Abstract and Introduction
Abstract
Background: Residual inflammation in people with HIV (PWH) despite suppression of HIV replication is associated with many comorbidities including cardiovascular disease. Targeting inflammation may decrease the risk of cardiovascular disease.
Methods: An open label randomized study was conducted to evaluate the effect of nine months of 81 mg aspirin versus 40 mg atorvastatin in antiretroviral therapy (ART) treated PWH and elite controllers (EC), not on ART. Biomarkers associated with inflammation and virologic indices were measured and analyzed using nonparametric and linear mixed effect models.
Results: Fifty-three participants were randomized and 44 were included in the final analysis. Median age was 54 years, 72% were male, 59% were Black. Median CD4+ count was 595 cells/μl in the aspirin and 717 cells/μl in the atorvastatin arm. After 9 months of treatment, plasma soluble (s) CD14+ was reduced in the aspirin group within both treated PWH and EC (P = 0.0229), yet only within treated PWH in the atorvastatin group (P = 0.0128). A 2.3% reduction from baseline in tissue factor levels was also observed in the aspirin arm, driven by the EC group. In the atorvastatin arm, there was a 4.3% reduction in interleukin-8 levels (P = 0.02) and a small decrease of activated CD4+ T cells (P < 0.001). No statistically significant differences were observed in the plasma HIV viral load and cell-associated (CA) HIV DNA and RNA.
Conclusions: Aspirin and atorvastatin could play a role in targeting HIV-associated inflammation. Elite controllers may warrant special consideration for anti-inflammatory strategies.
Introduction
People with HIV (PWH) are living longer since the introduction and optimization of combination antiretroviral therapy (ART). This has shifted the disease spectrum from acquired immunodeficiency syndrome (AIDS)-associated infections to noninfectious complications including cardiovascular disease (CVD), non-AIDS malignancies and other diseases linked to aging.[1,2] Age, hypertension, diabetes and smoking are recognized as important contributors to the risk of cardiovascular disease in PWH;[3] HIV associated inflammation is also thought to play a role in its pathogenesis.[4] In PWH with suppressed plasma HIV viremia, biomarkers of inflammation and coagulation such as soluble (s) CD14+, D-dimer, interleukin (IL)-6 and C-reactive protein (CRP) are higher than in HIV seronegative people and have been found to be independent predictors of non-AIDS complications and mortality.[3–5]
Elite controllers (ECs) represent a small subset of PWH able to maintain suppressed HIV RNA and stable CD4+ T cell counts in the absence of ART.[6] Despite the suppressed viral replication, they appear to have similar levels of immune activation and underlying inflammation to ART-treated individuals as well as evidence of increased risk of cardiovascular disease.[7–9] The etiology of chronic inflammation in PWH is multifactorial and includes residual viral replication, gut mucosal injury, co-infections such as CMV or HCV, tissue fibrosis and comorbidities including smoking or obesity.[10] Many strategies have been proposed to reduce coagulation and inflammation in PWH in order to improve cardiovascular health; these have included statins (rosuvastatin and atorvastatin),[11,12] lactoferrin or sevelamer to target gut mucosa and microbial translocation,[13] aspirin,[14,15] renin-angiotensin system inhibitors (i.e. lisinopril,[16] telmisartan[17] or losartan),[18] and the two anticoagulants vorapaxar[19] and edoxaban.[20]
Atorvastatin, an 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has several treatment effects beyond reduction of low-density cholesterol (LDL)-cholesterol and has been shown to reverse cardiovascular disease and atherosclerosis.[21] Several statins have already been used for their anti-inflammatory action in PWH and were found to not only reduce lipid levels but also reduce sCD14 after 6 months of treatment, with the caveat that participants had elevated levels of immune activation at baseline.[11] Moreover, a trial of a lower dose of atorvastatin in PWH showed changes in lipid levels (oxLDL and LpPLA2) but not sCD14.[22] Aspirin, a COX-1 inhibitor, has been evaluated in numerous studies for its antithrombotic and anti-inflammatory properties[23,24] and could potentially decrease inflammation and subsequent atherosclerosis associated with higher expression of P-selectin and sVCAM-1 in PWH. In addition, different doses and duration of aspirin treatment have been tried with an uncontrolled trial showing significant immunological benefit that was not replicated in a larger placebo controlled 3-month trial.[14,15]
In this study, the treatment effect of 81 mg of aspirin or 40 mg of atorvastatin was tested in two groups of PWH, a group of virologically suppressed ART-treated PWH (TPs) and ECs, who were virologically suppressed without receiving ART. This population was selected in order to assess the effect that the two drugs have in HIV-associated inflammation, as measured by sCD14, a marker of monocyte activation,[25] and to also test the potential effect of ART in therapeutic responses to anti-inflammatory drugs.
AIDS. 2023;37(12):1827-1835. © 2023 Lippincott Williams & Wilkins
Lippincott Williams & Wilkins
