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HIV vasculopathy: role of mononuclear cell-associated Krüppel-like factors 2 and 4.
Hale, AT, Longenecker, CT, Jiang, Y, Debanne, SM, Labatto, DE, Storer, N, Hamik, A, McComsey, GA
AIDS (London, England). 2015;(13):1643-50
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Abstract
OBJECTIVE To determine the relationships between Krüppel-like factors (KLF) 2 and 4, immune-activation, and subclinical vascular disease in HIV-infected patients on antiretroviral therapy (ART). DESIGN Double-blind, randomized, placebo-controlled trial. METHODS We studied 74 HIV-infected adults on ART enrolled in a randomized clinical trial of statin therapy. KLF2 and KLF4 gene expression was measured by quantitative PCR from peripheral blood mononuclear cells (PBMCs) at baseline and after 24 weeks of 10 mg daily rosuvastatin or placebo. At the same time points, T-cell and monocyte activation were assessed by flow cytometry and vascular health was assessed by cardiac computed tomography and carotid ultrasound. RESULTS KLF4 expression was negatively correlated with duration of ART (r = -0.351, P = 0.004) and positively correlated with measures of immune activation: proinflammatory monocytes [CD14CD16 (r = 0.343, P = 0.003)], patrolling monocytes [CD14CD16 (r = 0.276, P = 0.017)], and activated CD8 T-lymphocytes [CD8DRCD38 (r = 0.264, P = 0.023)]. KLF2 expression was negatively correlated with subclinical atherosclerosis: mean-mean common carotid artery intima-media thickness (r = -0.231, P = 0.048), mean-max carotid artery intima-media thickness (r = -0.271, P = 0.020), and coronary artery calcium score (r = -0.254, P = 0.029). There were no statistically significant changes in KLF2/4 expression in PBMCs after 24 weeks of rosuvastatin. CONCLUSION Expression of KLF4 in PBMCs positively correlates with cellular markers of immune activation, whereas KLF2 expression negatively correlates with markers of subclinical atherosclerosis in this HIV-infected population on ART. Additional studies are needed to determine if targeted interventions might alter KLF2/4 expression to reduce inflammation and vascular risk in humans.
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Effects of randomized rosuvastatin compared with placebo on bone and body composition among HIV-infected adults.
Erlandson, KM, Jiang, Y, Debanne, SM, McComsey, GA
AIDS (London, England). 2015;(2):175-82
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Abstract
BACKGROUND Statins have a beneficial effect on bone mineral density (BMD) and lean mass in some studies of HIV-uninfected adults; however, this has never been investigated in the setting of HIV infection. DESIGN HIV-infected individuals on stable antiretroviral therapy with a low-density lipoprotein cholesterol level of 130 mg/dl or less and evidence of heightened immune activation or inflammation were randomized to rosuvastatin 10 mg daily or placebo for 96 weeks. METHODS This was a prespecified interim analysis at 48 weeks. Between-group and within-group differences were compared; multivariable regression models were constructed. RESULTS Seventy-two individuals were randomized to statin therapy and 75 to placebo. Modest 48-week relative increases in trochanter BMD [0.9%; 95% confidence interval (95% CI) -0.9 to 0.6] and total hip BMD (0.6%; 95% CI 0.0-1.1) in the statin arm were significantly greater than placebo (P < 0.05). The relationship between statin use and total hip BMD change was robust to adjustment of age, sex, race and smoking status (P = 0.02) and strengthened by inclusion of baseline (P = 0.01) and week 48 change in soluble tumour necrosis factor-α receptor (sTNFR)-1 (P = 0.009). Relative increases in total body, trunk and limb fat were similar between statin and placebo arms (P ≥ 0.58). Although a significant gain in leg lean mass was seen in the statin arm, this was not significantly different compared with placebo (P = 0.36). CONCLUSION The improvements seen in total hip BMD after 48 weeks of rosuvastatin therapy support further potential benefits of statin therapy in HIV, beyond a reduction of cardiovascular risk.