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Background: REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) led to new guidelines for statin use among people with HIV (PWH) with low to moderate risk for atherosclerotic cardiovascular disease (ASCVD). Little is known about the natural history of diabetes mellitus (DM) or mechanisms contributing to statin effects on DM among this population., Objective: To determine the contribution of known DM risk factors to excess risk for DM with pitavastatin in REPRIEVE., Design: Phase 3, primary ASCVD prevention trial over a median of 5.6 years of follow-up. (ClinicalTrials.gov: NCT02344290)., Setting: Global, multicenter trial., Participants: 7731 PWH aged 40 to 75 years with low to moderate ASCVD risk (by the pooled cohort equations from the American College of Cardiology and American Heart Association) without DM at study entry., Intervention: Random 1:1 assignment to pitavastatin, 4 mg daily, or placebo., Measurements: New-onset DM was determined at each visit by clinical diagnosis requiring initiation of medication treatment for DM. The incidence of new-onset DM was assessed in relation to predefined demographic and metabolic risk factors, stratified by treatment group. Treatment effects of pitavastatin on progression to new DM in key subgroups were determined., Results: Participants with at least 3 DM risk factors (vs. no risk factors) had increased risk for DM in each treatment group (incidence rate, 3.24 per 100 person-years [PY] vs. 0.34 per 100 PY [pitavastatin] and 2.66 per 100 PY vs. 0.27 per 100 PY [placebo]). The incidence of DM was highest in South Asia. In adjusted analyses, high body mass index, prediabetes, and metabolic syndrome components were strongly associated with new-onset DM (all P  < 0.005)., Limitation: Pitavastatin was the only statin assessed; DM was assessed clinically., Conclusion: Metabolic risk factors, including prediabetes and obesity, contributed to new-onset DM in statin- and placebo-treated participants. A clinically significant effect of pitavastatin on DM was seen primarily among those with multiple risk factors for DM at entry. Strategies targeting key metabolic risk factors, like obesity and prediabetes, may help protect against DM among PWH., Primary Funding Source: National Heart, Lung, and Blood Institute of the National Institutes of Health., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Background: Among people with HIV (PWH), COVID-19 is common and potentially severe. We leveraged REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) to assess the effects of statin therapy for cardiovascular disease prevention on COVID-19 outcomes (incidence and serious cases) among a global cohort of PWH., Methods: COVID-19 data collection was implemented April 2020 to capture events from January 2020. COVID-19 was defined by positive test result or clinical diagnosis and serious COVID-19 according to the International Conference on Harmonisation definition. Among participants in follow-up on 1 January 2020, Cox proportional hazards modeling was used to estimate the hazard ratio (HR) of COVID-19 (pitavastatin/placebo), stratified by Global Burden of Disease region. Modification of statin effect following COVID-19 vaccination was evaluated via interaction with time-updated vaccination status., Results: Among 6905 PWH, 32% were natal female and 41% were Black or African American. The median age was 53 years and the 10-year atherosclerotic cardiovascular disease risk score 4.5%. Statin therapy did not reduce COVID-19 incidence (HR, 1.05; 95% CI, .95-1.15) but appeared to reduce incidence of serious COVID-19 (HR, 0.75; 95% CI, .52-1.09). Among 1701 PWH with COVID-19, the relative risk (pitavastatin/placebo) for serious COVID-19 was 0.73 (95% CI, .52-1.03). The treatment effect size for serious COVID-19 fell within the hypothesized range, but the 95% CI crossed 1 given fewer-than-anticipated cases (117 vs 200). Furthermore, 83% reported COVID-19 vaccination by end of study, with a strong protective effect on serious COVID-19 (HR, 0.27; 95% CI, .14-.53; P < .0001). A protective statin effect was observed prior to vaccination., Conclusions: Among PWH, statin therapy had no effect on COVID-19 incidence but showed potential to reduce risk of serious COVID-19 prior to COVID-19 vaccination., Clinical Trials Registration: NCT02344290 (ClinicalTrials.gov)., Competing Interests: Potential conflicts of interest. M. V. Z. reports grant support through her institution from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) and Gilead Sciences, Inc, relevant to the conduct of the study, as well as grants from NIH/NIAID and the NIH/National Heart, Lung, and Blood Institute (NHLBI); support for attending the Conference on Retroviruses and Opportunistic Infections and International Workshop for HIV and Women from conference organizing committee when abstract reviewer and/or speaker; and participation in a data and safety monitoring board for NIH funded studies, outside the submitted work. T. U. reports grants from NIH/NHLBI and Kowa Pharmaceuticals during the conduct of the study, as well as grants from NIH/NIAID and NIH/National Institute on Aging (NIA), outside the submitted work. C. J. F. reports research grants to his institution from Gilead Sciences, Merck, ViiV Healthcare and Moderna unrelated to this work. J. A. A. reports institutional research support for clinical trials from Emergent Biosolutions, Gilead Sciences, Glaxo Smith Kline, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare; personal fees for advisory boards from Glaxo Smith Kline/ViiV and Merck; and participation on a data and safety monitoring board for Kintor Pharmaceuticals, all outside the submitted work. E. T. O. reports grant support from Gilead Sciences, ViiV Healthcare, and Janssen; consulting fees from ViiV Healthcare; and employment with ViiV Healthcare Medical Affairs, all outside the submitted work. C. D. M. 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. S. C. reports consulting fees from Merck and Company and Resvirlogix, outside the submitted work. S. R. S. reports grant support through his institution from NIH/NIAID (T32 AI007387). K. M. E. reports grant support from NIH/NIA and Gilead Sciences, Inc; consulting fees paid to her institution from Gilead Sciences, Inc, ViiV Healthcare, and Janssen Therapeutics; and participation on an NIH data and safety monitoring board, all outside the submitted work. B. F. reports institutional research support from AstraZeneca, MedImmune, and MedTrace, as well as grants from NIH/NHLBI, all outside the submitted work. E. M. reports institutional research support from MSD and ViiV as well as honoraria for lectures or advisory boards from Gilead, Janssen, MDS, and ViiV. G. P. W. reports grant support through his institution from NIH/NIAID, NIH/National Institute of Diabetes and Digestive and Kidney Diseases, and Veterans Health Administration, all outside the submitted work. M. T. L. 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 the submitted work. H. J. R. reports grants from Kowa Pharmaceuticals during the conduct of the study, as well as grants from NIH/NIAID, NIH/NHLBI, NIH/National Institute of Diabetes and Digestive and Kidney Diseases, and NIH/NIA, outside the submitted work. S. K. G. 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Little is known about the potential benefits or harms of statins on physical function among people with HIV (PWH)., Methods: REPRIEVE was a double-blind randomized controlled trial evaluating pitavastatin for primary prevention of major adverse cardiovascular events (MACE) in PWH. Time to complete ten chair rises, 4-meter gait speed, grip strength, and a modified short physical performance test were assessed annually for up to 5 years in the ancillary study PREPARE and analyzed using linear mixed models., Findings: Of 602 PWH, 52% were randomized to pitavastatin and 48% to placebo. Median age was 51 years; 18% were female at birth; 2% transgender; 40% Black, and 18% Hispanic. Median PREPARE follow-up was 4.7 (4.3, 5.0) years. Muscle symptoms (grade ≥3 or treatment-limiting) occurred in 5% of both groups. There was no evidence of decline in chair rise rate in either treatment group, and no difference in the pitavastatin group compared to placebo (estimated difference -0.10 [95% CI: -0.30, 0.10] rises/min/year; p=0.31). Small declines over time were observed in other physical function tests in both treatment groups, with no apparent differences between groups., Interpretation: We observed minimal declines in physical function over 5 years of follow-up among middle-aged PWH, with no differences among PWH randomized to pitavastatin compared to placebo. This finding, combined with low prevalence of myalgias, supports the long-term safety of statin therapy on physical function, when used for primary prevention of MACE among PWH., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Coronary plaque is common among people with HIV (PWH) with low-to-moderate traditional atherosclerotic cardiovascular disease (ASCVD) risk., Objectives: The purpose of this study was to determine the association of high-sensitivity cardiac troponin T (hs-cTnT) levels with coronary plaque characteristics and evaluate if hs-cTnT improves identification of these features beyond traditional ASCVD risk factors among PWH., Methods: Among PWH receiving stable antiretroviral therapy with low-to-moderate ASCVD risk and no known history of ASCVD, hs-cTnT levels and measures of plaque by coronary computed tomography angiography were assessed. Primary outcomes included the association of hs-cTnT level with the presence of any plaque, vulnerable plaque, coronary artery calcium (CAC) score, and Leaman score. Assessment of model discrimination of hs-cTnT for plaque characteristics was also performed., Results: The cohort included 708 U.S. participants with a mean age of 51 ± 6 years, 119 (17%) females, a median ASCVD risk score of 4.4% (Q1-Q3: 2.5%-6.6%), and a median hs-cTnT level of 6.7 ng/L (detectable level ≥6 ng/L in 61%). Any plaque was present in 341 (48%), vulnerable plaque in 155 (22%), CAC>100 in 68 (10%), and a Leaman score >5 in 105 (15%). After adjustment for ASCVD risk score, participants with hs-cTnT >9.6 ng/L (highest category) versus an undetectable level (<6 ng/L) had a greater relative risk for any plaque (1.37, 95% CI: 1.12-1.67), vulnerable plaque (1.47, 95% CI: 1.16-1.87), CAC>100 (2.58, 95% CI: 1.37-4.83), and Leaman score >5 (2.13, 95% CI: 1.32-3.46). The addition of hs-cTnT level modestly improved the discrimination of ASCVD risk score to identify critical plaque features., Conclusions: In PWH without known ASCVD, hs-cTnT levels were strongly associated with and improved prediction of subclinical coronary plaque. (Evaluating the Use of Pitavastatin to Reduce the Risk of Cardiovascular Disease in HIV-Infected Adults [REPRIEVE]; NCT02344290)., Competing Interests: 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; or the U.S. Department of Health and Human Services. This study is supported through NIH grants U01HL123336, to the Clinical Coordinating Center, and U01HL123339, 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 Advancing Clinical Therapeutics Globally (ACTG) Network 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 SKG). Dr deFilippi has received grant support to his institution from Roche Diagnostics and consulting for Roche Diagnostics which manufacturers the troponin T assay; has received grants to his institution from Abbott Diagnostics, FujiRebio, Quidel/Ortho, Siemens Healthineers, and the NHLBI outside this submitted work; consulting for Abbott Diagnostics, FujiRebio, and Quidel/Ortho, and Siemens Healthineers; and serves as a member of the clinical endpoint committee for Siemens Healthineers. Dr Zanni is the principal investigator of research grants from 10.13039/100000002NIH (NIAID and NHLBI) and from 10.13039/100005564Gilead Sciences to her institution and participating in a DSMB for 10.13039/100000002NIH-funded studies involving no compensation. Dr Fichtenbaum has received grant support through his institution from 10.13039/100005564Gilead Sciences, 10.13039/100010877ViiV Healthcare, 10.13039/100004330GSK, 10.13039/100005565Janssen, 10.13039/100006483Abbvie, 10.13039/100004334Merck, 10.13039/100002429Amgen, and Cytodyn, outside the submitted work; and personal fees from Theratechnologies and ViiV for consulting and participation on Advisory Board unrelated to REPRIEVE with Theratechnologies and ViiV, and role as Chair on DSMB for Intrepid Study, outside the submitted work. Dr Aberg has received institutional research support for clinical trials from Emergent Biosolutions, Frontier Technologies, Gilead Sciences, GlaxoSmithKline, Janssen, MacroGenics, Merck, Pfizer, Regeneron, and ViiV Healthcare; and personal fees for advisory boards from Glaxo Smith Kline/Viiv and Merck and participation on DSMB for Kintor Pharmaceuticals, all outside the submitted work. Dr Malvestutto has received institutional research support by Lilly; and honoraria from 10.13039/100010877ViiV Healthcare and 10.13039/100005564Gilead Sciences for Advisory Board membership, outside the submitted work. Dr Pinto-Martinez has received honoraria from Gilead, Janssen, and ViiV Healthcare for presentations and educational events, outside the submitted work. Dr Stapleton has received institutional research support by 10.13039/100000002NIH. Dr Robbins has received grant support to his institution from Leonard-Meron Bioscience; consulting fees to his institution from Seed Inc and Teradyne Inc; payment for expert testimony from Tufts Medical Center, participation on a DSMB for an NIH trial, and unpaid membership on a review panel for DHHS OI Guidelines. Dr Taron has received support from 10.13039/501100001659Deutsche Forschungsgesellschaft (DFG, German Research Foundation) relevant to the present work; consulting fees from Universimed Cross Media Content GmbH, Core Lab Black Forrest GmbH; and payments or honoraria from Siemens Healthcare GmbH, Bayer AG, outside of the submitted work. Dr Foldyna has received institutional support from 10.13039/100004325AstraZeneca, 10.13039/501100004628MedImmune, and MedTrace, outside of the submitted work. Dr Lu has received grant support through his institution from Kowa Pharmaceuticals America, Inc, for the conduct of the study; grant support from 10.13039/501100004628MedImmune and 10.13039/100004325AstraZeneca; and personal fees from PQBypass, outside of the current work. Dr Ribaudo has received grants from 10.13039/100000002NIH/10.13039/100000050NHLBI and Kowa Pharmaceuticals during the conduct of the study as well as grants from 10.13039/100000002NIH/10.13039/100000060NIAID, and 10.13039/100000002NIH/10.13039/100000050NHLBI, 10.13039/100000002NIH/10.13039/100000062NIDDK, and 10.13039/100000002NIH/10.13039/100000049NIA outside the submitted work. Dr Grinspoon has received grant support through his institution from Kowa Pharmaceuticals America, Inc 10.13039/100005564Gilead Sciences, Inc; and 10.13039/100010877ViiV Healthcare for the conduct of the study, as well as grants from Theratechnologies and Navidea and personal fees from Theratechnologies and ViiV, all outside the submitted work; and is a member of the Scientific Advisory Board of Marathon Asset management. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Pericoronary adipose tissue (PCAT) may influence plaque development through inflammatory mechanisms. We assessed PCAT density, as a measure of pericoronary inflammation, in relationship to coronary plaque among people with human immunodeficiency virus (HIV [PWH]) and to a matched control population., Methods: In this baseline analysis of 727 participants of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) Mechanistic Substudy, we related computed tomography-derived PCAT density to presence and extent (Leaman score) of coronary artery disease (CAD), noncalcified plaque, coronary artery calcium (CAC), and vulnerable plaque features using multivariable logistic regression analyses. We further compared the PCAT density between PWH and age, sex, body mass index, CAC score, and statin use-matched controls from the community-based Framingham Heart Study (N = 464), adjusting for relevant clinical covariates., Results: Among 727 REPRIEVE participants (age 50.8 ± 5.8 years; 83.6% [608/727] male), PCAT density was higher in those with (vs without) coronary plaque, noncalcified plaque, CAC >0, vulnerable plaque, and high CAD burden (Leaman score >5) (P < .001 for each comparison). PCAT density related to prevalent coronary plaque (adjusted odds ratio [per 10 HU]: 1.44; 95% confidence interval, 1.22-1.70; P < .001), adjusted for clinical cardiovascular risk factors, body mass index, and systemic immune/inflammatory biomarkers. Similarly, PCAT density related to CAC >0, noncalcified plaque, vulnerable plaque, and Leaman score >5 (all P ≤ .002). PCAT density was greater among REPRIEVE participants versus Framingham Heart Study (-88.2 ± 0.5 HU versus -90.6 ± 0.4 HU; P < .001)., Conclusions: Among PWH in REPRIEVE, a large primary cardiovascular disease prevention cohort, increased PCAT density independently associated with prevalence and severity of coronary plaque, linking increased coronary inflammation to CAD in PWH., Competing Interests: Potential conflicts of interest. B. F. reports institutional research support from AstraZeneca, MedImmune, and MedTrace, all outside of the submitted work. M. V. Z. 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 (RO1AI123001 PI, R01 HL137562 PI, R01HL146267 PI, K24AI157882 PI, U01HL123336 Co-I, U01HL123336-06S2 Co-I, R01HL151283 Co-I) outside the submitted work; travel support from conference organizing committees for CROI and International Workshop for HIV and Women; and unpaid participation in DSMB for NIH-funded studies. A. L. reports institutional research support from NIH/NIA, outside of the submitted work. T. H. B. reports equity in Excision Bio Therapeutics and serves on its Scientific Advisory Board, outside the submitted work. G. S. B. reports research grants (R01HL157531, U01HL146382, R56HL152803, R01MD013493) and royalties from UpToDate.com. C. D. M. reports institutional research support by Lilly and personal fees from ViiV Healthcare, Pfizer, and Gilead Sciences for participation in advisory board meetings outside the submitted work. C. J. F. reports grant support through his institution from Gilead Sciences, ViiV Healthcare, GSK, Janssen, Abbvie, Merck, Amgen, and Cytodyn, outside the submitted work; and personal fees from Theratechnologies and ViiV for consulting and participation on Advisory Board unrelated to REPRIEVE with Theratechnologies and ViiV, and role as Chair on DSMB for Intrepid Study, outside the submitted work. J. A. A. reports institutional research support for clinical trials from Atea, Emergent Biosolutions, Frontier Technologies, Gilead Sciences, Glaxo Smith Kline, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare and personal fees for data safety monitoring or advisory boards from Kintor Pharmaceuticals, Glaxo Smith Kline, and Merck; all outside the submitted work. J. S. C. reports consulting fees from Merck and Company. H. J. R. reports grants from NIH/NHLBI and Kowa Pharmaceuticals during the conduct of the study as well as grants from NIH/NIAID, and NIH/NHLBI, NIH/NIDDK, and NIH/NIA outside the submitted work. U. H. reports institutional research support from Kowa, AstraZeneca, MedImmune, and HeartFlow; consulting fees from Recor Medical, Stanford University, Clinical Cardiovascular Sciences, MedTrace Inc., and Rapid AI; stock or stock options in Cleerly Inc. as Chief Scientific Officer; and personal fees from Duke University, all outside of the submitted work. M. T. L. reports grant support through his institution from NIH/NHLIBI and Kowa Pharmaceuticals America, Inc., for the conduct of the study; institutional grant support from MedImmune, CRICO, Ionis, Johnson & Johnson Innovation, National Academy of Medicine, and Astrazeneca; and personal fees from PQBypass, outside of the current work. P. S. D. reports consulting fees from Foresite Labs; receipt of equipment or drugs from Kowa and Caption Health; and an institutional grant for HeartFlow (outside of the current work). S. K. G. reports grants from NIH, KOWA Pharmaceuticals, Gilead Sciences, and ViiV Healthcare during the conduct of the study as well as personal consulting fees from TheraTechnologies, Navidea, and ViiV Healthcare, and Marathon Asset Management outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The risk of cardiovascular disease is increased among persons with human immunodeficiency virus (HIV) infection, so data regarding primary prevention strategies in this population are needed., Methods: In this phase 3 trial, we randomly assigned 7769 participants with HIV infection with a low-to-moderate risk of cardiovascular disease who were receiving antiretroviral therapy to receive daily pitavastatin calcium (at a dose of 4 mg) or placebo. The primary outcome was the occurrence of a major adverse cardiovascular event, which was defined as a composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral arterial ischemia, revascularization, or death from an undetermined cause., Results: The median age of the participants was 50 years (interquartile range, 45 to 55); the median CD4 count was 621 cells per cubic millimeter (interquartile range, 448 to 827), and the HIV RNA value was below quantification in 5250 of 5997 participants (87.5%) with available data. The trial was stopped early for efficacy after a median follow-up of 5.1 years (interquartile range, 4.3 to 5.9). The incidence of a major adverse cardiovascular event was 4.81 per 1000 person-years in the pitavastatin group and 7.32 per 1000 person-years in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.48 to 0.90; P = 0.002). Muscle-related symptoms occurred in 91 participants (2.3%) in the pitavastatin group and in 53 (1.4%) in the placebo group; diabetes mellitus occurred in 206 participants (5.3%) and in 155 (4.0%), respectively., Conclusions: Participants with HIV infection who received pitavastatin had a lower risk of a major adverse cardiovascular event than those who received placebo over a median follow-up of 5.1 years. (Funded by the National Institutes of Health and others; REPRIEVE ClinicalTrials.gov number, NCT02344290.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Mechanisms contributing to COVID-19 severity in people with HIV (PWH) are poorly understood. We evaluated temporal changes in plasma proteins following SARS-CoV-2 infection and identified pre-infection proteomic markers associated with future COVID-19., Methods: We leveraged data from the global Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE). Antiretroviral therapy (ART)-treated PWH with clinical, antibody-confirmed COVID-19 as of September 2021 were matched on geographic region, age, and sample timing to antibody negative controls. For cases and controls, pre COVID-19 pandemic specimens were obtained prior to January 2020 to assess change over time and relationship to COVID-19 severity, using false-discovery adjusted mixed effects modeling., Findings: We compared 257 unique plasma proteins in 94 COVID-19 antibody-confirmed clinical cases and 113 matched antibody-negative controls, excluding COVID-19 vaccinated participants (age 50 years, 73% male). 40% of cases were characterized as mild; 60% moderate to severe. Median time from COVID-19 infection to follow-up sampling was 4 months. Temporal patterns of protein changes differed based on COVID-19 disease severity. Among those experiencing moderate to severe disease vs. controls, NOS3 increased whereas ANG, CASP-8, CD5, GZMH, GZMB, ITGB2, and KLRD1 decreased. Higher pre-pandemic levels of granzymes A, B and H (GZMA, GZMB and GZMH) were associated with the future development of moderate-severe COVID-19 and were related to immune function., Interpretation: We identified temporal changes in proteins closely linked to inflammatory, immune, and fibrotic pathways which may relate to COVID-19-related morbidity among ART-treated PWH. Further we identified key granzyme proteins associated with future COVID-19 in PWH., Funding: This study is supported through NIH grants U01HL123336, U01HL123336-06 and 3U01HL12336-06S3, to the clinical coordinating center, and U01HL123339, to the data coordinating center as well as funding from Kowa Pharmaceuticals, Gilead Sciences, and a grant award through ViiV Healthcare. The NIAID supported this study through grants UM1 AI068636, which supports the AIDS Clinical Trials Group (ACTG) Leadership and Operations Center, and UM1 AI106701, which supports the ACTG Laboratory Center. This work was also supported by NIAID through grant K24AI157882 to MZ. The work of IS was supported by the intramural research program of NIAID/NIH., Competing Interests: Declaration of interests MK received financial support from the Ralph Schlaeger Fellowship Award from the Department of Radiology at Mass General Hospital (Boston, USA) outside of this project, and was also supported by the T32 fellowship 5T32HL076136 of the NIH. CD reports no disclosures. SM reports no disclosures. KVF reports no disclosures. MRD reports no disclosures. ESF reports no disclosures. HJR reports grant support from NIH/NIAID and NIH/NHLBI related to the conduct of the study, as well as grant support from NIH/NIAID, NIH/NHLBI, NIH/NIDDK, and NIH/NIA, outside the submitted work. CJF reports grant support through his institution from Gilead Sciences, ViiV Healthcare, GSK, Janssen, Abbvie, Merck, Amgen, and Cytodyn, outside the submitted work; and personal fees from Theratechnologies and ViiV for consulting and participation on Advisory Board unrelated to REPRIEVE with Theratechnologies and ViiV, and role as Chair on DSMB for Intrepid Study, outside the submitted work. JAA reports institutional research support for clinical trials from Atea, Emergent Biosolutions, Frontier Technologies, Gilead Sciences, GlaxoSmithKline, Janssen, MacroGenics, Merck, Pfizer, Regeneron, and ViiV Healthcare and personal fees for advisory boards from Glaxo Smith Kline/Viiv and Merck and participation on DSMB for Kintor Pharmaceuticals; all outside the submitted work. CDM reports institutional research support by Lilly and honoraria from ViiV Healthcare and Gilead Sciences for Advisory Board membership, outside the submitted work. JSC reports consulting fees from Merck and Company. JLC reports honoraria for presentations for Gilead, MSD, and Janssen, and honoraria from Viiv Healthcare and Gilead Sciences for Advisory Board membership, all outside the submitted work. FG has received compensation for lectures, presentations, speaker bureaus, educational events or advisory boards from Janssen-Cilag, Gilead Sciences and ViiV Healthcare, and support for attending meetings and/or travel from Janssen-Cilag and ViiV Healthcare, and participation on a DSMB or Advisory Board for Janssen-Cilag and ViiV Healthcare. IS reports no disclosures. PSD reports no disclosures. MVZ reports being Principal Investigator of research grants from NIH (NIAID and NHLBI) and from Gilead Sciences to her institution, receiving support from CROI and International Workshop for HIV and Women Conferences when invited to be an abstract reviewer and/or speaker, and participating in a DSMB for NIH-funded studies involving no compensation. SKG reports grant support through his institution from Kowa Pharmaceuticals America, Inc., Gilead Sciences, Inc., and ViiV Healthcare for the conduct of the study, as well as grants from Theratechnologies and Navidea and personal fees from Theratechnologies and ViiV, all outside the submitted work. He is a member of the Scientific Advisory Board of Marathon Asset management., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

People with HIV (PWH) appear to be at higher risk for suboptimal pathogen responses and for worse COVID-19 outcomes, but the effects of host factors and COVID-19 on the humoral repertoire remain unclear. We assessed the antibody isotype/subclass and Fc-receptor binding Luminex arrays of non-SARS-CoV-2 and SARS-CoV-2 humoral responses among antiretroviral therapy-treated (ART-treated) PWH. Among the entire cohort, COVID-19 infection was associated with higher cytomegalovirus (CMV) responses (vs. the COVID- cohort ), potentially signifying increased susceptibility or a consequence of persistent inflammation. Among the COVID+ participants, (a) higher BMI was associated with a striking amplification of SARS-CoV-2 responses, suggesting exaggerated inflammatory responses, and (b) lower nadir CD4 was associated with higher SARS-CoV-2 IgM and FcγRIIB binding capacity, indicating poorly functioning extrafollicular and inhibitory responses. Among the COVID-19- participants, female sex, older age, and lower nadir CD4 were associated with unique repertoire shifts. In this first comprehensive assessment of the humoral repertoire in a global cohort of PWH, we identify distinct SARS-CoV-2-specific humoral immune profiles among PWH with obesity or lower nadir CD4+ T cell count, underlining plausible mechanisms associated with worse COVID-19-related outcomes in this setting. Host factors associated with the humoral repertoire in the COVID-19- cohort enhance our understanding of these important shifts among PWH.

Background: Inflammasome activation is increased in people with human immunodeficiency virus (PWH), but its relationship with coronary plaque is poorly understood in this setting., Methods: In a large human immunodeficiency virus cardiovascular prevention cohort, relationships between caspase-1, interleukin (IL)-1β, and IL-18 and coronary plaque indices were assessed by multivariate logistic regression., Results: Higher IL-18 and IL-1β were associated with Leaman score, an integrative measure of plaque burden and composition., Conclusions: As Leaman score >5 is associated with cardiovascular events in the general population, future work is needed to determine how the inflammasome relates to events and whether strategies to reduce its activation affect events or plaque progression among PWH., Competing Interests: Potential conflicts of interest. SRS reports grant support through his institution from NIH/NIAID. THS reports grant support through her institution from NIH/NIAID and NIH/National Institute of Allergy and Infectious Diseases outside the submitted work. THB reports equity in Excision BioTherapeutics and serves on their Scientific Advisory Board, outside the submitted work. JTS reports grant support through his institution from NIH/NIAID, the US Department of Veterans Affairs, HRSA (Ryan White HIV/AIDS Program), and Abbvie, DSMB service for Transposon Therapeutics, Inc., and honoraria for lectures at Iowa State University, all outside the submitted work. JLC reports honoraria for presentations for Gilead, MSD, and Janssen and advisory board membership for ViiV Healthcare and Gilead Sciences, all outside the submitted work. JT reports funding by Deutsche Forschungsgesellschaft ([DFG], German Research Foundation), speakers bureau for Siemens Healthcare GmbH and Bayer AG, reviewer for Universimed Cross Media Content GmbH, and consultant for Core Lab Black Forrest GmbH, all outside the submitted work. JSC reports consulting fees from Merck, outside the submitted work. MVZ 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/National Heart, Lung, and Blood Institute (NHLBI) outside the submitted work. CM reports institutional research support by Lilly and honoraria from ViiV Healthcare and Gilead Sciences for advisory board membership, all outside the submitted work. CJF reports grant support through his institution from Gilead Sciences, ViiV Healthcare, GSK, Janssen, Abbvie, Merck, Amgen, and Cytodyn; personal fees from Theratechnologies and ViiV for consulting and participation on Advisory Board unrelated to REPRIEVE; and DSMB Chair for Intrepid Study, all outside the submitted work. JAA reports institutional research support for clinical trials from Atea, Emergent Biosolutions, Frontier Technologies, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare and personal fees for advisory boards from GlaxoSmithKline/ViiV and Merck; and participation on DSMB for Kintor Pharmaceuticals, all outside the submitted work. HJR reports grants from NIH/NHLBI and Kowa Pharmaceuticals during the conduct of the study, as well as grants from NIH/NIAID, NIH/NHLBI, NIH/National Institute of Diabetes and Digestive and Kidney Diseases, and NIH/National Institute on Aging, outside the submitted work. MTL reports grant support through his institution from Kowa Pharmaceuticals America, Inc., for the conduct of the study. He also reports grant support from MedImmune/AstraZeneca and personal fees from PQBypass, outside of the current work. SKG 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. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)