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Open Access Research article

A prospective study of endothelial activation biomarkers, including plasma angiopoietin-1 and angiopoietin-2, in Kenyan women initiating antiretroviral therapy

Susan M Graham123*, Nimerta Rajwans4, Kenneth A Tapia2, Walter Jaoko3, Benson BA Estambale5, R Scott McClelland1236, Julie Overbaugh7 and W Conrad Liles148

Author Affiliations

1 Department of Medicine, University of Washington, Seattle, WA 98195, USA

2 Department of Global Health, University of Washington, Seattle, WA 98195, USA

3 Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya

4 S.A. Rotman Laboratories, McLaughlin-Rotman Centre for Global Health, Toronto General Hospital-University Health Network, University of Toronto, Toronto, Ontario, M5G 2C4, Canada

5 University of Nairobi Institute of Tropical and Infectious Diseases (UNITID), College of Health Sciences, University of Nairobi, Nairobi, Kenya

6 Department of Epidemiology, University of Washington, Seattle, WA 98195, USA

7 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

8 Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, M5G 2C4, Canada

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BMC Infectious Diseases 2013, 13:263  doi:10.1186/1471-2334-13-263

Published: 4 June 2013

Abstract

Background

HIV-1-related inflammation is associated with increased levels of biomarkers of vascular adhesion and endothelial activation, and may increase production of the inflammatory protein angiopoietin-2 (ANG-2), an adverse prognostic biomarker in severe systemic infection. We hypothesized that antiretroviral therapy (ART) initiation would decrease endothelial activation, reducing plasma levels of ANG-2.

Methods

Antiretroviral-naïve Kenyan women with advanced HIV infection were followed prospectively. Endothelial activation biomarkers including soluble intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin, and plasma ANG-2 and angiopoietin-1 (ANG-1) were tested in stored plasma samples from 0, 6, and 12 months after ART initiation. We used Wilcoxon matched-pairs signed rank tests to compare endothelial activation biomarkers across time-points, generalized estimating equations to analyze associations with change in log10-transformed biomarkers after ART initiation, and Cox proportional-hazards regression to analyze associations with mortality.

Results

The 102 HIV-1-seropositive women studied had advanced infection (median CD4 count, 124 cells/μL). Soluble ICAM-1 and plasma ANG-2 levels decreased at both time-points after ART initiation, with concomitant increases in the beneficial protein ANG-1. Higher ANG-2 levels after ART initiation were associated with higher plasma HIV-1 RNA, oral contraceptive pill use, pregnancy, severe malnutrition, and tuberculosis. Baseline ANG-2 levels were higher among five women who died after ART initiation than among women who did not (median 2.85 ng/mL [inter-quartile range (IQR) 2.47–5.74 ng/mL] versus median 1.32 ng/mL [IQR 0.35–2.18 ng/mL], p = 0.01). Both soluble ICAM-1 and plasma ANG-2 levels predicted mortality after ART initiation.

Conclusions

Biomarkers of endothelial activation decreased after ART initiation in women with advanced HIV-1 infection. Changes in plasma ANG-2 were associated with HIV-1 RNA levels over 12 months of follow-up. Soluble ICAM-1 and plasma ANG-2 levels represent potential biomarkers for adverse outcomes in advanced HIV-1 infection.

Keywords:
HIV-1; HAART; ICAM-1; VCAM-1; E-selectin; Angiopoietin-1; Angiopoietin-2; Endothelium