Globally, an estimated 40.8 million people are living with HIV (PWH).¹ Advances in antiretroviral therapy (ART) have enabled PWH to achieve a near-normal life expectancy²; however, individuals taking ART remain at approximately twofold higher risk of developing atherosclerotic cardiovascular disease (ASCVD) compared with those without HIV due to chronic inflammation and ART-related metabolic effects. The prevalence of hyperlipidemia among PWH is estimated to range from 28% to 80%, with hypertriglyceridemia being the most common lipid abnormality. Statins effectively lower low-density lipoprotein cholesterol (LDL-C) levels,³ and are recommended by major international guidelines as the primary pharmacologic therapy for dyslipidemia management and ASCVD prevention among PWH. However, prior guideline recommendations have risked misclassification of ASCVD risk and underprescription of statins in PWH because prevalent ASCVD risk calculators lack HIV-specific adjustments and were validated in populations that do not adequately represent PWH. The landmark REPREIVE trial findings and subsequent guidelines reflect a welcome paradigm shift supporting broader statin use in PWH, with the potential to prevent massive numbers of cardiovascular (CV) events in this population at high risk.

In 2025, the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) updated their 2019 Guidelines for the Management of Dyslipidaemias, shifting from recommending statins only for PWH who have dyslipidemia (class IIa, level of evidence [LOE] C) to recommending statins for all PWH ≥40 years of age, irrespective of estimated CV risk or LDL-C levels (class I, LOE B).^4,5 This update was primarily informed by findings from the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV), which evaluated the efficacy of pitavastatin versus placebo in preventing major adverse cardiovascular events (MACE) among PWH at low-to-moderate predicted CV risk.³

The primary rationale for conducting the REPRIEVE was the growing recognition that conventional ASCVD risk calculators, such as the 2013 American Heart Association/American College of Cardiology (AHA/ACC) Pooled Cohort Equations (PCE), underestimate CV risk among PWH due to aforementioned HIV-specific risk-enhancing processes. Consequently, many PWH at elevated risk would not otherwise qualify for statins under existing guidelines.

To address this gap, the REPRIEVE investigators enrolled 7,769 PWH 40-75 years of age in 12 countries between 2015 and 2019. Approximately 30% of participants were women. All participants were taking ART with baseline CD4 counts ≥100 cells/mm³ and had a median 10-year ASCVD risk score of 4.5% according to the PCE.³ The REPRIEVE findings showed a 36% reduction in MACE over a median of 5.6 years among PWH taking daily pitavastatin compared with placebo, without any unanticipated safety effects.^3,6 The trial was stopped early for efficacy after a median of 5.1 years, and patients were followed through their final trial visit.⁶

According to the 2019 ESC/EAS guidelines on dyslipidemia, CV risk assessment and statin initiation in primary prevention were based on the SCORE (Systematic Coronary Risk Evaluation) system, which estimates the 10-year risk of fatal cardiovascular disease (CVD) events. For PWH, the guidelines recommended managing dyslipidemia according to LDL-C targets defined for individuals at high risk while acknowledging that the SCORE system may underestimate CV risk in this population because of their higher baseline risk of ASCVD.⁴

In contrast, the 2025 ESC/EAS focused update replaced the SCORE system with the SCORE2 (Systematic Coronary Risk Evaluation 2) and SCORE2-OP (Systematic Coronary Risk Evaluation 2–Older Persons) risk calculators, which estimate the 10-year risk of both fatal and nonfatal CV events.⁵ Notably, however, the 2025 ESC/EAS focused update did not rely on any ASCVD risk score to determine statin eligibility for PWH. Instead, the ESC and EAS issued a direct recommendation for statin therapy in all PWH ≥40 years of age for primary prevention, regardless of calculated risk. This recommendation represents a major departure from the 2019 framework, as well as from the approach used in the REPRIEVE, which employed PCE to determine statin eligibility.

The REPRIEVE findings also prompted the U.S. Department of Health and Human Services (HHS) Antiretroviral Treatment Guidelines Panel to issue a strong recommendation (rating of recommendation A, rating of evidence I) in 2024 for initiating statin therapy among PWH 40-75 years of age who have a 10-year ASCVD risk score of ≥5% as calculated by the PCE. For PWH with a 10-year risk score <5%, the guidelines panel provides a lower-grade recommendation (rating of recommendation C, rating of evidence I) favoring statin initiation, taking into consideration additional factors that may elevate CV risk.⁷

The AHA has also introduced an improved risk-prediction tool since the REPRIEVE used the PCE for risk assessment. The PREVENT (AHA Predicting Risk of CVD Events) equations were derived in 2023 in a much larger contemporary cohort, including risk factors and outcomes pertinent to kidney disease and heart failure, and supporting a longer predictive time-horizon for younger adults.⁸

Grinspoon et al. recently evaluated how predicted risk estimates differ among the PCE, PREVENT, and SCORE2 risk equations in the REPRIEVE cohort of PWH.⁹ Their findings demonstrated that the three risk equations yield substantially different absolute 10-year ASCVD risk estimates, with the PREVENT and SCORE2 providing lower predicted risk than the PCE. Consequently, substituting the PCE with the PREVENT or SCORE2 risk equations in the REPRIEVE without adjusting statin initiation thresholds would result in fewer PWH meeting eligibility criteria, potentially reducing statin use and increasing the incidence of ASCVD events in this population.⁹

All three risk scores were developed and externally validated predominantly in moderate- to high-income settings. The PCE and PREVENT models were derived from US cohorts, whereas the SCORE2 was developed using data from European populations, predominantly of white European ancestry.^8,10 These risk estimators, therefore, may have limited generalizability to PWH living in resource-constrained environments with different demographic, socioeconomic, and clinical epidemiologic profiles.

This limitation is concerning given that the global burden of HIV is concentrated in low- and middle-income countries, where CVD is an increasingly important contributor to morbidity and mortality among PWH. Developing and validating ASCVD risk estimators within high-HIV-burden populations in these regions is important to ensure accurate risk stratification and to inform context-appropriate prevention strategies. The recommendation by the 2025 ESC/EAS focused update to initiate statins in PWH independent of estimated CV risk offers a pragmatic approach to addressing the shortcomings of current risk estimators. By prioritizing broad statin access, the 2025 ESC/EAS focused update provides a model that could inform future international recommendations and help maximize the number of PWH who benefit from the cardioprotective effects of statins.

References

1. UNAIDS. UNAIDS Global AIDS Update 2025: AIDS, Crisis and the Power to Transform (UNAIDS website). 2025. Available at: https://www.unaids.org/en/resources/documents/2025/2025-global-aids-update. Accessed 01/02/2026.
2. Trickey A, Sabin CA, Burkholder G, et al. Life expectancy after 2015 of adults with HIV on long-term antiretroviral therapy in Europe and North America: a collaborative analysis of cohort studies. Lancet HIV. 2023;10(5):e295-e307. doi:10.1016/S2352-3018(23)00028-0
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8. Khan SS, Coresh J, Pencina MJ, et al. Novel prediction equations for absolute risk assessment of total cardiovascular disease incorporating cardiovascular-kidney-metabolic health: a scientific statement from the American Heart Association. Circulation. 2023;148(24):1982-2004. doi:10.1161/CIR.0000000000001191
9. Grinspoon SK, Zhao S, Martinez E, et al. Risk assessment in a global CVD prevention cohort of people with HIV by PCE, PREVENT, and SCORE2. Clin Infect Dis. Published online September 26, 2025. doi:10.1093/cid/ciaf542
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