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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: 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.)

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.

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.)

We explored factors associated with weight gain among people with HIV (PWH) on antiretroviral therapy (ART) at The Ohio State University Wexner Medical Center (OSUWMC). This was a retrospective cohort study of adult PWH on ART for ≥3 months. Patients with CD4 + T cell count <200 cells/mm 3 , viral load >200 copies/mL, history of malignancy, or pregnancy were excluded. Eight hundred seventy patients met criteria. The primary outcome was percent weight change over the follow-up period (Δ = relative effects). The secondary outcome was the odds of ≥5 kg weight gain over the study period. The effects of concurrent medications, medical comorbidities, ART combinations, and lifestyle behaviors on these outcomes were modeled using mixed effects regression analyses. Over a mean follow-up of 1.86 years, the study population gained a mean percent weight of 2.12% ± 0.21% ( p  < .001) with the odds of ≥5 kg weight gain of 0.293 ( p  < .001). Males gained an average of 1.88% ± 0.22% over follow up, while females gained an average of 3.37% ± 0.51% over follow up ( p  = .008 for the difference). In regression models, combination therapy with tenofovir alafenamide (TAF) and integrase strand transfer inhibitor (INSTI) containing regimens was associated with an increase in weight over the study period (Δ = 2.14% ± 0.45%, p  < .001 and Δ = 1.09% ± 0.39%, p  = .005, respectively). Increasing age was significantly associated with a decrease in percent weight change over the study period (Δ = -0.68% ± 0.18% per year, p  < .001). Self-reported improvement in diet was associated with a decrease in weight change (Δ = -1.99% ± 0.47%, p  ≤ .001) and reduced odds of ≥5 kg weight gain (odds ratio = 0.70, 95% confidence interval = 0.50-0.97, p  = .03). Factors associated with weight gain include therapy with TAF and INSTI. Diet may play an influential role in attenuating weight gain in PWH.

Objective: Skeletal muscle quality and mass are important for maintaining physical function during advancing age. We leveraged baseline data from Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) to evaluate whether paraspinal muscle density and muscle area are associated with cardiac or physical function outcomes in people with HIV (PWH)., Methods: REPRIEVE is a double-blind randomized trial evaluating the effect of pitavastatin for primary prevention of major adverse cardiovascular events in PWH. This cross-sectional analysis focuses on participants who underwent coronary computed tomography at baseline. Lower thoracic paraspinal muscle density (Hounsfield units [HU]) and area (cm 2 ) were assessed on noncontrast computed tomography., Results: Of 805 PWH, 708 had paraspinal muscle measurements. The median age was 51 years and 17% were natal female patients. The median muscle density was 41 HU (male) and 30 HU (female); area 13.2 cm 2 /m (male) and 9.9 cm 2 /m (female). In adjusted analyses, greater density (less fat) was associated with a lower prevalence of any coronary artery plaque, coronary artery calcium score >0, and high plaque burden ( P = 0.06); area was not associated with plaque measures. Among 139 patients with physical function measures, greater area (but not density) was associated with better performance on a short physical performance battery and grip strength., Conclusions: Among PWH, greater paraspinal muscle density was associated with a lower prevalence of coronary artery disease while greater area was associated with better physical performance. Whether changes in density or area are associated with changes in CAD or physical performance will be evaluated through longitudinal analyses in REPRIEVE., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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.)

Over 2-years of follow-up, integrase strand transfer inhibitor (INSTI)-use was associated with weight gain among those on an INSTI <2 years at entry (+0.27 kg/m2/year; 95% confidence interval [CI], .22 to .33 vs +0.17 kg/m2/year; 95% CI, .12 to .23; P = .01), but not those on an entry INSTI >2 years., Competing Interests: Potential conflicts of interest. C. D. M. reports institutional research grants from Lilly and personal fees from ViiV Healthcare and Gilead Sciences for participation in advisory board meetings outside the submitted work. J. L. reports consulting fees from ViiV Healthcare and Gilead Sciences, Inc, as well as investigator-initiated research grant support from ViiV Healthcare related to this work. C. J. F. reports grant support through their institution from Gilead Sciences, ViiV Healthcare, GSK, Janssen, AbbVie, Merck, Amgen, and Cytodyn, outside the submitted work; personal fees from Theratechnologies and ViiV Healthcare for consulting and participation on an advisory board unrelated to Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE); and a role as chair on the data and safety monitoring board (DSMB) for the Intrepid Study, outside the submitted work. J. A. A. reports institutional research support for clinical trials from Atea, Emergent Biosolutions, Frontier Technologies, Gilead Sciences, GSK, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare; personal fees for participation on advisory boards from GSK/ViiV Healthcare and Merck; and participation on a DSMB from Kintor, all outside the submitted work. M. V. Z. reports grant support through their 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, outside the submitted work; unpaid participation on a DSMB for NIH-funded studies; and support for meetings and/or travel from Conference on Retroviruses and Opportunistic Infections (CROI) and the International Workshop for HIV and Women from the conference organizing committee as an abstract reviewer and/or speaker. E. M. reports consulting fees and honoraria for lectures from Gilead Sciences, ViiV Healthcare, Janssen, and MSD; advisory board participation for ViiV Healthcare and MSD; and that their institution has received research grants from Gilead, Janssen, MSD, Theratechnologies, and ViiV Healthcare, unrelated to the submitted work. N. L. O. reports grants from NIH/NHLBI during the conduct of the study and consulting fees from Gilead Sciences unrelated to the submitted work. P. K. serves as a consultant and receives research funding from ViiV Healthcare, Merck, Theratechnologies, and Gilead and owns stock in Pfizer, Gilead, Merck, GSK, and Moderna. S. H. B. reports serving as a scientific advisor to Gilead Sciences including payment for expert testimony and research grants to their institution from Gilead Sciences, ViiV Healthcare, and Janssen unrelated to the submitted work. J. C. R. reports work supported by NIAID of the NIH. H. J. R. reports grants from NIH/NHLBI and Kowa Pharmaceuticals America, Inc, 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. S. K. G. reports grants from NIH, Kowa Pharmaceuticals America, Inc, Gilead Sciences, and ViiV Healthcare during the conduct of the study; personal consulting fees from Theratechnologies, ViiV Healthcare, and Marathon Asset Management outside the submitted work; and participation on the Marathon Asset Management Scientific Advisory Board. All remaining authors: No reported conflicts of interest. 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: 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.)

Objective: To investigate relationships between Life's Simple 7 (LS7), an assessment of cardiovascular health (CVH), and coronary plaque among people with HIV (PWH)., Design: Cross-sectional., Methods: Coronary computed tomography angiography, immune/inflammatory biomarkers, and characterization of LS7 were collected among a subset of ART-treated PWH enrolled in REPRIEVE, a primary prevention trial. Analyses adjusted for cardiovascular disease risk (ASCVD score)., Results: Median age of the 735 participants was 51(±6) years, 16% female, and median (Q1-Q3) CVD risk was 4.5% (2.6-6.9). Forty percent had poor (≤2 ideal components), 51% had intermediate (three or four ideal components), and only 9% had ideal CVH (≥5). Coronary plaque was present in 357 (49%); 167 (23%) had one or more vulnerable plaque features, 293 (40%) had noncalcified plaque, and 242 (35%) had a coronary artery calcium score >0. All three phenotypes were increasingly more prevalent with poorer CVH and these relationships remained after adjusting for ASCVD risk. Poor CVH was associated with higher high-sensitivity C-reactive protein, oxidized low-density cholesterol, and interleukin-6. The relationship of LS7 to plaque remained after adjusting for these biomarkers., Conclusions: Among PWH, poor CVH as measured by LS7 was associated with coronary plaque presence, vulnerable features, and calcification. LS7 was also associated with selected biomarkers; adjustment for these and ASCVD score reduced but did not eliminate LS7's association with plaque, suggesting the possibility of additional protective mechanisms against atherogenesis and plaque remodeling. Clinical use of LS7 and further exploration of its relationships with coronary artery disease may enhance efforts to reduce cardiovascular morbidity and mortality in PWH., Clinical Trials Registration: NCT02344290., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Among people with HIV (PWH), sex differences in presentations of atherosclerotic cardiovascular disease (ASCVD) may be influenced by differences in coronary plaque parameters, immune/inflammatory biomarkers, or relationships therein., Methods: REPRIEVE, a primary ASCVD prevention trial, enrolled antiretroviral therapy (ART)-treated PWH. At entry, a subset of US participants underwent coronary computed tomography angiography (CTA) and immune phenotyping (n = 755 CTA; n = 725 CTA + immune). We characterized sex differences in coronary plaque and immune/inflammatory biomarkers and compared immune-plaque relationships by sex. Unless noted otherwise, analyses adjust for ASCVD risk score., Results: The primary analysis cohort included 631 males and 124 females. ASCVD risk was higher among males (median: 4.9% vs 2.1%), while obesity rates were higher among females (48% vs 21%). Prevalence of any plaque and of plaque with either ≥1 visible noncalcified portion or vulnerable features (NC/V-P) was lower among females overall and controlling for relevant risk factors (RR [95% CI] for any plaque: .67 [.50, .92]; RR for NC/V-P: .71 [.51, 1.00] [adjusted for ASCVD risk score and body mass index]). Females showed higher levels of IL-6, hs-CRP, and D-dimer and lower levels of Lp-PLA2 (P < .001 for all). Higher levels of Lp-PLA2, MCP-1, and oxLDL were associated with higher plaque (P < .02) and NC/V-P prevalence, with no differences by sex. Among females but not males, D-dimer was associated with higher prevalence of NC/V-P (interaction P = .055)., Conclusions: Among US PWH, females had a lower prevalence of plaque and NC/V-P, as well as differences in key immune/inflammatory biomarkers. Immune-plaque relationships differed by sex for D-dimer but not other tested parameters. Clinical Trial Registration. ClinicalTrials.gov; identifier: NCT0234429 (date of initial registration: 22 January 2015)., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Among antiretroviral therapy (ART)-treated people with human immunodeficiency virus (PWH), persistent systemic immune activation contributes to atherogenesis atherosclerotic, cardiovascular disease (CVD) events, and mortality. Factors associated with key immune activation indices have not previously been characterized among a global primary CVD prevention cohort of PWH., Methods: Leveraging baseline Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) data, we evaluated factors associated with soluble CD14 (sCD14) and oxidized low-density lipoprotein (oxLDL)., Results: The primary analysis cohort included 4907 participants from 5 global-burden-of-disease regions (38% female, 48% Black, median age 50 years). In fully adjusted models for sCD14, female sex and White race (among those in high-income regions) were associated with higher sCD14 levels, while higher body mass index (BMI) and current use of nucleoside reverse transcriptase inhibitor + integrase strand transfer inhibitor ART were associated with lower sCD14 levels. In fully adjusted models for oxLDL, male sex, residence in high-income regions, White race (among those in high-income regions), and higher BMI were associated with higher oxLDL levels. In a subanalysis cohort of 1396 women with HIV, increased reproductive age was associated with higher sCD14 levels but not with higher oxLDL levels., Conclusions: Factors associated with sCD14 and oxLDL, 2 key indices of immune-mediated CVD risk, differ. Future studies will elucidate ways in which medications (eg, statins) and behavioral modifications influence sCD14 and oxLDL and the extent to which dampening of these markers mediates CVD-protective effects., Clinical Trials Registration: NCT0234429., Competing Interests: Potential conflicts of interest. S. E. L. reports travel reimbursement from the Association of Nurses in AIDS Care as an invited presenter and receipt of a 1-time conference travel reimbursement. A. K. reports grants from NIH/NIAID and NIH/NHLBI during the conduct of the study. T. H. B. reports equity in Excision Bio Therapeutics and serves on their scientific advisory board outside the submitted work. J. S. C. reports consulting fees from Merck and Company and Resvirlogix. C. J. F. reports grant support through his institution from Gilead Sciences, ViiV Healthcare, GlaxoSmithKline, Janssen, AbbVie, Merck, Amgen, and Cytodyn outside the submitted work and serves as chair of the data and safety monitoring board (DSMB) for the Intrepid Study. E. T. O. reports grant support through his institution from NIH, Gilead Sciences, ViiV, and GlaxoSmithKline and personal fees from Merck, ViiV Healthcare, and Theratechnologies outside the submitted work. J. A. A. 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 Healthcare and Merck, all outside the submitted work. C. D. M. reports personal fees from Gilead Sciences and ViiV Healthcare for participation in advisory board meetings outside the submitted work. K. M. E. reports grant support from Gilead Sciences and consulting fees from Gilead Sciences, ViiV Healthcare, and Janssen Therapeutics (all paid to the University of Colorado) outside the submitted work. M. C. reports serving as an executive board member for HIV Medicine Association and participation on boards for ViiV Healthcare and Gilead Sciences. M. M. reports personal fees from Merck and Company, Gilead Sciences, and ViiV outside the submitted work. M. T. L. reports grant support through his institution from Kowa Pharmaceuticals America, Inc, for the conduct of the study and reports grant support from MedImmune/AstraZeneca and personal fees from PQBypass outside the current work. S. K. G. reports grant support through his institution from Kowa Pharmaceuticals America, Inc, Gilead Sciences, and ViiV Healthcare for the conduct of the study, as well as grants from Theratechnologies and Navidea and personal fees from Theratechnologies Consulting, Navidea, and ViiV Healthcare Consulting, all outside the submitted work. H. J. R. reports grants from NIH/NIAID and NIH/NHLBI 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. M. V. Z. reports grant support through her institution from NIH/NIAID and Gilead Sciences, relevant to the conduct of the study, as well as grants from NIH/NIAID and NIH/NHLBI outside the submitted work; support for the Conference on Retroviruses and Opportunistic Infections and International Workshop for HIV and Women from the conference organizing committee as an abstract reviewer and/or speaker; and participation in DSMB for NIH-funded studies and received no payment., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Non-antiviral therapeutic options are required for the treatment of hospitalised patients with COVID-19. CD24Fc is an immunomodulator with potential to reduce the exaggerated inflammatory response to tissue injuries. We aimed to evaluate the safety and efficacy of CD24Fc in hospitalised adults with COVID-19 receiving oxygen support., Methods: We conducted a randomised, double-blind, placebo-controlled, phase 3 study at nine medical centres in the USA. Hospitalised patients (age ≥18 years) with confirmed SARS-CoV-2 infection who were receiving oxygen support and standard of care were randomly assigned (1:1) by site-stratified block randomisation to receive a single intravenous infusion of CD24Fc 480 mg or placebo. The study funder, investigators, and patients were masked to treatment group assignment. The primary endpoint was time to clinical improvement over 28 days, defined as time that elapsed between a baseline National Institute of Allergy and Infectious Diseases ordinal scale score of 2-4 and reaching a score of 5 or higher or hospital discharge. The prespecified primary interim analysis was done when 146 participants reached the time to clinical improvement endpoint. Efficacy was assessed in the intention-to-treat population. Safety was assessed in the as-treated population. This study is registered with ClinicalTrials.gov, NCT04317040., Findings: Between April 24 and Sept 22, 2020, 243 hospitalised patients were assessed for eligibility and 234 were enrolled and randomly assigned to receive CD24Fc (n=116) or placebo (n=118). The prespecified interim analysis was done when 146 participants reached the time to clinical improvement endpoint among 197 randomised participants. In the interim analysis, the 28-day clinical improvement rate was 82% (81 of 99) for CD24Fc versus 66% (65 of 98) for placebo; median time to clinical improvement was 6·0 days (95% CI 5·0-8·0) in the CD24Fc group versus 10·0 days (7·0-15·0) in the placebo group (hazard ratio [HR] 1·61, 95% CI 1·16-2·23; log-rank p=0·0028, which crossed the prespecified efficacy boundary [α=0·0147]). 37 participants were randomly assigned after the interim analysis data cutoff date; among the 234 randomised participants, median time to clinical improvement was 6·0 days (95% CI 5·0-9·0) in the CD24Fc group versus 10·5 days (7·0-15·0) in the placebo group (HR 1·40, 95% CI 1·02-1·92; log-rank p=0·037). The proportion of participants with disease progression within 28 days was 19% (22 of 116) in the CD24Fc group versus 31% (36 of 118) in the placebo group (HR 0·56, 95% CI 0·33-0·95; unadjusted p=0·031). The incidences of adverse events and serious adverse events were similar in both groups. No treatment-related adverse events were observed., Interpretation: CD24Fc is generally well tolerated and accelerates clinical improvement of hospitalised patients with COVID-19 who are receiving oxygen support. These data suggest that targeting inflammation in response to tissue injuries might provide a therapeutic option for patients hospitalised with COVID-19., Funding: Merck & Co, National Cancer Institute, OncoImmune., Competing Interests: Declaration of interests JW, JDP, ATC, CDM, EDW, DB, OKG, JEL, and SK had clinical trial agreements with OncoImmune. JDP reports payment for Baptist Medical Health COVID update (CME event). EDW was on the speaker's bureau at Merck & Co (before Merck's acquisition of OncoImmune). JEL is a consultant to Merck & Co for HIV-related studies. SK reports a grant from OncoImmune, during the conduct of the study; and grants from Merck & Co, Gilead Sciences, and Arbutus Pharmaceuticals, outside of the submitted work. ZL serves as a scientific advisory board member for Alphamab, Hengenix, and Ikonisys; and receives grants from Heat Biologics, National Institutes of Health, and Pelotonia, outside of the submitted work. EL, JiC, and XZ are employees of Edetek, the clinical data management and biostats service provider for OncoImmune. DB, DG, and AK are employees of Merck Sharp & Dohme, a subsidiary of Merck & Co, and could hold stocks or stock options in Merck & Co. H-YC, MD, RT, YL, and PZ are employees of OncoImmune, and received grants from National Institutes of Health and National Cancer Institute (R44CA246991-02S1), during the conduct of the study. MD, YL, and PZ have a patent or a patent pending. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) blunts the broad inflammatory response induced by damage-associated molecular patterns via binding to extracellular high mobility group box 1 and heat shock proteins, as well as regulating the downstream Siglec10-Src homology 2 domain-containing phosphatase 1 pathway. A recent randomized phase III trial evaluating CD24Fc for patients with severe COVID-19 (SAC-COVID; NCT04317040) demonstrated encouraging clinical efficacy., Methods: Using a systems analytical approach, we studied peripheral blood samples obtained from patients enrolled at a single institution in the SAC-COVID trial to discern the impact of CD24Fc treatment on immune homeostasis. We performed high dimensional spectral flow cytometry and measured the levels of a broad array of cytokines and chemokines to discern the impact of CD24Fc treatment on immune homeostasis in patients with COVID-19., Results: Twenty-two patients were enrolled, and the clinical characteristics from the CD24Fc vs. placebo groups were matched. Using high-content spectral flow cytometry and network-level analysis, we found that patients with severe COVID-19 had systemic hyper-activation of multiple cellular compartments, including CD8 + T cells, CD4 + T cells, and CD56 + natural killer cells. Treatment with CD24Fc blunted this systemic inflammation, inducing a return to homeostasis in NK and T cells without compromising the anti-Spike protein antibody response. CD24Fc significantly attenuated the systemic cytokine response and diminished the cytokine coexpression and network connectivity linked with COVID-19 severity and pathogenesis., Conclusions: Our data demonstrate that CD24Fc rapidly down-modulates systemic inflammation and restores immune homeostasis in SARS-CoV-2-infected individuals, supporting further development of CD24Fc as a novel therapeutic against severe COVID-19., (© 2022. The Author(s).)

Background: Patterns of antiretroviral therapy (ART) use and immunologic correlates vary globally, and contemporary trends are not well described., Methods: The REPRIEVE trial (Randomized Trial to Prevent Vascular Events in HIV) enrolled persons with human immunodeficiency virus (HIV) who were aged 40-75 years, receiving ART, and had low-to-moderate cardiovascular disease risk. ART use was summarized within Global Burden of Disease (GBD) super-regions, with adjusted linear and logistic regression analyses examining associations with immune parameters and key demographics., Results: A total of 7770 participants were enrolled, with a median age of 50 years (interquartile range, 45-55 years); 31% were female, 43% were black or African American, 15% were Asian, 56% had a body mass index >25 (calculated as weight in kilograms divided by height in meters squared), and 49% were current or former smokers. The median CD4 T-cell count was 620/µL (interquartile range, 447-826/ µ L), and the median duration of prior ART use, 9.5 years (5.3-14.8) years. The most common ART regimens were nucleoside/nucleotide reverse-transcriptase inhibitor (NRTI) plus nonnucleoside reverse-transcriptase inhibitor (43%), NRTI plus integrase strand transfer inhibitor (25%), and NRTI plus protease inhibitor (19%). Entry ART varied by GBD region, with shifts during the trial enrollment period. In adjusted analyses, entry CD4 cell count and CD4/CD8 ratio were associated with GBD region, sex, entry regimen, duration of ART, and nadir CD4 cell count; CD4 and CD8 cell counts were also associated with body mass index and smoking status., Conclusions: There were substantial variations in ART use by geographic region and over time, likely reflecting the local availability of specific medications, changes in treatment guidelines and provider/patient preferences. The analyses of CD4 cell counts and CD4/CD8 ratios may provide valuable insights regarding immune correlates and outcomes in people living with HIV., Clinical Trials Registration: NCT02344290., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background People who inject drugs (PWID) in rural areas of the United States have had limited access to syringe service programs (SSP). Rural SSP have recently surged, but accompanying research is lacking about PWID utilization, barriers, and preferences for SSP design and how those preferences vary by gender. Methods: Interviewer-administered surveys elicited information about utilization, barriers, and preferences for SSP design from 234 PWID recruited using respondent-driven sampling in Appalachian, Kentucky. Gender differences among reported barriers to utilizing SSP and preferences for program design were explored using Mantel-Haenszel chi-square tests. Results: Overall, 49% of PWID had ever utilized an SSP. The most common reasons for not utilizing an SSP were lack of awareness (23%), fear of being seen or disclosing drug use (19%), and lack of need (19%). The most preferred SSP design was located within a health department (74%) and operating during afternoon hours (66%). Men were more likely than women to prefer SSP in health departments (80% vs. 65%, p  = 0.01), while more women than men preferred staffing by health department personnel (62% vs. 46%, p  = 0.02). Women were less likely to favor evening hours (55% vs. 70%, p  = 0.02). Fewer women wanted SSP nurses (78% vs. 90%, p  = 0.01), social workers (11% vs. 24%, p  = 0.01), or people who use drugs (20% vs 34%, p  = 0.02) to staff SSP. Conclusions: Despite recent scale-up, SSP in Appalachia remain under-utilized. PWID were open to a range of options for SSP design and staffing, though there were variations by gender. Implementation research that identifies best strategies for tailored SSP scale-up in rural settings should be considered.

Tuberculosis is a healthcare concern that affects millions of individuals around the globe. Coinfection with HIV has changed both the clinical presentation and the outcome of the disease dramatically in the last few decades. Extrapulmonary tuberculosis is seen more frequently in the immunocompromised host. An unusual case of gastric tuberculosis in an AIDS patient is reported here. A 49-year-old female with AIDS was admitted for fever and epigastric pain. A gastric submucosal abscess was observed on imaging and confirmed by biopsy showing numerous neutrophils and acid-fast bacilli. Aspirate grew Mycobacterium tuberculosis. This report highlights a very unusual presentation of tuberculosis in an immunodeficient patient. High clinical suspicion for opportunistic infections in unusual locations should be maintained in these patients presenting with clinical syndromes that do not respond to standard treatments. New diagnostic modalities facilitate accurate identification of these infections.

Background: The drug-drug interactions between pitavastatin and darunavir/ritonavir (DRV/r) as well as pitavastatin and efavirenz (EFV) were examined in an open-label, parallel-arm, pharmacokinetic (PK) study in HIV-uninfected healthy volunteers., Methods: Subjects received a pitavastatin dose of 2 mg for 4 days, followed by either EFV 600 mg (n = 14) or DRV/r 800/100 mg (n = 14) daily for 10 days, and pitavastatin 2 mg coadministered with EFV 600 mg or DRV/r 800/100 mg for 4 days. Full PK profiles were determined for pitavastatin and its lactone metabolite on days 4 and 18 and for EFV or DRV on days 14 and 18., Results: In the EFV arm, the geometric mean area under the concentration time curve (AUC0-τ) and Cmax of pitavastatin were 85.3 ng·h·mL and 15.6 ng/mL, respectively, when given alone, versus 76 ng·h·mL and 18.8 ng/mL when coadministered with EFV. The geometric mean ratio for pitavastatin with EFV versus alone was 0.89 [90% confidence interval (CI): 0.73 to 1.09] for AUC0-τ and 1.20 (90% CI: 0.79 to 1.83) for Cmax. In the DRV/r arm, AUC0-τ and Cmax were 62.8 ng·h·mL and 24.0 ng/mL, respectively, when pitavastatin was administered alone, versus 56.9 ng·h·mL and 23.2 ng/mL when coadministered with DRV/r. The geometric mean ratio for pitavastatin with DRV/r versus alone was 0.91 (90% CI: 0.78 to 1.06) for AUC0-τ and 0.93 (90% CI: 0.72 to 1.19) for Cmax., Conclusions: There were no significant PK interactions between pitavastatin and EFV or DRV/r. No significant safety issues or lipid changes were noted.

Antiretroviral therapy has dramatically increased survival for HIV-infected individuals. As this population lives longer, coronary heart disease has become an important comorbid condition. Dyslipidemia in HIV-infected individuals is a complex condition, with multiple contributing factors including the HIV virus itself, individual genetic characteristics and antiretroviral therapy-induced metabolic changes. Effective management of dyslipidemia in this population is essential to reduce cardiovascular risk but presents multiple challenges due to interactions between antiretroviral therapy agents and lipid-lowering medications.

People infected with human immunodeficiency virus (HIV) are living longer thanks to effective antiretroviral therapy. As this population ages, cardiovascular disease is becoming an important cause of morbidity and death. The authors of this review discuss the magnitude and likely mechanisms of the risk and strategies for managing it.

Kidney disease is an important complication of HIV, particularly in minority populations. We describe the burden of chronic kidney disease among 1239 adults followed at an urban AIDS center, with an estimated prevalence of 15.5% (n = 192). Independent predictors of kidney disease included older age, black race, hepatitis C virus exposure, and lower CD4 cell count. These data suggest that chronic kidney disease remains a common complication of HIV infection in the era of antiretroviral therapy.

The baseline prevalence of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection among 2705 patients enrolled in HIV clinical trials in the Community Programs for Clinical Research on AIDS (CPCRA) was 16.6%. For men, multivariate logistic regression showed that the baseline prevalence of HIV-HCV coinfection was positively associated with history of injection drug use, older age, antiretroviral therapy naive status, African American or Latino ethnicity, and no history of having sex with men. No association was found with baseline CD4+ cell count or HIV RNA level. The prevalence of HCV coinfection in a diverse HIV clinical trials cohort provides additional information about risk behaviors and demographic factors that can be used in the analysis of clinical and virologic outcomes.