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Comment
. 2024 Apr 1;9(4):323-334.
doi: 10.1001/jamacardio.2023.5661.

Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers in HIV: Mechanistic Substudy of the REPRIEVE Randomized Clinical Trial

Michael T Lu  1 , Heather Ribaudo  2 , Borek Foldyna  1 , Markella V Zanni  3 , Thomas Mayrhofer  1   4 , Julia Karady  1   5 , Jana Taron  1   6 , Kathleen V Fitch  3 , Sara McCallum  3 , Tricia H Burdo  7 , Kayla Paradis  1 , Sandeep S Hedgire  1 , Nandini M Meyersohn  1 , Christopher DeFilippi  8 , Carlos D Malvestutto  9 , Audra Sturniolo  1 , Marissa Diggs  3 , Sue Siminski  10 , Gerald S Bloomfield  11 , Beverly Alston-Smith  12 , Patrice Desvigne-Nickens  13 , Edgar T Overton  14   15 , Judith S Currier  16 , Judith A Aberg  17 , Carl J Fichtenbaum  18 , Udo Hoffmann  19 , Pamela S Douglas  20 , Steven K Grinspoon  3 ; REPRIEVE Trial Writing Group
Collaborators, Affiliations
Comment

Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers in HIV: Mechanistic Substudy of the REPRIEVE Randomized Clinical Trial

Michael T Lu et al. JAMA Cardiol. .

Erratum in

  • Change to Open Access Status.
    [No authors listed] [No authors listed] JAMA Cardiol. 2024 May 1;9(5):487. doi: 10.1001/jamacardio.2024.0582. JAMA Cardiol. 2024. PMID: 38416454 Free PMC article. No abstract available.

Abstract

Importance: Cardiovascular disease (CVD) is increased in people with HIV (PWH) and is characterized by premature noncalcified coronary plaque. In the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), pitavastatin reduced major adverse cardiovascular events (MACE) by 35% over a median of 5.1 years.

Objective: To investigate the effects of pitavastatin on noncalcified coronary artery plaque by coronary computed tomography angiography (CTA) and on inflammatory biomarkers as potential mechanisms for MACE prevention.

Design, setting, and participants: This double-blind, placebo-controlled randomized clinical trial enrolled participants from April 2015 to February 2018 at 31 US clinical research sites. PWH without known CVD who were taking antiretroviral therapy and had low to moderate 10-year CVD risk were included. Data were analyzed from April to November 2023.

Intervention: Oral pitavastatin calcium, 4 mg per day.

Main outcomes and measures: Coronary CTA and inflammatory biomarkers at baseline and 24 months. The primary outcomes were change in noncalcified coronary plaque volume and progression of noncalcified plaque.

Results: Of 804 enrolled persons, 774 had at least 1 evaluable CTA. Plaque changes were assessed in 611 who completed both CT scans. Of 611 analyzed participants, 513 (84.0%) were male, the mean (SD) age was 51 (6) years, and the median (IQR) 10-year CVD risk was 4.5% (2.6-7.0). A total of 302 were included in the pitavastatin arm and 309 in the placebo arm. The mean noncalcified plaque volume decreased with pitavastatin compared with placebo (mean [SD] change, -1.7 [25.2] mm3 vs 2.6 [27.1] mm3; baseline adjusted difference, -4.3 mm3; 95% CI, -8.6 to -0.1; P = .04; 7% [95% CI, 1-12] greater reduction relative to placebo). A larger effect size was seen among the subgroup with plaque at baseline (-8.8 mm3 [95% CI, -17.9 to 0.4]). Progression of noncalcified plaque was 33% less likely with pitavastatin compared with placebo (relative risk, 0.67; 95% CI, 0.52-0.88; P = .003). Compared with placebo, the mean low-density lipoprotein cholesterol decreased with pitavastatin (mean change: pitavastatin, -28.5 mg/dL; 95% CI, -31.9 to -25.1; placebo, -0.8; 95% CI, -3.8 to 2.2). The pitavastatin arm had a reduction in both oxidized low-density lipoprotein (-29% [95% CI, -32 to -26] vs -13% [95% CI, -17 to -9]; P < .001) and lipoprotein-associated phospholipase A2 (-7% [95% CI, -11 to -4] vs 14% [95% CI, 10-18]; P < .001) compared with placebo at 24 months.

Conclusions and relevance: In PWH at low to moderate CVD risk, 24 months of pitavastatin reduced noncalcified plaque volume and progression as well as markers of lipid oxidation and arterial inflammation. These changes may contribute to the observed MACE reduction in REPRIEVE.

Trial registration: ClinicalTrials.gov Identifier: NCT02344290.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Lu reported grants from the National Heart, Lung, and Blood Institute and Kowa Pharmaceuticals America during the conduct of the study as well as grants from American Heart Association, AstraZeneca, Ionis, Johnson & Johnson Innovation, MedImmune, National Academy of Medicine, National Heart, Lung, and Blood Institute, and Risk Management Foundation of the Harvard Medical Institutions outside the submitted work. Dr Ribaudo reported grants from the National Heart, Lung, and Blood Institute, Kowa Pharmaceuticals, and Gilead Sciences during the conduct of the study as well as grants from National Institute of Allergy and Infectious Diseases, National Institute on Aging, and National Heart, Lung, and Blood Institute outside the submitted work. Dr Foldyna reported grants from the National Heart, Lung, and Blood Institute, AstraZeneca, MedImmune, and Medtrace outside the submitted work. Dr Zanni reported grants from Gilead Sciences during the conduct of the study. Dr Taron reported grants from the Deutsche Forschungsgesellschaft (German Research Foundation) during the conduct of the study as well as personal fees from Siemens Healthcare, Bayer AG, Universimed Cross Media Content, coreLab Black Forest, and Onc AI outside the submitted work. Dr Burdo reported grants from Massachusetts General Hospital during the conduct of the study as well as nonfinancial support from Excision BioTherpeutics outside the submitted work. Dr DeFilippi reported grants from Massachusetts General Hospital outside the submitted work. Dr Malvestutto reported grants from AIDS Clinical Trials Group during the conduct of the study; grants from Eli Lilly; and personal fees from ViiV Healthcare, Gilead Sciences, and Pfizer outside the submitted work. Dr Siminski reported grants from Massachusetts General Hospital during the conduct of the study. Dr Overton reported grants from the National Institutes of Health during the conduct of the study. Dr Currier reported personal fees from Merck outside the submitted work. Dr Aberg reported grants from Massachusetts General Hospital during the conduct of the study; grants from Emergent Biosolutions, Frontier Biotechnologies, Gilead Sciences, GlaxoSmithKline, Janssen, Macrogenics, Merck, Pfizer, Regeneron, and ViiV Healthcare; and personal fees from GlaxoSmithKline, Merck, and Kintor Pharmaceuticals outside the submitted work. Dr Fichtenbaum reported grants from ViiV Healthcare, Gilead Sciences, Merck, Moderna, and Lilly as well as personal fees from ViiV Healthcare and Theratechnologies outside the submitted work. Dr Hoffmann reported grants from the National Institutes of Health during the conduct of the study as well as personal fees from Stanford University, CCS, MedTrace, and RapidAI outside the submitted work. Dr Grinspoon reported grants from the National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare during the conduct of the study; personal fees from ViiV Healthcare, Theratechnologies, and Marathon Asset Management outside the submitted work; and has a patent for use of pitavastatin pending. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
REPRIEVE indicates Randomized Trial to Prevent Vascular Events in HIV.
Figure 2.
Figure 2.. Effect of Biomarkers on Relative Risk of Progression of Noncalcified Plaque
Effect size is per 25% decrease in the biomarker. The P value tests for a linearly increasing log relative risk. Mechanistic analyses were limited to the per-protocol population with paired biomarkers and plaque outcomes. hsCRP indicates high-sensitivity C-reactive protein; LDL, low-density lipoprotein; LpPLA-2, lipoprotein-associated phospholipase A2; NCP, noncalcified plaque.
See this image and copyright information in PMC

Comment on

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