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Rationale and design of the Mechanistic Substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE): Effects of pitavastatin on coronary artery disease and inflammatory biomarkers.

ABSTRACT: BACKGROUND:People with HIV (PWH) have increased cardiovascular events, inflammation, and high-risk coronary atherosclerosis. Statin therapy has been shown to lower the risk of cardiovascular disease (CVD) in the general population, but whether this results from reductions in coronary atherosclerosis and is mediated by decreased inflammation remains unknown. METHODS:REPRIEVE is a randomized, placebo-controlled trial of pitavastatin calcium (4 mg/day) vs. placebo enrolling at least 7500 PWH between 40-75 years, on antiretroviral therapy (ART), with low to moderate traditional CVD risk. The Mechanistic Substudy of REPRIEVE (A5333s) is co-enrolling 800 participants from 31 US sites. These participants undergo serial contrast enhanced coronary computed tomography angiography (CCTA) and measurements of biomarkers of inflammation and immune activation at baseline and after 2 years of follow-up. The primary objectives are to determine the effects of pitavastatin on noncalcified coronary atherosclerotic plaque (NCP) volume, low attenuation plaque, and positive remodeling and on changes in immune activation and inflammation and to assess relationships between the two. Changes in CAD will be assessed in a standardized fashion by a core lab with expert readers blinded to time points and participant information; immune activation and inflammation assessment is also performed centrally. RESULTS:To date the Mechanistic Substudy has completed planned enrollment, with 805 participants. CONCLUSION:This study represents the first large, randomized, CCTA-based assessment of the effects of a primary prevention strategy for CVD on high-risk CAD, immune activation and inflammation among PWH. The study will assess pitavastatin's effects on coronary plaque, and the interrelationship of these changes with biomarkers of immune activation and inflammation in PWH to determine mechanisms of CVD prevention and improved outcomes in this population.

SUBMITTER: Hoffmann U

PROVIDER: S-EPMC6596304 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Rationale and design of the Mechanistic Substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE): Effects of pitavastatin on coronary artery disease and inflammatory biomarkers.

Hoffmann Udo U Lu Michael T MT Olalere Devvora D Adami Elizabeth C EC Osborne Michael T MT Ivanov Alex A Aluru John Sukumar JS Lee Saeyun S Arifovic Nadja N Overton Edgar Turner ET Fichtenbaum Carl J CJ Aberg Judith A JA Alston-Smith Beverly B Klingman Karin L KL Waclawiw Myron M Burdo Tricia H TH Williams Kenneth C KC Zanni Markella V MV Desvigne-Nickens Patrice P Cooper-Arnold Katharine K Fitch Kathleen V KV Ribaudo Heather H Douglas Pamela S PS Grinspoon Steven K SK

American heart journal 20190304

<h4>Background</h4>People with HIV (PWH) have increased cardiovascular events, inflammation, and high-risk coronary atherosclerosis. Statin therapy has been shown to lower the risk of cardiovascular disease (CVD) in the general population, but whether this results from reductions in coronary atherosclerosis and is mediated by decreased inflammation remains unknown.<h4>Methods</h4>REPRIEVE is a randomized, placebo-controlled trial of pitavastatin calcium (4 mg/day) vs. placebo enrolling at least ...[more]

PMID: 30928823

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Project description:ImportanceCardiovascular 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.ObjectiveTo 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 participantsThis 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.InterventionOral pitavastatin calcium, 4 mg per day.Main outcomes and measuresCoronary CTA and inflammatory biomarkers at baseline and 24 months. The primary outcomes were change in noncalcified coronary plaque volume and progression of noncalcified plaque.ResultsOf 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 relevanceIn 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 registrationClinicalTrials.gov Identifier: NCT02344290.

Project description:BackgroundCardiovascular disease (CVD) is more frequent among people with HIV (PWH) and may relate to traditional and nontraditional factors, including inflammation and immune activation. A critical need exists to develop effective strategies to prevent CVD in this population.MethodsThe Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) (A5332) is a prospective, randomized, placebo-controlled trial of a statin strategy for the primary prevention of major adverse cardiovascular events (MACE) in PWH with low to moderate traditional risk. At least 7,500 PWH, 40-75 years of age, on stable antiretroviral therapy, will be randomized to pitavastatin calcium (4 mg/d) or identical placebo and followed for up to 8 years. Participants are enrolled based on the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) atherosclerotic cardiovascular disease (ASCVD) risk score and low-density lipoprotein cholesterol (LDL-C) level with a goal to identify a low- to moderate-risk population who might benefit from a pharmacologic CVD prevention strategy. Potential participants with a risk score ≤ 15% were eligible based on decreasing LDL-C thresholds for increasing risk score >7.5% (LDL-C <190 mg/dL for risk score <7.5%, LDL-C <160 mg/dL for risk score 7.6%-10%, and LDL-C<130 mg/dL for risk score 10.1%-15%). The primary objective is to determine effects on a composite end point of MACE. Formal and independent adjudication of clinical events will occur using standardized criteria. Key secondary end points include effects on MACE components, all-cause mortality, specified non-CVD events, AIDS and non-AIDS events, and safety.ResultsTo date, REPRIEVE has enrolled >7,500 participants at approximately 120 sites across 11 countries, generating a diverse and representative population of PWH to investigate the primary objective of the trial.ConclusionsREPRIEVE is the first trial investigating a primary CVD prevention strategy in PWH. REPRIEVE will inform the field of the efficacy and safety of a statin strategy among HIV-infected participants on antiretroviral therapy and provide critical information on CVD mechanisms and non-CVD events in PWH.

Project description:BackgroundChronic kidney disease is a common comorbid condition among persons living with human immunodeficiency virus (PWH). We characterized baseline kidney function in the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) trial cohort.MethodsREPRIEVE enrolled PWH with low to moderate cardiovascular risk based on traditional risk factors to evaluate the effect of statin therapy on cardiovascular events. We determined baseline estimated glomerular filtration rate (eGFR) with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease, and Cockcroft-Gault equations, and we evaluated baseline factors associated with eGFR <90 mL/min/1.73 m2 by logistic regression. We performed Bland-Altman plots and scatterplots to assess agreement between equations.ResultsAmong 7770 participants enrolled, the median age was 50 years, 31% were female (natal sex), 43% black or African American and 15% Asian, the median body mass index (calculated as calculated as weight in kilograms divided by height in meters squared) was 25.8, and the median CD4 cell count 620/µL. The median CKD-EPI eGFR was 97 mL/min/1.73 m2, and 38% had an eGFR <90 mL/min/1.73 m2. In the adjusted model, factors associated with eGFR <90 mL/min/1.73 m2 included white race, older age, higher body mass index, high-income region of enrollment, hypertension, and tenofovir disoproxil fumarate. The CKD-EPI and Modification of Diet in Renal Disease equations demonstrated strong agreement, particularly at lower eGFR values. Overall, there was 56% concordance between the 3 equations (categories <60, 60 to <90, ≥90 mL/min), improving to 73% after accounting for individual body surface area.ConclusionsREPRIEVE enrolled a diverse cohort including a substantial number of PWH with reduced kidney function. Factors associated with reduced eGFR included traditional risk factors and tenofovir disoproxil fumarate exposure. Three commonly used equations have only fair agreement, with potential implications for both clinical care and epidemiologic studies.Clinical trials registrationNCT02344290.

Dataset Information

Rationale and design of the Mechanistic Substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE): Effects of pitavastatin on coronary artery disease and inflammatory biomarkers.

Publications

Rationale and design of the Mechanistic Substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE): Effects of pitavastatin on coronary artery disease and inflammatory biomarkers.

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