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Randomized Controlled Trial
. 2026 Jan;46(1):168-177.
doi: 10.1161/ATVBAHA.125.322896. Epub 2025 Nov 6.

Clonal Hematopoiesis and Major Adverse Cardiac Events in People With HIV: Insights From the REPRIEVE Trial

Liying Xue #  1 , Romit Bhattacharya #  1   2   3 , Md Mesbah Uddin  1 , Tetsushi Nakao  1   2 , Roger Zou  2 , Aniruddh Patel  1   2   3 , Sara Haidermota  2 , Abhishek Niroula  4   5   6 , Victoria Viscosi  2 , Darina Postupaka  2 , Aarushi Bhatnagar  1   2 , Phoebe Finneran  2 , Rachel Bernardo  2   7 , Marissa R Diggs  8 , Kathleen V Fitch  8 , Sarah M Chu  8 , Sara McCallum  8 , Judith S Currier  9 , Carl J Fichtenbaum  10 , Carlos D Malvestutto  11 , Judith A Aberg  12 , Gerald S Bloomfield  13 , Heather J Ribaudo  14 , Markella V Zanni  8 , Peter Libby  3   15 , Whitney Hornsby  2 , Michael T Lu  16 , Pamela S Douglas  17 , Steven K Grinspoon  8 , Pradeep Natarajan  1   3
Affiliations
Randomized Controlled Trial

Clonal Hematopoiesis and Major Adverse Cardiac Events in People With HIV: Insights From the REPRIEVE Trial

Liying Xue et al. Arterioscler Thromb Vasc Biol. 2026 Jan.

Abstract

Background: People with HIV (PWH) experience higher cardiovascular disease event rates not fully explained by traditional risk factors. Clonal hematopoiesis of indeterminate potential (CHIP), an emerging risk factor for cardiovascular disease in the general population, has been reported to be more prevalent in PWH.

Methods: Using high-coverage targeted CHIP sequencing in the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) cardiovascular disease prevention trial, we investigated whether CHIP increases the risk of major adverse cardiovascular events (MACE) among PWH, as well as whether HIV-associated factors were associated with greater CHIP prevalence among PWH. We analyzed whole-exome and targeted sequencing from 4490 PWH without known cardiovascular disease; 1653 (36.8%) were female, and 2039 (45.4%) were Black. MACE was defined by including cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral artery disease, revascularization, or death from an undetermined cause.

Results: A total of 837 (18.6%) had CHIP driver mutations, with 385 (8.6%) at variant allele fraction ≥2% and 61 (1.4%) at variant allele fraction ≥10%. Although overall CHIP was not associated with MACE, the presence of large CHIP (variant allele fraction ≥10%) was associated with increased odds for the first occurrence of myocardial infarction or cardiac catheterization, or revascularization, despite low overall event rates. Adjustments for pitavastatin treatment did not attenuate this association. Furthermore, a larger CHIP clone size was associated with lower CD4 nadir and with increased risk of MACE.

Conclusions: In PWH in the REPRIEVE trial who were low-to-moderate risk for incident cardiovascular disease, CHIP was not associated with increased prospective risk of MACE. However, a large CHIP was associated with increased risk of myocardial infarction and revascularization.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02344290.

Keywords: cardiovascular diseases; clonal hematopoiesis; myocardial infarction; pitavastatin; risk factors.

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Conflict of interest statement

The views expressed in this manuscript 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 (NIH); or the US Department of Health and Human Services. J.S. Currier reports consulting fees from Merck and Company and Resvirlogix, outside the submitted work. C.J. Fichtenbaum reports research grant support through his institution from Gilead Sciences, ViiV Healthcare, GSK (GlaxoSmithKline), and Merck, all outside the submitted work. C.D. Malvestutto reports institutional research support by Lilly and honoraria from ViiV Healthcare, Gilead Sciences, and Pfizer for advisory board membership, all outside the submitted work. J.A. Aberg reports grants from Massachusetts General Hospital during the conduct of the study; institutional research support for clinical trials from Gilead Sciences, Glaxo Smith Kline, Janssen, Macrogenics, Merck, Pfizer, Regeneron, and ViiV Healthcare; personal fees for advisory boards from Glaxo Smith Kline/ViiV, Invivyd, and Merck; and participation on DSMB (Data Safety Monitoring Board) for Kintor Pharmaceuticals, all outside the submitted work. H.J. Ribaudo reports grants from Kowa Pharmaceuticals during the conduct of the study, as well as grants from NIH/NIAID (National Institute of Allergy and Infectious Diseases), NIH/National Heart, Lung, and Blood Institute (NHLBI), NIH/NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases), and NIH/NIA, outside of the submitted work. M.V. Zanni reports 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 (Conference on Retroviruses and Opportunistic Infections) and International Workshop for HIV and Women from conference organizing committee when abstract reviewer or speaker; and participation in DSMB for NIH funded studies, outside the submitted work. M.T. Lu reports grant support through his institution from the NIH/NHLBI and Kowa Pharmaceuticals America for the conduct of the study. He also reports 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. S.K. Grinspoon reports grant support through his institution from NIH, Kowa Pharmaceuticals America Inc, Gilead Sciences Inc, and ViiV Healthcare for the conduct of the study; personal fees from Theratechnologies and ViiV; and service on the Scientific Advisory Board of Marathon Asset Management, all outside the submitted work. P. Libby is an unpaid consultant to or involved in clinical trials for Amgen, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Novo Nordisk, Novartis, and Sanofi-Regeneron. P. Libby is a member of the scientific advisory board for Amgen, Caristo Diagnostics, CSL Behring, Elucid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Novartis, PlaqueTec, Polygon Therapeutics, TenSixteen Bio, Soley Therapeutics, and XBiotech Inc. P. Libby’s laboratory has received research funding in the last 2 years from Novartis, Novo Nordisk, and Genentech. P. Libby is on the Board of Directors of XBiotech Inc Dr Libby has a financial interest in Xbiotech, a company developing therapeutic human antibodies, in TenSixteen Bio, a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential to discover and develop novel therapeutics to treat age-related diseases, and in Soley Therapeutics, a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics. P. Libby’s interests were reviewed and are managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. The other authors report no conflicts.

Figures

Figure 1.
Figure 1.. Prevalence of CHIP in REPRIEVE targeted sequencing.
(A) Relative frequency of CHIP >=2% VAF driver mutations in known CHIP genes; (B) frequency of participants carrying 1 or greater number of CHIP clones>=2% VAF; (C) CHIP prevalence by age; (D) VAF distribution of CHIP driver mutations detected by targeted sequencing. The black dashed line indicates the mean VAF across all variants. CHIP, Clonal Hematopoiesis of Indeterminate Potential; VAF, variant allele fraction
Figure 2.
Figure 2.. HIV-Specific risk factors and odds of CHIP.
(A) CD4 nadir and ART duration with the presence of CHIP; (B) CD4 nadir and ART duration with the maximum CHIP VAF per individual. ART, antiretroviral therapy; CHIP, Clonal Hematopoiesis of Indeterminate Potential; VAF, variant allele fraction
Figure 3.
Figure 3.. CHIP and Odds of Major Adverse Cardiovascular Events (MACE).
(A) Odds of MACE stratified by CHIP clone size, and with each element comprising the MACE outcome [MACE ~ CHIP + covariates]; (B) Odds of MACE, MI and cardiac catheterization or revascularization as modeled with maximum CHIP VAF per individual as a continuous variable. CHIP, Clonal Hematopoiesis of Indeterminate Potential; MACE, major adverse cardiovascular events; MI, myocardial infarction; VAF, variant allele fraction
See this image and copyright information in PMC

References

    1. Grinspoon SK, Fitch KV, Zanni MV, et al. Pitavastatin to prevent cardiovascular disease in HIV infection. N Engl J Med. 2023;389:687–699. - PMC - PubMed
    1. Grinspoon SK, Ribaudo HJ, Douglas PS. Trial update of pitavastatin to prevent cardiovascular events in HIV infection. N Engl J Med. 2024;390:1626–1628. - PMC - PubMed
    1. Eyawo O, Brockman G, Goldsmith CH, et al. Risk of myocardial infarction among people living with HIV: an updated systematic review and meta-analysis. BMJ Open. 2019;9:e025874. - PMC - PubMed
    1. Mitka M Exploring statins to decrease HIV-related heart disease risk. JAMA. 2015;314:657. - PubMed
    1. Ntsekhe M, Baker JV. Cardiovascular disease among persons living with HIV: New insights into pathogenesis and clinical manifestations in a global context. Circulation. 2023;147:83–100. - PubMed

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