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RESEARCH ARTICLE

Elevated NT-Pro-Brain Natriuretic Peptide Level Is Independently Associated with AllCause Mortality in HIV-Infected Women in the Early and Recent HAART Eras in the Women’s Interagency HIV Study Cohort Matthew R. Gingo1*, Yingze Zhang1, Kidane B. Ghebrehawariat2, Jong-Hyeon Jeong2, Yanxia Chu1, Quanwei Yang1, Lorrie Lucht1, David B. Hanna3, Jason M. Lazar4, Mark T. Gladwin1,5, Alison Morris1,6

OPEN ACCESS Citation: Gingo MR, Zhang Y, Ghebrehawariat KB, Jeong J-H, Chu Y, Yang Q, et al. (2015) Elevated NTPro-Brain Natriuretic Peptide Level Is Independently Associated with All-Cause Mortality in HIV-Infected Women in the Early and Recent HAART Eras in the Women’s Interagency HIV Study Cohort. PLoS ONE 10(3): e0123389. doi:10.1371/journal.pone.0123389 Academic Editor: Claudio Passino, Fondazione G. Monasterio, ITALY Received: October 20, 2014 Accepted: February 18, 2015 Published: March 26, 2015 Copyright: © 2015 Gingo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: The authors do not own the data underlying this study. Data are available from the Women's Interagency HIV Study. Information for requesting data can be obtained at the website http://statepiaps.jhsph.edu/wihs/index-investinfo.htm. Funding: The Women’s Interagency HIV Study (WIHS) collected data in this manuscript. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH).

1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America, 2 Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, United States of America, 3 Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, United States of America, 4 Department of Medicine, SUNY Downstate Medical Center, Brooklyn, NY, United States of America, 5 Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh and UPMC, Pittsburgh, PA, United States of America, 6 Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America * [email protected]

Abstract Background HIV-infected individuals are at increased risk of right and left heart dysfunction. N-terminalpro-brain natriuretic peptide (NT-proBNP), a marker of cardiac ventricular strain and systolic dysfunction, may be associated with all-cause mortality in HIV-infected women. The aim of this study was to determine if elevated levels of NT-proBNP is associated with increased mortality in HIV-infected women.

Design Prospective cohort study.

Methods and Results We measured NT-proBNP in 936 HIV-infected and 387 age-matched HIV-uninfected women early (10/11/94 to 7/17/97) and 1082 HIV-infected and 448 HIV-uninfected women late (4/1/08 to 10/7/08) in the highly active antiretroviral therapy (HAART) periods in the Women’s Interagency HIV Study. An NT-proBNP >75th percentile was more likely in HIVinfected persons, but only statistically significant in the late period (27% vs. 21%, unadjusted p = 0.03). In HIV-infected participants, NT-proBNP>75th percentile was independently associated with worse 5-year survival in the early HAART period (HR 1.8, 95% CI 1.3–2.4,

PLOS ONE | DOI:10.1371/journal.pone.0123389 March 26, 2015

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BNP and Survival in HIV

WIHS (Principal Investigators): UAB-MS WIHS (Michael Saag), U01-AI-103401; Atlanta WIHS (Ighovwerha Ofotokun and Gina Wingood), U01-AI103408; Bronx WIHS (Kathryn Anastos), U01-AI035004; Brooklyn WIHS (Howard Minkoff and Deborah Gustafson), U01-AI-031834; Chicago WIHS (Mardge Cohen), U01-AI-034993; Metropolitan Washington WIHS (Mary Young), U01-AI-034994; Miami WIHS (Margaret Fischl and Lisa Metsch), U01AI-103397; UNC WIHS (Adaora Adimora), U01-AI103390; Connie Wofsy Women’s HIV Study, Northern California (Ruth Greenblatt, Bradley Aouizerat, and Phyllis Tien), U01-AI-034989; WIHS Data Management and Analysis Center (Stephen Gange and Elizabeth Golub), U01-AI-042590; Southern California WIHS (Alexandra Levine and Marek Nowicki), U01-HD-032632 (WIHS I – WIHS IV). The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute on Mental Health (NIMH). Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Deafness and other Communication Disorders (NIDCD), and the NIH Office of Research on Women’s Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA) and UL1-TR000454 (Atlanta CTSA). Investigator-initiated research grants were from Gilead and Roche. This study was supported by the following NIH grants: K23 HL108697 (to MRG); P01 HL103455 (to MTG, AM); R01 HL090339 (to AM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The corresponding author has read the journal's policy and the authors of this manuscript have the following competing interests: Gilead and Roche provided financial support in the form of investigator-initiated research grants. Gilead and Roche had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

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