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Effects of 96 Weeks of Rosuvastatin on Bone, Muscle, and Fat in HIV-Infected Adults on Effective Antiretroviral Therapy.
Erlandson, KM, Jiang, Y, Debanne, SM, McComsey, GA
AIDS research and human retroviruses. 2016;(4):311-6
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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.
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Rosuvastatin reduces vascular inflammation and T-cell and monocyte activation in HIV-infected subjects on antiretroviral therapy.
Funderburg, NT, Jiang, Y, Debanne, SM, Labbato, D, Juchnowski, S, Ferrari, B, Clagett, B, Robinson, J, Lederman, MM, McComsey, GA
Journal of acquired immune deficiency syndromes (1999). 2015;(4):396-404
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BACKGROUND Despite suppressive antiretroviral therapy (ART), increased levels of immune activation persist in HIV-infected subjects. Statins have anti-inflammatory effects and may reduce immune activation in HIV disease. METHODS Stopping Atherosclerosis and Treating Unhealthy bone with RosuvastatiN in HIV (SATURN-HIV) is a randomized, double-blind placebo-controlled trial assessing the effect of rosuvastatin (10 mg daily) on markers of cardiovascular risk and immune activation in ART-treated patients. T-cell activation was measured by expression of CD38, HLA-DR, and PD1. Monocyte activation was measured with soluble markers (sCD14 and sCD163) and by enumeration of monocyte subpopulations and tissue factor expression. Markers of systemic and vascular inflammation and coagulation were also measured. SATURN-HIV is registered on clinicaltrials.gov (identifier: NCT01218802). RESULTS Rosuvastatin, compared with placebo, reduced sCD14 (-10.4% vs 0.5%, P = 0.006), lipoprotein-associated phospholipase A2 (-12.2% vs -1.7%, P = 0.0007), and IP-10 (-27.5 vs -8.2%, P = 0.03) levels after 48 weeks. The proportion of tissue factor-positive patrolling (CD14CD16) monocytes was also reduced by rosuvastatin (-41.6%) compared with placebo (-18.8%, P = 0.005). There was also a greater decrease in the proportions of activated (CD38HLA-DR) T cells between the arms (-38.1% vs -17.8%, P = 0.009 for CD4 cells, and -44.8% vs -27.4%, P = 0.003 for CD8 cells). CONCLUSIONS Forty-eight weeks of rosuvastatin treatment reduced significantly several markers of inflammation and lymphocyte and monocyte activation in ART-treated subjects.
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Rosuvastatin Worsens Insulin Resistance in HIV-Infected Adults on Antiretroviral Therapy.
Erlandson, KM, Jiang, Y, Debanne, SM, McComsey, GA
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2015;(10):1566-72
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BACKGROUND Statins are associated with increased diabetes risk in large, human immunodeficiency virus (HIV)-uninfected cohorts; the impact of statins on insulin resistance or diabetes in HIV-infected persons has not been assessed within a randomized controlled study. METHODS HIV-infected participants on stable antiretroviral therapy with a low-density lipoprotein cholesterol level of ≤130 mg/dL and heightened immune activation or inflammation were randomized to rosuvastatin 10 mg daily or placebo for 96 weeks. Fasting serum glucose, insulin, and hemoglobin A1C (HgbA1C) were measured; insulin resistance was estimated by calculating the homeostatic model assessment of insulin resistance (HOMA-IR); and a 2-hour oral glucose tolerance test was administered. RESULTS Seventy-two participants were randomized to rosuvastatin therapy and 75 to placebo. Increases in fasting glucose were observed within both groups but were not different between study arms (P = .115); changes in glucose tolerance and HgbA1C did not differ between study arms (P = .920 and P = .650, respectively). Criteria for diabetes were met by 1 participant in the rosuvastatin and 3 in the placebo arm by week 96. Compared with placebo, rosuvastatin therapy was associated with significantly greater increases in insulin and HOMA-IR (P = .008 and P = .004, respectively). CONCLUSIONS We detected a significant worsening in insulin resistance and an increase in the proportion of participants with impaired fasting glucose but not a clinical diagnosis of diabetes in the rosuvastatin arm. Our findings suggest that prescription of statin therapy should be accompanied by a careful consideration of the risks and benefits, particularly in patients with lower cardiovascular disease risk. CLINICAL TRIALS REGISTRATION NCT01218802.
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Rosuvastatin treatment reduces markers of monocyte activation in HIV-infected subjects on antiretroviral therapy.
Funderburg, NT, Jiang, Y, Debanne, SM, Storer, N, Labbato, D, Clagett, B, Robinson, J, Lederman, MM, McComsey, GA
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2014;(4):588-95
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BACKGROUND Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have anti-inflammatory effects that are independent of their lipid-lowering properties. Despite suppressive antiretroviral therapy (ART), elevated levels of immune activation and inflammation often persist. METHODS The Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV (SATURN-HIV) trial is a randomized, double-blind, placebo-controlled study, designed to investigate the effects of rosuvastatin (10 mg/daily) on markers of cardiovascular disease risk in ART-treated human immunodeficiency virus (HIV)-infected subjects. A preplanned analysis was to assess changes in markers of immune activation at week 24. Subjects with low-density lipoprotein cholesterol <130 mg/dL and heightened immune activation (%CD8(+)CD38(+)HLA-DR(+) ≥19%, or plasma high-sensitivity C-reactive protein ≥2 mg/L) were randomized to receive rosuvastatin or placebo. We measured plasma (soluble CD14 and CD163) and cellular markers of monocyte activation (proportions of monocyte subsets and tissue factor expression) and T-cell activation (expression of CD38, HLA-DR, and PD1). RESULTS After 24 weeks of rosuvastatin, we found significant decreases in plasma levels of soluble CD14 (-13.4% vs 1.2%, P = .002) and in proportions of tissue factor-positive patrolling (CD14(Dim)CD16(+)) monocytes (-38.8% vs -11.9%, P = .04) in rosuvastatin-treated vs placebo-treated subjects. These findings were independent of the lipid-lowering effect and the use of protease inhibitors. Rosuvastatin did not lead to any changes in levels of T-cell activation. CONCLUSIONS Rosuvastatin treatment effectively lowered markers of monocyte activation in HIV-infected subjects on antiretroviral therapy. CLINICAL TRIALS REGISTRATION NCT01218802.
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Effect of 24 weeks of statin therapy on systemic and vascular inflammation in HIV-infected subjects receiving antiretroviral therapy.
Eckard, AR, Jiang, Y, Debanne, SM, Funderburg, NT, McComsey, GA
The Journal of infectious diseases. 2014;(8):1156-64
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BACKGROUND Human immunodeficiency virus (HIV)-infected individuals are at increased risk of cardiovascular disease (CVD) due in part to inflammation. Statins decrease inflammation in the general population, but their effect during HIV infection is largely unknown. METHODS This is an ongoing randomized, double-blinded, placebo-controlled trial to evaluate the effect of statin therapy on inflammatory markers during HIV infection. Subjects received rosuvastatin 10 mg daily or placebo for 24 weeks. Subjects were receiving stable (>12 weeks) antiretroviral therapy and had a low-density lipoprotein (LDL) cholesterol level of ≤130 mg/dL and evidence of heightened immune activation or inflammation. This was a prespecified interim analysis. RESULTS A total of 147 subjects were enrolled (78% were male, 70% were black, and the median age was 47 years). By 24 weeks, LDL cholesterol levels had decreased in the statin group, compared with an increase in the placebo group (-28% vs +3.8%; P < .01). A 10% reduction in the lipoprotein-associated phospholipase A2 (Lp-PLA2) level was seen in the statin group, compared with a 2% reduction in the placebo group (P < .01). In multivariable regression, receipt of statin treatment and having a nadir CD4(+) T-cell count of ≤100 cell/µL were the only statistically significant predictors of a decrease in Lp-PLA2 level. Markers of systemic inflammation did not change significantly between groups. CONCLUSIONS Twenty-four weeks of rosuvastatin therapy significantly decreased the level of Lp-PLA2, a vascular-specific, inflammatory enzyme that predicts cardiovascular events in the general population. Statins may hold promise as a means of attenuating CVD risk in HIV-infected individuals by decreasing Lp-PLA2 levels.