Cardiovascular-Kidney-Hepatic-Metabolic Syndrome in People With HIV

Background The cardiovascular–kidney–hepatic–metabolic (CKHM) framework integrates cardiovascular risk, kidney disease, liver health, and metabolic dysfunction in a patient-centered model. This study assessed CKHM stage prevalence, stage-to-stage transitions over 2005–2025, and clinical/metabolic factors associated with progression and reversion in people with HIV (PWH). Methods Longitudinal observational study of PWH attending Modena HIV Metabolic Clinic (2005–2025), divided into three periods (2005–2015, 2016–2020, 2021–2025). CKHM stages ranged from Stage 0 (no metabolic risk factors, preserved renal function) to Stage 4 (overt CVD, end-stage CKD, CAC >400, or organ transplantation), with intermediate stages reflecting progressive cardiometabolic, renal, and hepatic involvement. Transitions and death were modelled with Markov models, adjusted for age, sex, HIV duration, physical activity, and antiretroviral/statin use. Stages 4 and death were irreversible states. Results Among 3,838 PWH with ≥2 assessments (31,232 total observations; median follow-up 6.36 years; 171 deaths): Advanced CKHM stages (3–4) rose from 36% (2005–2015) to 63% (2021–2025), while earlier stages declined. More advanced stages were associated with older age (42→56 years), male sex (53→84%), longer HIV duration, lower nadir CD4, sedentary lifestyle, and smoking. Physical activity promoted regression from stage 1→0 (HR 1.48) and protected against progression from stage 1→2 (HR 0.76). Male sex and longer HIV duration predicted progression from stage 1 to stages 2–3. Older age and longer HIV duration drove progression from stage 2→3. INSTI use reduced likelihood of regression from stage 2→1 (HR 0.61); PI use reduced regression from stage 3→2 (HR 0.77). Mortality risk increased with advancing age. Conclusions PWH show a rising burden of advanced CKHM stages over time. Both HIV-related and traditional modifiable risk factors influence disease trajectory. The CKHM framework supports longitudinal cardiometabolic risk stratification and the design of integrated preventive strategies in PWH.