CROI 2025 Abstract eBook

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Oral Abstracts

Conclusions: Frailty was associated with markedly higher incidence of MACE, but did not appear to modify the protective effects of pitavastatin seen in the REPRIEVE primary analysis. The figure, table, or graphic for this abstract has been removed. Prognostic Value of Epigenetic Age Acceleration in People With Well-Controlled HIV Infection Patricia Martínez-Martín 1 , Andrés Esteban-Cantos 2 , Francisco Jurado 3 , Rocío Montejano Sanchez 2 , Lucía Gutiérrez 4 , Alejandro de Gea Grela 4 , Juan Carlos González 4 , Cristina Marcelo 4 , Alejandro Díez-Vidal 4 , María del Mar Arcos-Rueda 1 , Luis Ramos 2 , Rosa De Miguel Buckley 4 , María Jiménez-González 4 , Berta Rodés 4 , Jose R. Arribas 4 1 La Paz University Hospital, Madrid, Spain, 2 Hospital Universitario La Paz, Madrid, Spain, 3 Centro Nacional de Investigaciones Oncológicas, Madrid, Spain, 4 Hospital La Paz Institute for Health Research, Madrid, Spain Background: Epigenetic age acceleration has prognostic value in the general population. However, its role in predicting clinical outcomes in people with HIV (PWH) with long-term virological suppression remains unclear. Methods: Retrospective cohort of PWH with long-term virological suppression, followed at a single HIV unit. Blood DNA methylation was assessed using the Illumina Infinium MethylationEPIC BeadChip, and six epigenetic biomarkers of aging were evaluated (Horvath´s and Hannum´s clocks, PhenoAge, GrimAge, DNAmFitAge, and DNAmTL). EAA was calculated as the residuals resulting from the regression of epigenetic age on chronological age. After a 10-year follow-up period, serious non-AIDS events (SNAEs), and aging-related events (diabetes, hypertension, osteoporosis, cataracts, dementia) were recorded. Multivariant adjusted Cox proportional hazards regression models were employed to assess the association between EAA and clinical events. Results: 120 participants, mostly male (76.6%). At the moment of blood sample collection median age 44.6 years (IQR: 45-55), median time since HIV diagnosis 16.7 years (IQR: 11.6-20.7), median duration of virological suppression 7.5 years (IQR: 7,9-6,3), CD4 count 740 cells/mm 3 (IQR: 496-1000) and 77% were current or former smokers. During follow-up, virological failure occurred in 5 patients and 70 suffered an event: 23 age-related events, 20 SNAEs and 27 had both types of events. In adjusted Cox regression models, a one-year increase in GrimAge acceleration (GrimAA) and PhenoAge acceleration (PhenoAA) was associated with a 9% (HR: 1.09; 95% CI: 1.018-1.17; p=0.014) and a 6.7% increased hazard (HR: 1.07; 95% CI: 1.006-1.13; p=0.04) of SNAEs respectively. Specifically for non-AIDS-defining cancers (NADCs), having a positive PhenoAA or GrimAA was associated with an almost four-fold (HR: 3.73; 95% CI: 2.41-5.04; p=0.014) and more than six-fold increased risk (HR: 6.5; 95% CI: 4.63-8.37; p=0.003) respectively, whereas a positive GrimAA was linked to a five-fold increased risk of death (HR: 5.32; 95% CI: 3.75-6.88; p= 0.032) (Fig. 1). No significant associations were observed for any biomarker with all events combined or with age-related events alone. Horvath’s and Hannum’s clocks, DNAmFitAge and DNAmTL were not associated with the occurrence of any event. Conclusions: GrimAA has significant prognostic value for SNAEs, NADCs and mortality in people with well-controlled HIV and high CD4 cell counts, highlighting its potential as a biomarker for long-term health risks.

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Semaglutide Stabilizes Epigenetic Aging in People With HIV-Associated Lipohypertrophy Michael J. Corley 1 , Alina Pang 1 , Danielle Labbato 2 , Allison Ross Eckard 3 , Grace A. McComsey 4 1 Weill Cornell Medicine, New York, NY, USA, 2 University Hospitals Cleveland Medical Center, Cleveland, OH, USA, 3 Medical University of South Carolina, Charleston, SC, USA, 4 Case Western Reserve University, Cleveland, OH, USA Background: Semaglutide, a GLP-1 receptor agonist, is known to reduce weight and improve cardiometabolic disease outcomes. In a recent randomized, double blind, placebo-controlled phase 2b clinical trial, we observed significant effects of once-weekly semaglutide over 32 weeks on weight and visceral adiposity in people on stable antiretroviral therapy with HIV-associated lipohypertrophy. Semaglutide has been proposed to have pleiotropic benefits on biological aging; however, whether HIV-associated accelerated epigenetic aging is altered by semaglutide remains unknown. Methods: We measured longitudinal genome-wide DNA methylation (DNAm) epigenetic profiles in peripheral blood mononuclear cells at baseline and 32 weeks from 84 study participants who were randomized to semaglutide (n=45) or matching placebo (n=39) for 32 weeks. 1st, 2nd, and 3rd generation epigenetic clock algorithms with a principal component-based approach were used to calculate epigenetic ages for participants at entry and 32 weeks. The annual rate of change in each epigenetic clock was calculated for each individual. Student’s t-test was used to compare groups. Results: Overall, the mean age of participants was 49.2 years (35% female), BMI was 34.3 kg/m 2 , and CD4+ T cell count was 794 cells/mm 3 . Age, sex, BMI, and CD4+ T cell count did not significantly differ between participants randomly assigned to semaglutide versus placebo groups. The mean estimated annual rate of change in epigenetic age over 32 weeks was accelerated for the placebo group for PCHorvath1 (1.9 years), PCHorvath2 (1.9 years), PCHannum (2.3 years), PCPhenoAge (2.7 years), PCGrimAge (1.9 years). In contrast, the mean estimated annual rate of change in the semaglutide arm was: PCHorvath1 (0.25 years), PCHorvath2 (-0.07 years), PCHannum (-0.08 years), PCPhenoAge (-0.29 years), PCGrimAge (-0.58 years), and DunedinPACE (-0.04). The mean annual rate of change was significantly decreased in the semaglutide versus placebo arm for second-generation epigenetic clock PCGrimAge (p=0.02) and third-generation epigenetic clock DunedinPACE (p=0.02). An accelerated PCGrimAge at entry was associated with greater percent BMI change following semaglutide (β=-0.45, p=0.02) when controlling for sex. Conclusions: Semaglutide attenuated the accelerated epigenetic aging in people with HIV-associated lipohypertrophy. The target population and durability of semaglutide’s effects upon long-term epigenetic aging in PWH warrants further investigation.

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CROI 2025