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Background Accelerated epigenetic ageing can occur in untreated HIV infection and is partially reversible with effective antiretroviral therapy (ART). We aimed to make a long-term comparison of epigenetic ageing dynamics in people with HIV during untreated HIV infection and during suppressive ART. Methods In this longitudinal study, conducted over 17 years in HIV outpatient clinics in Switzerland, we applied 5 established epigenetic age estimators (epigenetic clocks) in peripheral blood mononuclear cells (PBMCs) in Swiss HIV Cohort Study participants before or during suppressive ART. All participants had a longitudinal set of PBMC samples available at four timepoints (T1-T4). T1 and T2 had to be 3 years or longer apart, as did T3 and T4. We assessed epigenetic age acceleration (EAA) and a novel rate of epigenetic ageing. Findings Between March 13, 1990, and Jan 18, 2018, we recruited 81 people with HIV from the Swiss HIV Cohort Study. We excluded one participant because a sample did not meet quality checks (transmission error). 52 (65%) of 80 patients were men, 76 (95%) were white, and the median patient age was 43 (IQR 37 center dot 5-47) years. Per year of untreated HIV infection (median observation 8 center dot 08 years, IQR 4 center dot 83-11 center dot 09), mean EAA was 0 center dot 47 years (95% CI 0 center dot 37 to 0 center dot 57) for Horvath's clock, 0 center dot 43 years (0 center dot 3 to 0 center dot 57) for Hannum's clock, 0 center dot 36 years (0 center dot 27 to 0 center dot 44) for SkinBlood clock, and 0 center dot 69 years (0 center dot 51 to 0 center dot 86) for PhenoAge. Per year of suppressive ART (median observation 9 center dot 8 years, IQR 7 center dot 2-11), mean EAA was -0 center dot 35 years (95% CI -0 center dot 44 to -0 center dot 27) for Horvath's clock, -0 center dot 39 years (-0 center dot 50 to -0 center dot 27) for Hannum's clock, -0 center dot 26 years (-0 center dot 33 to -0 center dot 18) for SkinBlood clock, and -0 center dot 49 years (-0 center dot 64 to -0 center dot 35) for PhenoAge. Our findings indicate that people with HIV epigenetically aged by a mean of 1 center dot 47 years for Horvath's clock, 1 center dot 43 years for Hannum's clock, 1 center dot 36 years for SkinBlood clock, and 1 center dot 69 years for PhenoAge per year of untreated HIV infection; and 0 center dot 65 years for Horvath's clock, 0 center dot 61 years for Hannum's clock, 0 center dot 74 years for SkinBlood clock, and 0 center dot 51 years for PhenoAge, per year of suppressive ART. GrimAge showed some change in the mean EAA during untreated HIV infection (0 center dot 10 years, 0 center dot 02 to 0 center dot 19) and suppressive ART (-0 center dot 05 years, -0 center dot 12 to 0 center dot 02). We obtained very similar results using the rate of epigenetic ageing. Contribution of multiple HIV-related, antiretroviral, and immunological variables, and of a DNA methylation-associated polygenic risk score to EAA was small. Interpretation In a longitudinal study over more than 17 years, epigenetic ageing accelerated during untreated HIV infection and decelerated during suppressive ART, highlighting the importance of limiting the duration of untreated HIV infection.
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