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Inflammation and Coagulation Markers Predict Clinical Risk in START Trial
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Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle
Mark Mascolini
Higher baseline levels of IL-6 (an inflammation marker) and D-dimer (a coagulation marker) proved the strongest predictors of serious AIDS and non-AIDS events in the international START trial [1]. These associations held true across a range of CD4 counts in both antiretroviral-naive and treated people.
The landmark START study confirmed that people who begin antiretroviral therapy (ART) immediately, at a CD4 count above 500, have lower rates of AIDS and serious non-AIDS events than people who defer ART until their CD4 count dips below 350 [2]. Previous work by START investigators found links between markers of inflammation and coagulation and AIDS or non-AIDS events. The new analysis aimed to explore the impact of those markers on these and additional clinical outcomes in START participants.
The analysis focused on 5 inflammation markers (IL-6, hsCRP, serum amyloid A [SAA], sICAM, sVCAM), 1 immune activation marker (IL-27), and 1 coagulation activation marker (D-dimer). The biomarker study involved 2124 people in the immediate ART group and 2175 in the deferred ART group who had at least 1 biomarker measured at baseline. At study entry participants had a median age of 36 years and had diagnosed HIV infection for a median of 1 year. Median baseline CD4 count stood at 651 and viral load at 12,911 copies. While 45% of participants were white, 30% were black and 25% Latino, Asian, or other.
During an average 3.2 years of follow-up, 129 people died or had a new AIDS disease or a serious non-AIDS event. Cox regression analysis of clinical outcomes across trial arms (adjusted for age, gender, and treatment arm and stratified by region) determined that twice-higher baseline levels of D-dimer, IL-6, and SAA were independently associated with these endpoints: hazard ratio (HR) 1.41 for D-dimer, 1.39 for IL-6, 1.61 for an IL-6/D-dimer score,* and 1.13 for SAA.
Twice-higher baseline levels of several markers independently predicted AIDS or AIDS death (57 events): HR 1.52 for D-dimer, 1.46 for IL-6, 1.73 for IL-6/D-dimer score, 1.15 for hsCRP, 1.17 for SAA, and 1.66 for sICAM. Three markers independently predicted a serious non-AIDS event or non-AIDS death (74 events): HR 1.37 for D-dimer, 1.41 for IL-6, and 1.61 for the IL-6/D-dimer score.
The START team recorded 50 new diagnoses of AIDS or non-AIDS cancer, 23 cases of tuberculosis, and 24 cardiovascular events. Twice-higher levels of 4 markers independently predicted tuberculosis: HR 1.72 for D-dimer, 1.79 for IL-6, 2.22 for the IL-6/D-dimer score, and 1.97 for sICAM. Two markers independently predicted cardiovascular disease: HR 1.64 for IL-6 and 1.84 for the D-dimer/IL-6 score. No markers predicted cancer. Tuberculosis drove associations with AIDS events, and cardiovascular disease drove associations with non-AIDS events.
The researchers noted that biomarker associations with AIDS, serious non-AIDS events, or death were homogenous across the immediate and deferred ART arms. Thus in START "greater inflammation and coagulation at entry added to the increased risk of starting ART at lower CD4 counts."
Combined with prior biomarker work in START, the investigators believe the new findings "demonstrate that IL-6 and D-dimer consistently predict clinical risk across a broad spectrum of CD4 counts, and for both ART-naive and ART-treated individuals."
*The IL-6/D-dimer score simultaneously considers the independent contributions IL-6 and D-dimer for risk of serious non-AIDS events. See: Grund B, Baker JV, Deeks SG, et al. Relevance of interleukin-6 and D-dimer for serious non-AIDS morbidity and death among HIV-positive adults on suppressive antiretroviral therapy. PLoS One. 2016;11:e0155100.
References
1. Baker J, Sharma S, Grund B, for the INSIGHT START Study Group. Association of inflammation and coagulation with clinical risk in the START trial. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 623.
2. INSIGHT Start Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795-807.
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