BACKGROUND:REPRIEVE findings catalyzed changes to multiple guidelines directing statin therapy prescribing for people with HIV (PWH). US guidelines use the pooled cohort equation (PCE)-derived 10-year atherosclerotic cardiovascular disease (ASCVD) risk score but may in the future incorporate the new Predicting Risk of CVD EVENTs (PREVENT) score. Meanwhile, European guidelines use Systematic Coronary Risk Evaluation 2 (SCORE2). METHODS:Leveraging Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), we compared effects of applying PCE versus either PREVENT according to US guidelines or SCORE2 according to European guidelines among a global primary CVD prevention cohort of PWH. RESULTS:Analysis cohort included 7757 participants with data for PREVENT and SCORE2 calculation. Ten-year ASCVD risk estimates (median [Q1, Q3]) were highest with PCE (4.4% [2.1%, 7.1%]) versus SCORE2 (3.3% [2.0%, 4.9%]) and PREVENT (2.2% [1.3%, 3.3%]). PREVENT- (vs PCE-) based scoring reclassified 38% of participants from a higher to a lower risk group (≥5% to <5%), while SCORE2-based scoring analogously shifted 27% of those age ≥50 years. Among placebo-assigned participants, median observed incidence of hard major adverse cardiovascular events (MACEs)/1000 person-years (PY) was higher than that predicted by PREVENT, except for those with ultralow predicted risk. The estimated cumulative incidence of primary MACE was higher and 5-year number needed to treat (NNT5) lower for most risk groups using PREVENT versus PCE. The NNT5 for the PREVENT-defined risk group of 2.5-5.0% was close to the NNT5 for the PCE-defined risk group of ≥5% (NNT5[95% CI]: 53 [31, 178] vs 47 [30, 109], respectively). CONCLUSIONS:Statin-prescribing guidelines for PWH based on REPRIEVE should account for differences in 10-year ASCVD risk estimates when scores other than PCE are used. FUNDING:National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare Clinical Trials Registration. REPRIEVE; NCT02344290; https://clinicaltrials.gov/study/NCT02344290.

BACKGROUND:Residual major adverse cardiovascular event (MACE) risk persists despite successful prevention of cardiovascular disease (CVD) with statin therapy among people with HIV (PWH). Identifying key biomarkers related to residual cardiovascular risk is critical for PWH. OBJECTIVES:The objective of the current analysis was to assess the association of immune, inflammatory, cardiac, and lipid-related biomarkers among contemporary antiretroviral therapy-treated PWH in the REPRIEVE global primary cardiovascular prevention trial in residual risk analyses. METHODS:We assessed relationships of baseline inflammatory, cardiac, and lipid-related biomarkers to incident MACE using Cox models adjusted for randomized statin treatment and atherosclerotic CVD risk. Population attributable fractions (PAFs) were assessed for biomarkers. RESULTS:Of the 7769 REPRIEVE participants, 7,005 (90%) had biomarker data available at baseline, with the median follow-up of 5.6 years. Relatively high percentages of participants had elevated inflammatory (high-sensitivity C-reactive protein >3 mg/L [49%], interleukin [IL]-6 ≥3.3 pg/mL [33%]) and cardiac markers (high-sensitivity troponin ≥6 ng/L [35%], N-terminal pro-B-type natriuretic peptide ≥50 pg/mL [33%]). Inflammatory biomarkers showed minimal correlation with cardiac or lipid biomarkers (apolipoprotein B-100, oxidized low-density lipoprotein, and lipoprotein(a)). Individual biomarkers were related to MACE in analyses adjusted for PCE and statin randomization, with the largest HRs for IL-6 (HR: 2.2; 95% CI: 1.3-3.9) and high-sensitivity troponin (HR: 2.2; 95% CI: 1.2-4.1) comparing those with highest vs lowest biomarker levels. PAFs were highest for IL-6, 18.6% (95% CI: 7.4%-30.5%) and high-sensitivity C-reactive protein 17.2% (95% CI: 1.6%-32.9%). CONCLUSIONS:Among PWH with low-moderate predicted CVD risk and well-controlled HIV, persistent inflammation, innate immune activation, and subclinical cardiac dysfunction are common, and strongly relate to residual MACE risk, accounting for a large PAF. (Evaluating the Use of Pitavastatin to Reduce the Risk of Cardiovascular Disease in HIV-Infected Adults [REPRIEVE]; NCT02344290.

BACKGROUND:People with human immunodeficiency virus (HIV, PWH) exhibit increased cardiovascular disease (CVD) risk and accelerated biological aging. REPRIEVE demonstrated that pitavastatin reduced major adverse cardiovascular events (MACE) in antiretroviral therapy (ART)-treated PWH with low-to-moderate traditional cardiovascular risk. It remains unknown whether statin therapy can modulate epigenetic aging in PWH. METHODS:We assessed epigenetic aging biomarkers using DNA methylation profiles from peripheral blood mononuclear cells (PBMCs) in a subset of 99 randomly selected US REPRIEVE participants (65 pitavastatin, 34 placebo) at baseline and 24 months. The primary outcomes were changes in second- and third-generation epigenetic clocks PCGrimAge (trained on mortality risk) and DunedinPACE (trained on rate of age-related multi-organ decline). RESULTS:Median chronological age was 57.0 (Q1, Q3: 56, 58) years and 100% of participants demonstrated epigenetic age acceleration, measured by the difference in PCGrimAge and chronological age (median difference 7.08 years [Q1, Q3: 4.69, 9.64]) at entry. Over 24 months, PCGrimAge remained accelerated with no significant differences between treatment arms (P = .89). However, the median pace of aging by the DunedinPACE increased in the placebo arm (0.036, Q1, Q3 [-0.018, 0.10], P = .021) but not in the pitavastatin arm (0.001, Q1, Q3 [-0.031, 0.036], [P = .77]), treatment group difference (P = .049). CONCLUSIONS:In this pilot study of REPRIEVE, epigenetic age acceleration was demonstrated at trial entry. The biological pace of aging increased over 24 months in the placebo group as compared to the statin group. These preliminary findings suggest pitavastatin may prevent an increase in the pace of biological aging in PWH and support further research into statin therapy as a potential intervention to mitigate accelerated aging. CLINICAL TRIALS REGISTRATION:NCT02344290 (date of initial registration: 22 January 2015).

BACKGROUND:Newcastle disease virus hexapro spike (NDV-HXP-S) is a recombinant vaccine designed to elicit both systemic and mucosal immunity against SARS-CoV-2. Intramuscular vaccines protect against severe disease but provide limited mucosal protection. We conducted a Phase 1 trial of live NDV-HXP-S administered intranasally (IN), intramuscularly (IM), or simultaneously (IN+IM) in previously vaccinated adults. METHODS:Thirty-five healthy adults without prior COVID-19 were enrolled at a single site in New York City (Feb 2022-Apr 2024). Participants received low- or high-dose NDV-HXP-S via IN, IM, or IN+IM routes, or placebo. Safety was monitored for 365 days; immune responses in serum and saliva were measured through day 84. FINDINGS:All 35 participants completed follow-up. NDV-HXP-S was safe and well tolerated, with only grade 1-2 adverse events. Placebo recipients showed waning antibody titers, whereas NDV-HXP-S maintained or boosted serum IgG and neutralizing activity. Salivary sIgA rose modestly. Participants with low baseline CD4+ T-cell activity exhibited increases by day 28. The study was not powered for statistical significance. INTERPRETATION:Live NDV-HXP-S was safe and well tolerated in this small Phase 1 study. Exploratory immunogenicity analyses showed variable systemic and mucosal responses, supporting further evaluation of updated NDV-HXP-S formulations in larger controlled studies. FUNDING:Supported by the Icahn School of Medicine Dean's Philanthropic Fund, CastleVax Inc., Mount Sinai CTSA (UL1TR004419), and philanthropic and federal grants. TRIAL REGISTRATION:ClinicalTrials.govNCT05181709.

Background:We evaluated baseline hypertension prevalence and control and risk of major adverse cardiovascular events (MACEs) among people with HIV in REPRIEVE who had low to moderate traditional cardiovascular disease (CVD) risk. Methods:Hypertension at baseline was defined by (1) a preexisting diagnosis regardless of antihypertensive treatment or (2) systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg without a prior diagnosis. We estimated the prevalence of the composite hypertension and control outcomes and calculated adjusted prevalence ratios controlling for traditional CVD risk factors using log binomial regression. We explored the relationship between hypertension and MACE using cause-specific Cox proportional hazards models. Results:Of 7769 participants enrolled from 5 regions, the median age was 50 years, and 2419 (31%) were women. The prevalence of baseline hypertension was 36% (n = 2780) with geographic variation. Among these, 1911 (69%) individuals had a preexisting hypertension diagnosis; the remainder (n = 869, 31%) were undiagnosed. Region and traditional CVD risk factors were associated with hypertension prevalence, with obese and overweight body mass index having the highest adjusted prevalence ratios (1.80 [95% CI, 1.67-1.95] and 1.38 [95% CI, 1.28-1.49], respectively). Among those with preexisting hypertension, 40% were uncontrolled, with regional variation. Hypertension at baseline was associated with an increased hazard of MACE (hazard ratio, 2.00; 95% CI, 1.57-2.55) and key components of MACE, including myocardial infarction and stroke. Conclusions:Approximately 1 in 3 REPRIEVE participants had hypertension at baseline. Hypertension was frequently suboptimally controlled. These findings highlight the need for improved screening and optimized treatment of hypertension in people with HIV.

BACKGROUND:The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) found a 36% reduction in major adverse cardiovascular events (MACE) with pitavastatin in people with HIV. Little is known about the relationship between lipid lowering and MACE in this population. We evaluated pitavastatin effects on lipids and examined mediation of pitavastatin effects on MACE through lipid lowering. METHODS:REPRIEVE was a randomised, double-blind, placebo-controlled phase 3 trial evaluating pitavastatin (4 mg daily) or placebo for prevention of MACE in people with HIV. Participants aged 40-75 years, on stable combination antiretroviral therapy (ART), and at low-to-moderate atherosclerotic cardiovascular disease risk with minimally elevated LDL were followed up for a median of 5·6 years. Centrally tested fasting lipids were captured at entry and annually thereafter. The primary MACE outcome, reported previously, was time to first MACE. Here, we report secondary outcomes on fasting lipids. Linear mixed-effects models were used for assessment of the pitavastatin effect on lipids, Cox regression for relationship of lipids to MACE, and Vansteelandt method for mediation analysis. FINDINGS:REPRIEVE enrolled 7769 participants from March 26, 2015, to July 31, 2019, in 12 countries across five Global Burden of Diseases super-regions. The median baseline LDL was 108 mg/dL, and similar across treatment groups. Pitavastatin effects were primarily observed on LDL, with a modest reduction in triglycerides and no apparent effect on HDL. Based on the longitudinal data modelling, the estimated treatment group difference in LDL at month 12 (pitavastatin minus placebo) was -30 mg/dL (95% CI -31 to -29), corresponding to a 30% reduction. The estimated risk of LDL of ≥100 mg/dL at month 12 was 0·18 in the pitavastatin group and 0·57 in the placebo group (relative risk 0·32, 95% CI 0·30-0·34). A 30% lower time-updated average LDL was associated with 20% lower risk of primary MACE (hazard ratio 0·80, 95% CI 0·68-0·94). Of the pitavastatin effect on MACE, 68% was estimated to be mediated through LDL, although with low precision (95% CI 15-574). INTERPRETATION:LDL is strongly related to MACE, and LDL lowering should be an important goal of primary cardiovascular prevention in people with HIV, even in those with minimally elevated LDL. Treatment should aim to achieve accepted primary care prevention targets for LDL. FUNDING:US National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare.

BACKGROUND:People living with HIV have an increased risk of cardiovascular disease, but data on the development and consequences of hypertension remain limited. Using data from REPRIEVE, a global randomised trial of pitavastatin for primary cardiovascular prevention among people with HIV, we evaluated whether pitavastatin reduces the incidence of hypertension among participants without hypertension at baseline and whether incident hypertension is associated with subsequent major adverse cardiovascular events (MACE). METHODS:We conducted a prespecified secondary analysis of participants without evidence of hypertension at REPRIEVE entry (baseline). REPRIEVE (NCT02344290) was a global, randomised, double-blind, placebo-controlled trial that enrolled adults with HIV aged 40-75 years at low-to-moderate atherosclerotic cardiovascular risk, receiving stable antiretroviral therapy. The primary outcome in this secondary analysis was incident hypertension based on clinical diagnosis according to standard criteria. Included participants were those without hypertension at baseline; excluded were those with documented hypertension, antihypertensive treatment use, systolic blood pressure of 140 mm Hg or higher, or diastolic blood pressure of 90 mm Hg or higher. The association between incident hypertension and a secondary outcome of MACE was evaluated in a time-updated analysis. Analyses used both Cox and Fine-Gray proportional hazards models and Poisson regression. FINDINGS:Of 7769 participants enrolled in REPRIEVE, 4989 (64%) without hypertension at baseline were included (2496 assigned to pitavastatin and 2493 to placebo) in this secondary analysis. The median age was 49 years (IQR 45-54); 1464 (29%) were women and 3525 (71%) men; and the median systolic and diastolic blood pressures at baseline were 102 mm Hg and 76 mm Hg, respectively. Over a median follow-up of 5·0 years (IQR 4·4-5·8), 668 (13%) participants developed hypertension. Participants randomly assigned to pitavastatin showed a modestly lower incidence of hypertension (24·7 per 1000 person-years vs 29·6 per 1000 person-years), corresponding to a 17% relative risk reduction (cause-specific hazard ratio [HR] 0·83, 95% CI 0·71-0·97; p=0·017). Risk factors of incident hypertension included old age, high BMI, metabolic syndrome, reduced estimated glomerular filtration rate (eGFR), and Black race in high-income regions. Among participants with incident hypertension, 581 (87%) initiated antihypertensive therapy. Of 213 who initiated antihypertensive therapy after diagnosis of hypertension, 159 (74·6%) were controlled 4 years after diagnosis. Incident hypertension was associated with a higher risk of MACE during follow-up (subdistribution HR 2·16, 95% CI 1·32-3·52) in modelling adjusted for baseline cardiovascular risk score. INTERPRETATION:These findings suggest additional cardiovascular benefits of pitavastatin on hypertension among people with HIV targeted for primary cardiovascular prevention. FUNDING:National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, ViiV Healthcare, Instituto de Salud Carlos III, and the European Regional Development Fund.

BACKGROUND:Persons with HIV face increased risks of major adverse cardiovascular events (MACE), partially mitigated by statin therapy. METHODS:We characterized factors associated with MACE and MACE subcomponents among PWH enrolled in REPRIEVE, globally. Our primary outcome measure was time-to-first primary MACE. Secondary outcome measures included time-to-first (1) hard MACE (cardiovascular disease [CVD] death, myocardial infarction [MI], or stroke), (2) MI, or (3) stroke. For each outcome, Cox proportional hazards models were used to estimate the hazard of baseline risk factors. RESULTS:Among participants (N = 7769), median age was 50 (Q1, Q3: 45, 55) years, and 31% were female. In fully adjusted models, risk of first MACE was higher for older individuals (50-59 and ≥60 vs 40-49 years; HR [95% CI]: 2.06 [1.54-2.76] and 2.53 [1.60-4.01]) and for those with Black/African-American race (vs White race, within HICs; HR: 1.65; 1.19-2.27), family history of premature CVD (HR: 1.53; 1.16-2.03), current cigarette smoking (HR: 2.27; 1.65-3.13), hypertension (HR: 1.77; 1.36-2.30), lower HDL cholesterol (HR: 1.21; 1.10-1.34), HIV-1 RNA ≥lower limit of quantification (LLQ) (HR: 1.40; 1.0-1.97), and a select antiretroviral therapy class combination (HR: 1.53; 1.01-2.31). Individuals from HICs had a higher risk of first MACE versus those from other regions, except South Asia. There was no apparent protective effect of female sex. Modeling for hard MACE, MI, and stroke yielded similar results for most variables. CONCLUSIONS:Among PWH in REPRIEVE, select modifiable risk factors were associated with first MACE after accounting for statin effects. Female sex was not protective. CLINICAL TRIALS REGISTRATION:NCT02344290 (ClinicalTrials.gov; date of initial registration: 22 January 2015).

OBJECTIVE:To determine whether pitavastatin reduces enterocyte injury, assessed by intestinal fatty acid-binding protein (I-FABP), among antiretroviral therapy-treated people with HIV (PWH) enrolled in the REPRIEVE mechanistic substudy. DESIGN:Randomized, double-blind, placebo-controlled trial. METHODS:We analyzed fasting plasma I-FABP at entry and month 24 among participants randomized to pitavastatin 4 mg daily or placebo. Baseline characteristics were summarized across I-FABP quartiles. Associations between entry I-FABP and inflammatory and immune activation biomarkers were assessed using Spearman correlations. Longitudinal changes were evaluated using intention-to-treat and per-protocol analyses and generalized estimating equation models. RESULTS:Among 710 participants with entry I-FABP measurements (median age 50 years; 18.5% female; 98% with undetectable viral load), median I-FABP levels were 2690 [Q1, Q3: 1888, 3770] (pg/mL). Entry I-FABP correlated modestly with markers of systemic inflammation and monocyte activation, including GDF-15 and soluble CD14. Over 24 months, I-FABP levels declined similarly in the pitavastatin and placebo arms, with no significant differences in absolute or fold change. CONCLUSIONS:In this well-treated HIV cohort, higher baseline I-FABP levels were associated with increased inflammatory markers at study entry. However, pitavastatin did not reduce I-FABP over follow-up. These findings suggest that the cardiovascular benefit of pitavastatin in REPRIEVE is unlikely to be mediated through reductions in enterocyte injury, although gut-barrier effects of other statins cannot be excluded.

BACKGROUND:Integrase strand-transfer inhibitors (INSTIs) are linked to weight gain, but data on their cardiometabolic effects, particularly major adverse cardiovascular events (MACE), are scarce. We aimed to estimate the risk of obesity, diabetes, hypertension, and MACE after switching to an INSTI in people with HIV at low-to-moderate cardiovascular risk. METHODS:In this retrospective cohort study, we used data from the global Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) to emulate a series of trials comparing switching to an INSTI versus remaining on a non-INSTI regimen on risk of incident obesity, diabetes, hypertension, and MACE. The REPRIEVE trial collected data across 12 countries from participants aged 40-75 years, on a stable antiretroviral therapy regimen for at least 6 months, with a CD4 count of >100 cells per μL, and with low-to-moderate risk for atherosclerotic cardiovascular disease. From this cohort, we included participants without a previous diagnosis of the outcomes or previous INSTI use and used data for a follow-up period of 5 years, until the outcome event, loss to follow-up, death, or study end. Data from emulated trials were pooled and hazard ratios (HRs) were estimated with weighted Cox proportional hazard models, accounting for competing events. FINDINGS:5114 participants met eligibility criteria for at least one emulated trial, representing 99 357 person-trials (median age 49 years [45-54]; 62 826 [63·2%] of 99 357 were male; 36 531 [36·8%] were female). 2981 (58·3%) of 5114 participants were captured as an INSTI switcher in at least one trial. Most switchers (2412 [80·9%] of 2981) initiated a dolutegravir-based regimen and most (47 263 [67·1%] of 70 458) non-switchers were on an efavirenz-based regimen. The HR of obesity (HR 1·41, 95% CI 1·22-1·59), diabetes (1·50, 1·24-1·81), and hypertension (1·45, 1·26-1·67) was higher in switchers than non-switchers. We did not observe an effect on MACE (1·17, 0·87-1·57). INTERPRETATION:The increase in cardiometabolic risk profile suggests long-term observation of people with HIV switching to INSTIs will be crucial to ensure appropriate management of comorbidities and to assess for future development of MACE. FUNDING:National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare.

BACKGROUND:Given the pleiotropic effects of statins beyond lipid-lowering, statins might positively impact other, non-cardiovascular diseases (non-CVDs). In this study, we prospectively assessed statin effects on non-CVD events and their incidence among people with HIV globally. METHODS:The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE; ClinicalTrials.gov, NCT02344290) was a randomised, placebo-controlled trial of pitavastatin for CVD prevention took place from 2015 to 2023 at 145 research sites in 12 countries and is completed. In this analysis of prespecified secondary outcomes of REPRIEVE, we assessed effects of pitavastatin 4 mg daily (vs placebo) on major non-CVD events (including AIDS-defining events, non-AIDS-defining cancers, renal disease, and liver disease) and the Strategic Timing of Antiretroviral Treatment (START) trial outcome (a collective measure of morbidity including CVD among people with HIV) using Cox proportional hazards regression, stratified by sex and CD4 cell count. FINDINGS:Among the 7769 people with HIV enrolled (3888 in the pitavastatin group and 3881 in the placebo group), 6402 participants completed the study (3201 in each group). Over a median 5·6 years (IQR 4·7-6·3) of follow-up, the incidence of major non-CVD events was 9·17 per 1000 person-years in the pitavastatin group and 9·90 per 1000 person-years in the placebo group (hazard ratio [HR], cause-specific: 0·92, 95% CI 0·76-1·13; p=0·44). The incidence of the START outcome was 15·2 per 1000 person-years in the pitavastatin and 18·3 per 1000 person-years in the placebo group (HR 0·83, 95% CI 0·71-0·97; p=0·016), driven by the effect on CVD. In the placebo group, incidences of the non-AIDS-defining cancer and CVD components of the START Trial outcome were highest (5·83 per 1000 person-years and 5·48 per 1000 person-years) whereas AIDS-defining events were less frequent (3·60 per 1000 person-years), and varied across global regions. With pitavastatin, the incidence of CVD was lower compared with placebo (3·36 per 1000 person-years), however non-AIDS-defining cancers remained high (5·40 per 1000 person-years). Non-AIDS-defining cancers were the leading cause of mortality for both groups. INTERPRETATION:Among a global cohort of people with HIV, treatment with pitavastatin showed no major reduction in non-CVD events, including non-AIDS-defining cancers. These findings outline the limitations of statin therapy for the prevention of non-CVD, highlighting the need for other strategies for such events. FUNDING:National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare.

BACKGROUND:In the REPRIEVE trial of statin therapy in people with HIV, pitavastatin reduced major adverse cardiovascular events (MACE) among those with low-to-moderate risk of cardiovascular disease (CVD). We aimed to investigate associations between former and current use of antiretroviral therapy (ART) on entry into the REPRIEVE trial and the development of MACE. METHODS:This longitudinal cohort analysis was a prespecified secondary analysis of the REPRIEVE trial, a double-blind, placebo-controlled, multicentre, phase 3 randomised trial conducted at 137 sites in 12 countries. REPRIEVE enrolled people with HIV aged 40-75 years, currently on ART, with a CD4 count of more than 100 cells per μL and low-to-moderate CVD risk, and randomly assigned them to receive pitavastatin or placebo. For this secondary analysis, participants' history of ART use, including lifetime exposure to selected agents, was collected at baseline. The primary outcome of interest was time-to-first MACE. Stratified Cox proportional hazards models were used to estimate the relative hazards of MACE associated with ART exposures. Effects of no previous exposure, former exposure, and current exposure to ART at entry to the study were compared using models unadjusted and adjusted for entry risk factors and ART regimen at entry. All analyses were conducted in the intention-to-treat population. The REPRIEVE trial is registered at ClinicalTrials.gov, NCT02344290, and is complete. FINDINGS:Between March 26, 2015, and July 31, 2019, 7769 participants were enrolled into the REPRIEVE trial. 2419 (31·1%) of 7769 participants were assigned female at birth and 5350 (68·9%) were assigned male at birth. 3208 (41·3%) of 7769 participants were Black or African American, 2704 (34·8%) were White, 1138 (14·6%) were Asian, and 719 (9·3%) were of other races. Participants had a median age of 50·0 years (IQR 45·0-55·0), LDL cholesterol concentration of 106 mg/dL (86-128), 10-year atherosclerotic cardiovascular disease risk score of 4·5% (2·1-7·0), and CD4 cell count of 621 cells per μL (448-827). 5867 (97·8%) of 5997 participants for whom data on this measure were available had an HIV-1 viral load of less than 400 copies per mL. The median duration of ART use at entry was 9·6 years (5·3-14·8). Overall, 1702 (21·9%) of 7769 participants reported previous exposure to abacavir, 6681 (86·0%) to tenofovir disoproxil fumarate, 3832 (49·3%) to thymidine analogues (zidovudine or stavudine), and 3683 (47·4%) to protease inhibitors. At study entry, 984 (12·6%) participants were using abacavir, 4743 (61·0%) were using tenofovir disoproxil fumarate, 756 (9·7%) were using thymidine analogues, and 1990 (25·6%) were using protease inhibitors. In adjusted analyses, former exposure (hazard ratio 1·62, 95% CI 1·14-2·30) and current exposure (1·41, 1·01-1·96) to abacavir was associated with a higher hazard of MACE than in participants who were never exposed. Associations between former or current exposure to other ART agents and MACE were not consistently apparent. INTERPRETATION:Previous and current use of abacavir increases the hazard of MACE among people with HIV at low-to-moderate CVD risk, suggesting that abacavir should be avoided and previous exposure considered when assessing the risk of MACE in this population. FUNDING:National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare.

Background:Prior analyses suggest that the nucleoside reverse transcriptase inhibitor (NRTI) abacavir (ABC), but not tenofovir (TFV), is associated with a 2-fold increase in the hazard of myocardial infarction. the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) is ideally suited to evaluate the role of ABC and the TFV backbones, tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF), in major adverse cardiovascular events (MACE). Methods:We compared hazard of first MACE among people living with human immunodeficiency virus (HIV) at low-to-moderate cardiovascular risk using ABC (n = 883), TAF (n = 957), and TDF (n = 4274) at entry. Overlap weights balanced biasing factors, including age, sex at birth, atherosclerotic cardiovascular disease risk, CD4 count, estimated glomerular filtration rate, and anchor antiretroviral therapy. Associations between entry NRTI and MACEs were estimated using a marginal Cox proportional hazards model. Change of NRTI, or "switching," was common during follow-up. Additional associations were estimated by further censoring at first switch and applying time-updated inverse probability of censoring weighting (IPCW). Results:Baseline-adjusted associations suggest clinically relevant increases in hazard of first MACE for ABC versus TAF (hazard ratio [HR], 1.5 [95% confidence interval {CI}, .9-2.3]) and ABC versus TDF (HR, 1.4 [95% CI, .9-2.1]), but not TAF versus TDF (HR, 0.9 [95% CI, .6-1.5]). With censoring at switch, HRs increased to 1.6 (95% CI, .9-2.7) for ABC versus TAF, 2.0 (95% CI, 1.2-3.4) for ABC versus TDF, and 1.2 (95% CI, .7-2.2) for TAF versus TDF. The largest HR observed was for ABC versus TDF and myocardial infarction (IPCW HR, 3.5 [95% CI, 1.3-9.4]). Conclusions:Antiretroviral therapies with ABC backbones are associated with an increase in MACE compared to TFV backbones among people living with HIV at low-to-moderate cardiovascular risk. Clinical Trials Registration:NCT02344290.

BACKGROUNDStatin therapy lowers the risk of major adverse cardiovascular events (MACE) among people with HIV (PWH). Residual risk pathways contributing to excess MACE beyond LDL-cholesterol (LDL-C) are not well understood. Our objective was to evaluate the association of statin-responsive and other inflammatory and metabolic pathways with MACE in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE).METHODSCox proportional hazards models were used to assess the relationship between MACE and proteomics measurements at study entry and year 2, adjusting for time-updated statin use and the baseline 10-year atherosclerotic cardiovascular disease risk score. We built a machine-learning (ML) model to predict MACE using baseline protein values with significant associations.RESULTSFor 765 individuals (age: 50.8 ± 5.9 years, 82% men, 18% women), among 7 proteins changing with statin versus placebo, angiopoietin-related protein 3 (ANGPTL3) related most strongly to MACE (adjusted HR [aHR]: 2.31 per 2-fold-higher levels; 95% CI: 1.11-4.80; P = 0.03), such that lower levels of ANGPTL3 achieved with statin therapy were associated with lower MACE risk. Among 248 proteins that did not change in response to statin therapy, 26 were associated with MACE at a FDR below 0.05. These proteins represented a predominantly humoral immune response, leukocyte chemotaxis, and cytokine pathways. Our proteomics ML model achieved a 10-fold cross-validated concordance index (C-index) of 0.74 ± 0.11 to predict MACE, improving on models using traditional risk prediction scores only (C-index: 0.61 ± 0.18).CONCLUSIONSANGPTL3, as well as key inflammatory pathways, may contribute to a residual risk of MACE among PWH, beyond LDL-C.TRIAL REGISTRATIONClinicalTrials.gov: NCT02344290.FUNDINGNIH, Kowa Pharmaceuticals America, Gilead Sciences, ViiV Healthcare.

Background With antiretroviral therapy, people with HIV (PWH) have an increased burden of cardiovascular disease. The REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) trial demonstrated that pitavastatin reduces major adverse cardiovascular events (MACEs) among PWH at low to moderate traditional atherosclerotic risk. Electrocardiographic abnormalities are common in PWH, but little is known about their association with MACEs. We sought to examine whether baseline electrocardiographic abnormalities are associated with increased MACE risk among a global primary cardiovascular disease prevention cohort of PWH in REPRIEVE. Methods In this observational analysis, entry electrocardiographic abnormalities were adjudicated and classified as major or minor abnormalities. Multivariable cause‐specific Cox proportional hazards models assessed the association of electrocardiographic abnormalities with MACEs while stratifying for treatment effect. The model improvement with the addition of the ECG to a model with the pooled cohort equations risk score was examined. Results Among 7719 participants (median age, 50 years; 69% men), 49% had ≥1 electrocardiographic abnormality, with 3% classified as major. Over a median of 5.6 years, a major electrocardiographic abnormality was associated with a 2.42‐fold (95% CI, 1.49–3.91) higher hazard of incident MACEs, whereas minor abnormalities were not. Specific abnormalities associated with MACEs were chamber enlargement and infarct/ischemia pattern. No significant subgroup‐ or treatment‐related interaction was observed. Adding electrocardiographic findings to traditional risk factors increased the C‐statistic modestly (+0.01). Conclusions Among PWH in REPRIEVE, electrocardiographic abnormalities were common, but major electrocardiographic abnormalities were rare. Though major abnormalities were associated with increased hazard of MACEs, routine electrocardiographic screening is unlikely to improve the prediction of future cardiovascular events in this primary prevention population with low to moderate cardiovascular risk.

OBJECTIVE:Effects of statins on neurocognitive function remain poorly understood, with some studies suggesting harm and others suggesting benefit. Limited observational data among people with HIV (PWH) is biased by indication for statin prescription. We sought to assess statin effects on neurocognitive function among PWH. DESIGN:We leveraged data from participants co-enrolled in REPRIEVE (randomized trial of pitavastatin vs. placebo among PWH with low-to-moderate cardiovascular risk) and HAILO (observational study involving repeated neurocognitive measures). METHODS:Participants with at least one measure of neurocognitive function before and after REPRIEVE randomization were included. Neurocognitive function was determined by NPZ-4, the average of the Z scores from Hopkins Verbal Learning Test Revised, Trailmaking A and B, and Digit Symbol Test every 48 weeks. Trajectories before and after randomization were analyzed with generalized estimating equation models. RESULTS:Of 181 co-enrolled participants (pitavastatin 88, placebo 93), changes over median 2.3 years on overall and individual neurocognitive scores were small, not meeting a clinically relevant threshold of more than 0.5/year, and similar between arms. Although subgroup analyses were limited by a small sample size, we observed trends toward improved Trailmaking A in participants with baseline impairment who were randomized to pitavastatin vs. placebo and towards worsened NPZ-4 in women randomized to pitavastatin vs. placebo that similarly did not reach threshold for clinical relevance. Other subgroup effects were minimal and not statistically or clinically significant. CONCLUSION:We found no evidence of a detrimental effect of pitavastatin use on a limited battery of neurocognitive assessments among PWH, even among PWH with baseline neurocognitive impairment.

BACKGROUND:In REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV), pitavastatin prevented major adverse cardiovascular events (MACE) and reduced noncalcified coronary plaque (NCP) among people with HIV and low-to-moderate traditional cardiovascular disease (CVD) risk. OBJECTIVES:The purpose of this study was to assess the relationship of coronary plaque, inflammation, and subclinical myocardial injury with MACE. METHODS:A total of 804 REPRIEVE Mechanistic Substudy participants enrolled from April 2015 to February 2018 at 31 U.S. sites, randomized to pitavastatin 4 mg/day or placebo, and followed for incident MACE (median 6.2 years [Q1-Q3 5.4-7.1]), were assessed for relationships of baseline NCP, markers of inflammation (high-sensitivity C-reactive protein [hs-CRP], interleukin (IL)-6, oxidized low-density lipoprotein, and lipoproprotein-associated phospholipase A2), and subclinical myocardial injury (high-sensitivity cardiac troponin T [hs-cTnT]) with MACE. RESULTS:Among enrolled participants (17% female [139/804], 47% non-White [379/804], median age 51 years, median low-density lipoprotein 105 mg/dL, 10-year atherosclerotic CVD [ASCVD] risk 4.6%, 40% [299/755] with noncalcified plaque), MACE incidence was 7.26/1,000 (95% CI: 4.51-11.7) person-years (17 events) for pitavastatin and 9.15/1,000 person-years (95% CI: 5.97-14.0) (21 events) for placebo. The hazard of MACE was greater in those with (vs without) noncalcified plaque (HR: 2.5; [95% CI: 1.3-4.8]; P = 0.008), with higher levels of hs-CRP (P = 0.049), IL-6 (P = 0.033), and hs-cTnT (P = 0.003) at study entry, persisting after ASCVD risk adjustment. In exploratory prediction modeling, adding hs-CRP, IL-6, and hs-cTnT to ASCVD risk increased the integrated area under the curve to 0.72 and C-statistic to 0.73 (0.62-0.84) vs 0.58 and 0.56 (0.45-0.67) compared to ASCVD risk alone. CONCLUSIONS:NCP and higher hs-CRP, IL-6, and hs-cTnT were associated with MACE and improved risk prediction over traditional risk factors in people with HIV without cardiac symptoms and low-to-moderate ASCVD risk. (Evaluating the Use of Pitavastatin to Reduce the Risk of Cardiovascular Disease in HIV-Infected Adults [REPRIEVE]; NCT02344290).

Background: People with HIV (PWH) are at increased risk for atherosclerotic cardiovascular diseases (ASCVDs) and geriatric syndromes, including frailty. REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) demonstrated a 36% reduction in major adverse cardiovascular events (MACE) with pitavastatin vs placebo but the role of statins for ASCVD prevention among frail PWH is not known. Objectives: The purpose of this study was to evaluate whether frailty is associated with MACE and whether pitavastatin prevents MACE regardless of frailty. Methods: We conducted a post hoc analysis of the REPRIEVE trial, a randomized, blinded trial of pitavastatin 4 mg vs placebo. Participants included PWH without ASCVD, aged 40 to 75 years. Frailty was measured with a 32-item frailty index. Cox proportional hazards models were used to estimate cause-specific hazard of MACE by frailty status. Pitavastatin effect modification by frailty status was assessed via interaction with treatment. Results: Of 7769 REPRIEVE participants, 7,740 (>99%) had sufficient data to calculate frailty index. Median age was 50 years (Q1, Q3: 45, 55), 67% were nonfrail, 29% prefrail, and 4% frail at baseline; median follow-up was 5.6 years. Adjusted for age, sex, ASCVD risk score, and treatment group, MACE hazard increased with frailty (P < 0.0001): HR: 1.76 (95% CI: 1.35-2.30) among prefrail, and 2.14 (95% CI: 1.33-3.45) among frail compared to nonfrail. There was no evidence that pitavastatin effect differed by frailty status (P = 0.44). Conclusions: Frailty was associated with markedly higher hazard of MACE. Though frailty did not appear to modify the protective effects of pitavastatin seen in the primary trial, the efficacy in frail PWH remains uncertain due to the limited number of frail individuals.

BACKGROUND:The effects of statin therapy on pericoronary adipose tissue (PCAT) and its relationship with plaque progression and outcomes in people with HIV (PWH) remain poorly understood. OBJECTIVES:The aim of this study was to evaluate PCAT density changes over time; statin effects on PCAT; and associations among PCAT changes, coronary plaque, and clinical outcomes. METHODS:In the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) mechanistic computed tomographic (CT) substudy (n = 753, mean age: 51 ± 6 years, 17% women), PCAT density was measured from noncontrast CT images at baseline and 2 years, while coronary plaque volumes (total, calcified, and noncalcified) were assessed from contrast-enhanced CT angiograms. Analyses were stratified by coronary artery disease burden (segment involvement score 0, 1-3, or ≥4) and adjusted for technical parameters, atherosclerotic cardiovascular disease risk, body mass index, inflammatory biomarkers, and statin allocation. Associations among PCAT, plaque changes, and events (all-cause mortality, major adverse cardiovascular events [MACE], and MACE or death) were evaluated. RESULTS:Baseline PCAT density was -87.7 ± 10.5 HU, increasing by 4.5 HU (95% CI: 3.8-5.2; P < 0.001) over 2 years. Pitavastatin prevented this increase in participants with segment involvement scores ≥4 (-1.7 HU vs +3.8 HU; P = 0.016, pitavastatin vs placebo, respectively). Greater PCAT density was associated with higher noncalcified plaque volume (per +10 HU, +5.0 mm3; P = 0.075) and reduced calcified plaque progression (-3.2 mm3; P = 0.031). Over a median of 6.3 years, 4.2% of patients died. Baseline PCAT density was independently associated with all-cause mortality (HR per +10 HU: 1.95; 95% CI: 1.03-3.69; P = 0.040), but not MACE. CONCLUSIONS:PCAT density increases over time in PWH, but pitavastatin mitigates this in those with high coronary artery disease burden. PCAT density is associated with vulnerable plaque morphology and all-cause mortality, supporting its potential as a prognostic imaging biomarker in PWH. (Randomized Trial to Prevent Vascular Events in HIV [REPRIEVE]; NCT02344290).

Background: There is limited evidence concerning the relationship between cardiometabolic characteristics and health-related quality of life (HRQoL), and potential effects of statin therapy among people with HIV (PWH). Methods: The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) enrolled PWH aged 40-75 years on antiretroviral therapy (ART) with low-to-moderate ASCVD risk. Coronary computed tomography angiography assessed coronary plaque among a subset of participants in the REPRIEVE Mechanistic Substudy at baseline and 24 months. The Short Form-36-Item Health Survey Version 2 was collected at baseline, and physical (PCS) and mental (MCS) component summary scores were determined. We explored the relationship of PCS and MCS with cardiometabolic characteristics, coronary atherosclerosis, and assessed change in score by treatment group (pitavastatin vs. placebo). Results: Of 733 participants, median age was 51 years, 84% were male, 34% were Black non-Hispanic, and median years diagnosed with HIV was 15. At baseline, for participants randomized to pitavastatin vs. placebo the median PCS was 54.5 (Q1,Q3: 46.9, 57.7) vs. 54.1 (47.5, 58.0), and the median MCS was 52.9 (44.1, 57.6) vs. 52.8 (44.0, 57.9). In fully adjusted analyses, older age, Black non-Hispanic race/ethnicity, ART regimen class, elevated BMI, and cigarette smoking were associated with lower PCS. No clear trends were apparent with MCS. Between baseline and month 24, declines in PCS and MCS were minimal with no apparent difference by treatment group. Conclusions: Among this cohort of ART-treated PWH, baseline cardiometabolic risk factors were associated with worse self-reported physical HRQoL, with no apparent effect of statin therapy. Trial Registration: REPRIEVE; NCT02344290; https://clinicaltrials.gov/study/NCT02344290