Effect of Pitavastatin on Epigenetic Aging Biomarkers in People With HIV: Pilot Substudy of the REPRIEVE Trial.

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).