AEGiS-15CROI [139]: Elevated Levels of Interleukin-6 and D-dimer Are Associated with an Increased Risk of Death in Patients with HIV

15th Conference on Retroviruses and Opportunistic Infections

Boston, Massachusetts - February 3-6, 2008

ELEVATED LEVELS OF INTERLEUKIN-6 AND D-DIMER ARE ASSOCIATED WITH AN INCREASED RISK OF DEATH IN PATIENTS WITH HIV

Conf Retrovir Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 139)

Lewis Kuller and SMART Study Group
Univ of Pittsburgh, PA, US

BACKGROUND: In SMART, CD4-guided intermittent antiretroviral treatment (ART) as compared to continuous ART resulted in an increased risk of cardiovascular disease (CVD) and of all-cause mortality, the latter primarily due to non-AIDS diagnoses. To explore reasons for these increased risks, we evaluated four inflammatory (high sensitivity-C reactive protein [hsCRP], interleukin-6 [IL-6], amyloid A, and amyloid P) and two coagulation (D-dimer and prothrobmin fragment 1+2 [F1.2]) markers that have high laboratory and biological reproducibility and that have been associated with mortality and CVD in the general population.

METHODS: Patients with CD4+ count >350 cells/mm³ were randomized to viral suppression (VS) (continuous ART) (N=2,752) or to drug conservation (DC) (CD4-guided intermittent ART) (N=2,720). To assess the short-term effect of intermittent ART on the biomarkers, stored plasma samples at baseline and one month after randomization for a random subset of DC (N=249) and VS (N=250) patients were analyzed. In addition, a nested case control study was carried out in which two controls were matched (age, gender, country, date of randomization) to each death (N=85) and case of CVD (N=136). Adjusted odds ratios (ORs) for the 4^th versus 1^st quartile of each biomarker at baseline were estimated using logistic regression.

RESULTS: IL-6 and D-dimer levels increased by 30% and 16%, respectively, one month after randomization in the DC group and changed little in the VS group (5% and 0%) (P<0.0001 for treatment difference for each biomarker). For DC patients, increases in IL-6 and D-dimer after one month were related in a graded manner to the increases in HIV RNA at month 1 (P<0.0001 for each biomarker). IL-6 and D-dimer determined at baseline were strongly related to mortality with ORs greater than 12 for those in 4^th versus 1^st quartile. Associations with CVD were more modest and were significant for IL-6 and amyloid P. ORs are summarized in the table below.

Biomarker	All Case Mortality			Fatal or Non-Fatal CVD
Biomarker	OR	95%CI	P-value	OR	95%CI	P-value
hs-CRP	3.5	1.5-8.1	0.004	1.6	0.8-3.1	0.20
IL-6	12.6	4.3-37.4	<0.0001	2.8	1.4-5.5	0.003
Amyloid A	2.3	0.9-5.5	0.08	1.6	0.9-2.9	0.12
Amyloid P	1.1	0.5-2.4	0.90	2.8	1.4-5.3	0.002
D-dimer	13.3	4.4-40.3	<0.0001	2.0	1.0-3.9	0.06
F1.2	1.4	0.6-3.5	0.45	0.8	0.4-1.6	0.56

Associations of baseline levels of the biomarkers with all-cause mortality and with CVD were similar for DC and VS patients.

CONCLUSIONS: ART interruption results in significant increases in IL-6 and D-dimer. Elevated levels of D-dimer and IL-6 identify a subgroup of HIV-infected patients at high risk of death in both treatment groups. Increases in IL-6 and D-dimer may explain, in part, the increased risk of mortality and CVD in the DC group.

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2008-02-03
139

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