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Randomized Controlled Trial
. 2012;7(3):e24243.
doi: 10.1371/journal.pone.0024243. Epub 2012 Mar 20.

Pre-ART levels of inflammation and coagulation markers are strong predictors of death in a South African cohort with advanced HIV disease

Lotty Ledwaba  1 , Jorge A Tavel, Paul Khabo, Patrick Maja, Jing Qin, Phumele Sangweni, Xiao Liu, Dean Follmann, Julia A Metcalf, Susan Orsega, Beth Baseler, James D Neaton, H Clifford Lane; Project Phidisa Biomarkers Team
Collaborators, Affiliations
Randomized Controlled Trial

Pre-ART levels of inflammation and coagulation markers are strong predictors of death in a South African cohort with advanced HIV disease

Lotty Ledwaba et al. PLoS One. 2012.

Abstract

Background: Levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer predict mortality in HIV patients on antiretroviral therapy (ART) with relatively preserved CD4+ T cell counts. We hypothesized that elevated pre-ART levels of these markers among patients with advanced HIV would be associated with an increased risk of death following the initiation of ART.

Methods: Pre-ART plasma from patients with advanced HIV in South Africa was used to measure hsCRP, IL-6 and D-dimer. Using a nested case-control study design, the biomarkers were measured for 187 deaths and two controls matched on age, sex, clinical site, follow-up time and CD4+ cell counts. Odds ratios were estimated using conditional logistic regression. In addition, for a random sample of 100 patients, biomarkers were measured at baseline and 6 months following randomization to determine whether ART altered their levels.

Results: Median baseline biomarkers levels for cases and controls, respectively, were 11.25 vs. 3.6 mg/L for hsCRP, 1.41 vs. 0.98 mg/L for D-dimer, and 9.02 vs. 4.20 pg/mL for IL-6 (all p<0.0001). Adjusted odds ratios for the highest versus lowest quartile of baseline biomarker levels were 3.5 (95% CI: 1.9-6.7) for hsCRP, 2.6 (95%CI 1.4-4.9) for D-dimer, and 3.8 (95% CI: 1.8-7.8) for IL-6. These associations were stronger for deaths that occurred more proximal to the biomarker measurements. Levels of D-dimer and IL-6, but not hsCRP, were significantly lower at month 6 after commencing ART compared to baseline (p<0.0001).

Conclusions: Among patients with advanced HIV disease, elevated pre-ART levels of hsCRP, IL-6 and D-dimer are strongly associated with early mortality after commencing ART. Elevated levels of inflammatory and coagulation biomarkers may identify patients who may benefit from aggressive clinical monitoring after commencing ART. Further investigation of strategies to reduce biomarkers of inflammation and coagulation in patients with advanced HIV disease is warranted.

Trial registration: Parent study: ClinicalTrials.gov NCT00342355.

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Conflict of interest statement

Competing Interests: Authors Beth Basseler and Xiao Liu are employees of SAIC Frederick, Inc. There are no patents, products in development or marketed products to declare. This does not alter the authors′ adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Phidisa II Study Design and Flow Diagram for Case-Control Substudy.
See this image and copyright information in PMC

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