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. 2025 Sep;4(9):102077.
doi: 10.1016/j.jacadv.2025.102077. Epub 2025 Aug 20.

Frailty, Pitavastatin, and Major Adverse Cardiovascular Events Among People With HIV

Kristine M Erlandson  1 , Ariela R Orkaby  2 , Triin Umbleja  3 , Heather J Ribaudo  3 , Todd T Brown  4 , Markella V Zanni  5 , Marissa R Diggs  5 , Sarah M Chu  5 , Kathleen V Fitch  5 , Carl J Fichtenbaum  6 , Carlos Malvestutto  7 , Judith A Aberg  8 , Gerald S Bloomfield  9 , Judith S Currier  10 , Karen T Tashima  11 , Marcus Vinícius Guimarães de Lacerda  12 , Sonya L Heath  13 , Michael T Lu  14 , Alan Landay  15 , George A Kuchel  16 , Pamela S Douglas  17 , Steven K Grinspoon  18
Affiliations
Free article

Frailty, Pitavastatin, and Major Adverse Cardiovascular Events Among People With HIV

Kristine M Erlandson et al. JACC Adv. 2025 Sep.
Free article

Abstract

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.

Keywords: HIV; frailty; major adverse cardiovascular event; statin.

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Conflict of interest statement

Funding support and author disclosures This study is supported through NIH grants U01HL123336 and 1UG3HL164285, to the Clinical Coordinating Center, and U01HL123339 and 1U24HL164284, to the Data Coordinating Center, R01AG054366 as well as funding from Kowa Pharmaceuticals America, Inc, Gilead Sciences, and ViiV Healthcare. The NIAID supported this study through grants UM1 AI068636, which supports the ACTG Leadership and Operations Center; and UM1 AI106701, which supports the ACTG Laboratory Center. This work was also supported by the Nutrition Obesity Research Center at Harvard (P30DK040561 to SKG). The National Institutes of Health supported the study and had a role in study design and oversight of the study. Kowa Pharmaceuticals America, Inc, Gilead Sciences, and ViiV Healthcare provided financial support for the study but did not have a role in study design, collection of data, analysis, writing, or decision to publish. Dr Erlandson has received grants from NIH/NIA during the conduct of the study, as well as a grant from Gilead and consulting payments from Gilead, ViiV, and Merck (all to her employer) outside of the submitted work. Dr Umbleja has received grants from NIH/NHLBI, Kowa Pharmaceuticals, and NIH/NIA during the conduct of the study, as well as grants from NIH/NIAID, outside the submitted work. Dr Ribaudo has received grants from Kowa Pharmaceuticals during the conduct of the study, as well as grants from NIH/NIAID, NIH/NHLBI, NIH/NIDDK, and NIH/NIA, outside of the submitted work. Dr Zanni has received grant support through her institution from NIH/NIAID and Gilead Sciences, Inc, relevant to the conduct of the study, as well as grants from NIH/NIAID and NIH/NHLBI; support for attending CROI and International Workshop for HIV and Women from conference organizing committee when abstract reviewer and/or speaker; and participation in DSMB for NIH funded studies, outside the submitted work. Dr Fichtenbaum has received research grant support through his institution from Gilead Sciences, ViiV Healthcare, GSK, and Merck, all outside the submitted work. Dr Malvestutto has received institutional research support by Lilly and honoraria from ViiV Healthcare, Gilead Sciences, and Pfizer for advisory board membership, all outside the submitted work. Dr Aberg has received institutional research support for clinical trials from Emergent Biosolutions, Gilead Sciences, Glaxo Smith Kline, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare and personal fees for advisory boards from Glaxo Smith Kline/ViiV and Merck; and participation on DSMB for Kintor Pharmaceuticals, all outside the submitted work. Dr Currier has received consulting fees from Merck and Company and Resvirlogix, outside the submitted work. Dr Heath has received institutional research support for clinical trials from Abbvie, Gilead Sciences, Glaxo Smith Kline, Merck, Regeneron, and Viiv Healthcare; and also participates on DSMB for Pfizer. All activities are outside the scope of the submitted work. Dr Lu has received grant support through his institution from the NIH/NHLBI and Kowa Pharmaceuticals America for the conduct of the REPRIEVE trial; and also has received research support to his institution from the American Heart Association, AstraZeneca, Ionis, Johnson & Johnson Innovation, MedImmune, the National Academy of Medicine, the NIH/NHLBI, and the Risk Management Foundation of the Harvard Medical Institutions Incorporated outside of the submitted work. Dr Grinspoon has received grant support through his institution from NIH, Kowa Pharmaceuticals America, Inc, Gilead Sciences, Inc, and ViiV Healthcare for the conduct of the study; personal fees from Theratechnologies and ViiV; and has served on the Scientific Advisory Board of Marathon Asset Management, all outside the submitted work. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute or the National Institute of Allergy and Infectious Diseases; the National Institutes of Health; or the U.S. Department of Health and Human Services. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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