Rosuvastatin treatment reduces markers of monocyte activation in HIV-infected subjects on antiretroviral therapy

Abstract

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.

Keywords: HIV-1; monocytes; rosuvastatin; tissue factor.

Figure 1.

Patient enrollment flowchart. Two hundred two patients were screened for enrollment; 55 patients failed screening, resulting in 147 patients being enrolled (n = 72 in the rosuvastatin arm, n = 75 in the placebo arm). *High-sensitivity C-reactive protein level <2 mg/L. **CD8⁺ T-cell expression of CD38 and HLA-DR antigens <19%. ^†Patient found to have very high coronary calcium score by computed tomography on same day as screening, deemed unethical for patient to be potentially randomized to placebo. Abbreviations: CrCL, creatinine clearance; HIV-1, human immunodeficiency virus type 1; hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; LFTs, liver function tests; TG, triglycerides.

Figure 2.

Statin treatment reduces levels of monocyte activation. Plasma samples were thawed and levels of soluble CD14 (sCD14) were measured by enzyme-linked immunosorbent assay. A, Patients receiving statin treatment had a relative reduction in sCD14 levels from baseline (13.4%), whereas patients receiving placebo had an increase in sCD14 levels (1.2%), and this difference was significant between groups (P = .0017). B, Tissue factor (TF) expression on patrolling (CD14^DimCD16⁺) monocytes was also reduced by statin treatment (−38.8%), and this change differed significantly from the change measured in the placebo arm (11.9%, P = .04).

Figure 3.

Rosuvastatin-treated subjects receiving a protease inhibitor (PI)–based antiretroviral therapy regimen had a statistically significant decrease in the proportion of CD14^DimCD16⁺ cells. Monocyte subsets were identified in fresh whole-blood samples using size and granularity, and by expression of CD14 and CD16. Proportions of patrolling (CD14^DimCD16⁺) monocytes were reduced in patients receiving PI-based antiretroviral therapy (ART) (−22%), but not in patients receiving non-PI-based ART (20%, P = .0252).