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

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.

Severity of cardiovascular disease outcomes among patients with HIV is related to markers of inflammation and coagulation.

BACKGROUND: In the general population, raised levels of inflammatory markers are stronger predictors of fatal than nonfatal cardiovascular disease (CVD) events. People with HIV have elevated levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and D-dimer; HIV-induced activation of inflammatory and coagulation pathways may be responsible for their greater risk of CVD. Whether the enhanced inflammation and coagulation associated with HIV is associated with more fatal CVD events has not been investigated. METHODS AND RESULTS: Biomarkers were measured at baseline for 9764 patients with HIV and no history of CVD. Of these patients, we focus on the 288 that experienced either a fatal (n=74) or nonfatal (n=214) CVD event over a median of 5 years. Odds ratios (ORs) (fatal versus nonfatal CVD) (95% confidence intervals [CIs]) associated with a doubling of IL-6, D-dimer, hsCRP, and a 1-unit increase in an IL-6 and D-dimer score, measured a median of 2.6 years before the event, were 1.39 (1.07 to 1.79), 1.40 (1.10 to 1.78), 1.09 (0.93 to 1.28), and 1.51 (1.15 to 1.97), respectively. Of the 214 patients with nonfatal CVD, 23 died during follow-up. Hazard ratios (95% CI) for all-cause mortality were 1.72 (1.28 to 2.31), 1.73 (1.27 to 2.36), 1.44 (1.15 to 1.80), and 1.88 (1.39 to 2.55), respectively, for IL-6, D-dimer, hsCRP, and the IL-6 and D-dimer score. CONCLUSIONS: Higher IL-6 and D-dimer levels reflecting enhanced inflammation and coagulation associated with HIV are associated with a greater risk of fatal CVD and a greater risk of death after a nonfatal CVD event. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrial.gov Unique identifier: SMART: NCT00027352, ESPRIT: NCT00004978, SILCAAT: NCT00013611.