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Inflammation-Related Morbidity and Mortality Among HIV-Positive Adults: How Extensive Is It?

Hart, Brian, B., BA*; Nordell, Anna, D., MS; Okulicz, Jason, F., MD‡,§; Palfreeman, Adrian, MD; Horban, Andrzej, MD; Kedem, Eynat, MD#; Neuhaus, Jacqueline, MS*; Jacobs, David, R., Jr, PhD**; Duprez, Daniel, A., MD, PhD††; Neaton, James, D., PhD*for the INSIGHT SMART and ESPRIT Groups

JAIDS Journal of Acquired Immune Deficiency Syndromes: January 1, 2018 - Volume 77 - Issue 1 - p 1–7
doi: 10.1097/QAI.0000000000001554

Objective: To determine the rate of grade 4, potentially life-threatening events not attributable to AIDS, cardiovascular disease (CVD), or non-AIDS cancer among participants on antiretroviral therapy and to describe associations of these events with interleukin-6 (IL-6) and D-dimer.

Design: Cohort study.

Methods: HIV-infected participants on antiretroviral therapy (N = 3568) with an HIV-RNA level ≤ 500 copies/mL were followed for grade 4, AIDS, CVD, non-AIDS cancer, and all-cause mortality events. Grade 4 events were further classified masked to biomarker levels as reflecting chronic inflammation–related disease (ChrIRD) or not (non-ChrIRD). Associations of baseline IL-6 and D-dimer with events were studied using Cox models.

Results: Over a median follow-up of 4.3 years, 339 participants developed a grade 4 event (22.9 per 1000 person-years); 165 participants developed a ChrIRD grade 4 event (10.7 per 1000 person-years). Grade 4 events were more common than AIDS (54 participants), CVD (132), and non-AIDS cancer (80) events, any of which developed in 252 participants (17.1 per 1000 person-years). Grade 4 and AIDS events were associated with similar risks of death. Higher IL-6 [hazard ratio (HR) = 1.19 per doubling of biomarker; P = 0.003] and D-dimer (HR = 1.23; P < 0.001) levels were associated with an increased risk of grade 4 events. IL-6 associations were stronger for ChrIRD (HR = 1.38; P < 0.001) than non-ChrIRD grade 4 events (HR = 1.11; P = 0.21).

Conclusions: Morbidity and mortality associated with activation of inflammatory and coagulation pathways include conditions other than AIDS, CVD, and non-AIDS cancer events. Effective inflammation-dampening interventions could greatly affect the health of people with HIV.

*Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN;

North American Science Associates, Minneapolis, MN;

Infectious Disease Service, San Antonio Military Medical Center, Fort Sam Houston, TX;

§Department of Preventive Medicine and Biostatistics, Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD;

Department of Infectious Diseases, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom;

Department of Adult Infectious Diseases, Medical University of Warsaw, Warsaw, Poland;

#Department of Immunology, Allergy and AIDS, Rambam Health Care Center, Haifa, Israel;

**Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN; and

††Cardiovascular Division, University of Minnesota, Minneapolis, MN.

Correspondence to: Brian B. Hart, BA, 2221 University Avenue SE, Suite 200, Minneapolis, MN 55414-3080 (e-mail:

The SMART and ESPRIT studies were funded by the NIAID. Grant numbers were U01AI042170 and U01AI46362 for SMART and U01AI46957 and U01AI06841 for ESPRIT studies.

The authors have no conflicts of interest to disclose.

A.D.N., B.B.H., J.D.N., D.R.J., and D.A.D. constructed the concept for the work and helped to prepare the first draft of the manuscript. B.B.H. performed the analysis for the manuscript. All authors helped to critically revise the manuscript and approved the final draft.

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Received March 07, 2017

Accepted August 30, 2017

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