonavir, or raltegravir and achieved plasma HIV-1 RNA <50 copies per milliliter by week 24 and thereafter. Associations between plasma RANKL, OPG, or RANKL/OPG ratio levels with total, hip, and spine bone mineral density (BMD) loss or progression of carotid artery intima-media thickness were assessed longitudinally over 96 weeks.

Results

Over 96 weeks, all treatment groups had similar and sustained declines in plasma RANKL, increases in plasma OPG, and subsequently, decreases in the RANKL/OPG ratio. There were no associations between plasma RANKL or RANKL/OPG ratio levels with total, hip, and spine BMD loss or progression of carotid artery intima-media thickness; however, plasma OPG in successfully treated HIV-infected patients (week 48 and 96) was associated with spine BMD loss.

Conclusions

In virologically suppressed HIV-infected patients, the evolution of bone disease could be linked to plasma OPG levels; however, the role of plasma levels of RANKL and RANKL/OPG ratio in the prediction of morbidity in treated HIV-1 infection may be limited.

It is unclear whether differential roles of CD4(+) versus CD8(+) T-cell senescence/exhaustion and effects of antiretroviral therapy (ART) on these processes may contribute to morbidity in treated human immunodeficiency virus type 1 (HIV) infection. In a prospective 96-week trial, 328 HIV-infected ART-naive participants were randomly assigned to receive tenofovir-emtricitabine plus either atazanavir/ritonavir, darunavir/ritonavir, or raltegravir. Markers of CD4(+) T-cell senescence (ie, the percentage of CD28(-)CD57(+) cells among CD4(+) T cells ) and CD4(+)/CD8(+) T-cell exhaustion (ie, the percentage of PD-1(+) cells among CD4(+)/CD8(+) T cells) decreased after ART. There were no changes in markers of CD8(+) T-cell senescence after ART and no differential changes in all markers in ART groups. Senescent CD4(+) and CD8(+) T cells may have differential roles in HIV pathogenesis.

Objective

The pathogenesis of immune dysfunction in chronic HIV-1 infection is unclear, and a potential role for oxidized lipids has been suggested. We hypothesize that both oxidized HDL and LDL (HDLox and LDLox) contribute to HIV-1-related immune dysfunction.

Study

In the AIDS Clinical Trials Group A5260, 234 HIV-infected antiretroviral therapy (ART)-naive participants were randomized to receive tenofovir-emtricitabine and protease inhibitors or raltegravir and had HIV-1 RNA less than 50 copies/ml by week 24 and thereafter.

Methods

Associations between biomarkers of inflammation (IL-6, high-sensitivity C-reactive protein and D-dimer), immune activation (sCD163, sCD14, soluble IL-2 receptor, CD38 and HLA-DR), inflammatory monocytes (CD14CD16), T-cell senescence (CD28 and CD57) and exhaustion (PD1), and HDLox, LDLox were assessed at entry and after ART (week 96) with Spearman (partial) correlations.

Results

HDLox declined and LDLox increased over 96 weeks of ART. Positive associations were observed at baseline and over time between HDLox (but not consistently for LDLox) and most markers of inflammation and immune activation (but not senescence/exhaustion), even after adjustment for multiple comparisons, demographics, entry CD4 cell count and HIV-1 RNA. HDLox was positively associated with IL-6 (r = 0.19 - 0.29, P < 0.01) and sCD163 (r = 0.14 - 0.41, P ≤ 0.04) at all time points.

Conclusion

These prospective longitudinal data suggest that oxidized lipoproteins may contribute to persistent immune activation on ART.

Background

Fat accumulation and insulin resistance remain a threat to the success of antiretroviral therapy (ART). The role of gut dysfunction in metabolic complications associated with ART initiation is unclear.

Methods

Human immunodeficiency virus (HIV)-infected ART-naive participants were randomized to tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir (RAL). Changes in the gut integrity markers zonulin, lipopolysaccharide-binding protein (LBP), and intestinal fatty acid and ileal bile acid binding proteins (I-FABP and I-BABP) were assessed over 96 weeks. Wilcoxon rank-sum tests were used to compare changes between groups and linear regression models to quantify associations between gut markers, insulin resistance, body mass index (BMI), and visceral, subcutaneous, and total adipose tissue (VAT, SAT, and TAT).

Results

: 90% were male and 48% were White non-Hispanic. The median age was 36 years, HIV-1 ribonucleic acid was 4.56 log10 copies/mL, and CD4 count was 338 cells/µL. An overall 1.7-fold increase in I-FABP was observed throughout 96 weeks, with no difference between arms. Zonulin levels increased with RAL compared to protease inhibitor-based regimens (week 96, P = .02); minimal changes in I-BABP or LBP levels were observed. Higher baseline I-FABP levels were associated with increases in VAT, TAT, and BMI (16%, 9%, and 2.5%, respectively; P < .04) over 96 weeks.

Conclusions

While ART induces changes in the markers of gut barrier dysfunction, the extent to which they improve or worsen the gut barrier function remains unclear. Nevertheless, markers of gut barrier dysfunction in ART-naive individuals predict increases in total and visceral abdominal fat with treatment initiation.