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Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial.

ABSTRACT: BACKGROUND:People with HIV (PWH) demonstrate increased cardiovascular disease (CVD), due in part to increased immune activation, inflammation, and endothelial dysfunction. METHODS:In a randomized trial (INTREPID), 252 HIV-infected participants with dyslipidemia and no history of coronary artery disease were randomized (1:1) to pitavastatin 4?mg vs. pravastatin 40?mg for 52?weeks. Using a proteomic discovery approach, 92 proteins biomarkers were assessed using Proximity Extension Assay technology to determine the effects of statins on key atherosclerosis and CVD pathways among PWH. 225 participants had specimens available for biomarker analysis pre- and post-baseline. FINDINGS:The mean age was 49.5?±?8.0 (mean?±?SD), LDL-C 155?±?25?mg/dl and CD4 count 620?±?243 cell/mm3. Among all participants, three proteins significantly decreased: tissue factor pathway inhibitor [TFPI; t-statistic?=?-6.38, FDR p-value<0.0001], paraoxonase 3 [PON3; t-statistic?=?-4.64, FDR p-value?=?0.0003], and LDL-receptor [LDLR; t-statistic?=?-4.45, FDR p-value?=?0.0004]; and two proteins significantly increased galectin-4 [Gal-4; t-statistic?=?3.50, FDR p-value?=?0.01] and insulin-like growth factor binding protein 2 [IGFBP-2; t-statistic?=?3.21, FDR p-value?=?0.03]. The change in TFPI was significantly different between the pitavastatin and pravastatin groups. Among all participants, change in TFPI related to the change in LDL-C (r?=?0.43, P?

SUBMITTER: Toribio M

PROVIDER: S-EPMC6156703 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial.

Toribio Mabel M Fitch Kathleen V KV Stone Lauren L Zanni Markella V MV Lo Janet J de Filippi Chris C Sponseller Craig A CA Lee Hang H Grundberg Ida I Thompson Melanie A MA Aberg Judith A JA Grinspoon Steven K SK

EBioMedicine 20180831

<h4>Background</h4>People with HIV (PWH) demonstrate increased cardiovascular disease (CVD), due in part to increased immune activation, inflammation, and endothelial dysfunction.<h4>Methods</h4>In a randomized trial (INTREPID), 252 HIV-infected participants with dyslipidemia and no history of coronary artery disease were randomized (1:1) to pitavastatin 4 mg vs. pravastatin 40 mg for 52 weeks. Using a proteomic discovery approach, 92 proteins biomarkers were assessed using Proximity Extension A ...[more]

PMID: 30174281

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Project description:ObjectivesThis study sought to determine whether coronary artery calcium (CAC) could be used to optimize statin allocation among individuals for whom trial-based evidence supports efficacy of statin therapy.BackgroundRecently, allocation of statins was proposed for primary prevention of atherosclerotic cardiovascular disease (ASCVD) based on proven efficacy from randomized controlled trials (RCTs) of statin therapy, a so-called trial-based approach.MethodsThe study used data from MESA (Multi-Ethnic Study of Atherosclerosis) with 5,600 men and women, 45 to 84 years of age, and free of clinical ASCVD, lipid-lowering therapy, or missing information for risk factors at baseline examination.ResultsDuring 10 years' follow-up, 354 ASCVD and 219 hard coronary heart disease (CHD) events occurred. Based on enrollment criteria for 7 RCTs of statin therapy in primary prevention, 73% of MESA participants (91% of those >55 years of age) were eligible for statin therapy according to a trial-based approach. Among those individuals, CAC = 0 was common (44%) and was associated with low rates of ASCVD and CHD (3.9 and 1.7, respectively, per 1,000 person-years). There was a graded increase in event rates with increasing CAC score, and in individuals with CAC >100 (27% of participants) the rates of ASCVD and CHD were 18.9 and 12.7, respectively. Consequently, the estimated number needed to treat (NNT) in 10 years to prevent 1 event varied greatly according to CAC score. For ASCVD events, the NNT was 87 for CAC = 0 and 19 for CAC >100. For CHD events, the NNT was 197 for CAC = 0 and 28 for CAC >100.ConclusionsMost MESA participants qualified for trial-based primary prevention with statins. Among the individuals for whom trial-based evidence supports efficacy of statin therapy, CAC = 0 and CAC >100 were common and associated with low and high cardiovascular risks, respectively. This information may guide shared decision making aimed at targeting evidence-based statins to those who are likely to benefit the most.

Project description:Most Internet online resources for investigating HIV biology contain either bioinformatics tools, protein information or sequence data. The objective of this study was to develop a comprehensive online proteomics resource that integrates bioinformatics with the latest information on HIV-1 protein structure, gene expression, post-transcriptional/post-translational modification, functional activity, and protein-macromolecule interactions. The BioAfrica HIV-1 Proteomics Resource http://bioafrica.mrc.ac.za/proteomics/index.html is a website that contains detailed information about the HIV-1 proteome and protease cleavage sites, as well as data-mining tools that can be used to manipulate and query protein sequence data, a BLAST tool for initiating structural analyses of HIV-1 proteins, and a proteomics tools directory. The Proteome section contains extensive data on each of 19 HIV-1 proteins, including their functional properties, a sample analysis of HIV-1HXB2, structural models and links to other online resources. The HIV-1 Protease Cleavage Sites section provides information on the position, subtype variation and genetic evolution of Gag, Gag-Pol and Nef cleavage sites. The HIV-1 Protein Data-mining Tool includes a set of 27 group M (subtypes A through K) reference sequences that can be used to assess the influence of genetic variation on immunological and functional domains of the protein. The BLAST Structure Tool identifies proteins with similar, experimentally determined topologies, and the Tools Directory provides a categorized list of websites and relevant software programs. This combined database and software repository is designed to facilitate the capture, retrieval and analysis of HIV-1 protein data, and to convert it into clinically useful information relating to the pathogenesis, transmission and therapeutic response of different HIV-1 variants. The HIV-1 Proteomics Resource is readily accessible through the BioAfrica website at: http://bioafrica.mrc.ac.za/proteomics/index.html.

Dataset Information

Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial.

Publications

Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial.

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