Inflammatory and coagulation biomarkers and mortality in patients with HIV infection

Abstract

Background: In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.

Methods and findings: Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case-control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0-4.1; p = 0.05), 8.3 (95% CI, 3.3-20.8; p < 0.0001), and 12.4 (95% CI, 4.2-37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case-control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1-3.1; p = 0.02) to 1.5 (95% CI, 0.8-2.8) and 1.4 (95% CI, 0.8-2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively.

Conclusions: IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation.

Trial registration: ClinicalTrials.gov NCT00027352.

Conflict of interest statement

Competing Interests: Bruno Ledergerber reported travel grants, grants or honoraria from Abbott, Aventis, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Roche and Tibotec. Jens Lundgren reported honoraria and research grants from Boehringer-Ingelheim, Roche, Abbott, Bristol-Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, Tibotec, Pfizer, and Gilead. Russell Tracy reported the following activities: (1) Wake Forest University Pepper Center on Aging—External Advisory Board; (2) Johns Hopkins University Pepper Center on Aging—External Advisory Board; (3) University of Florida Pepper Center on Aging—External Advisory Board; (4) Haematologic Technologies—owner; thrombosis and fibrinolysis biochemical reagents and blood collection tubes; contract research in this area; and (5) Ashcraft & Gerel Attorneys at Law—consulting on mechanisms in inflammation, atherosclerosis and thrombosis.

Figures

Figure 1. SMART Study Design and Flow Diagram for Case–Control Study

Figure 2. SMART Study Design and Flow Diagram for Random Sample

Figure 3. Change in Log10 IL-6 (pg/ml) from Baseline to 1 mo According to HIV-RNA Level at 1 mo for Participants in the Drug Conservation (DC) Group (CD4+ Guided Intermittent ART) with an HIV-RNA level 400 Copies/ml or Less at Baseline

Figure 4. Change in Log10 D-dimer (μg/ml) from Baseline to 1 mo According to HIV-RNA Level at 1 mo for Participants in the Drug Conservation (DC) Group (CD4+ Guided Intermittent ART) with an HIV-RNA level 400 Copies/ml or less at Baseline