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

Abstract

BackgroundDespite 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.MethodsIn 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.ResultsOver 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.ConclusionsBoth 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.

Immunosenescence and hurdles in the clinical management of older HIV-patients

“…9 despite suppressive therapy; 7,18 moreover in SMART study IL-6 and DD values predicted both mortality and non-AIDS related events in HIV patients. 13,18 Numerous factors are involved in the persistence of inflammation during HIV infection: a) ongoing HIV production; b) viral coinfections and microbial translocation; c) loss of T-regulatory cells; d) irreversible fibrosis of the thymus and lymphoid tissues and e) oxidative stress from smoking, obesity and HAART toxicities. 7,13 In spite of the benefit in survival due to HAART, event therapy itself may contribute to cellular activation and senescence.…”

“…16 The higher level of inflammation in HIV individuals is measured by inflammatory biomarkers: in particular interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer (DD), cystatin C-dimers and cystatin D-dimers. 7,13,[17][18][19] In HIVinfected individuals these biomarkers are higher than in uninfected adults. They have been studied in HIV patients during HAART and they remain elevated Adapted by permission of James L. Kirkland.…”

“…8 However HAART is not able to normalize these phenomena. 8,18 The explanation of these finding may be related to the microbial translocation due to HIV gut mucosal injury, tissue fibrosis, coinfections as cytomegalovirus (CMV) and hepatitis C virus, and homeostatic drive. 48 The contribution of each of these phenomena may vary according to the timing of HAART introduction (started during acute or chronic infection), the degree of immune suppression (number of CD4 T-cells), age, comorbidities, and genetic background.…”

D-Dimer: A Novel Predictor of Survival in Patients with Cardiac Light- Chain Amyloidosis

“…D-dimer levels are widely used clinically to detect patients with suspected disseminated intravascular coagulation, thromboembolic events, and myocardial infarction [15]. Furthermore, D-dimer is an independent correlate of increased mortality and venous thrombosis across a variety of disease states [14,20]. D-dimer positively correlates with biomarkers of inflammation.…”

In silico thrombin generation: Plasma composition imbalance and mortality in human immunodeficiency virus

“…Increases in many chronic diseases would be expected with prolonged life expectancy,6 but a key factor contributing to excess rates of non‐AIDS events among treated HIV+ patients includes persistent abnormalities in systemic inflammation and coagulation activity 7, 8, 9. Higher levels of biomarkers such as d ‐dimer and interleukin‐6 (IL‐6)8, 9, 10 among HIV+ patients have been shown to be positively associated with anemia,11 cancer,12 cardiovascular disease,10 type 2 diabetes,13 progression to AIDS,14 and composite non‐AIDS related clinical events and all‐cause mortality 7, 8, 15. However, a mechanistic basis for the connection between HIV‐associated alterations in coagulation activity and risk for a broad spectrum of non‐AIDS defining diseases has yet to be elucidated.…”