Rosuvastatin reduces vascular inflammation and T-cell and monocyte activation in HIV-infected subjects on antiretroviral therapy

Abstract

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.

Conflict of interest statement

Conflicts of Interest:

GAM served as a consultant, speaker, and has received research funding from Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Merck, and Tibotec. GAM also chaired a DSMB for a Pfizer-funded study. All other authors declare no conflicts of interest.

Figures

Figure 1. Rosuvastatin treatment reduces levels of vascular inflammation and immune activation

Plasma samples were thawed and levels of soluble CD14, lipoprotein-associated phospholipase A2 (Lp-PLA2), and interferon γ–inducible protein 10 (IP-10/CXCL10) were measured by ELISA. A) The monocyte activation marker sCD14 was also decreased in the statin arm (10.4%), while patients receiving placebo had an increase in sCD14 levels (0.5%) and this difference was significant between groups (p=0.018). B) Tissue factor expression on patrolling (CD14DimCD16+) monocytes was also reduced by statin treatment (−41.6%) and this change was significantly different from the change measured in the placebo arm (−18.8%, p=0.005). C) Patients receiving statin treatment had a relative reduction in Lp-PLA2 levels from baseline (−12.2%) and this reduction was significantly greater than was the decrease measured in the placebo arm (−1.7%, p=0.0007). D) Patients receiving statin treatment had a relative reduction in IP-10 levels from baseline (−27.5%) and this reduction was significantly greater than was the decrease measured in the placebo arm (−8.2%, p=0.027).

Figure 2. Rosuvastatin treatment reduces markers of T cell activation

Measurement of T cell activation was performed by comparing expression of surface markers (CD38, HLA-DR, and PD-1) on cryopreserved PBMC samples from baseline, week 24 and 48 for each patient. Samples were thawed and analyzed in batch. The proportions of CD38+HLA-DR+ cells among A) CD4+ and B) CD8+ Tcells were reduced by rosuvastatin treatment (−38.1% and −44.8%) and these changes were statistically significantly different from the changes measured in the placebo arm (−17.8%, p=0.0009, and −27.4%, p=0.004).