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IL-6 Plus D-dimer Predict Non-AIDS Diagnoses and Death in 3-Cohort HIV Group
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20th Conference on Retroviruses and Opportunistic Infections, March 3-6, 2013, Atlanta
"every 25% reduction in IL-6 and D-dimer would cut the combined endpoint risk 37%."
Mark Mascolini
Interleukin 6 (IL-6) and D-dimer each predicted development of non-AIDS disease or death in an analysis of 3766 people with well-controlled HIV replication in three trial cohorts [1]. When combined, IL-6 and D-dimer improved predictive precision.
IL-6 (an inflammation marker) and D-dimer (a blood clot marker) see frequent use in studies trying to parse the impact of ongoing HIV-associated inflammation and coagulation on clinical outcomes. For example, an earlier SMART analysis linked higher IL-6 and D-dimer to all-cause mortality [2].
In the new analysis, researchers from two IL-2 trials (ESPRIT and SILCAAT) and the SMART antiretroviral interruption trial combined their study cohorts to assess the impact of log-transformed IL-6 and D-dimer--separately and together--on development of serious non-AIDS diseases (including cancer and heart, liver, and kidney disease) and all-cause death.
The analysis focused on people in the control arms of these three trials, so everyone was taking a continuous standard antiretroviral regimen throughout the study and everyone had suppressed viral replication--1748 in SMART, 1446 in ESPRIT, and 572 in SILCAAT. Follow-up averaged 2.7 years in SMART, 6.7 in ESPRIT, and 7.0 in SILCAAT. Median CD4 count for the combined study group stood at 500 (707 in SMART, 497 in ESPRIT, and 203 in SILCAAT). Median baseline marker levels were 1.7 pg/mL (interquartile range [IQR] 1.1 to 2.7) for IL-6 and 0.22 ug/mL (IQR 0.15 to 0.35) for D-dimer.
After an average follow-up of 4.9 years, 262 people (7% of 3766) reached the combined endpoint of a serious non-AIDS disease or death. The most prevalent endpoints were cancer in 36%, cardiovascular disease in 26%, and death or other non-AIDS conditions (excluding cancer, heart, liver, and kidney disease) in 27%. Kaplan-Meier analysis estimated a cumulative 7% rate of serious non-AIDS disease/death after 5 years of follow-up.
In Cox proportional hazards models adjusted for age and sex, every 2-fold higher IL-6 and D-dimer level was independently associated with a higher risk of reaching the combined endpoint when IL-6 and D-dimer were considered separately or together:
Markers considered separately:
-- Each 2-fold higher log2 IL-6: hazard ratio [HR] 1.44, P < 0.001
-- Each 2-fold higher log2 D-dimer: HR 1.25, P < 0.001
Markers considered together:
-- Each 2-fold higher log2 IL-6: HR 1.39, P < 0.001
-- Each 2-fold higher log2 D-dimer: HR 1.15, P = 0.02
The combined score added an IL-6 level of 0.33 x log2 and a D-dimer level of 0.14 x log 2 to predict risk of a serious non-AIDS disease or all-cause death. A Cox model adjusted for age and sex determined that every 2-fold higher combined IL-6 and D-dimer level boosted risk of the combined endpoint 60% while doubling the risk of all-cause death:
Each 2-fold higher log2 IL-6 + D-dimer:
-- HR 1.60 for combined endpoint (P < 0.001)
-- HR 1.37 for cardiovascular disease (P = 0.03)
-- HR 1.51 for cancer (P < 0.001)
-- HR 2.88 for renal/liver disease (P < 0.001)
-- HR 2.01 for all-cause death (P < 0.001)
The researchers proposed that a phase 3 clinical endpoint trial could be planned to determine how decreasing both IL-6 and D-dimer levels 25% would affect the risk of serious non-AIDS diagnoses or death. In further modeling, they calculated that such reductions would lower the non-AIDS/death risk 18%. After adjustment for regression dilution (dilution or attenuation in a regression coefficient when a single measured value of a covariate is used instead of the usual or average value over time) every 25% reduction in IL-6 and D-dimer would cut the combined endpoint risk 37%.
Because combining the two markers improved predictive precision, the researchers suggested both pathways contribute to risk of serious non-AIDS diagnoses or all-cause death. They proposed that the combined score "could be used to compare drugs with different mechanisms of action (targeting IL-6, D-dimer, or both) for their potential to reduce serious non-AIDS events/death."
In the discussion after this presentation, one attended noted that clinicians already have demonstrably effective interventions--such as smoking cessation--and suggested that resources might better be directed to improving implementation of those strategies.
References
1. Grund B, Baker J, Deeks S, et al. Combined effect of interleukin-6 and D-dimer on the risk of serious non-AIDS conditions: data from 3 prospective cohorts. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 60.
2. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5:e203.
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0050203
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