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.