Changes in oxidized lipids drive the improvement in monocyte activation and vascular disease after statin therapy in HIV

Abstract

Background Oxidative stress plays a significant role in atherosclerosis development. HIV infection has been linked with heightened cardiovascular disease risk. HMG-CoA reductase inhibitors may reduce oxidative stress and subsequently subclinical vascular disease in HIV. Design/methods This is a randomized, placebo-controlled trial to evaluate the effect of rosuvastatin in HIV-infected adults on stable antiretroviral therapy with low-density lipoprotein less than 130 mg/dl and increased inflammation or T-cell activation on subclinical vascular disease. Changes over 48 weeks in oxidative stress markers, oxidized low-density lipoprotein (oxLDL) and F2-isoprostane/creatinine ratio (F2-Iso-P/Cr), were compared between groups. Spearman correlation and multivariable linear regression were used to evaluate relationships between changes in markers of oxidative stress, inflammation and monocyte activation and carotid intima media thickness (CIMT). Results One hundred and forty-seven adults enrolled (72 to rosuvastatin and 75 to placebo). In the rosuvastatin group, oxLDL decreased significantly over 24 weeks compared to placebo [mean absolute change in log-oxLDL for rosuvastatin −0.2 ± 0.468 log U/l (P < 0.001 within-group) vs. placebo −0.018 ± 0.456 log U/l (P = 0.83 within-group); P = 0.004 between groups] and this change was linked with changes in soluble CD14 and proportion of patrolling monocytes (CD14dimCD16+). Although oxLDL levels increased after initially declining and were not different from placebo at week 48, the early improvement in oxLDL was associated with improved CIMT at week 48. Changes in F2-IsoP/Cr were not significant between groups. Conclusion Rosuvastatin decreases oxLDL levels early after initiation and is associated with decreased monocyte activation. Early improvement in oxLDL is linked with improved CIMT in treated HIV infection.

Epidemiology of ischemic heart disease in HIV

“…101, 104–106 In contrast, rosuvastatin did not influence immune activation markers but did increase the CD4/CD8 ratio in another study. 107 With regards to outcomes in HIV populations, statins appear to slow progression of cIMT and reduce non-calcified coronary plaque in treated patients 99, 108 and have been associated with reductions in mortality in virally suppressed patients.…”

Cardiovascular Disease, Statins, and HIV

“…Notably, many of these immune activation and exhaustion markers, in addition to sCD14, that decreased levels with statin use are associated with increased all-cause mortality and HIV disease progression [34,70]. Also in SATURN-HIV, oxLDL levels decreased after 24 weeks of statin therapy and predicted changes in carotid intima-media thickness [27], suggesting that decreased oxidative stress after statin therapy may favorably affect monocyte activation. More longitudinal, randomized, controlled studies are needed, however, to determine whether any of these reductions with statin therapy decrease the risk of cardiovascular events, HIV progression, or mortality.…”

“…However, it should be noted that newer PIs have not demonstrated a clear association with inflammation when compared to other non-PI therapies [26]. Similarly, integrase inhibitors show a broadly neutral effect on lipids, and there is some evidence to suggest that they may cause a modest decline in inflammation and immune activation [26,27].…”

Effect of statin on arginine metabolites in treated HIV-infection

“…Levels of ADMA also decrease with ART initiation 18 . Our group has shown that statin therapy in HIV-infected patients can decrease inflammation, monocyte and lymphocyte immune activation, and carotid vascular disease 19–22 , however, to our knowledge, the effect of statin therapy on ADMA concentration in HIV-infected patients has never been studied.…”