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Short Communication: The Effect of Rosuvastatin on Vascular Disease Differs by Smoking Status in Treated HIV Infection.
Hileman, CO, McComsey, GA
AIDS research and human retroviruses. 2018;(3):282-285
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Abstract
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 (SATURN-HIV), 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.
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Significant Decrease in Plasma Levels of D-Dimer, Interleukin-8, and Interleukin-12 After a 12-Month Treatment with Rosuvastatin in HIV-Infected Patients Under Antiretroviral Therapy.
Calza, L, Colangeli, V, Magistrelli, E, Contadini, I, Bon, I, Re, MC, Conti, M, Mancini, R, Viale, P
AIDS research and human retroviruses. 2017;(2):126-132
Abstract
OBJECTIVES Statins have shown anti-inflammatory and immune-modulatory properties in both general and HIV-infected population, but their effect on plasma D-dimer levels is controversial and it has not been investigated to date in HIV-positive patients. The aim of our study was to assess the effect of rosuvastatin on D-dimer and other serum inflammation markers among these subjects. METHODS Prospective, cohort study of HIV-1-infected adult patients receiving a stable combination antiretroviral therapy (cART), who started a lipid-lowering therapy with rosuvastatin (10 mg daily) and were followed up for at least 12 months. The primary endpoint was the change at month 12 in the median plasma concentration of D-dimer. The secondary endpoints included the variation in median plasma levels of these inflammatory biomarkers: interleukin-8 (IL-8), interleukin-10 (IL-10), and interleukin-12 (IL-12). RESULTS Sixty-two patients were enrolled in the study, and the endpoints were available for 54 subjects. After 12 months, a significant decrease in median plasma concentration of D-dimer was observed (-21.4%; interquartile range [IQR], -35.5; -4.2; p = .029). With regard to the inflammatory biomarkers, a significant decrease in median levels of IL-8 (-24.6%; IQR, -30.8; -1.8; p = .012) and IL-12 (-18.7%; IQR, -25.8; +2.5; p = .033) was also observed. Rosuvastatin led to a significant reduction in serum lipid values and showed a good tolerability profile. CONCLUSIONS Our findings show that a 12-month treatment with rosuvastatin associated with an effective cART can significantly decrease the plasma levels of D-dimer, IL-8, and IL-12, and suggest a potential role for this statin to reduce activated coagulation and systemic inflammation among HIV-infected persons.
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Autoantibodies and immune complexes to oxidation-specific epitopes and progression of aortic stenosis: Results from the ASTRONOMER trial.
Capoulade, R, Chan, KL, Mathieu, P, Bossé, Y, Dumesnil, JG, Tam, JW, Teo, KK, Yang, X, Witztum, JL, Arsenault, BJ, et al
Atherosclerosis. 2017;:1-7
Abstract
BACKGROUND AND AIMS Elevated levels of lipoprotein(a) [Lp(a)] and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) predict the progression of pre-existing mild-to-moderate calcific aortic valve stenosis (CAVS). Whether indirect markers of oxidation-specific epitopes (OSE) are also predictive is not known. The association between IgG and IgM autoantibodies and malondialdehyde-modified low density lipoprotein (MDA-LDL) and IgG and IgM apolipoprotein B immune complexes (apoB-IC), and the hemodynamic progression rate of CAVS was determined in the ASTRONOMER (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin, NCT00800800) trial. METHODS Plasma levels of IgG and IgM MDA-LDL and apoB-IC were measured in 220 patients with mild-to-moderate CAVS from the ASTRONOMER trial. The endpoint of this study was the progression rate of CAVS, measured by the annualized increase in peak aortic jet velocity (Vpeak) over a median follow-up of 3.5 [2.9-4.5] years. RESULTS There was no difference in the progression rate of CAVS across tertiles of IgG and IgM MDA-LDL and apoB-IC levels (all p > 0.05). After multivariable analysis, no marker reached significance level to predict faster CAVS progression or need for aortic valve replacement (all p > 0.05). There was no interaction between the OSE antibody titers and plasma levels of Lp(a) or OxPL-apoB, as well as age, with regards to the progression rate of CAVS. CONCLUSIONS Autoantibody titers to MDA-LDL and apoB-IC, which are an indirect measurement of OSE, unlike direct measurements of OxPL-apoB or their major lipoprotein carrier Lp(a), do not predict the progression of CAVS or need for AVR.
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Baseline Vitamin D Deficiency Decreases the Effectiveness of Statins in HIV-Infected Adults on Antiretroviral Therapy.
Hileman, CO, Tangpricha, V, Sattar, A, McComsey, GA
Journal of acquired immune deficiency syndromes (1999). 2017;(5):539-547
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Abstract
OBJECTIVE Vitamin D deficiency is common in HIV. Statins may increase vitamin D, and it is unknown whether vitamin D modifies the effect of statins on cardiovascular disease. DESIGN SATURN-HIV was a 96-week, randomized, placebo-controlled trial designed to evaluate the effect of rosuvastatin on immune activation and subclinical vascular disease in HIV-infected adults on antiretroviral therapy. This analysis focuses on the prespecified secondary endpoint 25-hydroxyvitamin D [25(OH)D] concentrations. METHODS Mixed effects linear modeling and analysis of variance were used to assess the rosuvastatin effect on plasma 25(OH)D concentrations over time and to determine whether baseline vitamin D modifies the rosuvastatin effect on changes in outcomes over the trial. RESULTS Hundred forty-seven adults were randomized (72 to rosuvastatin and 75 to placebo); 78% were men, 68% African American, with a mean age of 45 years. Baseline 25(OH)D concentrations were similar (overall mean 18 ng/mL) with 65% of participants below 20 ng/mL. Changes in 25(OH)D at 96 weeks were small and not significant within- or between-rosuvastatin and placebo groups. There were significant group by vitamin D status interactions for changes in low-density lipoprotein-cholesterol, proportion of patrolling monocytes expressing tissue factor (CD14dimCD16+TF+), lipoprotein-associated phospholipase A2, and common carotid artery intima media thickness at most time points. For each of these outcomes, the beneficial effects of rosuvastatin were either not apparent or attenuated in participants with 25(OH)D <20 ng/mL. CONCLUSIONS Although 25(OH)D did not change with rosuvastatin, baseline vitamin D deficiency decreased the effectiveness of rosuvastatin. Vitamin D supplementation may be warranted for deficient patients initiating statin therapy.
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Effects of Fostamatinib on the Pharmacokinetics of Oral Contraceptive, Warfarin, and the Statins Rosuvastatin and Simvastatin: Results From Phase I Clinical Studies.
Martin, P, Gillen, M, Ritter, J, Mathews, D, Brealey, C, Surry, D, Oliver, S, Holmes, V, Severin, P, Elsby, R
Drugs in R&D. 2016;(1):93-107
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Abstract
BACKGROUND AND OBJECTIVES Fostamatinib is a spleen tyrosine kinase inhibitor that has been investigated as therapy for rheumatoid arthritis and immune thrombocytopenic purpura. The present studies assessed the potential for pharmacokinetic interaction between fostamatinib and the commonly prescribed medications oral contraceptive (OC), warfarin, and statins (rosuvastatin, simvastatin) in healthy subjects. METHODS The OC study was a crossover study over two 28-day treatment periods (Microgynon(®) 30 plus placebo or fostamatinib). Concentrations of OC constituents (ethinyl estradiol/levonorgestrel) were measured. Effects on warfarin pharmacokinetics and pharmacodynamics were assessed (21-day study). Warfarin was administered on days 1 and 14, fostamatinib on days 8-20. The statin study was a two-period, fixed-sequence study of the effects of fostamatinib on exposure to rosuvastatin or simvastatin (single doses). Safety was assessed throughout. RESULTS Fostamatinib co-administration with OC increased exposure to ethinyl estradiol [area under the plasma concentration-time curve at steady state (AUCss) 28% [confidence interval (CI 90%) 21-36]; maximum plasma concentration (Cmax) at steady state (Cmax,ss) 34% (CI 26-43)], but not levonorgestrel (AUCss 5%; Cmax,ss -3%), while exposure to luteinizing hormone and follicle-stimulating hormone decreased (≈ 20%). Fostamatinib did not affect the pharmacokinetics/pharmacodynamics of warfarin to a clinically relevant extent, but caused an upward trend in AUC for both R- and S-warfarin [18% (CI 13-23) and 13% (CI 7-19)]. Fostamatinib increased rosuvastatin AUC by 96% (CI 78-115) and Cmax by 88% (CI 69-110), and increased simvastatin acid AUC by 74% (CI 50-102) and Cmax by 83% (CI 57-113). CONCLUSION Fostamatinib exhibits drug-drug interactions when co-administered with OC, simvastatin, or rosuvastatin, with the AUC of statins almost doubling. Fostamatinib did not exhibit a clinically relevant DDI on warfarin.
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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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Abstract
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 slows progression of subclinical atherosclerosis in patients with treated HIV infection.
Longenecker, CT, Sattar, A, Gilkeson, R, McComsey, GA
AIDS (London, England). 2016;(14):2195-203
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Abstract
OBJECTIVE To determine the effect of statins on the progression of subclinical atherosclerosis in a population of HIV-infected adults on antiretroviral therapy. DESIGN Double-blind, randomized clinical trial. METHODS Stopping Atherosclerosis and Treating Unhealthy Bone with RosuvastatiN in HIV infection was a 96-week double-blind, randomized clinical trial of 10 mg daily rosuvastatin (n = 72) vs. placebo (n = 75) in a population of HIV-infected subjects on stable antiretroviral therapy with LDL-cholesterol 130 mg/dl or less (≤3.36 mmol/l) and evidence of heightened T-cell activation (CD8CD38HLA-DR ≥19%) or increased inflammation [high sensitivity C-reactive protein ≥2 mg/l (≥19 mmol/l)]. Change in common carotid artery intima-media thickness (IMT) (CCA-IMT) was the primary outcome. Secondary outcomes were changes in LDL and coronary artery calcium. RESULTS Median (Q1, Q3) age was 46 (40, 53) years; 78% were man and 68% African-American; 49% were on a protease inhibitor. Mean (95% confidence interval) change in LDL was -21 (-27 to -15) mg/dl [-0.54 (-0.70 to -0.39) mmol/l] in the rosuvastatin arm. In a multivariable linear mixed-effects model, assignment to statin was associated with 0.019 mm (95% confidence interval: 0.002-0.037 mm) less progression of CCA-IMT over 96 weeks. We did not find substantial effect modification by level of inflammation or immune activation biomarkers, except for a borderline statistically significant interaction for soluble vascular cell adhesion molecule (P = 0.065). There was no difference in coronary artery calcium change (P = 0.61). CONCLUSION Rosuvastatin effectively lowers LDL and appears to substantially slow progression of CCA-IMT in patients with treated HIV infection. Future study is needed to determine whether subjects with higher levels of inflammation or immune activation derive greater cardiovascular benefit from statin therapy.
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Rosuvastatin Is Effective to Decrease CD8 T-Cell Activation Only in HIV-Infected Patients With High Residual T-Cell Activation Under Antiretroviral Therapy.
Weiss, L, Chevalier, MF, Assoumou, L, Paul, JL, Alhenc-Gelas, M, Didier, C, Taibi, S, Manea, EM, Campa, P, Girard, PM, et al
Journal of acquired immune deficiency syndromes (1999). 2016;(4):390-8
Abstract
OBJECTIVE The aim of the trial was to evaluate in patients under antiretroviral therapy (ART) the effect of rosuvastatin on cellular and soluble markers of immune activation/inflammation, as well as to identify patients who better benefit from statin administration. METHODS IMEA-043-CESAR was a phase II open-label pilot trial that enrolled patients under suppressive ART and CD4 <500/mm. Patients received rosuvastatin (20 mg/d) for 12 weeks. The primary outcome was the variation at week 12 (W12) in the proportion of CD38HLA-DRCD8 T lymphocytes. Secondary outcomes included evolution of other markers of T-cell activation and of inflammatory biomarkers between baseline, W12, and W24. RESULTS Fifty patients were enrolled; end points were available for 43 patients. When considering all patients, the proportion of CD38HLA-DRCD8 T cells did not significantly decline throughout the follow-up. However, the proportion of CD38CD8T cells significantly decreased at W12 [median percentage change of -22.2% (-32.3; +1.4)]. Principal component analysis allowed identification of 3 groups of patients based on their baseline activation/inflammation profiles, 1 group with elevated levels of CD8 T-cell activation, and a small group with high levels of systemic inflammation and low levels of T-cell activation. Half of the patients exhibited relatively low levels of inflammation and activation. The proportion of activated CD8 T cells significantly decreased only in the particular group of patients with high baseline CD8 T-cell activation. CONCLUSIONS This study shows that combining rosuvastatin with effective ART can result in a sustained decrease in CD8 T-cell activation and highlights the importance of identifying patients who can benefit from specific immunotherapeutic strategies.