Coronary Plaque, Inflammation, Subclinical Myocardial Injury, and Major Adverse Cardiovascular Events in the REPRIEVE Substudy

Michael T Lu¹, Heather J Ribaudo², Sara McCallum³, Markella V Zanni³, Christopher deFilippi⁴, Jana Taron⁵, Julia Karady⁶, Borek Foldyna⁶, Kayla Paradis⁶, Sarah M Chu³, Marissa R Diggs³, Tricia H Burdo⁷, Judith S Currier⁸, Gerald S Bloomfield⁹, Carl J Fichtenbaum¹⁰, Carlos D Malvestutto¹¹, Judith A Aberg¹², Thomas Mayrhofer¹³, Pamela S Douglas¹⁴, Steven K Grinspoon¹⁵; REPRIEVE Investigators

Affiliations

¹ Cardiovascular Imaging Research Center, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. Electronic address: mlu@mgh.harvard.edu.
² Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
³ Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁴ Inova Schar Heart and Vascular, Falls Church, Virginia, USA.
⁵ Cardiovascular Imaging Research Center, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Radiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Breisgau, Germany.
⁶ Cardiovascular Imaging Research Center, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁷ Department of Medicine, Rutgers Institute of Translational Medicine and Science, Robert Wood Johnson Medical School, Rutgers, The University of New Jersey, New Brunswick, New Jersey, USA.
⁸ Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁹ Department of Medicine, Duke Global Health Institute and Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁰ Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
¹¹ Division of Infectious Diseases, Ohio State University Medical Center, Columbus, Ohio, USA.
¹² Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹³ Cardiovascular Imaging Research Center, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Center for Preventive Medicine and Digital Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹⁴ Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁵ Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. Electronic address: sgrinspoon@mgh.harvard.edu.

PMID: 40373520
PMCID: PMC12138200
DOI: 10.1016/j.jacadv.2025.101781

Coronary Plaque, Inflammation, Subclinical Myocardial Injury, and Major Adverse Cardiovascular Events in the REPRIEVE Substudy

Michael T Lu et al. JACC Adv. 2025 Jun.

. 2025 Jun;4(6 Pt 1):101781.

doi: 10.1016/j.jacadv.2025.101781. Epub 2025 May 14.

Authors

Affiliations

¹ Cardiovascular Imaging Research Center, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. Electronic address: mlu@mgh.harvard.edu.
² Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
³ Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁴ Inova Schar Heart and Vascular, Falls Church, Virginia, USA.
⁵ Cardiovascular Imaging Research Center, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Radiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Breisgau, Germany.
⁶ Cardiovascular Imaging Research Center, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁷ Department of Medicine, Rutgers Institute of Translational Medicine and Science, Robert Wood Johnson Medical School, Rutgers, The University of New Jersey, New Brunswick, New Jersey, USA.
⁸ Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁹ Department of Medicine, Duke Global Health Institute and Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁰ Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
¹¹ Division of Infectious Diseases, Ohio State University Medical Center, Columbus, Ohio, USA.
¹² Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹³ Cardiovascular Imaging Research Center, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Center for Preventive Medicine and Digital Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹⁴ Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁵ Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. Electronic address: sgrinspoon@mgh.harvard.edu.

PMID: 40373520
PMCID: PMC12138200
DOI: 10.1016/j.jacadv.2025.101781

Abstract

Background: In REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV), pitavastatin prevented major adverse cardiovascular events (MACE) and reduced noncalcified coronary plaque (NCP) among people with HIV and low-to-moderate traditional cardiovascular disease (CVD) risk.

Objectives: The purpose of this study was to assess the relationship of coronary plaque, inflammation, and subclinical myocardial injury with MACE.

Methods: A total of 804 REPRIEVE Mechanistic Substudy participants enrolled from April 2015 to February 2018 at 31 U.S. sites, randomized to pitavastatin 4 mg/day or placebo, and followed for incident MACE (median 6.2 years [Q1-Q3 5.4-7.1]), were assessed for relationships of baseline NCP, markers of inflammation (high-sensitivity C-reactive protein [hs-CRP], interleukin (IL)-6, oxidized low-density lipoprotein, and lipoproprotein-associated phospholipase A2), and subclinical myocardial injury (high-sensitivity cardiac troponin T [hs-cTnT]) with MACE.

Results: Among enrolled participants (17% female [139/804], 47% non-White [379/804], median age 51 years, median low-density lipoprotein 105 mg/dL, 10-year atherosclerotic CVD [ASCVD] risk 4.6%, 40% [299/755] with noncalcified plaque), MACE incidence was 7.26/1,000 (95% CI: 4.51-11.7) person-years (17 events) for pitavastatin and 9.15/1,000 person-years (95% CI: 5.97-14.0) (21 events) for placebo. The hazard of MACE was greater in those with (vs without) noncalcified plaque (HR: 2.5; [95% CI: 1.3-4.8]; P = 0.008), with higher levels of hs-CRP (P = 0.049), IL-6 (P = 0.033), and hs-cTnT (P = 0.003) at study entry, persisting after ASCVD risk adjustment. In exploratory prediction modeling, adding hs-CRP, IL-6, and hs-cTnT to ASCVD risk increased the integrated area under the curve to 0.72 and C-statistic to 0.73 (0.62-0.84) vs 0.58 and 0.56 (0.45-0.67) compared to ASCVD risk alone.

Conclusions: NCP and higher hs-CRP, IL-6, and hs-cTnT were associated with MACE and improved risk prediction over traditional risk factors in people with HIV without cardiac symptoms and low-to-moderate ASCVD risk. (Evaluating the Use of Pitavastatin to Reduce the Risk of Cardiovascular Disease in HIV-Infected Adults [REPRIEVE]; NCT02344290).

Keywords: HIV; biomarkers; coronary plaque; inflammation; major adverse cardiovascular events; myocardial injury.

PubMed Disclaimer

Conflict of interest statement

Funding support and author disclosures This study is supported through NIH grants U01HL123336 and 1UG3HL164285, to the Clinical Coordinating Center, and U01HL123339 and 1U24HL164284, to the Data Coordinating Center, as well as funding from Kowa Pharmaceuticals America, Inc, Gilead Sciences, and ViiV Healthcare. The NIAID supported this study through grants UM1 AI068636, which supports the ACTG Leadership and Operations Center; and UM1 AI106701, which supports the ACTG Laboratory Center. This work was also supported by the Nutrition Obesity Research Center at Harvard (P30DK040561 to Dr Grinspoon). The views expressed in this paper are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute or the National Institute of Allergy and Infectious Diseases; the National Institutes of Health; or the U.S. Department of Health and Human Services. Dr Lu has received grant support through his institution from the NIH/NHLBI and Kowa Pharmaceuticals America for the conduct of the study; and also has received research support to his institution from the American Heart Association, AstraZeneca, Ionis, Johnson & Johnson Innovation, MedImmune, the National Academy of Medicine, the NIH/NHLBI, and the Risk Management Foundation of the Harvard Medical Institutions Incorporated outside of the submitted work. Dr Ribaudo has received grants from Kowa Pharmaceuticals during the conduct of the study, as well as grants from NIH/NIAID, NIH/NHLBI, NIH/NIDDK, and NIH/NIA, outside of the submitted work. Dr Zanni has received grant support through her institution from NIH/NIAID and Gilead Sciences, Inc, relevant to the conduct of the study, as well as grants from NIH/NIAID and NIH/NHLBI; support for attending CROI and International Workshop for HIV and Women from conference organizing committee when abstract reviewer and/or speaker; and participation in DSMB for NIH funded studies, outside the submitted work. Dr deFilippi has received grants from Massachusetts General Hospital outside the submitted work; has received grants/contracts from Abbott Diagnostics, FujiRebio, Quidel:Ortho, Randox, Roche Diagnostics, and Siemens Healthineers outside this submitted work; and also has received consulting income from Abbott Diagnostics, Polymedco, Quidel:Ortho, Roche Diagnostics, Siemens Healthineers, and Tosoh. Dr Taron has received grants from the Deutsche Forschungsgesellschaft (German Research Foundation, TA 1438/1-2) during the conduct of the study as well as personal fees from Universimed Cross Media Content, coreLab Black Forest, and Onc AI outside the submitted work. Dr Foldyna has received grants from the National Heart, Lung, and Blood Institute, AstraZeneca, MedImmune, MedTrace, and Cleerly Health outside the submitted work. Dr Burdo has received grants from Massachusetts General Hospital during the conduct of the study and is a member of the scientific advisory board and has equity in Excision BioTherpeutics, outside the submitted work. Dr Currier has received consulting fees from Merck and Company, outside the submitted work. Dr Fichtenbaum has received research grant support through his institution from Gilead Sciences, ViiV Healthcare, GSK, and Merck, all outside the submitted work. Dr Malvestutto has received institutional research support by Lilly and honoraria from ViiV Healthcare, Gilead Sciences, and Pfizer for advisory board membership, all outside the submitted work. Dr Aberg has received grants from Massachusetts General Hospital during the conduct of the study; has received institutional research support for clinical trials from Emergent BioSolutions, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare, and has received personal fees for advisory boards from GlaxoSmithKline/ViiV, Invivyd, Merck and Regeneron; and participation on DSMB for Kintor Pharmaceuticals, all outside the submitted work. Dr Grinspoon has received grant support through his institution from NIH, Kowa Pharmaceuticals America, Inc, Gilead Sciences, Inc, and ViiV Healthcare for the conduct of the study; has received personal fees from Theratechnologies and ViiV; and has served on the scientific advisory board of Marathon Asset Management and Exavir Therapeutics, all outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

**Figure 1**
Estimated Baseline Plaque Effect on Subdistribution Hazard of MACE (A) Unadjusted. (B) Adjusted for ASCVD risk score. (C) Adjusted for ASCVD risk score components. Subdistribution hazard ratio estimates with 95% CIs for biomarker effect. For visual purposes, the x-axis is shown in the log scale. ASCVD = atherosclerotic cardiovascular disease; CAC = coronary artery calcium; MACE = major adverse cardiovascular events; NCP = noncalcified coronary plaque.

**Central Illustration**
Plaque, Inflammation, Subclinical Myocardial Injury, and MACE in the REPRIEVE Mechanistic Substudy This central illustration summarizes the main findings of our study. We assessed the relationship of coronary plaque, as well as indices of inflammation and subclinical myocardial injury, with MACE among 804 participants in the REPRIEVE Mechanistic Substudy. The hazard of MACE was greater over 6.2 years in those with noncalcified plaque (NCP) at study entry (P = 0.008), higher levels of hs-CRP (P = 0.049), IL-6 (P = 0.033) and hs-cTnT (P = 0.003), in modeling stratified by statin randomization. Abbreviations as in Figures 1 and 3.

**Figure 2**
Cumulative Incidence of MACE Over Time, By Baseline Noncalcified Plaque Cumulative incidence of MACE over time, by baseline (A) and presence of noncalcified plaque and (B) noncalcified plaque volume. Cumulative incidence was calculated using the Aalen estimator for probability of subdistribution of failure of interest. The bands represent point-wise 95% CIs. Participant follow-up was calculated in calendar months (30.44 days) from randomization to the first event or last contact, whichever was earlier; participants with no contact after entry were included with 1 day imputed as censoring time. Abbreviations as in Figure 1.

**Figure 3**
Estimated Baseline Biomarker Effect on Subdistribution Hazard of MACE (A) Unadjusted. (B) Adjusted for ASCVD risk score. (C) Adjusted for ASCVD risk score and presence of NCP at baseline. Subdistribution HR estimates with 95% CIs for biomarker effect; all models were stratified for randomized treatment. For visual purposes, the x-axis is shown in the log scale. ASCVD risk score components: natal sex, age, race, fasting cholesterol (mg/dL), fasting HDL (mg/dL), smoking status, and hypertension. Number of participants with specific biomarker assessed at entry as shown. All continuous biomarker effects are for a doubling in the biomarker level. Baseline biomarker distributions are shown in Supplemental Figure 2. HDL = high-density lipoprotein; hs-CRP = high-sensitivity C-reactive protein; hs-cTnT = high-sensitivity cardiac troponin T; Lp-PLA2 = lipoproprotein-associated phospholipase A2; IL = interleukin; oxLDL = oxidized LDL; other abbreviations as in Figure 1.

See this image and copyright information in PMC

References

1. Hoffmann U., Lu M.T., Olalere D., et al. Rationale and design of the Mechanistic Substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE): effects of pitavastatin on coronary artery disease and inflammatory biomarkers. Am Heart J. 2019;212:1–12. - PMC - PubMed
1. Grinspoon S.K., Fitch K.V., Overton E.T., et al. Rationale and design of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) Am Heart J. 2019;212:23–35. - PMC - PubMed
1. Grinspoon S.K., Fitch K.V., Zanni M.V., et al. Pitavastatin to prevent cardiovascular disease in HIV infection. N Engl J Med. 2023;389:687–699. - PMC - PubMed
1. Grinspoon S.K., Ribaudo H.J., Douglas P.S. Trial update of pitavastatin to prevent cardiovascular events in HIV infection. N Engl J Med. 2024;390:1626–1628. - PMC - PubMed
1. Hoffmann U., Lu M.T., Foldyna B., et al. Assessment of coronary artery disease with computed tomography angiography and inflammatory and immune activation biomarkers among adults with HIV eligible for primary cardiovascular prevention. JAMA Netw Open. 2021;4 - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Coronary Plaque, Inflammation, Subclinical Myocardial Injury, and Major Adverse Cardiovascular Events in the REPRIEVE Substudy

Affiliations

Coronary Plaque, Inflammation, Subclinical Myocardial Injury, and Major Adverse Cardiovascular Events in the REPRIEVE Substudy

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous