Risk factors for clonal hematopoiesis of indeterminate potential in people with HIV: a report from the REPRIEVE trial.

"Conflict-of-interest disclosure: R.B. has served as a medical adviser to Casana Care Inc, unrelated to present work. M.T.L. reports research support to his institution from the 10.13039/100000968American Heart Association, 10.13039/100004325AstraZeneca, Ionis, Johnson & Johnson Innovation, Kowa Pharmaceuticals America, 10.13039/501100004628MedImmune, the 10.13039/100009645National Academy of Medicine, and the National Institutes of Health (NIH)/ National Heart, Lung, and Blood Institute (10.13039/100000050NHLBI) and the Risk Management Foundation of the Harvard Medical Institutions Incorporated outside of the submitted work. C.M. reports research support to his institution from Lilly and serves on the advisory boards for ViiV Healthcare, Gilead Sciences, and Pfizer unrelated to the present work. J.A.A. reports institutional research support for clinical trials from Emergent Biosolutions, Frontier Technologies, Gilead Sciences, GlaxoSmithKline (GSK), Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare; personal fees for advisory boards from GSK/ViiV and Merck; and participation on data safety monitoring Board for Kintor Pharmaceuticals, all outside the submitted work. C.J.F. reports grant support through his institution from 10.13039/100005564Gilead Sciences, 10.13039/100010877ViiV Healthcare, GSK, 10.13039/100005565Janssen, 10.13039/100006483AbbVie, 10.13039/100004334Merck, 10.13039/100002429Amgen, and Cytodyn; personal fees from Theratechnologies and ViiV for consulting and participation on advisory board unrelated to REPRIEVE; and data safety monitoring board Chair for Intrepid Study, all outside the submitted work. H.J.R. reports receiving grants from NIH/10.13039/100000050NHLBI and Kowa Pharmaceuticals during the conduct of the study, as well as grants from NIH/ National Institute of Allergy and Infectious Diseases (10.13039/100000060NIAID), NIH/10.13039/100000050NHLBI, NIH/National Institute of Diabetes and Digestive and Kidney Diseases, and NIH/National Institute on Aging, outside the submitted work. P.L. is an unpaid consultant to or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron; is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech, Inc; and P.L.’s laboratory has received research funding in the last 2 years from 10.13039/100004336Novartis, 10.13039/501100004191Novo Nordisk, and 10.13039/100004328Genentech; P.L. is on the board of directors of XBiotech, Inc; 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 (CHIP) 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; and P.L.’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. B.L.E. has received research funding from 10.13039/100006436Celgene, Deerfield, 10.13039/100004336Novartis, and Calico; consulting fees from GRAIL; and is a member of the scientific advisory board and shareholder for Neomorph Inc, TenSixteen Bio, Skyhawk Therapeutics, and Exo Therapeutics. M.V.Z. reports grant support through her institution from NIH/10.13039/100000060NIAID and 10.13039/100005564Gilead Sciences, Inc, relevant to the conduct of the study, as well as grants from NIH/10.13039/100000060NIAID and NIH/10.13039/100000050NHLBI outside the submitted work. S.K.G. reports grant support through his institution from NIH/NIDDK, Kowa Pharmaceuticals America, Inc, 10.13039/100005564Gilead Sciences, Inc, and 10.13039/100010877ViiV 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.N. reports research grants from Allelica, 10.13039/100017567Apple, 10.13039/100002429Amgen, Boston Scientific, Genentech/Roche, and 10.13039/100004336Novartis; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, and Novartis; scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio; and is a scientific cofounder of TenSixteen Bio, equity in Preciseli and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. The remaining authors declare no competing financial interests."

"This study is supported through National Institutes of Health (NIH) grants U01HL123336 to the Clinical Coordinating Center, and U01HL123339 to the Data Coordinating Center as well as funding from Kowa Pharmaceuticals America, Inc, 10.13039/100005564Gilead Sciences, and 10.13039/100010877ViiV Healthcare. The 10.13039/100000060NIAID supported this study through grants UM1 AI068636 which supports the ACTG Leadership and Operations Center; and UM1 AI106701, which supports the ACTG Laboratory Center."

"Clonal hematopoiesis of indeterminate potential (CHIP), the clonal expansion of myeloid cells with leukemogenic mutations, results in increased coronary artery disease (CAD) risk. CHIP is more prevalent among people with HIV (PWH), but the risk factors are unknown. CHIP was identified among PWH in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) using whole-exome sequencing. Logistic regression was used to associate sociodemographic factors and HIV-specific factors with CHIP adjusting for age, sex, and smoking status. In the studied global cohort of 4486 PWH, mean age was 49.9 (standard deviation [SD], 6.4) years; 1650 (36.8%) were female; and 3418 (76.2%) were non-White. CHIP was identified in 223 of 4486 (4.97%) and in 38 of 373 (10.2%) among those aged ≥60 years. Age (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.05-1.09; P < .0001) and smoking (OR, 1.37; 95% CI, 1.14-1.66; P < .001) associated with increased odds of CHIP. Globally, participants outside of North America had lower odds of CHIP including sub-Saharan Africa (OR, 0.57; 95% CI, 0.4-0.81; P = .0019), South Asia (OR, 0.45; 95% CI, 0.23-0.80; P = .01), and Latin America/Caribbean (OR, 0.56; 95% CI, 0.34-0.87; P = .014). Hispanic/Latino ethnicity (OR, 0.38; 95% CI, 0.23-0.54; P = .002) associated with significantly lower odds of CHIP. Among HIV-specific factors, CD4 nadir <50 cells/mm3 associated with a 1.9-fold (95%CI, 1.21-3.05; P = .006) increased odds of CHIP, with the effect being significantly stronger among individuals with short duration of antiretroviral therapy (ART; OR, 4.15; 95% CI, 1.51-11.1; P = .005) (Pinteraction= .0492). Among PWH at low-to-moderate CAD risk on stable ART, smoking, CD4 nadir, North American origin, and non-Hispanic ethnicity associated with increased odds of CHIP. This trial was registered at www.ClinicalTrials.gov as NCT02344290."