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

Abstract

Background: Despite 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.

Methods: In 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.

Results: Over 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.

Conclusions: Both 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.

Fig 1. Composition of the serious non-AIDS disease or death (SNA/death) endpoint.

Only the first event per participant is counted.

Fig 2

Kaplan-Meier estimates of the cumulative proportion of participants who experienced serious non-AIDS disease or death (SNA/death), by quartiles of IL-6 (A), D-dimer (B), hsCRP (C), and the IL-6 & D-dimer score (D). Biomarkers were measured at study entry. At 5 years, the risk of SNA/death was 12.0% for participants in the highest quartile of IL-6, compared with 3.5% for participants in the two lowest quartiles. Abbreviations: IL-6 = Interleukin-6; hsCRP = high-sensitivity C-reactive protein.

Fig 3. Hazard ratios (HRs) for serious non-AIDS conditions or death (SNA/death) per 2x higher levels of IL-6, D-dimer, and hsCRP.

Panel A shows HRs for differences in baseline biomarker levels (a one-time measurement), estimated using proportional hazards models for each biomarker separately, and in a joint biomarker model containing both IL-6 and D-dimer. Panel B shows HRs for differences in “usual” (the within-subject long-term average) biomarker levels, estimated in separate and joint biomarker models after adjustment for regression dilution bias. All models were adjusted for age, sex, and study indicator (SMART, ESPRIT, SILCAAT). Abbreviations: IL-6 = Interleukin-6; hsCRP = high-sensitivity C-reactive protein.

Fig 4. Estimated hazard ratios (HR) for the composite endpoint of serious non-AIDS or death (SNA/death) and its components.

Hazard ratios are estimated per 2x higher level of IL-6 and D-dimer, with 95% confidence intervals. Two times higher biomarker levels corresponds to 1 unit higher on the log₂ biomarker scale, and 0.49 units higher for the IL-6 & D-dimer score. Hazard ratios were estimated in proportional hazards models adjusted for age, sex and study. Footnotes: Of the 144 deaths, 37 were due to non-AIDS cancer, 33 CVD, 11 non-cancer hepatic disease, 1 renal failure, 15 AIDS-related, 9 due to violence, accident or suicide, 38 due to other or unknown causes. Abbreviations: CI = confidence interval; CVD = cardiovascular disease (myocardial infarction, stroke, and death due to CVD); HR = hazard ratio.

Fig 5. Estimated risk reduction.

Panel A: Contour plot of the estimated reduction in the risk of serious non-AIDS conditions or death (SNA/death) when “usual” (within-person long-term average) levels of IL-6 and/or D-dimer are decreased by 0–40%, possibly through an intervention. Solid lines show predicted risk reductions of 5%, 10%, etc. Panels B and C show the lower and upper 95% confidence limits, respectively. For a 25% reduction in IL-6 and D-dimer, the risk of SNA/death is predicted to decline by 37% (95% CI: 28 to 46%). Footnotes: The reduction in the risk was estimated using Cox proportional hazards models, adjusted for regression dilution bias, and for age, sex, and study. Reliability coefficients for the regression dilution adjustment were estimated using longitudinal mixed models for biomarker data collected at baseline, years 1 and 3 for 235 participants on stable ART in the ESPRIT study. Abbreviations: CI = confidence interval; IL-6 = Interleukin-6.