Inflammatory Biomarkers Predicting Major Adverse Cardiovascular Events in People Living With HIV: A Systematic Review and Meta-Analysis

Introduction: Chronic inflammation is a unique contributor to cardiovascular disease (CVD) risk among people living with HIV, yet there is a lack of consensus on the predictive utility of inflammatory biomarkers in this population. We conducted a systematic review assessing the predictive value of inflammatory biomarkers for major adverse cardiovascular events in people living with HIV to inform their potential integration into CVD risk assessment. Methods: MEDLINE, Embase and Google Scholar were searched for articles published up to 01 May 2024. We included prospective cohort and nested case-control studies of adults living with HIV with inflammatory biomarker measurements in blood and at least one year of follow-up to major adverse cardiovascular events. Risk of bias was assessed using the Quality in Prognostic Studies (QUIPS) tool. Where at least two studies reported the same type of effect measure for a biomarker, results were pooled using an inverse variance heterogeneity model. Results: Among 5156 screened citations, 21 studies reporting 31 inflammatory biomarkers met inclusion criteria. Meta-analysis showed high-sensitivity C-reactive protein (hsCRP) positively associated with future cardiovascular events (hazard ratio = 1.86 per log10 unit; 95% CI 1.39–2.50, n = 5,254). Three biomarkers, interleukin 6 (IL-6), D-dimer, and N-terminal pro-brain natriuretic peptide (NT-proBNP), demonstrated positive, statistically significant associations with adverse cardiovascular outcomes in at least two non-overlapping studies, though heterogeneous effect measures precluded meta-analysis. Most research (14/21 studies) was conducted exclusively in high-income settings, and female representation was low (median proportion = 15.5%; IQR 8.4–20.9%). All but three studies had a moderate or high risk of bias in at least one domain. Discussion: We identified several inflammatory biomarkers with potential prognostic value, but most associations were derived from single or heterogeneous studies. The certainty of evidence is reduced by methodological heterogeneity, few high-quality studies and the underrepresentation of low- and middle-income countries (LMICs). Conclusions: Consistent positive associations between inflammatory biomarkers and future CVD in people living with HIV support a central role of inflammation in HIV-related CVD. Representative, large-scale studies that include women and LMICs are needed to guide the integration of candidate biomarkers into CVD risk prediction models. PROSPERO Number: CRD42024542944.