Is bone loss linked to chronic inflammation in antiretroviral-naive HIV-infected adults? A 48-week matched cohort study.

OBJECTIVE: Antiretroviral therapy (ART) has been implicated in bone loss in HIV. The role of inflammation and vitamin D is unclear and better investigated in ART-naive individuals. DESIGN AND METHODS: This is a 48-week, prospective cohort study to compare baseline and change in hip and spine bone mineral density (BMD) measured by dual-energy X-ray absorptiometry in HIV-infected, ART-naive adults and healthy controls matched by age, sex, and race. We also studied associations between bone loss and inflammation markers and plasma 25-hydroxyvitamin D [25(OH)D] using logistic regression. RESULTS: Forty-seven HIV-infected adults and 41 controls were included. Baseline 25(OH)D, BMD at total hip, trochanter, and spine, and prevalence of osteopenia and osteoporosis were similar between groups. In the HIV-infected group, total hip and trochanter, but not spine, BMD decreased over 48 weeks [hip -0.005 (-0.026-0.008) g/cm², P = 0.02 within group; trochanter -0.013 (-0.03-0.003), P < 0.01]. BMD did not change at any site within controls. The HIV-infected group was more likely to have bone loss at the trochanter (P = 0.03). This risk persisted after adjustment for age, sex, race, BMI, smoking, and hepatitis C (odds ratio 4, 95% confidence interval 1.2-15.8). In the HIV-infected group, higher interleukin-6 concentrations (P = 0.04) and Caucasian race (P < 0.01) were independently associated with progression to osteopenia or osteoporosis, but not 25(OH)D levels. CONCLUSION: BMD at the total hip and trochanter sites decreased in the HIV-infected, ART-naive adults, but not controls, over this 48-week study. Higher serum interleukin-6 concentrations were associated with progression to osteopenia or osteoporosis status in the HIV-infected group.

Soluble CD14 is independently associated with coronary calcification and extent of subclinical vascular disease in treated HIV infection.

OBJECTIVE: To use multimodality imaging to explore the relationship of biomarkers of inflammation, T-cell activation and monocyte activation with coronary calcification and subclinical vascular disease in a population of HIV-infected patients on antiretroviral therapy (ART). DESIGN: Cross-sectional. METHODS: A panel of soluble and cellular biomarkers of inflammation and immune activation was measured in 147 HIV-infected adults on ART with HIV RNA less than 1000 copies/ml and low-density lipoprotein cholesterol (LDL-C) 130  mg/dl or less. We examined the relationship of biomarkers to coronary calcium (CAC) score and multiple ultrasound measures of subclinical vascular disease. RESULTS: Overall, median (interquartile range, IQR) age was 46 (40-53) years; three-quarters of participants were male and two-thirds African-American. Median 10-year Framingham risk score was 6%. Participants with CAC more than 0 were older, less likely to be African-American and had higher current and lower nadir CD4 T-cell counts. Most biomarkers were similar between those with and without CAC; however, soluble CD14 was independently associated with CAC after adjustment for traditional risk factors. Among those with a CAC score of zero, T-cell activation and systemic inflammation correlated with carotid intima-media thickness and brachial hyperemic velocity, respectively. Compared with normal participants and those with CAC only, participants with increasing degrees of subclinical vascular disease had higher levels of sCD14, hs-CRP and fibrinogen (all P<0.05). CONCLUSION: Soluble CD14 is independently associated with coronary artery calcification, and, among those with detectable calcium, predicts the extent of subclinical disease in other vascular beds. Future studies should investigate the utility of multimodality imaging to characterize vascular disease phenotypes in this population.

Perivascular fat, inflammation, and cardiovascular risk in HIV-infected patients on antiretroviral therapy.

BACKGROUND: HIV-infection is characterized by chronic immune activation that persists despite effective antiretroviral therapy (ART) and is associated with elevated cardiovascular risk. Whether specific perivascular fat depots are associated with inflammation in HIV is unknown. METHODS: In a cross-sectional study, epicardial (EAT) and thoracic periaortic (TAT) adipose tissue volumes were measured by computed tomography in 100 HIV-infected adults, on stable ART, with LDL-cholesterol ≤130 mg/dL and evidence of heightened T-cell activation (CD8+CD38+HLA-DR+ ≥19%) or increased inflammation (high sensitivity C-reactive protein ≥2 mg/L). RESULTS: Overall, 77% were males and 70% African American. Mean (standard deviation) age and body mass index were 47 (10) years and 28 (6.4) kg/m(2), respectively. All subjects had HIV-1 RNA <1000 copies/mL with mean (standard deviation) CD4+ T cell count of 665 (280) cells/µL; 50% were on a protease inhibitor. EAT and TAT were correlated with each other (r = 0.766, p < 0.0001). Both were associated with metabolic syndrome, atherogenic lipid profile, insulin resistance, total and central body fat, serum biomarkers of inflammation, and soluble CD163, but not with cellular immune activation markers. In multivariable models that adjusted for age, sex, and other measures of adiposity, both perivascular fat depots were independently associated with the presence of coronary calcium. CONCLUSIONS: Perivascular fat is associated with soluble CD163, biomarkers of inflammation, insulin resistance, and subclinical atherosclerosis in this population of virologically suppressed HIV-infected patients on ART. The association of perivascular fat with coronary artery calcification appears to be independent of other measures of adiposity.

Rate and predictors of carotid artery intima media thickness progression in antiretroviral-naive HIV-infected and uninfected adults: a 48-week matched prospective cohort study.

BACKGROUND: Carotid intima media thickness (CIMT) progresses faster in HIV-infected adults on antiretroviral therapy (ART) than the general population. It is unclear if the rate of progression is similarly faster in ART-naive, HIV-infected adults. METHODS: This was a 48-week prospective cohort study to compare change in CIMT and inflammation markers in ART-naive, HIV-infected adults in no immediate need of ART (HIV-positive/ART-naive) and age/sex/body mass index (BMI)-matched controls (HIV-negative). RESULTS: A total of 85 HIV-positive/ART-naive and 45 HIV-negative participants were enrolled. In the HIV-positive/ART-naive group, median baseline CD4+ T-cell count and HIV-1 RNA were 535 cells/mm3 and 6,916 copies/ml. Baseline common carotid artery (CCA) and bulb CIMTs were similar between groups. Changes in CIMT to 48 weeks at both sites were not different within- or between-groups (median [IQR] change in HIV-positive/ART-naive versus HIV-negative CCA CIMT -0.0071 mm [-0.0267-0.0233] versus 0.0113 mm [-0.0117-0.0306]; P = 0.19 between-groups; and bulb CIMT 0.0017 mm [-0.0367-0.06167] versus 0.01 mm [-0.0383-0.0625]; P = 0.54). After adjustment for cardiovascular disease (CVD) risk factors, change in CCA CIMT was greater in HIV-negative participants (-0.0046 versus 0.0177 mm for HIV-positive/ART-naive versus HIV-negative; P = 0.01). In HIV-positive/ART-naive, interleukin (IL)-6, soluble tumour necrosis factor-α receptor (sTNFR)-II, vascular cell adhesion molecule-1 and intercellular adhesion molecule (ICAM)-1 were higher at both time points and D-dimer was higher at week 48 (P < 0.01 for all). IL-6, sTNFR-I and D-dimer increased over 48 weeks in HIV-positive/ART-naive participants (P < 0.01 for all). In HIV-positive/ART-naive participants, independent predictors of greater change in CCA CIMT were higher BMI (P = 0.05) and family history of CVD (P < 0.01) and of greater change in bulb CIMT were higher sTNFR-I (P = 0.03) and higher diastolic blood pressure (P < 0.01). CONCLUSIONS: In ART-naive HIV-infected adults at low risk of HIV disease progression and low cardiovascular risk, CIMT progression rate was similar to matched controls. In addition to traditional CVD risk factors, higher levels of sTNFR-I predicted greater bulb CIMT changes.

Elevated D-dimer is independently associated with endothelial dysfunction: a cross-sectional study in HIV-infected adults on antiretroviral therapy.

BACKGROUND: D-Dimer elevations have been associated with a striking increase in mortality in HIV-infected patients. However, D-Dimer has not been directly linked to endothelial dysfunction in HIV. METHODS: In this cross-sectional study, we used flow-mediated dilation (FMD) of the brachial artery to measure endothelial function and several biomarkers to measure systemic inflammation and coagulation activation in HIV-infected adults on stable antiretroviral therapy with HIV-1 RNA levels <400 copies/ml. Multivariable linear regression was used to model FMD by these markers, traditional cardiovascular risk factors and HIV-related characteristics. RESULTS: Analysis included 98 subjects (88% male, median age 47.5 years, CD4(+) T-cells 578.5 cells/mm(3)); all on ART (52% on protease inhibitors). The only factors independently associated with FMD were D-Dimer and body mass index. CONCLUSIONS: We show for the first time an independent association between D-Dimer and endothelial dysfunction in virologically suppressed, HIV-infected adults on stable antiretroviral therapy, potentially explaining the link between D-Dimer and mortality in HIV.

Vitamin D supplementation and endothelial function in vitamin D deficient HIV-infected patients: a randomized placebo-controlled trial.

BACKGROUND: Studies suggest that vitamin D deficiency is a risk factor for cardiovascular disease and diabetes. Vitamin D deficiency is prevalent in HIV patients but the effect of vitamin D supplementation on cardiovascular risk in this population is unknown. METHODS: We conducted a randomized, double-blind, placebo-controlled trial among 45 HIV-infected adults in Cleveland (OH, USA) on stable antiretroviral therapy with durable virological suppression and a baseline serum 25-hydroxyvitamin D level of ≤20 ng/ml. Participants were randomized 2:1 to vitamin D3 4,000 IU daily or placebo for 12 weeks. The primary outcome was a change in flow-mediated brachial artery dilation (FMD). RESULTS: Baseline demographics were similar except for age (vitamin D versus placebo, mean ±sd 47 ±8 versus 40 ±10 years; P=0.009). Both groups had reduced FMD at baseline (median values 2.9% [IQR 1.6-4.8] for vitamin D versus 2.5% [IQR 1.7-6.4] for placebo; P=0.819). Despite an increase in the concentration of serum 25-hydroxyvitamin D from baseline to 12 weeks (5.0 ng/ml [IQR -0.9-7.4] versus -1.9 ng/ml [IQR -4.0-0.1] for vitamin D versus placebo, respectively; P=0.003), there was no difference in FMD change (0.55% [IQR -1.05-2.13] versus 0.29% [IQR -1.61-1.77]; P=0.748). Vitamin D supplementation was associated with a decrease in total and non-high-density lipoprotein cholesterol, and an increase in indices of insulin resistance. CONCLUSIONS: Among HIV-infected individuals with vitamin D deficiency, supplementation with 4,000 IU vitamin D3 daily for 12 weeks modestly improved vitamin D status and cholesterol but worsened insulin resistance without change in endothelial function. The mechanisms of resistance to standard doses of vitamin D and the complex role of vitamin D in glucose metabolism in this population require further investigation.

Omega-3 fatty acids do not improve endothelial function in virologically suppressed HIV-infected men: a randomized placebo-controlled trial.

Omega-3 fatty acids decrease cardiovascular disease (CVD) mortality possibly due to antiinflammatory effect. Inflammation and endothelial dysfunction likely play a role in the heightened CVD risk in HIV. Our goal was to evaluate the effect of omega-3 fatty acids primarily on endothelial function and inflammation in HIV-infected adults with moderate CVD risk on stable antiretroviral therapy. We conducted a 24-week, randomized, double-blind, placebo-controlled study to evaluate the effect of omega-3-acid ethyl esters 1 g twice a day. Flow-mediated dilation (FMD) of the brachial artery, lipoproteins and markers of inflammation, endothelial activation, coagulation, and insulin resistance were measured at entry and week 24. There were no within- or between-group differences in change in FMD over 24 weeks (mean change in FMD -0.13% vs. 1.5% for treatment vs. placebo; p=0.21). There were no between-group differences in changes in lipoprotein levels or biomarkers tested, except soluble tumor necrosis factor receptor-I, which favored omega-3-acid ethyl esters. Omega-3 fatty acids did not improve endothelial function or activation, coagulation, or insulin resistance in virologically suppressed, HIV-infected men with moderate CVD risk; however, inflammation tended to improve. This suggests that omega-3 fatty acids may not be potent enough to counteract the enhanced inflammation and endothelial dysfunction due to HIV and antiretrovirals.