Relevance of interleukin-6 and D-dimer for serious non-AIDS morbidity and death among HIV-positive adults on suppressive antiretroviral therapy

Birgit Grund, Jason V. Baker, Steven G. Deeks, Julian Wolfson, Deborah Wentworth, Alessandro Cozzi-Lepri, Calvin J. Cohen, Andrew Phillips, Jens D. Lundgren, James D. Neaton

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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.

Original languageEnglish (US)
Article numbere0155100
JournalPloS one
Volume11
Issue number5
DOIs
StatePublished - May 1 2016

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interleukin-6
morbidity
Interleukin-6
HIV
death
Morbidity
therapeutics
Biomarkers
C-reactive protein
C-Reactive Protein
Acquired Immunodeficiency Syndrome
Therapeutics
biomarkers
Risk Reduction Behavior
risk reduction
Coagulation
coagulation
Hazards
Joints
inflammation

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Relevance of interleukin-6 and D-dimer for serious non-AIDS morbidity and death among HIV-positive adults on suppressive antiretroviral therapy. / Grund, Birgit; Baker, Jason V.; Deeks, Steven G.; Wolfson, Julian; Wentworth, Deborah; Cozzi-Lepri, Alessandro; Cohen, Calvin J.; Phillips, Andrew; Lundgren, Jens D.; Neaton, James D.

In: PloS one, Vol. 11, No. 5, e0155100, 01.05.2016.

Research output: Contribution to journalArticle

Grund, Birgit ; Baker, Jason V. ; Deeks, Steven G. ; Wolfson, Julian ; Wentworth, Deborah ; Cozzi-Lepri, Alessandro ; Cohen, Calvin J. ; Phillips, Andrew ; Lundgren, Jens D. ; Neaton, James D. / Relevance of interleukin-6 and D-dimer for serious non-AIDS morbidity and death among HIV-positive adults on suppressive antiretroviral therapy. In: PloS one. 2016 ; Vol. 11, No. 5.
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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.",
author = "Birgit Grund and Baker, {Jason V.} and Deeks, {Steven G.} and Julian Wolfson and Deborah Wentworth and Alessandro Cozzi-Lepri and Cohen, {Calvin J.} and Andrew Phillips and Lundgren, {Jens D.} and Neaton, {James D.}",
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T1 - Relevance of interleukin-6 and D-dimer for serious non-AIDS morbidity and death among HIV-positive adults on suppressive antiretroviral therapy

AU - Grund, Birgit

AU - Baker, Jason V.

AU - Deeks, Steven G.

AU - Wolfson, Julian

AU - Wentworth, Deborah

AU - Cozzi-Lepri, Alessandro

AU - Cohen, Calvin J.

AU - Phillips, Andrew

AU - Lundgren, Jens D.

AU - Neaton, James D.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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.

AB - 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.

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