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Associations of Inflammatory Markers With AIDS and Non-AIDS Clinical Events After Initiation of Antiretroviral Therapy: AIDS Clinical Trials Group A5224s, a Substudy of ACTG A5202

McComsey, Grace A. MD*; Kitch, Douglas MS; Sax, Paul E. MD; Tierney, Camlin PhD; Jahed, Nasreen C. MS§; Melbourne, Kathleen PharmD; Ha, Belinda MD; Brown, Todd T. MD#; Bloom, Anthony MS**; Fedarko, Neal MD††; Daar, Eric S. MD‡‡

JAIDS Journal of Acquired Immune Deficiency Syndromes: February 1st, 2014 - Volume 65 - Issue 2 - p 167–174
doi: 10.1097/01.qai.0000437171.00504.41
Clinical Science

Background: The association of inflammatory biomarkers with clinical events after antiretroviral therapy initiation is unclear.

Methods: A5202 randomized 1857 treatment-naive subjects to abacavir/lamivudine or tenofovir-DF/emtricitabine with efavirenz or atazanavir/ritonavir. Substudy A5224s measured inflammatory biomarkers on subjects with available plasma from baseline and week 24 or 96. An exploratory analysis of the association of high-sensitivity C-reactive protein, interleukin-6 (IL-6), soluble receptors of tumor necrosis factor α (sTNF)-RI, sTNF-RII, TNF-α, soluble vascular cellular adhesion molecules (sVCAM-1), and soluble intercellular adhesion molecules (sICAM-1) with times to AIDS and to non-AIDS events used Cox proportional hazards models.

Results: Analysis included 244 subjects; 85% men and 48% white non-Hispanic with median age 39 years, HIV-1 RNA of 4.6 log10 copies per milliliter, and CD4 of 240 cells per microliter. Overall, 13 AIDS events (9 opportunistic infections, 3 AIDS-cancers, and 1 recurrent bacterial pneumonia) and 18 non-AIDS events (6 diabetes, 4 cancers, 3 cardiovascular, and 5 pneumonias) occurred. Higher baseline IL-6, sTNF-RI, sTNF-RII, and sICAM-1 were significantly associated with increased risk of AIDS-defining events. Adjustment for baseline HIV-1 RNA did not change results, whereas adjusting for baseline CD4 count left only sTNF-RI and sICAM-1 significantly associated with increased risk. Time-updated values of IL-6, sTNFR-I and II, and sICAM-1 were also associated with an increased risk. For non-AIDS events, only higher baseline high-sensitivity C-reactive protein was significantly associated with increased risk, whereas higher IL-6 was marginally associated with higher risk. Analyses of time-updated biomarker values showed tumor necrosis factor α to be significantly associated with increased risk, even after adjustment for antiretroviral therapy, and CD4 count or HIV-1 RNA.

Conclusions: Higher levels of several inflammatory biomarkers were independently associated with increased risk of AIDS and non-AIDS events.

Supplemental Digital Content is Available in the Text.

*Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OH;

Harvard School of Public Health, Boston, MA;

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA;

§Social & Scientific Systems, Inc., Silver Spring, MD;

Gilead Sciences, Foster City, CA;

GlaxoSmithKline, Research Triangle, NC;

#Department of Medicine, Johns Hopkins University, Baltimore, MD;

**Frontier Science and Technology Research Foundation, Amherst, NY;

††Department of Geriatric Medicine and Gerontology, Johns Hopkins University, Baltimore, MD;

‡‡Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.

Correspondence to: Grace A. McComsey, MD, Departments of Pediatrics and Medicine, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106 (e-mail:

Supported by Award No. U01AI068636, AI068634, AI38855, and AI065348 from the National Institute of Allergy and Infectious Diseases, and UL1 RR 025005 from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health.

G.A.M. has served as a scientific advisor or speaker for Bristol-Myers Squibb, GlaxoSmithKline, Merck, Janssen, and Gilead Sciences, has received research grants from Bristol-Myers Squibb, GlaxoSmithKline, and Gilead Sciences, and is currently serving as the DSMB Chair for a Pfizer-sponsored study. P.E.S. serves as a consultant for Abbott, BMS, Gilead, GSK, Merck, Janssen, and ViiV and receives grant support from Gilead, GSK, Merck, and Janssen. C.T. is a member of a Data Monitoring Committee for Tibotec. K.M. is an employee of Gilead Sciences and owns stock in Gilead Sciences. B.H. is an employee of GlaxoSmithKline. T.T.B. has served as a scientific consultant for Bristol-Myers Squibb, GlaxoSmithKline, Abbott, Janssen, and Gilead Sciences and has received research grants from GlaxoSmithKline and Merck. E.S.D. serves as a consultant for Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, ViiV and receives research grant support from Abbott Laboratories, Merck, Gilead, ViiV, and Pfizer. The remaining authors have no conflicts of interest to disclose. GlaxoSmithKline and Gilead funded the cost of the inflammation marker assays. Study medications were provided by Abbott Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline.

All authors played a role in editing the article and approved the text as submitted. G.A.M. designed the study and wrote the article. P.S. and E.D. assisted in the design of the study, reviewed and edited the article. D.K. and C.T. performed the data analysis and assisted in the interpretation of statistical data. K.M., N.J., A.B., B.H., and T.B. reviewed and edited the article. N.F. ran the biomarker assays and reviewed and edited the article. Data in this article were collected by AIDS Clinical Trials Group.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Clinical trials registry: NCT00118898. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.

Received June 04, 2013

Accepted August 27, 2013

© 2014 by Lippincott Williams & Wilkins