Evaluation of antiretroviral therapy on metabolomics and atherogenic markers in HIV patients
Authors: Frias M , Berarpour N , Pagano S , Sidibe J , Kamau F , Lecour S , Strijdom H , Thomas A , Vuilleumier N 
Published: November 2020

Abstract

Background
HIV-infected patients display an increased risk of cardiovascular events. HIV and antiretroviral therapy (ART) have both been suggested to increase the risk of cardiovascular events but their specific role remains unclear.

Purpose
The aim of this study was to analyse the metabolomic profile in a cohort of HIV-free, ART experienced and naïve HIV-infected patients and to identify the metabolite associated with atherosclerosis development and endothelial dysfunction. The impact of ART on inflammatory and autoimmune biomarkers known to underlie atherosclerosis burden was also investigated.

Methods
144 participants from a South African cohort were divided in three groups: HIV-free (n=50), HIV-infected/ART experienced (n=50) and HIV-infected/ART naïve (n=44). Targeted metabolomic analyses were performed using standard operating procedures. Atherosclerosis development was evaluated using coronary intima-media thickness (CITM) and endothelial dysfunction by flow-mediated dilation (FMD). Inflammatory biomarkers were measured with the Meso Scale Discovery® platform. The levels of autoantibodies against apolipoprotein A1 (anti-apoA1 IgG) and its specific C-terminal domain (anti-F3L1) levels were assessed by homemade ELISA assays.

Results
257 endogenous metabolites were identified in the 144 samples. Regarding the association of metabolites with the vascular markers, eight metabolites were found to be associated with FMD and eleven with CIMT. Among these metabolites, cytosine was negatively correlated with FMD (r=−0.22, p=0.009), while positively with CIMT (r=0.20, p=0.026). Interestingly, from the list of these 18 metabolites, ART-experienced patients displayed an increase in kynurenine (p=0.0007) and 3–2-hydroxyphenyl-propanoate (p=0.0009) levels and a decrease in itaconate (p=0.021) levels compared to ART-naïve patients. HIV-infected patients displayed a more proatherogenic profile compared to HIV-free subjects. Inflammatory markers (IFNg, IL-6, IL-10, TNFα, CRP all p&lt;0.05), circulating adhesion molecules (ICAM-1 and VCAM-1, p&lt;0.05), anti-apoA1 IgG and anti-F3L1 (p&lt;0.05) and CIMT (p=0.05) were increased while FMD (p=0.054) was decreased in HIV-infected patients compared to HIV-free participants. While ART treatment significantly reduced IFNg, IL-10, TNFα, VCAM-1, anti-apoA1 IgG and anti-F3L1, no significant differences were observed in other biomarkers between ART-experienced and naïve participants.

Conclusion
Metabolomic analysis identified metabolites that were differentially expressed in the 3 groups. 18 metabolites were significantly correlated with FMD or CITM, among which the levels of kynurenine, 3–2-hydroxyphenyl-propanoate and itaconate were modulated by ART. HIV patients displayed increased levels of inflammatory markers, circulating adhesion molecules and anti-apoA1 IgG which was downregulated by ART.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): Fondation De Reuter; Fondation Schmidheiny; Fondation Prévot; SwissLife AG; Fondation pour la lutte pour le cancer et la recherche bio-médicale