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Key Points

QuestionÌý Can pitavastatin reduce noncalcified coronary plaque and inflammatory biomarkers in people with HIV?

FindingsÌý In this substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) including 611 people with HIV, compared with the placebo arm, the pitavastatin arm had a significant 7% relative reduction in noncalcified plaque. Pitavastatin use was associated with reductions in oxidized low-density lipoprotein cholesterol and lipoprotein-associated phospholipase A2.

MeaningÌý In this study, among people with HIV at low to moderate cardiovascular risk, pitavastatin showed promise to reduce noncalcified coronary plaque as well as markers of lipid oxidation and arterial inflammation.

ImportanceÌý 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.

ObjectiveÌý 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 ParticipantsÌý 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.

InterventionÌý Oral pitavastatin calcium, 4 mg per day.

Main Outcomes and MeasuresÌý 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.

ResultsÌý 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 RelevanceÌý 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 RegistrationÌý ClinicalTrials.gov Identifier:

People with HIV (PWH) are at 1.5-fold to 2-fold risk of major adverse cardiovascular events (MACE), including myocardial infarction and stroke, and develop coronary artery disease (CAD) at an earlier age compared with people without HIV.^1,2 Increased MACE in PWH is thought to be related, in part, to traditional mechanisms as well as to residual inflammation and immune activation.^3-5 Premature CAD in PWH is characterized by increased noncalcified coronary plaque, which may contribute to increased cardiovascular events.⁶ As PWH are increasingly likely to die of non–HIV-related causes, including cardiovascular disease (CVD),⁷ it is important to develop a strategy to improve CAD and cardiovascular outcomes in PWH.

The Randomized Trial to Prevent Vascular Event in HIV (REPRIEVE) trial is a phase 3 multicenter randomized clinical trial of oral pitavastatin calcium, 4 mg per day, vs matched placebo for primary prevention of atherosclerotic CVD (ASCVD) events in PWH at low to moderate risk for ASCVD.⁸ In REPRIEVE, the pitavastatin arm had 35% less incident MACE compared with placebo over a median (IQR) of 5.1 (4.3-5.9) years, an effect beyond that anticipated from low-density lipoprotein (LDL) cholesterol reduction alone.⁹

The mechanistic substudy embedded within REPRIEVE was designed to determine potential statin effects to reduce noncalcified plaque volume and progression as assessed by entry and 2-year coronary computed tomography angiography (CTA). Moreover, the substudy sought to identify effects on lipid parameters and circulating biomarkers of inflammation.¹⁰

The design of REPRIEVE and the mechanistic substudy have been previously described,^8,10 and the trial protocol and statistical analysis plan are available in Supplement 1. In brief, 31 REPRIEVE sites, primarily from the AIDS Clinical Trial Group, were selected to participate in the mechanistic substudy based on capabilities for coronary CTA and blood biomarker acquisition. The trial was designed by study principal investigators in consultation with the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, and the AIDS Clinical Trials Group. Institutional review board/ethics committee approval and any other applicable regulatory entity approvals were obtained from the Mass General Brigham Institutional Review Board and each clinical research site. Participants were provided with study information, including discussion of risks and benefits, and signed the approved declaration of informed consent. This study followed the Consolidated Standards of Reporting Trials () reporting guideline.

For the main REPRIEVE trial, eligible individuals were aged 40 to 75 years, had documented HIV, were taking antiretroviral therapy for 180 days or more, had a CD4 cell count greater than 100 cells/mm³, estimated glomerular filtration rate of 60 mL/min/1.73 m² or greater, had an alanine transaminase level 2.5-fold the upper limit of normal or lower, and low to moderate 10-year ASCVD risk as calculated by the 2013 Pooled Cohort Equation risk calculator, with LDL cholesterol less than threshold for a given risk score.⁸ Statin use in the 90 days before entry or prior history of CVD were exclusionary. Race and ethnicity were self-reported via a questionnaire; options included Asian, Black or African American, White, or other race, which included participants identifying as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or having more than 1 or unknown race. The REPRIEVE mechanistic substudy enrolled REPRIEVE participants without contraindications to coronary CTA. Detailed inclusion and exclusion criteria are available in the eMethods in Supplement 2.¹⁰

REPRIEVE participants were randomized 1:1 to pitavastatin calcium, 4 mg per day, and to matched placebo. Randomization was accomplished using a centralized computer system, stratified by sex, CD4 cell count, and participation in the mechanistic substudy. Study investigators and participants were blinded to randomization. Participants received information on heart-healthy lifestyle, diet, and smoking cessation.

Coronary CTA was performed on CT scanners using 64 slices or more according to Society of Cardiovascular CT guidelines.¹¹ Deidentified coronary CTA images were transmitted to the central REPRIEVE CT core laboratory, as previously described.^10,12 Coronary plaque volume and composition were quantified using semi-automated plaque analysis software (QAngio CT; Medis Medical Imaging).^13,14 The coronary tree was automatically extracted. Plaque length was established visually with markers at the proximal and distal edges of plaque, and each participant’s CTs were read side-by-side blinded to scan order so that the same portion of the coronary artery was measured to minimize interscan variability. The inner and outer borders of the coronary wall were defined by the software and manually edited. Voxels between the outer wall of the coronary artery and the lumen were considered plaque; plaque composition was assigned based on voxel attenuation in Hounsfield units (HU; calcified plaque was defined as ≥350 HU, noncalcified plaque as <350 HU and low attenuation as <30 HU).^15,16 Participants were randomly assigned to 1 of 3 experienced CT core laboratory readers (B. F., J. K., and J. T.), who read CTs blinded to clinical information, order of CT acquisition, and randomization. Interobserver reproducibility for the primary outcome, noncalcified coronary plaque volume, was excellent (intraclass correlation coefficient, 0.97; 95% CI, 0.95-0.99) in a subset of 40 baseline and follow-up CTs.

The primary outcomes were change in noncalcified coronary plaque volume and progression of noncalcified coronary plaque, defined as any increase in noncalcified plaque volume or new noncalcified plaque. Supportive outcomes included change in total plaque volume (including both noncalcified and calcified components) and change in the composition of plaque (ratio of noncalcified to total plaque volume). An additional exploratory plaque outcome was change in low-attenuation plaque volume.^17,18

Blood was obtained fasting at entry, month 4, and month 24 for assessment of lipids (LDL and non–high-density lipoprotein cholesterol), inflammatory (high-sensitivity C-reactive protein [hsCRP], lipoprotein-associated phospholipase A2 [LpPLA2], and oxidized low-density lipoprotein [oxLDL]), and immune activation biomarkers (monocyte chemoattractant protein 1, IL-6, IL-10, IL-1β, IL-18, soluble CD14, and soluble CD163). Lipids and hsCRP were measured from serum at Quest Diagnostics, Secaucus, New Jersey. Inflammatory and immune biomarkers were measured from plasma using enzyme-linked immunosorbent assay kits (R&D Systems) except for oxLDL (Mercodia) at Temple University, Philadelphia, Pennsylvania.

The statistical analysis plan is provided in Supplement 1. While the main trial (N = 7769) was powered for a reduction in cardiovascular events, target enrollment for the mechanistic substudy was 800 participants to provide 90% power to detect an approximate 6% relative difference between the pitavastatin and placebo arms in noncalcified plaque volume over 2 years and a 27% relative change in the risk of plaque progression, assuming 50% had noncalcified plaque at entry and 15% dropout.¹⁹ Given the expected mixed population of participants with and without noncalcified plaque at entry, power was estimated via a simulation study including a 5% type error with no adjustment for the dual primary outcomes.

Participants completing a parent trial entry visit and a separate substudy registration were considered enrolled (Figure 1). The modified intention-to-treat population for plaque outcomes was limited to participants who had at least 1 evaluable CT. Primary analyses included participants with complete case outcomes (eg, paired entry and year 2); sensitivity analyses used multiple imputation in the population with at least 1 evaluable CT (Statistical Analysis Plan in Supplement 1). A per-protocol analysis was conducted including only those participants who completed their 2-year course of pitavastatin or placebo. A planned secondary analysis was restricted to participants with quantified coronary plaque at entry (ie, excluding those with no plaque).

Data are presented as counts with percentages, means with SDs, and medians with IQRs. Changes from baseline in continuous outcomes are presented as means with 95% CIs. Treatment group differences in plaque volumes were based on differences in means adjusted for entry plaque volume using linear regression. Analyses adjusting for race and ethnicity, sex, and ASCVD risk score did not change the findings and are not presented. Analyses were conducted on the measured scale and with a log transformation to reflect both absolute and relative changes. Probability of noncalcified and total plaque volume progression was compared by treatment group using a χ² test with the effect size presented as a relative risk (stratified on plaque presence at entry). Statin effects on lipids and markers of immune function and inflammation were assessed via Wilcoxon test for continuous variables.

Associations with changes in LDL cholesterol as well as immune and inflammatory biomarkers were assessed using linear regression for noncalcified coronary plaque volume and using log binomial regression for noncalcified plaque progression. These mechanistic analyses were limited to the per-protocol population with paired biomarkers and plaque outcomes (overall and the subpopulations with plaque at entry). The effects of biomarker changes on noncalcified coronary plaque volume at 4 and 24 months were examined to find the relationship of short-term and longer-term biomarkers changes to longer-term changes in noncalcified plaque volume. We also assessed whether adjusting for these biomarkers impacted the pitavastatin effect on plaque.

All inference used a 5% type I error with no adjustment for multiple comparisons, and all P values were 2-tailed. All analyses were conducted with SAS version 9.4M7 (SAS Institute).

A total of 804 participants from 31 US sites were enrolled from April 2015 to February 2018. Baseline characteristics of the enrolled population were previously reported and are compared with the parent REPRIEVE trial in eTable 1 in Supplement 2.¹² Of the 804 enrolled participants, 774 had at least 1 evaluable CT (eTable 2 in Supplement 2). Of these, 611 had complete data for evaluation of noncalcified plaque progression, and 587 had complete data for change in noncalcified plaque volume. Among the 611 complete case participants (Table 1), 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 median (IQR) HIV diagnosis duration at enrollment was 15 (9-22) years. The median (IQR) 10-year ASCVD risk score was 4.5% (2.6-7.0), with 338 (55.3%) having an ASCVD risk score less than 5%. The median (IQR) LDL cholesterol level was 108 (87-126) mg/dL (to convert to millimoles per liter, multiply by 0.0259). The median (IQR) body mass index (calculated as weight in kilograms divided by height in meters squared) was 26.9 (24.3-30.1). Participants had good virologic control, with a median (IQR) CD4 cell count of 609 (442-783) cells/mm³; 364 (59.6%) had been taking antiretroviral therapy for more than 10 years.

At baseline, the mean (SD) noncalcified plaque volume was 52.3 (193.5) mm³ in the pitavastatin arm and 57.7 (109.2) mm³ in the placebo arm (Table 2). Noncalcified plaque volume decreased in the pitavastatin arm compared with the placebo arm at month 24 (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). Analyzed as a relative change from baseline, the treatment effect represented a 7% (95% CI, 1-12) greater decrease in noncalcified plaque volume compared with placebo (fold change, 0.93; 95% CI, 0.88-0.99; P = .02). Progression of noncalcified plaque was less likely in the pitavastatin arm (relative risk, 0.67; 95% CI, 0.52-0.88; P = .003). The sensitivity analysis using multiple imputation to account for missing data and the per-protocol analysis including only participants who completed treatment as randomized supported these findings (eTables 3 and 4 in Supplement 2).

In a preplanned subgroup analysis, a larger effect size was seen among the subgroup with plaque at baseline (−8.8 mm³; 95% CI, −17.9 to 0.4; eTable 5 in Supplement 2), representing a 12% greater decrease in noncalcified plaque in pitavastatin compared with placebo arms. There was similar reduction in progression of noncalcified plaque compared with placebo (relative risk, 0.71; 95% CI, 0.55-0.93). Example images of plaque progression and regression are provided in eFigure 1 in Supplement 2.

There was a nonsignificantly smaller increase in total plaque volume (ie, noncalcified and calcified) with pitavastatin (mean [SD] change: pitavastatin, 2.3 [28.7] mm³; placebo, 6.9 [32.3] mm³; treatment effect, −4.3 mm³; 95% CI, −9.2 to 0.62). With respect to plaque composition, the percentage of noncalcified plaque decreased a mean (SD) of −6.6% (14.3) in the pitavastatin arm and −2.6% (9.2) in the placebo arm, for a treatment effect of −4.1% (95% CI, −7.0 to −1.3). Low-attenuation plaque volume also decreased on average in the pitavastatin arm compared with the placebo arm (mean [SD] change, −0.9 [10.0] mm³ vs −0.1 [8.2] mm³; baseline adjusted difference, −1.2 mm³; 95% CI, −2.2 to −0.1).

At baseline, the mean (SD) calcified plaque volume was 10.4 (30.6) mm³ in the pitavastatin arm and 13.1 (42.4) mm³ in the placebo arm. Calcified plaque volume increased in both the pitavastatin and placebo arms at month 24 (mean [SD] change, 4.1 [13.2] mm³ vs 4.2 [15.4] mm³).

Entry and month 24 circulating lipids and measures of inflammation are provided in Table 3 and eTable 6 in Supplement 2. Available month 4 values are provided in eTable 7 in Supplement 2. As in the parent REPRIEVE trial, LDL cholesterol levels were similar at baseline and changed from a median (IQR) of 105 (88-124) mg/dL to 75 (59-93) mg/dL in the pitavastatin group and from 107 (90-129) mg/dL to 108 (87-128) mg/dL in the placebo group at year 2. Similar effects were seen for non–high-density lipoprotein cholesterol.

The pitavastatin arm demonstrated a greater reduction in oxLDL at year 2 (pitavastatin, −29%; 95% CI, −32 to −26; placebo, −13%; 95% CI, −17 to −9; P < .001). Pitavastatin also reduced LpPLA2 by −7% (95% CI, −11 to −4), while there was a 14% (95% CI, 10-18) increase in LpPLA2 in the placebo arm (P < .001) at year 2. There was a nonsignificant decrease in hsCRP (Table 3). No significant effects were seen on markers of immune activation.

There was no significant association between change in LDL cholesterol and change in continuous noncalcified plaque volume (eFigure 2 in Supplement 2). Change in LDL cholesterol and an achieved LDL cholesterol level less than 70 mg/dL at 24 months were associated with lower risk of noncalcified plaque progression, though these relationships were not significant after adjustment for baseline plaque volume (Figure 2). No significant associations between changes in oxLDL, hsCRP, or LpPLA2 and noncalcified plaque progression or change in noncalcified plaque volume were apparent. The association between pitavastatin and changes in noncalcified plaque did not change after adjustment for these biomarkers (eFigures 3 and 4 in Supplement 2).

REPRIEVE demonstrated that primary cardiovascular prevention with pitavastatin reduced the risk of MACE by 35% over a median (IQR) of 5.1 (4.3-5.9) years in PWH at low to moderate traditional cardiovascular risk,⁹ an effect beyond that anticipated from LDL cholesterol reduction alone. Within the embedded REPRIEVE mechanistic substudy, the pitavastatin arm demonstrated a relative reduction (treatment effect, −4.3 mm³; 95% CI, −8.6 to −0.1; a 7% [95% CI, 1-12] greater reduction relative to placebo) in noncalcified coronary plaque volume over 2 years, with an estimated 33% lower risk of plaque progression. The pitavastatin arm also had a reduction in LDL cholesterol and biomarkers of lipid oxidation (oxLDL) and arterial inflammation (LpPLA2), although there was not clear association with changes in noncalcified plaque volume. These findings provide insight into how pitavastatin may prevent MACE.

In designing the mechanistic substudy, we sought to assess the effects of a statin intervention on coronary plaque and inflammation in PWH. Coronary CTA allows for noninvasive quantification of changes in plaque in response to therapy.^20-22 Here, we quantified noncalcified and low-attenuation coronary plaque, which are thought to be the biologically active component of plaque and are associated with MACE.^18,23 Among PWH, increased noncalcified coronary plaque may be a mechanism of increased CVD.^12,24-28 Noncalcified plaque was seen in a higher-than-expected percentage of participants at baseline in REPRIEVE, a relatively young primary prevention population with low to moderate traditional CVD risk.¹² The observed reduction in plaque volume may therefore represent an important statin benefit potentially contributing to the reduced MACE observed with statin in REPRIEVE. Studies have shown that relatively small effects on atheroma volume of 1% can lead to large reductions in MACE.²⁹ Other studies suggest decreases in noncalcified plaque with statin therapy may be due in part to conversion to calcified plaque, which may contribute to plaque stabilization.^30,31 In this study, there were similar increases in calcified plaque volume between arms, while noncalcified plaque volume decreased more in the pitavastatin arm than the placebo arm. Indeed, there was a decrease in the proportion of noncalcified plaque by −4.1% (95% CI, −7.0 to −1.3) in the pitavastatin arm compared with the placebo arm, suggesting relatively greater effects of pitavastatin to reduce noncalcified plaque than to increase calcified plaque in this population with low to moderate ASCVD risk.

The observation of a reduction in noncalcified coronary plaque in the pitavastatin arm compared with the placebo arm in REPRIEVE builds on an earlier trial of atorvastatin in PWH,¹⁹ which found that atorvastatin reduced noncalcified plaque volume in 40 PWH with preexisting plaque. The amount of baseline noncalcified plaque and change in noncalcified plaque were relatively small but occurred in a population very different from that investigated in other trials of high-risk cohorts^20,21 with more risk factors^32,33 or with established CAD.^17,34 Consistent with this, the effects of our statin intervention on plaque were larger among those with plaque at baseline in REPRIEVE. The reduction in noncalcified plaque volume among those with preexisting plaque in REPRIEVE was similar to that seen in a metanalysis of 3 CTA statin studies.³⁵

While the focus was on the salutary effects of pitavastatin, the placebo arm also provides a valuable look at the natural history of CAD in PWH. In this group with low to moderate traditional CVD risk who would not normally qualify for statin, there was on average progression of noncalcified coronary plaque over 2 years. These findings support previous observations of accelerated CAD in PWH,^19,24,28,36 which, along with the 35% reduction in MACE seen in the parent trial,⁹ build the case for primary prevention in this population.

The pitavastatin arm had a reduction in oxLDL and LpPLA2 compared with the placebo arm, in addition to LDL cholesterol. These changes are notable, as specific inflammatory pathways have been hypothesized to increase the risk of CVD in PWH.⁴ Prior studies have shown increased arterial inflammation using fludeoxyglucose-18 positron emission tomography in PWH compared with controls without HIV in the general population,³⁷ linking arterial inflammation to noncalcified plaque among PWH.³⁸ In this regard, LpPLA2 is a platelet-activating factor that hydrolyzes oxidized lipids, thought to play a proinflammatory role in atherogenesis and is a marker of arterial inflammation in PWH.^39,40 In contrast, markers of generalized inflammation, such as CRP, may not be increased in well-treated PWH taking antiretroviral therapy, potentially explaining the more modest changes in CRP observed in our study. oxLDL is a marker of oxidative stress, which increases the atherogenic properties of LDL cholesterol and induces foam cell formation through localized macrophage activation and endothelial activation, key processes in plaque formation.⁴¹ In contrast, no significant effects on immune pathways were found.

Among studies in the general population, there is an overall association between achieved LDL cholesterol and reductions in coronary plaque volume, though considerable heterogeneity exists at the level of the individual study.²² Similarly, in REPRIEVE, there was a suggestion that achieved LDL cholesterol less than 70 mg/dL at 24 months was associated with a lower risk of noncalcified plaque progression in unadjusted analyses. Our population was unusual, as it was composed of PWH at low to moderate CVD risk with lower entry LDL cholesterol levels in contrast to other higher-risk populations with higher LDL cholesterol levels, in which statin effects on LDL may relate more strongly to changes in plaque. Decreases in systemic markers of lipid oxidation and arterial inflammation were not significantly associated with the changes in noncalcified plaque. However, effects of statins may modify inflammatory pathways through lipid effects occurring at the local plaque level, leading to reductions in inflammation in the plaque microenvironment as a mechanism of their anti-inflammatory effect.⁴² Moreover, changes in inflammatory pathways may be related to MACE, even if not related to changes in plaque volume, a hypothesis that will be further tested in the main REPRIEVE population. Further research is needed into the mechanism by which statins reduce noncalcified plaque among PWH, including potential effects related to atheroma formation, lipid uptake, and foam cell formation. Other effects of statins at the plaque surface to stabilize plaque, reduce inflammation within the plaque, and reduce plaque rupture, may be critical to preventing MACE in PWH. The data from REPRIEVE add to our growing understanding of the potential mechanisms of statin effects on CVD.⁴³

Limitations of this study should be considered. Although our results are specific to pitavastatin, other statins may have similar effects. REPRIEVE was an international trial with 145 sites from 12 countries; the mechanistic substudy necessarily included a more limited population from 31 US sites and thus may not be representative of other regions. The substudy population was generally similar to the overall trial population in terms of ASCVD risk but included a higher proportion of male participants (eTable 1 in Supplement 2). A multiple imputation analysis addressed missing data and supported the overall conclusion of the study. The results may not be generalizable to higher-risk populations, with higher baseline LDL cholesterol and more plaque.

In conclusion, in a primary prevention trial of PWH at low to moderate ASCVD risk, 2 years of pitavastatin reduced noncalcified coronary plaque volume and inflammatory biomarkers. These effects may contribute to the observed effects of pitavastatin on MACE in the parent REPRIEVE trial.

Accepted for Publication: December 28, 2023.

Published Online: February 21, 2024. doi:10.1001/jamacardio.2023.5661

Correction: This article was corrected on February 28, 2024, to change the article to open access under the CC-BY License.

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2024 Lu MT et al. JAMA Cardiology.

Corresponding Authors: Michael T. Lu, MD, MPH, Cardiovascular Imaging Research Center, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 165 Cambridge St, Ste 400, Boston, MA 02114 (mlu@mgh.harvard.edu); Steven K. Grinspoon, MD, Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, 50 Staniford St, Room 768, Boston, MA 02114 (sgrinspoon@mgh.harvard.edu).

Author Contributions: Drs Lu and Grinspoon had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lu, Ribaudo, Foldyna, Fitch, Bloomfield, Alston-Smith, Aberg, Fichtenbaum, Hoffmann, Douglas, Grinspoon.

Acquisition, analysis, or interpretation of data: Lu, Ribaudo, Foldyna, Zanni, Mayrhofer, Karády, Taron, McCallum, Burdo, Paradis, Hedgire, Meyersohn, deFilippi, Malvestutto, Sturniolo, Diggs, Siminski, Desvigne-Nickens, Overton, Currier, Aberg, Fichtenbaum, Hoffmann, Grinspoon.

Drafting of the manuscript: Lu, Ribaudo, Foldyna, Karády, McCallum, Malvestutto, Grinspoon.

Critical review of the manuscript for important intellectual content: Lu, Ribaudo, Foldyna, Zanni, Mayrhofer, Taron, Fitch, Burdo, Paradis, Hedgire, Meyersohn, deFilippi, Sturniolo, Diggs, Siminski, Bloomfield, Alston-Smith, Desvigne-Nickens, Overton, Currier, Aberg, Fichtenbaum, Hoffmann, Douglas, Grinspoon.

Statistical analysis: Ribaudo, Mayrhofer, McCallum.

Obtained funding: Lu, Ribaudo, Zanni, Taron, Currier, Hoffmann, Douglas, Grinspoon.

Administrative, technical, or material support: Lu, Foldyna, Taron, Fitch, Burdo, Paradis, Hedgire, Meyersohn, Malvestutto, Sturniolo, Diggs, Bloomfield, Desvigne-Nickens, Overton, Currier, Aberg, Fichtenbaum, Hoffmann, Douglas.

Study supervision: Lu, Burdo, Hedgire, Desvigne-Nickens, Hoffmann, Douglas, Grinspoon.

Conflict of Interest Disclosures: Dr Lu reported grants from the National Heart, Lung, and Blood Institute and Kowa Pharmaceuticals America during the conduct of the study as well as grants from American Heart Association, AstraZeneca, Ionis, Johnson & Johnson Innovation, MedImmune, National Academy of Medicine, National Heart, Lung, and Blood Institute, and Risk Management Foundation of the Harvard Medical Institutions outside the submitted work. Dr Ribaudo reported grants from the National Heart, Lung, and Blood Institute, Kowa Pharmaceuticals, and Gilead Sciences during the conduct of the study as well as grants from National Institute of Allergy and Infectious Diseases, National Institute on Aging, and National Heart, Lung, and Blood Institute outside the submitted work. Dr Foldyna reported grants from the National Heart, Lung, and Blood Institute, AstraZeneca, MedImmune, and Medtrace outside the submitted work. Dr Zanni reported grants from Gilead Sciences during the conduct of the study. Dr Taron reported grants from the Deutsche Forschungsgesellschaft (German Research Foundation) during the conduct of the study as well as personal fees from Siemens Healthcare, Bayer AG, Universimed Cross Media Content, coreLab Black Forest, and Onc AI outside the submitted work. Dr Burdo reported grants from Massachusetts General Hospital during the conduct of the study as well as nonfinancial support from Excision BioTherpeutics outside the submitted work. Dr DeFilippi reported grants from Massachusetts General Hospital outside the submitted work. Dr Malvestutto reported grants from AIDS Clinical Trials Group during the conduct of the study; grants from Eli Lilly; and personal fees from ViiV Healthcare, Gilead Sciences, and Pfizer outside the submitted work. Dr Siminski reported grants from Massachusetts General Hospital during the conduct of the study. Dr Overton reported grants from the National Institutes of Health during the conduct of the study. Dr Currier reported personal fees from Merck outside the submitted work. Dr Aberg reported grants from Massachusetts General Hospital during the conduct of the study; grants from Emergent Biosolutions, Frontier Biotechnologies, Gilead Sciences, GlaxoSmithKline, Janssen, Macrogenics, Merck, Pfizer, Regeneron, and ViiV Healthcare; and personal fees from GlaxoSmithKline, Merck, and Kintor Pharmaceuticals outside the submitted work. Dr Fichtenbaum reported grants from ViiV Healthcare, Gilead Sciences, Merck, Moderna, and Lilly as well as personal fees from ViiV Healthcare and Theratechnologies outside the submitted work. Dr Hoffmann reported grants from the National Institutes of Health during the conduct of the study as well as personal fees from Stanford University, CCS, MedTrace, and RapidAI outside the submitted work. Dr Grinspoon reported grants from the National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare during the conduct of the study; personal fees from ViiV Healthcare, Theratechnologies, and Marathon Asset Management outside the submitted work; and has a patent for use of pitavastatin pending. No other disclosures were reported.

Funding/Support: This study is supported through National Institutes of Health grants to the Clinical Coordinating Center (U01HL123336 and 1UG3HL164285) and to the Data Coordinating Center (U01HL123339 and 1U24HL164284) as well as funding from Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare. The National Institute of Allergy and Infectious Diseases supported this study through grants UM1 AI068636, which supports the AIDS Clinical Trials Group Leadership and Operations Center, and UM1 AI106701, which supports the AIDS Clinical Trials Group Laboratory Center.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: Members of the REPRIEVE Trial Writing Group appear in Supplement 3.

Disclaimer: The views expressed are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, the National Institutes of Health, or the US Department of Health and Human Services.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank the study participants, site staff, and study-associated personnel for their ongoing participation in the trial. In addition, we thank the following: the AIDS Clinical Trial Group (ACTG) for clinical site support; ACTG Clinical Trials Specialists for regulatory support; the data management center, Frontier Science Foundation, for data support; the Center for Biostatistics in AIDS Research for statistical support; the Community Advisory Board for input for the community; and the National Heart, Lung, and Blood Institute and National Institute of Allergy and Infectious Diseases team members for help with the trial. See full acknowledgment in the eAppendix in Supplement 2.