Relevance of Interleukin-6 and D-Dimer for Serious Non-AIDS Morbidity and Death among HIV-Positive Adults on Suppressive Antiretroviral Therapy

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Abstract

Background

Despite effective antiretroviral treatment (ART), HIV-positive individuals are at increased risk of serious non-AIDS conditions (cardiovascular, liver and renal disease, and cancers), perhaps due in part to ongoing inflammation and/or coagulation. To estimate the potential risk reduction in serious non-AIDS conditions or death from any cause that might be achieved with treatments that reduce inflammation and/or coagulation, we examined associations of interleukin-6 (IL-6), D-dimer, and high-sensitivity C-reactive protein (hsCRP) levels with serious non-AIDS conditions or death in 3 large cohorts.

Methods

In HIV-positive adults on suppressive ART, associations of IL-6, D-dimer, and hsCRP levels at study entry with serious non-AIDS conditions or death were studied using Cox regression. Hazard ratios (HR) adjusted for age, gender, study, and regression dilution bias (due to within-person biomarker variability) were used to predict risk reductions in serious non-AIDS conditions or death associated with lower “usual” levels of IL-6 and D-dimer.

Results

Over 4.9 years of mean follow-up, 260 of the 3766 participants experienced serious non-AIDS conditions or death. IL-6, D-dimer and hsCRP were each individually associated with risk of serious non-AIDS conditions or death, HR = 1.45 (95% CI: 1.30 to 1.63), 1.28 (95% CI: 1.14 to 1.44), and 1.17 (95% CI: 1.09 to 1.26) per 2x higher biomarker levels, respectively. In joint models, IL-6 and D-dimer were independently associated with serious non-AIDS conditions or death, with consistent results across the 3 cohorts and across serious non-AIDS event types. The association of IL-6 and D-dimer with serious non-AIDS conditions or death was graded and persisted throughout follow-up. For 25% lower “usual” IL-6 and D-dimer levels, the joint biomarker model estimates a 37% reduction (95% CI: 28 to 46%) in the risk of serious non-AIDS conditions or death if the relationship is causal.

Conclusions

Both IL-6 and D-dimer are independently associated with serious non-AIDS conditions or death among HIV-positive adults with suppressed virus. This suggests that treatments that reduce IL-6 and D-dimer levels might substantially decrease morbidity and mortality in patients on suppressive ART. Clinical trials are needed to test this hypothesis.

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Most cited references 47

Record: found
Abstract: not found
Article: not found

Multimodel Inference: Understanding AIC and BIC in Model Selection

K. Burnham (2004)

0 comments Cited 1117 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection

Jens D Lundgren, Abdel Babiker, Fred Gordin … (2015)

New England Journal of Medicine, 373(9), 795-807

0 comments Cited 507 times – based on 0 reviews      Review now

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Record: found
Abstract: found
Article: not found

C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis

George Davey Smith (2010)

Summary Background Associations of C-reactive protein (CRP) concentration with risk of major diseases can best be assessed by long-term prospective follow-up of large numbers of people. We assessed the associations of CRP concentration with risk of vascular and non-vascular outcomes under different circumstances. Methods We meta-analysed individual records of 160 309 people without a history of vascular disease (ie, 1·31 million person-years at risk, 27 769 fatal or non-fatal disease outcomes) from 54 long-term prospective studies. Within-study regression analyses were adjusted for within-person variation in risk factor levels. Results Loge CRP concentration was linearly associated with several conventional risk factors and inflammatory markers, and nearly log-linearly with the risk of ischaemic vascular disease and non-vascular mortality. Risk ratios (RRs) for coronary heart disease per 1-SD higher loge CRP concentration (three-fold higher) were 1·63 (95% CI 1·51–1·76) when initially adjusted for age and sex only, and 1·37 (1·27–1·48) when adjusted further for conventional risk factors; 1·44 (1·32–1·57) and 1·27 (1·15–1·40) for ischaemic stroke; 1·71 (1·53–1·91) and 1·55 (1·37–1·76) for vascular mortality; and 1·55 (1·41–1·69) and 1·54 (1·40–1·68) for non-vascular mortality. RRs were largely unchanged after exclusion of smokers or initial follow-up. After further adjustment for fibrinogen, the corresponding RRs were 1·23 (1·07–1·42) for coronary heart disease; 1·32 (1·18–1·49) for ischaemic stroke; 1·34 (1·18–1·52) for vascular mortality; and 1·34 (1·20–1·50) for non-vascular mortality. Interpretation CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size. The relevance of CRP to such a range of disorders is unclear. Associations with ischaemic vascular disease depend considerably on conventional risk factors and other markers of inflammation. Funding British Heart Foundation, UK Medical Research Council, BUPA Foundation, and GlaxoSmithKline.

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Author and article information

Contributors

Esaki M. Shankar: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 12 May 2016

Publication date Collection: 2016

Volume: 11

Issue: 5

Electronic Location Identifier: e0155100

Affiliations

[1 ]School of Statistics, University of Minnesota, Minneapolis, MN, United States of America

[2 ]Hennepin County Medical Center, Minneapolis, MN, United States of America

[3 ]Department of Medicine, University of Minnesota, Minneapolis, MN, United States of America

[4 ]University of California San Francisco, San Francisco, CA, United States of America

[5 ]San Francisco General Hospital, San Francisco, CA, United States of America

[6 ]Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, United States of America

[7 ]University College London, London, United Kingdom

[8 ]Medical Affairs Department, Gilead Sciences, Foster City, CA, United States of America

[9 ]Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

University of Malaya, MALAYSIA

Author notes

Competing Interests: The authors have the following potentially competing interests: AP received fees for speaking from Gilead Sciences, consulting from GSK Biologicals, and advisory board membership from AbbVie. CJC is currently receiving salary support from Gilead Sciences. The other authors reported no competing interests. While the SILCAAT and ESPRIT trials were supported by Chiron-Novartis, none of the authors received salary support from Chiron-Novartis, or have any competing interests with respect to ChironNovartis. The potentially competing interests do not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: BG JVB SGD JW CJC AP JDL JDN. Analyzed the data: BG DW. Wrote the paper: BG JVB SGD JW CJC AC-L AP JDL JDN.

¶ Complete membership of the author group can be found in the Acknowledgments.

* E-mail: birgit@ 123456ccbr.umn.edu

Author information

Birgit Grund http://orcid.org/0000-0003-4275-7880

Article

Publisher ID: PONE-D-15-55322

DOI: 10.1371/journal.pone.0155100

PMC ID: 4865234

PubMed ID: 27171281

SO-VID: d00a0769-c639-4ed4-ae28-5ff6ea3b0f44

License:

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.

History

Date received : 21 December 2015

Date accepted : 25 April 2016

Page count

Figures: 5, Tables: 1, Pages: 16

Funding

Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: U01-AI068641