Pre-frailty in people with HIV: inflammatory immune signatures and opportunities for early identification

Frailty is an emerging concern in the ageing population of people with HIV. Pre-frailty, an intermediate but reversible stage, offers a vital window for early intervention. Despite effective antiretroviral therapy, persistent immune activation and systemic inflammation accelerate biological ageing and increase vulnerability to functional decline. This review synthesizes evidence linking inflammatory immune signatures to pre-frailty in people with HIV. Elevated levels of IL-6, TNF-α, CRP, and soluble activation markers such as sCD14, sCD163, CXCL10, and D-dimer underscore contributions from microbial translocation, macrophage activation, and coagulation pathways. Immune cell alterations, including low CD4/CD8 ratios, activated CD8+ T cells, and NK cell dysfunction, further highlight the role of immune senescence. Sex- and age-related trends indicate heightened inflammatory responses in women, particularly during menopause, and distinct metabolic and immunological risks in men. Notably, most data originate from high-income settings, with limited evidence from sub-Saharan Africa. Immune profiling shows promise for early screening and risk stratification of pre-frailty in people with HIV, but challenges related to assay standardization, cost, and predictive validation remain.