Lifesaving ART for HIV could also be Anti-Aging

Antiretroviral therapy (ART) partially reversed the accelerated aging found in persons living with HIV, in a study that measured multiple biomarkers of epigenetic aging before and after ART.

The accelerated aging was more pronounced in those with severe infections, marked by low CD4 counts and high viral loads, but was reduced--albeit remaining higher than age-matched non-infected controls--after 2 years of treatment with either of 2 ART regimens.

"To our knowledge, this is the first study to assess changes in biomarkers of epigenetic aging after ART initiation in a population of participants with HIV enrolled in a clinical trial," declared Andrés Esteban-Cantos, MSc, and colleagues of the Europe-based HIV/AIDS and Infectious Disease Research Group and the NEAT (European AIDS Treatment Network) 001 and ANRS (French Agency for Research on AIDS and Viral Hepatitis) 143 Study Groups.

Esteban-Cantos and colleagues identified 168 participants of the NEAT001/ANRS143 trial, which had demonstrated the non-inferiority over 96 weeks of ritonavir-boosted darunavir combined with raltegravir versus ritonavir-boosted darunavir combined with tenofovir disoproxil fumarate and emtriciabine in ART-naive adults with HIV ≥18 years of age.Half of those selected for the current study had received one regimen (n=84) and half the other. A control group was constituted with 44 non-infected, age and gender matched individuals.

Four biomarkers of epigenetic aging were analyzed for each of the participants at baseline before commencing ART in the infected groups, and after 96 weeks of treatment or that interval for controls: Horvath's clock, Hannum's clock, GrimAge, and PhenoAge.

The investigators describe these biomarkers of aging as "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 aging."

They characterize the Horvath's and Hannum's clocks as strongly correlated with chronological age and supporting estimates of epigenetic age acceleration affecting age-related comorbidities and mortality.The more recently developed GrimAge, a measure of 513 CpG sites, and PhenoAge, an amalgam measure of chronological age, sex and DNA methylation-based surrogates for 7 plasma proteins and smoking pack-years, have been used in predictions of healthspan--the period of time in which a person is in good health-- and time to death and comorbidities.

At baseline, before ART was initiated for those with HIV, infected individuals showed greater epigenetic age acceleration (EAA) compared to age- and sex- matched, uninfected controls , ranging from 1.4 years to 7.3 years across all 4 estimators; with only the Hannum-EAA not being statistically significantly different.Epigentic aging was more advanced in those who had CD4 counts less than 200cell/μL or viral loads over 100,000 copies/ml.

After 96 weeks of either ART regimen, the investigators found that EAA was reduced, withdifferences per the estimators compared to baseline in reduction of -1.1 years (95% CI -1.51 to -0.66) for Horvath-EAA; -1.6 years (-2.08 to -1.21) for Hannum-EAA; -0.6years (-1.14 to -0.05) for GrimAge-EAA, and -3.6 years (-4.27 to -2.88) for PhenoAge-EAA.The overall difference in the biological age between individual living with HIV and age-matched uninfected controls was 2.5 years before and 1.5 years after ART.

"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," Esteban-Cantos and colleagues report.

In accompanying, invited commentary, Jacqueline Capeau, MD, PhD, Sorbonne Université, Faculty of Medicine and Director, Saint-Antoine Research Centre, INSERM, Paris, France, pointed out that the substudy participants were mainly male and white.

"Whether these results could apply in a real-life setting, in women and people of other ethnicities is unclear," Capeau observed."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."

"Moreover, the role of advanced biological age in the worsening of clinical outcomes needs to be investigated in people living with HIV," Capeau indicated.