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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.
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Background: People with HIV (PWH) have a high burden of coronary plaques; however, the comparison to people without known HIV (PwoH) needs clarification. Objectives: The purpose of this study was to determine coronary plaque burden/phenotype in PWH vs PwoH. Methods: Nonstatin using participants from 3 contemporary populations without known coronary plaques with coronary CT were compared: the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) studying PWH without cardiovascular symptoms at low-to-moderate risk (n = 755); the SCAPIS (Swedish Cardiopulmonary Bioimage Study) of asymptomatic community PwoH at low-to-intermediate cardiovascular risk (n = 23,558); and the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) of stable chest pain PwoH (n = 2,291). The coronary plaque prevalence on coronary CT was compared, and comparisons were stratified by 10-year atherosclerotic cardiovascular disease (ASCVD) risk, age, and coronary artery calcium (CAC) presence. Results: Compared to SCAPIS and PROMISE PwoH, REPRIEVE PWH were younger (50.8 ± 5.8 vs 57.3 ± 4.3 and 60.0 ± 8.0 years; P < 0.001) and had lower ASCVD risk (5.0% ± 3.2% vs 6.0% ± 5.3% and 13.5% ± 11.0%; P < 0.001). More PWH had plaque compared to the asymptomatic cohort (48.5% vs 40.3%; P < 0.001). When stratified by ASCVD risk, PWH had more plaque compared to SCAPIS and a similar prevalence of plaque compared to PROMISE. CAC = 0 was more prevalent in PWH (REPRIEVE 65.2%; SCAPIS 61.6%; PROMISE 49.6%); among CAC = 0, plaque was more prevalent in PWH compared to the PwoH cohorts (REPRIEVE 20.8%; SCAPIS 5.4%; PROMISE 12.3%, P < 0.001). Conclusions: Asymptomatic PWH in REPRIEVE had more plaque than asymptomatic PwoH in SCAPIS but had similar prevalence to a higher-risk stable chest pain cohort in PROMISE. In PWH, CAC = 0 does not reliably exclude plaque.
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Hígado Graso , Péptidos Similares al Glucagón , Infecciones por VIH , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/efectos adversos , Masculino , Persona de Mediana Edad , Hígado Graso/tratamiento farmacológico , Femenino , Adulto , Hipoglucemiantes/uso terapéuticoRESUMEN
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.
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Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , Infecciones por VIH , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Placa Aterosclerótica , Quinolinas , Humanos , Masculino , Persona de Mediana Edad , Femenino , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Método Doble Ciego , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Enfermedades Cardiovasculares/tratamiento farmacológico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Biomarcadores , Lipoproteínas LDLRESUMEN
BACKGROUND: Cytomegalovirus (CMV) seropositivity is associated with poor outcomes, including physical function impairment, in people without HIV. We examined associations between CMV IgG titer and physical function in virologically suppressed people with HIV (PWH). METHODS: REPRIEVE is a double-blind randomized trial evaluating pitavastatin for primary prevention of atherosclerotic cardiovascular disease in PWH. This analysis focused on participants enrolled in a substudy with additional biomarker testing, imaging [coronary CT angiography], and physical function measures at entry. CMV IgG was measured using quantitative enzyme immunoassay, physical function by Short Physical Performance Battery, and muscle density and area by CT. Associations between CMV IgG (risk factor) and outcomes were evaluated using the partial Spearman correlation and linear and log-binomial regression. RESULTS: Among 717 participants, 82% male, the median CMV IgG was 2716 (Q1, Q3: 807, 6672) IU/mL, all above the limit of quantification. Among 631 participants with imaging, there was no association between CMV IgG and CT-based muscle density or area, controlling for age (r = -0.03 and r = -0.01, respectively; P ≥ 0.38). Among 161 participants with physical function data, higher CMV IgG was associated with poorer overall modified Short Physical Performance Battery score ( P = 0.02), adjusted for age, nadir CD4, and high-sensitivity C-reactive protein. CONCLUSIONS: Higher CMV IgG titer was associated with poorer physical function, not explained by previous immune compromise, inflammation, or muscle density or area. Further mechanistic studies are needed to understand this association and whether CMV-specific therapy can affect physical function in PWH.
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Infecciones por Citomegalovirus , Infecciones por VIH , Humanos , Masculino , Femenino , Citomegalovirus , Infecciones por Citomegalovirus/complicaciones , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Músculos , Inmunoglobulina G , Anticuerpos AntiviralesRESUMEN
ABSTRACT: Clonal hematopoiesis of indeterminate potential (CHIP), the clonal expansion of myeloid cells with leukemogenic mutations, results in increased coronary artery disease (CAD) risk. CHIP is more prevalent among people with HIV (PWH), but the risk factors are unknown. CHIP was identified among PWH in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) using whole-exome sequencing. Logistic regression was used to associate sociodemographic factors and HIV-specific factors with CHIP adjusting for age, sex, and smoking status. In the studied global cohort of 4486 PWH, mean age was 49.9 (standard deviation [SD], 6.4) years; 1650 (36.8%) were female; and 3418 (76.2%) were non-White. CHIP was identified in 223 of 4486 (4.97%) and in 38 of 373 (10.2%) among those aged ≥60 years. Age (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.05-1.09; P < .0001) and smoking (OR, 1.37; 95% CI, 1.14-1.66; P < .001) associated with increased odds of CHIP. Globally, participants outside of North America had lower odds of CHIP including sub-Saharan Africa (OR, 0.57; 95% CI, 0.4-0.81; P = .0019), South Asia (OR, 0.45; 95% CI, 0.23-0.80; P = .01), and Latin America/Caribbean (OR, 0.56; 95% CI, 0.34-0.87; P = .014). Hispanic/Latino ethnicity (OR, 0.38; 95% CI, 0.23-0.54; P = .002) associated with significantly lower odds of CHIP. Among HIV-specific factors, CD4 nadir <50 cells/mm3 associated with a 1.9-fold (95%CI, 1.21-3.05; P = .006) increased odds of CHIP, with the effect being significantly stronger among individuals with short duration of antiretroviral therapy (ART; OR, 4.15; 95% CI, 1.51-11.1; P = .005) (Pinteraction= .0492). Among PWH at low-to-moderate CAD risk on stable ART, smoking, CD4 nadir, North American origin, and non-Hispanic ethnicity associated with increased odds of CHIP. This trial was registered at www.ClinicalTrials.gov as NCT02344290.
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Hematopoyesis Clonal , Infecciones por VIH , Humanos , Femenino , Persona de Mediana Edad , Masculino , Factores de Riesgo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/complicaciones , América del Norte , EtnicidadRESUMEN
Plasma vascular endothelial growth factor (VEGF) coreceptor neuropilin-1 (NRP-1) had the largest association with coronary plaque in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) proteomics analysis. With little known about NRP-1 in people with human immunodeficiency virus (PWH), we explored its relation to other proteins in REPRIEVE and validated our findings through a Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) case-cohort study by assessing its relation to host factors and incident cardiovascular disease and cancer. Within REPRIEVE, NRP-1 was associated with proteins involved in angiogenesis, signal transduction, immunoregulation, and cell migration/adhesion. Within CNICS, NRP-1 was associated with key host factors, including older age and male sex. NRP-1 was associated with an increased hazard of multiple cancers but a decreased prostate cancer risk. Finally, NRP-1 was most strongly associated with mortality and type 2 myocardial infarction. These data suggest that NRP-1 is part of a clinically relevant immunoregulatory pathway related to multiple comorbidities in PWH. Clinical Trials Registration. NCT02344290.
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BACKGROUND: Hepatic steatosis, including nonalcoholic fatty liver disease (NAFLD), is common among people with HIV (PWH). We present baseline steatosis prevalence and cardiometabolic characteristics among REPRIEVE substudy participants. METHODS: REPRIEVE is an international, primary cardiovascular disease prevention, randomized, controlled trial of pitavastatin calcium vs. placebo among 7769 PWH ages 40-75âyears on antiretroviral therapy (ART) and with low-to-moderate cardiovascular risk. A subset of participants underwent noncontrast computed tomography, with hepatic steatosis defined as mean hepatic attenuation less than 40 HU or liver/spleen ratio less than 1.0, and NAFLD defined as steatosis in the absence of frequent alcohol use or viral hepatitis. RESULTS: Of 687 evaluable persons, median age was 51âyears, BMI 27âkg/m 2 , CD4 + T-cell count 607 cells/µl; 17% natal female sex, 36% Black, 24% Hispanic, and 98% HIV-1 RNA less than 400âcopies/ml. Hepatic steatosis prevalence was 22% (149/687), and NAFLD 21% (96/466). Steatosis/NAFLD prevalence was higher in men and with older age, non-Black race, and higher BMI and waist circumference. Both were associated with BMI greater than 30âkg/m 2 , metabolic syndrome components, higher atherosclerotic cardiovascular disease (ASCVD) risk score, HOMA-IR, LpPLA-2 and hs-CRP, and lower high-density lipoprotein cholesterol. Of HIV-specific/ART-specific characteristics, only history of an AIDS-defining illness was more common among persons with steatosis/NAFLD. After adjusting for age, sex and race/ethnicity, BMI greater than 30âkg/m 2 , HOMA-IR greater than 2.0, Metabolic syndrome and each of its components were associated with NAFLD prevalence. CONCLUSION: In this cohort with controlled HIV and low-to-moderate cardiovascular risk, hepatic steatosis and NAFLD were common and associated with clinically relevant metabolic and inflammatory disturbances but not current HIV-related or ART-related factors.
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Enfermedades Cardiovasculares , Infecciones por VIH , Síndrome Metabólico , Enfermedad del Hígado Graso no Alcohólico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/complicaciones , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Síndrome Metabólico/complicaciones , Síndrome Metabólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Prevención Primaria , Adulto , AncianoRESUMEN
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.
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Enfermedad de la Arteria Coronaria , Infecciones por VIH , Placa Aterosclerótica , Humanos , Masculino , Persona de Mediana Edad , Tejido Adiposo/diagnóstico por imagen , Biomarcadores , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/complicaciones , Vasos Coronarios/diagnóstico por imagen , VIH , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Inflamación/complicaciones , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/epidemiología , Placa Aterosclerótica/complicacionesRESUMEN
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.).
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Enfermedades Cardiovasculares , Infecciones por VIH , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Persona de Mediana Edad , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Método Doble Ciego , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infarto del Miocardio/epidemiología , Infarto del Miocardio/prevención & control , Quinolinas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéuticoRESUMEN
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.
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Enfermedad de la Arteria Coronaria , Infecciones por VIH , Placa Aterosclerótica , Humanos , Masculino , Femenino , Persona de Mediana Edad , Angiografía Coronaria/métodos , Vasos Coronarios/diagnóstico por imagen , Estudios Transversales , Factores de Riesgo , Infecciones por VIH/complicaciones , Angiografía por Tomografía Computarizada , Enfermedad de la Arteria Coronaria/complicaciones , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/complicaciones , Músculo EsqueléticoRESUMEN
A combination of forces have markedly increased challenges to research-active faculty achieving sustained success. This article describes how one department at the University of Cincinnati College of Medicine (UCCOM) implemented a strategic plan, the Research Initiative Supporting Excellence at the University of Cincinnati (RISE-UC), to promote the research activity of its research-active faculty, fiscal year (FY) 2011-FY 2021. RISE-UC was implemented and regularly updated to address evolving needs. RISE-UC supported faculty members pursuing research via fiscal and administrative services to grow a critical mass of investigators; establish a shared governance model; create pathways for developing physician-scientists; develop discrete and targeted internal research funding; establish an Academic Research Service (ARS) unit (as infrastructure to support research); enhance faculty member mentorship; and recognize, celebrate, and reward research success. RISE-UC was informed by shared governance and resulted in substantial increases in total size of the faculty and external funding. More than 50% of Physician-Scientist Training Program graduates are active researchers at UCCOM. The internal awards program realized a return on investment of ~16.4-fold, and total external direct cost research funds increased from ~$55,400,000 (FY 2015) to ~$114,500,000 (FY 2021). The ARS assisted in the submission of 57 grant proposals and provided services faculty members generally found very helpful or helpful. The peer-mentoring group for early-career faculty members resulted in 12 of 23 participants receiving major grant funding (≥ $100,000; spring 2017-spring 2021) from sources including National Institutes of Health awards, Department of Defense funding, Veterans Affairs funding, and foundation awards. Research recognition included ~$77,000/year in incentive payments to faculty members for grant submissions and grants awarded. RISE-UC is an example of a comprehensive approach to promote research faculty member success and may serve as a model for other institutions with similar aspirations.
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Medicina , Tutoría , Estados Unidos , Humanos , Docentes , Mentores , National Institutes of Health (U.S.)RESUMEN
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.
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COVID-19 , Masculino , Humanos , Persona de Mediana Edad , Femenino , SARS-CoV-2 , Pandemias/prevención & control , Proteómica , Proteínas Sanguíneas , Anticuerpos Antivirales , AntirretroviralesRESUMEN
Cardiovascular disease (CVD) is a leading cause of enhanced morbidity and mortality in persons with HIV (PWH) in the era of highly active antiretroviral therapy (AART). However, the underlying mechanisms are not fully understood. Regulatory T cells (Treg), notably the highly suppressive memory subset, have been shown to limit CVD. Importantly, memory Treg cell numbers remain low in many treated PWH. High density lipoproteins (HDL) also protect from CVD, and we previously found that Treg-HDL interactions reduce oxidative stress in these cells. Here, we evaluated Treg-HDL interactions in PWH and whether they were operative in those higher CVD risk. To do that, we recruited a cohort of PWH with intermediate/high CVD risk (median ASCVD risk score of 13.2%, n=15) or low/borderline risk (median ASCVD risk score of 3.6%, n=14), as well as a group of statins treated PWH with intermediate/high CVD risk (median ASCVD risk score of 12.7%, n=14). We evaluated Treg frequency, phenotype and response to HDL. PWH with Int/High CVD risk had a significantly lower number of memory Treg, but memory Treg were more activated and displayed an inflammatory phenotype, versus those with Low/BL CVD risk. In untreated patients, Treg absolute numbers were negatively correlated with ASCVD score. Although HDL decreased oxidative stress in memory Treg in all subjects, memory Treg from PWH with Int/High CVD risk were significantly less responsive to HDL than those from PWH with Low/BL CVD risk. The level of oxidative stress in memory Treg positively correlated with ASCVD scores. In contrast, plasma HDL from PWH, regardless of CVD risk, retained their anti-oxidative properties, suggesting that the defect in memory Treg response to HDL is intrinsic. Statin treatment partially ameliorated the memory Treg defect. In conclusion, the defective HDL-Treg interactions may contribute to the inflammation-induced increased CVD risk observed in many AART-treated PWH.
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Enfermedades Cardiovasculares , Infecciones por VIH , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Lipoproteínas HDL , Linfocitos T Reguladores , Enfermedades Cardiovasculares/complicaciones , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológicoRESUMEN
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)-1ß, and IL-18 and coronary plaque indices were assessed by multivariate logistic regression. Results: Higher IL-18 and IL-1ß 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.
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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.
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Infecciones por VIH , Inhibidores de Integrasa VIH , Integrasa de VIH , VIH-1 , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Índice de Masa Corporal , Inhibidores de Integrasa VIH/uso terapéutico , Inhibidores de Integrasa VIH/farmacología , Farmacorresistencia ViralRESUMEN
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.
Asunto(s)
COVID-19 , Femenino , Humanos , Antirretrovirales , Anticuerpos Antivirales , Linfocitos T CD4-Positivos , SARS-CoV-2 , Infecciones por VIH/tratamiento farmacológicoAsunto(s)
Fármacos Anti-VIH , Enfermedades Cardiovasculares , Infecciones por VIH , Humanos , Enfermedades Cardiovasculares/inducido químicamente , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/efectos adversos , Didesoxinucleósidos/efectos adversosRESUMEN
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.
Asunto(s)
Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , Infecciones por VIH , Placa Aterosclerótica , Femenino , Masculino , Humanos , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedades Cardiovasculares/complicaciones , Factores de Riesgo , Estudios Transversales , Infecciones por VIH/complicaciones , Biomarcadores , Placa Aterosclerótica/diagnóstico por imagenRESUMEN
BACKGROUND: REPRIEVE, the Randomized Trial to Prevent Vascular Events in HIV, is a multicenter, primary prevention trial evaluating whether a statin can prevent major cardiovascular events in people with HIV. REPRIEVE is conducted at >100 clinical research sites (CRSs) globally. Detailed, comprehensive, and novel methods for evaluating and communicating CRS performance are required to ensure trial integrity and data quality. In this analysis we describe a comprehensive multidimensional methodology for evaluating CRS performance. METHODS: The REPRIEVE Data Coordinating and Clinical Coordinating Centers developed a robust system for evaluation of and communication with CRSs, designed to identify potential issues and obstacles to performance, provide real-time technical support, and make recommendations for process improvements to facilitate efficient trial execution. We describe these systems and evaluate their impact on participant retention, data management, and specimen management from 2019 to 2022, corresponding to the period from end of recruitment to present. This evaluation was based on pre-defined metrics, regular reviews, and bidirectional communication. RESULTS: Participant retention, data management, and specimen management all remained steady over the three-year period, although metrics varied by country of enrollment. Targeted messaging relating to certain performance metrics was effective. CONCLUSION: Site performance is vital to ensure trial integrity and achievement of key trial goals. This analysis demonstrates that utilization of a comprehensive approach allows for a thorough evaluation of CRS performance, facilitates data and specimen management, and enhances participant retention. Our approach may serve as a guidepost for maximizing future large-scale clinical trials' operational success and scientific rigor. CLINICALTRIALS: gov Identifier: NCT02344290.