733 
Does Activation of Inflammatory and Coagulation Pathways Independently Predict the Development of Opportunistic Disease in Patients with HIV Infection?
Alison Rodger*1, Z Fox1, J Lundgren2, L Kuller3, C Boesecke4, D Gey2, A Skoutelis5, M Goetz6, A Phillips1, and for the INSIGHT SMART Study Group
1Univ Coll London, UK; 2Ctr for Viral Diseases, KMA, Copenhagen, Denmark; 3Univ of Pittsburgh, PA, US; 4Natl Ctr in HIV Epi and Clinical Res, Sydney, Australia; 5Patras Univ Med Sch, Greece; and 6VA Greater Los Angeles Hlthcare System, CA, US
Background: The SMART trial demonstrated a higher risk
of opportunistic disease in patients on intermittent ART compared to those on continuous
ART. Markers of activation of inflammatory and coagulation pathways were
measured in a nested case control design within SMART to examine associations
between biomarker levels and the risk of opportunistic disease.
Methods: Patients (n = 5472) with CD4 count >350
cells/µL were randomized to continuous ART or to CD4-guided intermittent ART. For
patients who developed opportunistic disease (n = 91) and matched controls (n =
182), inflammatory (high-sensitivity C-reactive protein [hs-CRP], interleukin-6
[IL-6], amyloid A, and amyloid P) and coagulation (D-dimer and prothrobmin
fragment 1+2) markers were determined at baseline and during follow-up (at time
of latest plasma sample prior to the opportunistic disease event for the case
and at a matched time-point for the control). Conditional logistic regression
analyses were carried out to assess the associations between both baseline and
latest levels of each biomarker with opportunistic disease.
Results: There were 91 cases of opportunistic
disease during SMART: infective (n = 72, 79%), malignant (n = 12, 13%), and other
(n = 7, 8%). After adjustment for baseline CD4 count, baseline HIV RNA levels,
age and prior AIDS, both IL-6 and CRP demonstrated a significant trend towards
an increased risk of opportunistic disease with increasing biomarker levels at baseline.
Patients with hs-CRP levels ³5 mg/mL had 3.5 (95%CI 1.5 to 8.1) higher odds
of an opportunistic disease compared to those with CRP levels <1 mg/mL, ptrend = 0.003, and patients
with IL-6 ³3 pg/mL had 2.4 (95%CI 1.0 to
5.4) higher odds of an opportunistic disease compared to those with an IL-6
<1.5 pg/mL, ptrend = 0.02. No other baseline biomarkers
were predictive of development of an opportunistic disease. After adjustment
for baseline factors and the latest CD4 counts and HIV RNA levels, the latest hsCRP
(OR 7.6, 95%CI 2.0 to 28.5) for those with hs-CRP ³5 mg/mL versus those
with hsCRP <1 mg/mL, Ptrend =
0.002) and the latest IL-6 (OR 2.4, 95%CI 0.7 to 8.8) for patients with IL-6 ³3 pg/mL versus those with IL-6 <1.5 pg/mL,
ptrend = 0.04) were independently associated with
development of an opportunistic disease.
Conclusions: Higher levels of IL-6 and hs-CRP were
independently associated with development of an opportunistic disease. Although
reverse causality may have influenced this association, the fact that baseline levels
also predicted opportunistic disease events makes it less likely. Use of these biomarkers
could provide additional prognostic information for predicting risk of development
of opportunistic disease.
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