DNA methylation-based estimator of blood telomere length (DNAmTL) outperforms qPCR-based telomere length in reflecting clinical and sociodemographic factors in people with HIV infection

Telomere length (TL) is a widely used biomarker of biological aging, and is shortened in people living with HIV (PWH) due to chronic inflammation and immune-activation. The DNA methylation-based estimator of TL (DNAmTL) has emerged as a promising alternative to classical TL measurements, but their comparative performance in PWH remains poorly characterized. We conducted a cross-sectional study comparing DNAmTL and monochrome multiplex quantitative PCR-based TL (qPCR-TL) in two cohorts of PWH: 160 ART-naïve individuals and 143 long-term treated individuals with sustained viral suppression. DNAmTL was derived from blood DNA methylation profiles generated using the Infinium MethylationEPIC arrays, while qPCR-TL was measured using a standardized assay. We evaluated the agreement between methods using correlation, Bland-Altman analysis and Cohen’s Kappa coefficient, and their associations with demographic, clinical and immunological factors were assessed using multivariable linear regression. DNAmTL and qPCR-TL were moderately correlated in both ART-naïve (r = 0.54, p < 0.001) and ART-treated participants (r = 0.46, p < 0.001), showing reasonable to fair agreement across continuous and categorical assessments. Both measures were inversely correlated with chronological age, although associations were stronger for DNAmTL. Compared to qPCR-TL, DNAmTL demonstrated more robust and independent associations with female sex and ethnicity, immunovirological markers of HIV disease severity such as plasma HIV-RNA viral load and the CD4:CD8 ratio, as well as with comorbidities including type 2 diabetes and hepatitis C virus coinfection. DNAmTL provides a more biologically informative measure of aging and disease burden in PWH. Further research is warranted to validate these results and to determine its predictive value for clinical outcomes.