HIV This Week

Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, Ledergerber B, Lundgren J, Neuhaus J, Nixon D, Paton NI, Neaton JD; INSIGHT SMART Study Group Inflammatory and coagulation biomarkers and mortality in patients with HIV infection.. PLoS Med. 2008;5(10):e203.

In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (drug conservation [DC]) than continuous antiretroviral treatment (viral suppression [VS]). Kuller et al hypothesized that increased HIV-RNA levels following antiretroviral treatment interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis. 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 participants in the drug conservation and viral suppression trial arms 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 drug conservation and 250 viral suppression participants at study entry and 1 month following randomization. Higher levels of high sensitivity C-reactive protein (hsCRP), interleukin-6 (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 drug conservation and viral suppression groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 month by 30% and 16% in the drug conservation group and by 0% and 5% in the viral suppression group (p < 0.0001 for treatment difference for both biomarkers); increases in the drug conservation group were related to HIV-RNA levels at 1 month (p < 0.0001). In an expanded case-control analysis (four controls per case), the odds ratio (drug conservation/viral suppression) 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. The authors conclude that 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.

Editors’ note: Confidence intervals for the odd ratios in this analysis are wide, due to the low number of deaths in the SMART study which enrolled relatively health people living with HIV, and they lose statistical significance in the expanded case-control analysis. In any case most deaths were not HIV-related. Increases in inflammatory markers from the first study visit to the study preceding death appear to be associated with increased risk of death and several were more commonly found in people in the treatment interruption arm. HIV induces activation of inflammatory and coagulation pathways and it is these inflammatory changes that may be associated with premature mortality in people living with HIV. It should be recalled however that biomarker levels just before death may reflect reverse causality – they may be the result of an already present disease process rather than causing it. More research is needed.