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Rosuvastatin slows progression of subclinical atherosclerosis in patients with treated HIV infection
Published by François RAFFI

Updated: 1 December, 2016

Longenecker CT et al. AIDS. 2016 Sep 10;30(14):2195-203

Objective: To determine the effect of statins on the progression of subclinical atherosclerosis in a population of HIV-infected adults on antiretroviral therapy.

Methods: SATURN-HIV was a 96-week double-blind, randomized clinical trial of 10 mg daily rosuvastatin (n=72) versus placebo (n=75). Participants were HIV-infected subjects ≥ 18 years of age without known coronary disease or uncontrolled diabetes, and on stable antiretroviral therapy for at least 3 months with HIV-1 RNA <1,000 copies/mL. Inclusion criteria were LDL-cholesterol ≤ 130mg/dL (≤ 3.36mmol/L) and evidence of heightened T-cell activation (CD8+CD38+HLA-DR+ ≥ 19%) or increased inflammation (high sensitivity C-reactive protein ≥ 2mg/L (≥ 19mmol/L)). Randomization was stratified by use of protease inhibitors and by presence or absence of CAC at study screening. At baseline, 48, and 96 weeks, all participants underwent high resolution ultrasound scanning of the carotid arteries on a Philips iU22 with L9-3 MHz linear array transducer. The distal one centimeter of the common carotid artery (CCA) was imaged at three angles (anterior, lateral, posterior) bilaterally. Far-wall CCA-IMT was measured offline by a single reader. At baseline, 48, and 96 weeks, all participants also had a non-contrast computed tomography (CT) scan of the chest for coronary artery calcium scoring. Several biomarkers of systemic inflammation, monocyte activation, endothelial activation, and coagulation were measured in plasma at the baseline visit : interleukin-6 (IL-6), soluble tumor necrosis factor-α receptors I and II (sTNFR-I and II), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), sCD14 and sCD163, plasma cystatin C, high sensitivity C-reactive protein (hsCRP), and fibrinogen, D-dimer. Change in mean common carotid artery IMT (CCA-IMT) was the primary outcome. The study was powered to detect a mean difference in 0 to 96 week IMT change of 0.118 mm with 84% power. Secondary outcomes were changes in LDL and coronary artery calcium (CAC). To measure the effects of statin treatment, the IMT change (baseline IMT value subtracted) outcome variable was analyzed using flexible linear mixed-effects (LME) models with random intercept and random slope.

Results: Median (Q1, Q3) age was 46 (40, 53) years; 78% were male and 68% African American; 49% were on a protease inhibitor. Twenty-eight of the 147 participants (9 rosuvastatin; 19 placebo) withdrew or were lost to follow-up prior to the 96 week visit, none due to drug-related adverse events. Mean (95% CI) change in LDL at week 24 was -24 (-29 to - 18) mg/dL [-0.62 (-0.75 to -0.47) mmol/L] in the rosuvastatin arm.
In a multivariable linear mixed-effects model, assignment to statin was associated with 0.019mm (95% CI: 0.002- 0.037mm) less progression of CCA-IMT over 96 weeks (p=0.03). The difference in IMT change between statin and placebo groups was statistically significant at 48 weeks (p=0.025) and borderline significant at 96 weeks (p=0.061) despite a mean (95% CI) annualized rate of CCA-IMT progression in the placebo group that was slower than anticipated [0.015 (0.005-0.025) mm/yr]. There was no 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). Among the 73 participants (n=40 statin; n=33 placebo) without detectable coronary calcium at baseline, there was no difference in detectable CAC after 96 weeks of statin [15% vs. 6%, statin vs. placebo; p=0.19]. Among the 45 participants (n=22 statin; n=23 placebo) with detectable CAC at baseline, there was no difference in mean (95% CI) 0-96 week CAC change [12 (-2.6 to 28) vs. 37 (8 to 67), statin vs. placebo; p=0.61], but statin use was associated with significantly less mean CCA-IMT progression in this subgroup [-0.017 (-0.060 to 0.026) mm vs. 0.041 (0.001 to 0.081), statin vs. placebo; p=0.023].

Conclusions: Rosuvastatin, at 10 mg of daily dose, 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.