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Association between activation of inflammatory and coagulation pathways and mortality during long-term follow up in SMART
N. Paton, The INSIGHT SMART Study Group
MRC Clinical Trials Unit, London, United Kingdom
Background: Activation of inflammatory and coagulation pathways (as shown by elevated interleukin-6 [IL-6] and D-dimer respectively) was associated with early mortality in SMART. We aimed to determine whether this association persists with longer follow up.
Methods: A nested case control study was conducted using the full follow-up data set of 5472 SMART patients (CD4+ count >350 cells/mm3 at study entry). Patients who died from any cause were included as cases, and were further classified as early deaths (≤2 years after randomization, n = 95) or late deaths (>2 years, n = 71). Two controls were selected for each case, matched for country, age, gender and date of randomisation. IL-6 and D-dimer were measured in stored plasma samples at study entry. Odds ratios were calculated comparing the highest to the lowest quartile for each biomarker.
Results: Median levels of biomarkers were elevated in early and late deaths versus controls (3.58 and 3.72 versus 2.14 and 2.33 pg/ml respectively for IL-6; 0.45 and 0.31 versus 0.24 and 0.24 µg/ml, respectively for D-dimer). Higher baseline IL-6 levels were associated with both increased early (OR = 5.7, 2.6 - 12.6; P < 0.0001) and late (OR = 5.0, 2.0 - 12.9; P = 0.0007) mortality (p=0.46 for difference between time periods). Similarly, higher D-dimer levels were also associated with increased early (OR = 5.7, 2.6 - 12.8; P < 0.0001) and late (OR = 4.9, 1.6 - 14.5; P = 0.005) mortality (p=0.83 for difference).
Conclusions:
HIV-infected patients with elevated D-dimer and IL-6 are at increased risk of death, and this association persists, with minimal attenuation, in long-term follow up. The strength and durability of the association suggest that activation of inflammatory and coagulation pathways play an important role in HIV pathogenesis. Further research to establish the aetiology and to evaluate potential therapeutic interventions is warranted.
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