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.
Bibliographical noteFunding Information:
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 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 acknowledge the SMART and ESPRIT participants and investigators (see N Engl J Med 2006;355:2283?2296 for the complete list of SMART investigators and N Engl J Med 2009;361:1548?1559 for the ESPRIT investigators).
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- Grade 4 events
- Serious non-AIDS