Inflammatory Phenotypes Predict Changes in Arterial Stiffness Following Antiretroviral Therapy Initiation

Christine Kelly; Willard Tinago; Dagmar Alber; Patricia Hunter; Natasha Luckhurst; Jake Connolly; Francesca Arrigoni; Alejandro Garcia Abner; Ralph Kamngona; Irene Sheha; Mishek Chammudzi; Kondwani Jambo; Jane Mallewa; Alicja Rapala; Robert S. Heyderman; Patrick W.G. Mallon; Henry Mwandumba; A. Sarah Walker; Nigel Klein; Saye Khoo

doi:10.1093/cid/ciaa186

Inflammatory Phenotypes Predict Changes in Arterial Stiffness Following Antiretroviral Therapy Initiation

Christine Kelly, Willard Tinago, Dagmar Alber, Patricia Hunter, Natasha Luckhurst, Jake Connolly, Francesca Arrigoni, Alejandro Garcia Abner, Ralph Kamngona, Irene Sheha, Mishek Chammudzi, Kondwani Jambo, Jane Mallewa, Alicja Rapala, Robert S. Heyderman, Patrick W.G. Mallon, Henry Mwandumba, A. Sarah Walker, Nigel Klein, Saye Khoo

Clinical Sciences

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2389-2397
Number of pages	9
Journal	Clinical Infectious Diseases
Volume	71
Issue number	9
Early online date	27 Feb 2020
DOIs	https://doi.org/10.1093/cid/ciaa186
Publication status	Published - 3 Dec 2020

Keywords

arterial stiffness
inflammatory phenotype
ub-Saharan Africa

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Inflammatory Phenotype PaperAccepted author manuscript, 667 KBLicence: CC BY

Cite this

Kelly, C., Tinago, W., Alber, D., Hunter, P., Luckhurst, N., Connolly, J., Arrigoni, F., Abner, A. G., Kamngona, R., Sheha, I., Chammudzi, M., Jambo, K., Mallewa, J., Rapala, A., Heyderman, R. S., Mallon, P. W. G., Mwandumba, H., Walker, A. S., Klein, N., & Khoo, S. (2020). Inflammatory Phenotypes Predict Changes in Arterial Stiffness Following Antiretroviral Therapy Initiation. Clinical Infectious Diseases, 71(9), 2389-2397. https://doi.org/10.1093/cid/ciaa186

@article{1ecef525fe024730b800053e3943d2fd,

title = "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.",

keywords = "arterial stiffness, inflammatory phenotype, ub-Saharan Africa",

author = "Christine Kelly and Willard Tinago and Dagmar Alber and Patricia Hunter and Natasha Luckhurst and Jake Connolly and Francesca Arrigoni and Abner, \{Alejandro Garcia\} and Ralph Kamngona and Irene Sheha and Mishek Chammudzi and Kondwani Jambo and Jane Mallewa and Alicja Rapala and Heyderman, \{Robert S.\} and Mallon, \{Patrick W.G.\} and Henry Mwandumba and Walker, \{A. Sarah\} and Nigel Klein and Saye Khoo",

year = "2020",

month = dec,

day = "3",

doi = "10.1093/cid/ciaa186",

language = "English",

volume = "71",

pages = "2389--2397",

journal = "Clinical Infectious Diseases",

issn = "1058-4838",

publisher = "Oxford University Press",

number = "9",

}

Kelly, C, Tinago, W, Alber, D, Hunter, P, Luckhurst, N, Connolly, J, Arrigoni, F, Abner, AG, Kamngona, R, Sheha, I, Chammudzi, M, Jambo, K, Mallewa, J, Rapala, A, Heyderman, RS, Mallon, PWG, Mwandumba, H, Walker, AS, Klein, N & Khoo, S 2020, 'Inflammatory Phenotypes Predict Changes in Arterial Stiffness Following Antiretroviral Therapy Initiation', Clinical Infectious Diseases, vol. 71, no. 9, pp. 2389-2397. https://doi.org/10.1093/cid/ciaa186

TY - JOUR

T1 - Inflammatory Phenotypes Predict Changes in Arterial Stiffness Following Antiretroviral Therapy Initiation

AU - Kelly, Christine

AU - Tinago, Willard

AU - Alber, Dagmar

AU - Hunter, Patricia

AU - Luckhurst, Natasha

AU - Connolly, Jake

AU - Arrigoni, Francesca

AU - Abner, Alejandro Garcia

AU - Kamngona, Ralph

AU - Sheha, Irene

AU - Chammudzi, Mishek

AU - Jambo, Kondwani

AU - Mallewa, Jane

AU - Rapala, Alicja

AU - Heyderman, Robert S.

AU - Mallon, Patrick W.G.

AU - Mwandumba, Henry

AU - Walker, A. Sarah

AU - Klein, Nigel

AU - Khoo, Saye

PY - 2020/12/3

Y1 - 2020/12/3

N2 - 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.

AB - 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.

KW - arterial stiffness

KW - inflammatory phenotype

KW - ub-Saharan Africa

U2 - 10.1093/cid/ciaa186

DO - 10.1093/cid/ciaa186

M3 - Article

SN - 1058-4838

VL - 71

SP - 2389

EP - 2397

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

IS - 9

ER -

Inflammatory Phenotypes Predict Changes in Arterial Stiffness Following Antiretroviral Therapy Initiation

Abstract

Keywords

UN SDGs

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