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Inflammatory biomarkers prior to antiretroviral therapy as prognostic markers of 12-month mortality in South Africa and Uganda

Siedner, Mark J.a,b,c,d; Bwana, Mwebesa Boscoc; Asiimwe, Stephenc; Musinguzi, Nicholasc; Castillo-Mancilla, Josee; Amanyire, Gideonc; Tracy, Russell P.f; Bangsberg, David R.g,h; Orrell, Catherinei; Haberer, Jessica E.a,b On behalf of the META Study Investigators

doi: 10.1097/QAD.0000000000002305
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Objective: To determine the utility of biomarkers of immune activation, systemic inflammation, and coagulopathy prior to antiretroviral therapy to predict mortality during the first year of antiretroviral therapy (ART) in sub-Saharan Africa

Design: Prospective, observational cohort

Methods: We measured soluble CD14, interleukin-6, and D-dimer in non-pregnant individuals initiating ART in South Africa and Uganda in the Measuring Early Treatment Adherence (META) Study. We used survival analysis methods to estimate their association with 12-month mortality, and fit receiver operator curves (ROC) to assess the prognostic value of each biomarker.

Results: Six-hundred sixty individuals were enrolled and had pre-treatment biomarkers measured. Approximately 60% were female, with a median CD4 of 187 (IQR 111-425) and approximately half were enrolled each from South Africa and Uganda. We observed 34 deaths for a crude mortality of 5.3 deaths/100 person-years (95%CI 3.8–7.4), which ranged from 0/100py to 13.7/100py in the lowest and highest tertile of pre-treatment sCD14, respectively. In Cox models, all three biomarkers were strongly predictive of the hazard of death (AHR 3–6, all P < 0.01). In multivariable models including biomarkers, both pre-treatment CD4 count and pre-treatment viral load became borderline or non-significantly associated with mortality. The c-statistic for area under ROC was higher for all three biomarkers than for CD4 count (P < 0.01).

Conclusions: Biomarkers of immune activation, systemic inflammation, and coagulopathy prior to ART initiation are strongly predictive of early death on treatment after adjustment for CD4 count. Such biomarkers might serve as important prognostic indicators for patient triage in this population.

aHarvard Medical School, Boston, MA

bMassachusetts General Hospital, Boston, MA

cMbarara University of Science and Technology, Mbarara, Uganda

dAfrica Health Research Institute, Kwa-Zulu Natal, South Africa

eUniversity of Colorado, Denver, CO

fUniversity of Vermont, Burlington, VT

gBrigham and Women's Hospital, Boston, MA

hOregon Health Sciences University-Portland State University School of Public Health, Portland, OR

iUniversity of Cape Town, Cape Town, South Africa.

1The META Study Team Includes the following scientific investigators: Principal Investigators: Dr. Jessica Haberer, Dr. Catherine Orrell, Dr. Norma Ware, Dr. Mwebesa Bosco Bwana, Dr. Asiimwe Stephen, Dr. Amanyire Gideon, Hon. Dr. Tumwesigye Elioda, Dr. David Bangsberg; Co-Investigators: Dr. Alexander C. Tsai, Dr. Mark Siedner, Dr. Lynn Matthews, Dr. Ingrid Katz, Monique Wyatt

Correspondence to Mark J. Siedner, Massachusetts General Hospital Global Health, 125 Nashua Street, Boston, MA 02114 USA. Tel: +1 617 726 4686; fax: +1 617 724 1637; e-mail: msiedner@mgh.harvard.edu

Received 13 April, 2019

Revised 24 June, 2019

Accepted 27 June, 2019

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This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

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