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Epigenetic age acceleration changes 2 years after antiretroviral therapy initiation in adults with HIV: a substudy of the NEAT001/ANRS143 randomised trial
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9 year gap in Life Expectancy for HIV+ & 6.8 years for those starting ART early
Comparison of Overall and Comorbidity-Free Life Expectancy Between Insured Adults With and Without HIV Infection, 2000-2016 - Updated HIV Life Expectancy Study: 9 yrs difference; 6.8 for HIV+ >500 CD4 at ART start
aging, epigenetic testing studies
Acceleration of Age-Associated Methylation Patterns in HIV-1-Infected Adults.... adults appeared to be approximately 14 years older than their chronologic age MACS Men
Acceleration of Age-Associated Methylation Patterns in HIV-1-Infected Adults.... adults appeared to be approximately 14 years older than their chronologic age MACS Men
Comment - Ageing with HIV: is the virus or the treatment guilty?
Jacqueline Capeau April, 2021 HIV Lancet
People living with HIV endure diverse age-related comorbidities at a higher prevalence than do the general population, including cardiometabolic, bone, liver, and kidney diseases and some cancers.1, 2 This observation has led to the hypothesis that people living with HIV might have premature ageing,1 meaning that their so called biological age is higher than their numerical age.
Biological age can be estimated by analysis of epigenetic changes that affect specific DNA methylation sites. In The Lancet HIV, Andrés Esteban-Cantos and colleagues3 used four epigenetic age estimators (Horvath's clock, Hannum's clock, GrimAge, and PhenoAge) in 168 antiretroviral therapy (ART)-naive people with HIV from the NEAT001/ANRS143 study. Participants were followed up 2 years after initiation of ritonavir-boosted darunavir combined with either raltegravir or tenofovir disoproxil fumarate and emtricitabine. People with HIV were compared with 44 HIV-negative control participants. The authors observed that whatever the epigenetic age evaluator, ART-naive people with HIV were biologically older than age-matched controls and epigenetic age was consistently reduced 2 years after ART initiation, with no difference between the two ART regimens, but epigenetic age remained higher overall in participants with HIV compared with control participants. Therefore, biological age only partly improved with ART. Previous smaller studies indicated advanced epigenetic age in people with ART-naive and ART-controlled HIV.4
Several important points are raised by this study. The severity of the initial HIV infection increases epigenetic age. The persistent role of HIV, even controlled, could result from greater HIV reservoirs, remaining immune dysfunction, gut dysbiosis, and chronic low-grade inflammation. 5 Nadir CD4 and CD4 to CD8 levels reflect this severity and are recorded in medical records. Studies indicate that people living with HIV have enhanced—rather than premature or accelerated—ageing, which occurs during the initial untreated period. Thus, brain ageing, assessed by neuroimaging and function, was higher but worsened at the same rate in people with ART-controlled HIV versus non-infected individuals in the COBRA study,6 stressing the important beneficial role of ART.
However, the role of ART could be beneficial or deleterious. Controlling infection and restoring immunity could explain the beneficial effect of ART on epigenetic ageing in Esteban-Cantos and colleagues' study,3 but their follow-up was short and patients were relatively young (median age 38⋅1 years, IQR 30⋅5-46⋅5). Some ART classes have been associated with a higher occurrence of some age-related comorbidities.5, 7 Whether long-term ART is beneficial or deleterious in terms of biological age and associated comorbidities is an important clinical issue.
Epigenetic markers differ between leucocyte subsets. In Esteban-Cantos and colleagues' study, 3 leucocyte composition was markedly different between people with ART-naive and ART-treated HIV and control participants. After adjustment for leucocyte composition, the epigenetic differences were no longer present for Horvath's clock and GrimAge. This point needs to be further investigated.
Esteban-Cantos and colleagues compared people living with HIV with a control group for whom only age and sex data were recorded.3 This is concerning. In a previous study,8 use of a control group paired for most environment-related factors markedly reduced the difference between biological ages estimated by a complex set of parameters. People living with HIV had a mean advancement of biological age of 13⋅2 years and remained biologically older than non-infected matched participants, who has a biological age advancement of 5⋅5 years, but both groups differed substantially from healthy control blood donors (-7 years).8
The proportion of participants with cytomegalovirus (CMV) coinfection, which was not investigated by Esteban-Cantos and colleagues,3 is generally higher in people living with HIV than in the general population. This parameter accounted for the high and similar levels of immunosenescent T cells found in people living with HIV and paired uninfected control participants in the COBRA study, which were markedly higher than in healthy blood donors.9
The difference in the biological age between people living with HIV and control participants reported in Esteban-Cantos and colleagues' study3 was 2⋅5 years before and 1⋅5 years after ART. This is much fewer than in previous studies that estimated the epigenetic age of people with ART-controlled HIV compared with control participants in blood (5⋅2 years greater) and brain (7⋅4 years greater), similar to the 7⋅7 years difference observed in the COBRA study.4, 8
This substudy of the NEAT001/ANRS143 trial studied mainly male and white patients. Whether these results could apply in a real-life setting, in women and people of other ethnicities, is unclear. For example, studies have found that some integrase inhibitors induce weight gain in women and Black people with HIV, whereas white men are minimally affected.10 Moreover, the role of advanced biological age in the worsening of clinical outcomes needs to be investigated in people living with HIV.
What clinical recommendations can be made regarding evaluation of epigenetic age in people living with HIV, especially since the advance in age is small and not associated with clinical outcomes? Perhaps not evaluation of epigenetic age at the individual level, but in clinical studies, especially in ageing people living with HIV, such evaluation could be useful. The role of coinfections (such as CMV, hepatitis C virus, and hepatitis B virus) and some ART in relation to epigenetic age warrants further investigation. Nevertheless, enhanced epigenetic age in those who initiate ART late, even if their HIV is well controlled thereafter, indicates a need for careful follow-up in terms of age-related comorbidities.
I report grants paid to my institution from ViiV Healthcare and MSD and personal fees for educational presentations from ViiV Healthcare, MSD, Janssen, and Gilead, outside the submitted comment.
Epigenetic age acceleration changes 2 years after antiretroviral therapy initiation in adults with HIV: a substudy of the NEAT001/ANRS143 randomised trial
In this study, we found that ART-naive adults with HIV had accelerated epigenetic ageing, which was more pronounced in those with CD4 counts less than 200 cells per μL or viral loads over 100 000 copies per mL. We observed a partial reversal of epigenetic ageing after only 2 years of ART, with no difference between participants on ritonavir-boosted darunavir with raltegravir or ritonavir-boosted darunavir with tenofovir disoproxil fumarate and emtricitabine. However, it is possible that other antiretrovirals could have a more pronounced effect on reversing EAA. The epigenetic ageing reversal was more marked in participants with more severe baseline CD4 immunodeficiency, and was accompanied by a shift of leucocyte subsets towards undifferentiated T-cell phenotypes and reduced proinflammatory leucocytes. These findings support that ART initiation partly reverses HIV-induced EAA, and is one of the first examples, to our knowledge, of how epigenetic clocks can capture the initial beneficial effect of a therapeutic intervention that significantly improves survival. In support of these data, we previously found a positive effect of ART initiation on blood telomere length, another biomarker of ageing, in data from the same clinical trial.19
In our study, we evaluated, for the first time to our knowledge in participants with HIV, the PhenoAge and GrimAge measures, two novel biomarkers of epigenetic ageing that have a greater ability to predict all-cause mortality and morbidities in the general population compared with traditional epigenetic clocks.11, 12 Although we found that EAA decreased after ART initiation according to the four selected indicators, PhenoAge-EAA and GrimAge-EAA were the only indicators that remained significantly elevated in participants with HIV after 2 years of follow-up. We could speculate that PhenoAge-EAA and GrimAge-EAA remained elevated because of the increased risk of morbidities, such as cardiovascular disease or malignancies, associated even with adequately treated HIV, and also because PhenoAge is associated with various markers of immunosenescence.7
Our longitudinal data are consistent with a previous study that found an improvement in epigenetic ageing 7-11 years after ART introduction based on Horvath's epigenetic clock in a group of 19 ART-naive US veterans with HIV from the Veterans Aging Cohort Study.23 Other cross-sectional studies have shown that HIV infection is associated with increased EAA. A study that compared age-related methylation patterns between ART-naive participants with HIV and a population of age-matched participants without HIV reported that untreated HIV infection induced an age advancement of 14 years.24 Regarding chronic HIV infection on ART, two previous studies found that people living with HIV had an EAA around 5 years, according to Horvath's epigenetic clock.14, 15 In this study, we found a smaller effect on ART-naive participants with HIV before starting ART and 2 years after ART initiation (2⋅5 and 1⋅5 years, respectively), and a similar observation of restricted EAA among people with HIV on ART has been reported.25 Although these data suggest that long-term chronic infection might have a negative effect on epigenetic ageing, we think these differences could also be explained by different sociodemographic, immunological, and virological characteristics of the study populations.
All previous studies we mentioned suggest an association between HIV infection and EAA, but the underlying causes of this process remain unclear. Since this study was done with frozen whole blood samples, we estimated the composition of the main leucocyte subsets to investigate their relationship with EAA. As expected, ART-naive participants with HIV had substantial immune dysregulation, with reduced levels of naive CD4 and CD8 T cells and increased levels of exhausted CD8 T cells, monocytes, and natural killer cells. We observed that the association between HIV status and higher levels of Horvath-EAA, Hannum-EAA, and PhenoAge-EAA disappeared after adjusting for estimated leucocyte composition in a multivariable model, and a similar finding has been previously reported.23
As different leucocyte subsets have different methylation patterns,26 this could indicate that these associations are driven by changes in cell composition. However, given that HIV infection is the cause of the immune dysregulation, the infection itself might be confounding the association between the estimated leucocyte composition and epigenetic ageing. Additionally, this hypothesis would not explain the accelerated ageing effects also reported in brain tissue samples from people with HIV.14 Thus, further studies in specific blood cell subsets are needed to better understand what leads to epigenetic ageing in people with HIV.
The main limitation of our study is the selection of the HIV-uninfected group. The sample size was small (n=44), and chronological age and sex were the only available variables. Thus, comparisons between people with HIV and people without HIV could not be adjusted for potential confounders, such as socioeconomic status, lifestyle (eg, obesity, alcohol consumption, or smoking), and prevalence of cytomegalovirus co-infection, which have been shown to be associated with epigenetic ageing.27 A previous study revealed that people living with HIV on ART and people without HIV with similar lifestyles had signs of age advancement compared with healthy blood donors.
28 Future studies are needed to know the real impact of HIV infection on epigenetic ageing, including control groups with similar lifestyle behaviours to people living with HIV (eg, alcohol, drug, and tobacco consumption or diet). However, our study shows that controlling HIV replication has a positive effect on ageing. Another limitation is the fact that we could not determine real counts of all leucocyte subsets by flow cytometry. Nevertheless, our data and other previously reported data support that estimated leucocyte composition based on DNA-methylation patterns has good strong correlation with corresponding flow cytometry measurements.29
The clinical relevance of the EAA observed in people living with HIV is not completely understood. Sánchez-Conde and colleagues30 found that an older HIV-infected frail population had accelerated epigenetic ageing of up to 10 years compared with non-frail people with HIV who were matched for age and nadir CD4 count.30
Another study that analysed post-mortem brain tissue samples from a group of people with HIV found that individuals who had been diagnosed with HIV-associated neurocognitive disorder within a year of death had higher EAA compared with those who were neurocognitively healthy.
Thus, although more studies are necessary to assess the relationship between epigenetic ageing and other pathologies, epigenetic ageing biomarkers could be useful tools to identify which individuals living with HIV have an elevated risk of age-related comorbidities, and therefore might benefit from more aggressive preventive interventions.
In conclusion, our results showed the ability of ART to partly reverse the EAA and leucocyte dysregulation associated with untreated HIV infection. Further research is needed to evaluate the long-term effect of ART in epigenetic ageing dynamics and to reveal the clinical relevance of epigenetic ageing biomarkers in people living with HIV.
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