Plasma biomarkers of immune regulation and senescence are associated with incident skeletal-related events in people with HIV: a case-cohort study

Persistent immune dysregulation in people with HIV (PWH) on antiretroviral therapy (ART) contributes to an increased risk of skeletal-related events (SREs), serving as a critical paradigm for understanding accelerated aging and age-related diseases. We investigated the association between plasma biomarkers of immune regulation and senescence with incident SRE risk and evaluated potential effect modification by sex. In a case-cohort study nested within the Spanish CoRIS cohort (65 incident SRE cases; 252 subcohort, including 5 overlapping cases), we quantified 24 baseline biomarkers of immune checkpoints and senescence-associated secretory phenotype factors. We estimated adjusted hazard ratios (aHR) using Borgan II-weighted cause-specific Cox regression models adjusted for clinical confounders (age, region of origin, prior AIDS diagnosis, CD4 + T-cell count, coinfections, and lifestyle factors). Sex-biomarker interactions were assessed as exploratory endpoints. Nineteen biomarkers were independently associated with increased SRE risk ( p < 0.05 & q < 0.10). Angiogenic factors (VEGF-A; aHR = 1.94; 95% CI, 1.40–2.68), immune checkpoints (PD-L2; aHR = 1.95; 95% CI, 1.09–3.49), and tissue remodeling markers (MMP-1; aHR = 1.91; 95% CI, 1.08–3.39) displayed independent associations, alongside consistent signals for TIM-3, PD-L1, and IL-8. Pairwise correlation analysis demonstrated clustering between checkpoints and inflammatory cytokines. Exploratory interaction analysis indicated that sex modified these associations; signals for seven markers (e.g., IL-1α, VEGF-A) were stronger in females, although the limited number of events warrants caution. Circulating biomarkers of immune exhaustion, inflammation, and senescence are independently associated with incident SREs in PWH on long-term ART. Our findings indicate a systemic pro-inflammatory signature and suggest that females exhibit higher sensitivity to inflammatory damage.