Inflammatory Phenotypes Predict Changes in Arterial Stiffness Following Antiretroviral Therapy Initiation

Abstract

Background: Inflammation drives vascular dysfunction in HIV, but in low-income settings causes of inflammation are multiple, and include infectious and environmental factors. We hypothesized 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/μL 2 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 participants with HIV grouped into 3 inflammatory clusters 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 PD-1 versus cluster-2 and cluster-3 (all P < .0001). Although small, cluster-3 had significantly higher levels of cytokines reflecting inflammation (IL-6, IFN-γ, IP-10, IL-1RA, IL-10), chemotaxis (IL-8), systemic and vascular inflammation (CRP, ICAM-1, VCAM-1), and SAA (all P < .001). In mixed-effects models, cfPWV changes over time were similar for cluster-2 versus cluster-1 (relative fold-change, 0.99; 95% CI, .86-1.14; P = .91), but greater in cluster-3 versus cluster-1 (relative fold-change, 1.45; 95% CI, 1.01-2.09; P = .045).

Conclusions: Two inflammatory clusters were identified: one defined by high T-cell PD-1 expression and another by a hyperinflamed profile and increases in cfPWV on ART. Further clinical characterization of inflammatory phenotypes could help target vascular dysfunction interventions to those at highest risk.

Clinical trials network: NCT01825031.

Keywords: arterial stiffness; inflammatory phenotype; ub-Saharan Africa.

Figure 1.

Identification of 3 distinct inflammatory biomarker clusters for 211 patients with HIV infection. Clusters plotted against the first 2 principal components (percentage total variation explained). Abbreviations: Dim, dimension; HIV, human immunodeficiency virus.

Figure 2.

Heat map of 22 inflammatory biomarkers according to inflammatory cluster. Abbreviations: bFGF, basic fibroblastic growth factor; CRP, C-reactive protein; IL, interleukin; IFN, interferon; IP, interferon gamma-induced protein; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; sVCAM, soluble vascular cell adhesion molecule; sICAM, intracellular adhesion molecule; sCD, soluble cluster of differentiation; SAA, serum amyloid A; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

Figure 3.

Change in cfPWV over 42 weeks of ART according to inflammatory cluster. Abbreviations: ART, antiretroviral therapy; cfPWV, carotid femoral pulse-wave velocity; HIV, human immunodeficiency virus.