Pitavastatin, Procollagen Pathways, and Plaque Stabilization in Patients With HIV
Authors: Kolossváry Márton , Schnittman Samuel R. , Zanni Markella V. , Fitch Kathleen V. , Fichtenbaum Carl J. , Aberg Judith A. , Bloomfield Gerald S. , Malvestutto Carlos D. , Currier Judith , Diggs Marissa R. , deFilippi Christopher , Eckard Allison Ross , Curran Adrian , Centinbas Murat , Sadreyev Ruslan , Foldyna Borek , Mayrhofer Thomas , Karady Julia , Taron Jana , McCallum Sara , Lu Michael T. , Ribaudo Heather J. , Douglas Pamela S. , Grinspoon Steven K. 
Published: December 2024

Importance

In a mechanistic substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) randomized clinical trial, pitavastatin reduced noncalcified plaque (NCP) volume, but specific protein and gene pathways contributing to changes in coronary plaque remain unknown.

Objective

To use targeted discovery proteomics and transcriptomics approaches to interrogate biological pathways beyond low-density lipoprotein cholesterol (LDL-C), relating statin outcomes to reduce NCP volume and promote plaque stabilization among people with HIV (PWH).

Design, Setting, and Participants

This was a post hoc analysis of the double-blind, placebo-controlled, REPRIEVE randomized clinical trial. Participants underwent coronary computed tomography angiography (CTA), plasma protein analysis, and transcriptomic analysis at baseline and 2-year follow-up. The trial enrolled PWH from April 2015 to February 2018 at 31 US research sites. PWH without known cardiovascular diseases taking antiretroviral therapy and with low to moderate 10-year cardiovascular risk were eligible. Data analyses were conducted from October 2023 to February 2024.

Intervention

Oral pitavastatin calcium, 4 mg per day.

Main Outcomes and Measures

Relative change in plasma proteomics, transcriptomics, and noncalcified plaque volume among those receiving treatment vs placebo.

Results

Among 558 individuals (mean [SD] age, 51 [6] years; 455 male [82%]) included in the proteomics assessment, 272 (48.7%) received pitavastatin and 286 (51.3%) received placebo. After adjusting for false discovery rates, pitavastatin increased abundance of procollagen C-endopeptidase enhancer 1 (PCOLCE), neuropilin 1 (NRP-1), major histocompatibility complex class I polypeptide-related sequence A (MIC-A) and B (MIC-B), and decreased abundance of tissue factor pathway inhibitor (TFPI), tumor necrosis factor ligand superfamily member 10 (TRAIL), angiopoietin-related protein 3 (ANGPTL3), and mannose-binding protein C (MBL2). Among these proteins, the association of pitavastatin with PCOLCE (a rate-limiting enzyme of collagen deposition) was greatest, with an effect size of 24.3% (95% CI, 18.0%-30.8%; P &amp;lt; .001). In a transcriptomic analysis, individual collagen genes and collagen gene sets showed increased expression. Among the 195 individuals with plaque at baseline (88 [45.1%] taking pitavastatin, 107 [54.9%] taking placebo), changes in NCP volume were most strongly associated with changes in PCOLCE (%change NCP volume/log2-fold change = −31.9%; 95% CI, −42.9% to −18.7%; P &amp;lt; .001), independent of changes in LDL-C level. Increases in PCOLCE related most strongly to change in the fibro-fatty (&amp;lt;130 Hounsfield units) component of NCP (%change fibro-fatty volume/log2-fold change = −38.5%; 95% CI, −58.1% to −9.7%; P = .01) with a directionally opposite, although nonsignificant, increase in calcified plaque (%change calcified volume/log2-fold change = 34.4%; 95% CI, −7.9% to 96.2%; P = .12).

Conclusions and Relevance

Results of this secondary analysis of the REPRIEVE randomized clinical trial suggest that PCOLCE may be associated with the atherosclerotic plaque stabilization effects of statins by promoting collagen deposition in the extracellular matrix transforming vulnerable plaque phenotypes to more stable coronary lesions.

Trial Registration

ClinicalTrials.gov Identifier: NCT02344290