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 (MRS_CRP) 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 MRS_CRP 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 MRS_CRP 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: MRS_CRP showed moderate correlation with CRP (r = 0.38) and other inflammatory biomarkers (r = 0.25-0.34). MRS_CRP 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 MRS_CRP decreased by 0.254 standard deviation units between baseline and follow-up among PWH receiving ART, confirmed by linear mixed-effects models. Conclusions: MRS_CRP showed associations with chronic inflammation and cardiometabolic diseases. The observed decline in MRS_CRP following ART initiation may reflect changes in inflammatory status among PWH. These findings highlight the potential of MRS_CRP as a marker of inflammation-related changes and comorbidity risk in PWH.