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 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.

Inflammatory pathways amongst people living with HIV in Malawi differ according to socioeconomic status

“…Lastly, although the socioeconomic variables associated with arterial stiffness (car and TV ownership, electricity connection) were not the same as those associated with T cell activation, they were consistent with a higher socio-economic status and perhaps a more sedentary lifestyle. Taken together with previous data showing that T cell exhaustion is linked with arterial stiffness during the first 3 months of anti-retroviral therapy4 , there is a suggestion that there may be a relationship between T cell activation, sedentary lifestyles and increased cardiovascular risk amongst PLWH in low income SSA setting. The observation that T cell activation may be increased amongst PLWH of higher socioeconomic status has not been previously described.However, T cell activation, exhaustion and senescence have been previously linked to premature ageing and sedentary lifestyles 21 22 .…”

“…Given the increased risk of NCDs amongst people living with HIV (PLWH) in high income countries, there is concern that the ageing HIV population will be particularly at risk form NCD related morbidity and mortality in SSA, placing further strain on already under-resourced healthcare systems. Persistent inflammation and resultant endothelial damage amongst PLWH is implicated in the pathogenesis of NCDs amongst PLWH across healthcare settings [2][3][4][5][6] . Studies to date identify several drivers of inflammation, including microbial translocation through a compromised gut mucosa, subclinical coinfection, or low level persistent HIV viraemia [7][8][9] .…”

“…The enrolment visit for HIV-positive participants was 2 weeks after ART initiation to minimise visit burden in this unwell group. The cohort has been previously reported in detail 4 . In brief, participants underwent a detailed clinical assessment and blood draw for markers of immune activation at enrolment and 42 weeks post ART initiation.…”

“…We previously demonstrated that heightened inflammation amongst PLWH in Malawi is heterogeneous in nature, with different immunological pathways predicting different trajectories in endothelial damage during the first year of antiretroviral therapy (ART) 5 . In this low-income setting, the picture of persistent inflammation amongst PLWH is likely to be further impacted by socio-economic factors such as poor water and housing quality, overcrowded living conditions, low incomes and uncertain food stability leading to increased risk of gastrointestinal infections, malaria, TB, malnutrition and decreasing ability to present for routine care for acute or chronic illness 11-16 .…”

Meta-analysis of transcriptome datasets: An alternative method to study IL-6 regulation in coronavirus disease 2019

“…Many of the genes we found to be upregulated by IL-6 are supported by experimental evidence. Among them, ICAM1 (a well-known gene involved in viral infection and cardiovascular disease) expression has been demonstrated to be consistent with IL-6 expression in mouse macrophages [28] , [29] . Some treatments, such as Phoenix 20 and soluble matrine 2, can induce the co-expression of ICAM1 and IL-6 [30] , [31] .…”