Inflammatory Phenotypes Predict Changes in Arterial Stiffness following ART Initiation

BACKGROUND: Inflammation drives vascular dysfunction in HIV, but in low-income settings causes of inflammation are multiple, and include infectious and environmental factors. We hypothesised that patients with advanced immunosuppression could be stratified into inflammatory phenotypes that predicted changes in vascular dysfunction on ART. METHODS: We recruited Malawian adults with CD4<100 cells/ul two weeks after starting ART in the REALITY trial (NCT01825031). Carotid femoral pulse wave velocity (cfPWV) measured arterial stiffness 2, 12, 24 and 42 weeks post-ART initiation. Plasma inflammation markers were measured by electrochemiluminescence at weeks 2 and 42. Hierarchical clustering on principal components identified inflammatory clusters. RESULTS: 211 HIV-positive participants grouped into three clusters of inflammatory marker profiles representing 51 (24%) (cluster-1), 153 (73%) (cluster-2) and 7 (3%) (cluster-3) individuals. Cluster-1 showed markedly higher CD4 and CD8 T-cell expression of HLADR and PD1 vs cluster-2 and cluster-3 (all p<0.0001). Although small, individuals in cluster-3 had significantly higher levels of cytokines reflecting inflammation (IL6, IFNɣ, IP10, IL1RA, IL10), chemotaxis (IL8), systemic and vascular inflammation (CRP, ICAM1, VCAM1) and SAA (all p<0.001). In mixed-effects models, cfPWV changes over time were similar for cluster-2 vs cluster-1 (relative-fold-change 0.99 (95% CI 0.86-1.14, p=0.91, but greater in cluster-3 vs cluster-1 (relative-fold-change 1.45 (95% CI 1.01-2.09, p=0.045). CONCLUSIONS: Two inflammatory clusters were identified: one defined by high T-cell PD1 expression and another by a hyper-inflamed profile and increases in cfPWV on ART. Further clinical characterisation of these inflammatory phenotypes could help target vascular dysfunction interventions to those at highest risk.