Longitudinal Changes in Inflammation-Related Methylation Risk Score for C-Reactive Protein Among People with HIV

Background/Objectives: Human immunodeficiency virus (HIV) infection is characterized by chronic systemic inflammation. Antiretroviral therapy (ART) can reduce persistent inflammation, as measured by C-reactive protein (CRP). The CRP methylation risk score (MRSCRP) acts as proxy for plasma CRP, but longitudinal changes in this score for people with HIV (PWH) before and after initiating ART have not been described. Methods: We evaluated a previously published MRSCRP in the Emory Twin Study (N = 352), testing its correlation with plasma CRP and CRP-responsive biomarkers, as well as associations with cardiometabolic traits using generalized estimating equations (GEEs). We then applied MRSCRP in the HIV AIDS Drug Resistance Surveillance Study (ADReSS) cohort (N = 440) to assess longitudinal changes before and after ART, using paired t-tests and linear mixed-effects models. Results: MRSCRP showed moderate correlation with CRP (r = 0.38) and other inflammatory biomarkers (r = 0.25–0.34). MRSCRP was associated with hypertension, type 2 diabetes, coronary artery disease, and obesity, and remained independently associated with obesity (odds ratio = 1.49) after adjusting for measured CRP. Z-score-standardized MRSCRP decreased by 0.254 standard deviation units between baseline and follow-up among PWH receiving ART, confirmed by linear mixed-effects models. Conclusions: MRSCRP showed associations with chronic inflammation and cardiometabolic diseases. The observed decline in MRSCRP following ART initiation may reflect changes in inflammatory status among PWH. These findings highlight the potential of MRSCRP as a marker of inflammation-related changes and comorbidity risk in PWH.