Journal of Infectious Diseases Advance Access published February 4, 2015 1

Early ART after Cryptococcal Meningitis is associated with Cerebrospinal Fluid Pleocytosis and Macrophage Activation in a Multisite Randomized Trial

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James E. Scriven1,2,3,*, Joshua Rhein4,5,*, Katherine Huppler Hullsiek6, Maximilian von Hohenberg4, Grace Linder4, Melissa A. Rolfes4, Darlisha A. Williams4,5, Kabanda Taseera7, David B. Meya4,5,8, Graeme Meintjes1,2,9,10, David R. Boulware4, and COAT Team

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Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa

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Liverpool School of Tropical Medicine, Liverpool, U.K

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Division of Infectious Diseases & International Medicine, Dept. of Medicine, University of Minnesota, Minneapolis, MN, USA

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Infectious Disease Institute, Makerere University, Kampala, Uganda

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Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA

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Mbarara University of Science and Technology, Mbarara, Uganda

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Department of Medicine, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda

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Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Department of Medicine, Imperial College London, UK

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Infectious Diseases Unit, GF Jooste Hospital, Cape Town, South Africa

Corresponding Author: David R Boulware, MTRF 3-222, 2001 6th Street SE, Minneapolis, MN 55455, Email: [email protected]

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*These authors contributed equally to the manuscript

© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Downloaded from http://jid.oxfordjournals.org/ at Tulane University on May 17, 2015

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2 Abstract Introduction: Earlier antiretroviral therapy(ART) initiation in cryptococcal meningitis resulted in higher

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mortality compared with deferred ART initiation (1-2 weeks vs. 5-weeks post meningitis diagnosis). We hypothesized this was due to ART-associated immune pathology, without clinically recognized IRIS. Methods: Three macrophage activation markers and 19 cytokines/chemokines were measured from

cryopreserved CSF and serum during the Cryptococcal Optimal ART Timing (COAT) trial. Comparisons

Results: More participants with early ART initiation had CSF white cell count (WCC) ≥5/L at day 14

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(58% vs. 40%, P=.047), after a median of 6-days ART. Differences were mainly driven by participants with CSF WCC

Early ART After Cryptococcal Meningitis Is Associated With Cerebrospinal Fluid Pleocytosis and Macrophage Activation in a Multisite Randomized Trial.

Earlier antiretroviral therapy (ART) initiation in cryptococcal meningitis resulted in higher mortality compared with deferred ART initiation (1-2 wee...
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