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Randomized Controlled Trial
. 2025 Mar 1;10(3):254-264.
doi: 10.1001/jamacardio.2024.4115.

Pitavastatin, Procollagen Pathways, and Plaque Stabilization in Patients With HIV: A Secondary Analysis of the REPRIEVE Randomized Clinical Trial

Márton Kolossváry  1 , Samuel R Schnittman  1   2 , Markella V Zanni  1 , Kathleen V Fitch  1 , Carl J Fichtenbaum  3 , Judith A Aberg  4 , Gerald S Bloomfield  5 , Carlos D Malvestutto  6 , Judith Currier  7 , Marissa R Diggs  1 , Christopher deFilippi  8 , Allison Ross Eckard  9 , Adrian Curran  10 , Murat Centinbas  11   12 , Ruslan Sadreyev  11   13 , Borek Foldyna  14 , Thomas Mayrhofer  14   15 , Julia Karady  14   16 , Jana Taron  11   17 , Sara McCallum  1 , Michael T Lu  14 , Heather J Ribaudo  18 , Pamela S Douglas  19 , Steven K Grinspoon  1
Affiliations
Randomized Controlled Trial

Pitavastatin, Procollagen Pathways, and Plaque Stabilization in Patients With HIV: A Secondary Analysis of the REPRIEVE Randomized Clinical Trial

Márton Kolossváry et al. JAMA Cardiol. .

Abstract

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 < .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 < .001), independent of changes in LDL-C level. Increases in PCOLCE related most strongly to change in the fibro-fatty (<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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Schnittman reported being employed by Amgen as of June 24, 2024, unrelated to the submitted work; he did not participate in revisions of the submitted manuscript after this change in employment. Dr Zanni reported receiving grants from Gilead to her institution (MGH) outside the submitted work. Dr Fichtenbaum reported receiving grants from ViiV, Gilead, and Merck to his institution outside the submitted work. Dr Aberg reported receiving grants from the National Institutes of Health (NIH) subcontract Mass General Hospital, Emergent Biosolutions (COVID-19 trial), Gilead Sciences (multicenter trials), GlaxoSmithKline/ViiV (multicenter trials), Merck (multicenter trials), Pfizer (multicenter trials), Janssen (multicenter trials), Regeneron (multicenter trials), and ViiV Healthcare (investigator-initiated study) and data safety monitoring board fees/advisory board fees from Kintor Pharmaceuticals, GSK, Merck, and ViiV Healthcare outside the submitted work. Dr Malvestutto reported receiving advisory board fees from ViiV Healthcare and Gilead Sciences outside the submitted work. Dr Currier reported receiving advisory board fees from Merck outside the submitted work. Dr deFilippi reported receiving consulting fees for Abbott Diagnostics, QuidelOrtho, Roche Diagnostics, and Siemens Healthineers; speaking fees from Polymedco (makes an NT-proBNP assay); and institutional funding where serving as the principal investigator from the NIH, Abbott Diagnostics, FujiRebio, QuidelOrtho, Randox, Roche Diagnostics, and Siemens Healthineers. Dr Eckard reported receiving grants from the NIH during the conduct of the study and advisory board fees from Theratechnologies and Gilead Sciences outside the submitted work. Dr Curran reported receiving grants and personal fees from Gilead Sciences and ViiV Healthcare and personal fees from MSD and Janssen Cilag outside the submitted work. Dr Foldyna reported receiving grants from the NIH/National Heart, Lung, and Blood Institute (NHLBI), AstraZeneca, and Medtrace during the conduct of the study. Dr Taron reported receiving grants from German Research Foundation during the conduct of the study and consulting fees from Onc.AI outside the submitted work. Dr Lu reported receiving grants from the NHLBI, Kowa Pharmaceuticals America, the American Heart Association, AstraZeneca, Ionis, Johnson & Johnson Innovation, MedImmune, National Academy of Medicine, and Risk Management Foundation of the Harvard Medical Institutions outside the submitted work. Dr Ribaudo reported receiving grants from the NIH/NHLBI, Kowa Pharmaceuticals, ViiV Healthcare, and Gilead Sciences outside the submitted work. Dr Grinspoon reported receiving grants from the NIH, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare and advisory board fees from Theratechnologies, ViiV Healthcare, and Marathon Asset Management outside the submitted work. No other disclosures were reported.

References

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