Antiretroviral therapy (ART) has transformed HIV infection into a chronic and manageable disease in which life expectancy among people living with HIV approaches that of the general population.1 However, this prolonged survival in people living with HIV has been linked to an increased burden of age-related comorbidities, such as cardiovascular disease, cancer, cognitive impairment, osteoporosis, and frailty.2, 3 Although the cause of this accelerated or accentuated ageing is not completely understood, it might be related to residual immunosenescence and inflammation that persists despite successful ART.4, 5
Until roughly the past 5 years, the study of ageing and its consequences lacked precise and reproducible biomarkers. Although blood telomere length is negatively associated with chronological age, its ability to predict life expectancy is restricted.6 Among the most reliable biomarkers of age are so-called epigenetic clocks, mathematical algorithms that predict epigenetic age as a surrogate of biological age based on the DNA methylation levels of different sets of CpG dinucleotide sites in the genome that are known to change with ageing.7 The first to be developed were Horvath's multi-tissue epigenetic clock, based on 353 CpG sites,8 and Hannum's epigenetic clock for blood samples, based on 71 CpG sites.9 These epigenetic clocks are attractive biomarkers of ageing because they have a strong correlation with chronological age and because epigenetic age acceleration (EAA), defined as an epigenetic age greater than that predicted based on chronological age, predicts the occurrence of age-related comorbidities and mortality.7, 10 In the past two years, two new DNA methylation-based estimators of ageing have been developed: PhenoAge and GrimAge. PhenoAge predicts a surrogate measure of phenotypic age based on 513 CpG sites, and is considered an accurate predictor of mortality, healthspan (ie, the period of time in which a person is in good health), cardiovascular disease, and other morbidities.11 The GrimAge estimator, which is calculated based on chronological age, sex, and DNA methylation-based surrogates for seven plasma proteins and smoking pack-years, also predicts time to death and comorbidities.12 There are almost no data concerning the evolution of these biomarkers after successful treatment of diseases that shorten the lifespan. An example of such a disease is HIV, which has a median survival from age 25 of 19·9 years when untreated, compared with 51·1 years for people without HIV.13
Research in context
Evidence before this study
Data on the effect of HIV and antiretroviral therapy (ART) on epigenetic biomarkers of ageing are scarce. We searched PubMed for reports published in English, with no restrictions on publication date, using combinations of the following keywords: “HIV infection”, “antiretroviral therapy”, “premature aging”, “epigenetic clocks”, “epigenetic aging”, and “epigenetic age acceleration”. We also searched for relevant publications from international HIV congresses (2017–20) using the same search criteria. Our search yielded six publications. Five of these reports found an association between HIV infection and epigenetic age acceleration (EAA), both in untreated and treated HIV infection. Nevertheless, none of these studies evaluated the effect of ART on epigenetic ageing in treatment-naive adults with HIV in the context of a clinical trial. We found only one longitudinal study that reported a positive effect of ART initiation on epigenetic ageing in people with HIV. However, this study included a small number of participants (n=19) and was not fully powered to establish how epigenetic ageing dynamics change immediately after introducing ART.
Added value of this study
To our knowledge, this is the first study to assess changes in biomarkers of epigenetic ageing after ART initiation in a population of participants with HIV enrolled in a clinical trial (NEAT001/ANRS143). Our results support evidence that untreated HIV infection is associated with EAA, which is more pronounced in participants with severe immunodeficiency. Our study also suggests that ART partly reverses epigenetic ageing only 2 years after initiation. We also compared, for the first time to our knowledge, the effect of different ART regimens on epigenetic ageing dynamics. We found no significant difference in epigenetic ageing reversal between participants receiving darunavir and ritonavir plus raltegravir or darunavir and ritonavir plus tenofovir disoproxil fumarate and emtricitabine regimens.
Implications of all the available evidence
To our knowledge, our study is one of the first examples of how biomarkers of epigenetic ageing can capture the initial beneficial effect of a therapeutic intervention that significantly prolongs lifespan. The partial reversal of HIV-induced EAA supports an additional beneficial effect of ART. EAA predicts a higher risk of emergence of comorbidities and mortality in the general population, but its clinical relevance in people living with HIV remains to be appropriately defined. More evidence is needed to elucidate whether biomarkers of epigenetic ageing could help to identify people with chronic HIV who are more likely to suffer premature age-related comorbidities.
Previous studies have reported that HIV is associated with accelerated epigenetic ageing in adults and perinatally HIV-infected children on ART.14, 15, 16 Furthermore, in a cohort of 31 injection drug users, this accelerated ageing started soon after HIV seroconversion.17 However, there is a paucity of data concerning the effect of ART and specific antiretroviral regimens on the evolution of epigenetic ageing. We aimed to investigate, for the first time to our knowledge, a range of epigenetic ageing biomarkers in a substudy of the NEAT001/ANRS143 clinical trial, which compared ritonavir-boosted darunavir combined with either raltegravir or tenofovir disoproxil fumarate and emtricitabine in ART-naive adults.18 We hypothesised that ART would have a beneficial effect on epigenetic ageing.