Pretreatment levels of soluble cellular receptors and interleukin-6 are associated with HIV disease progression in subjects treated with highly active antiretroviral therapy

Abstract

Background: To identify inflammatory pathways that may contribute to the pathogenesis of human immunodeficiency virus (HIV) disease, we explored associations between AIDS or death and different inflammatory markers, including selected soluble tumor necrosis factor superfamily receptors (sTNFRs) and ligands, interleukin (IL)-6, and CD8 T cell activation, in individuals treated with highly active antiretroviral therapy (HAART).

Methods: A case-control study of subjects in AIDS Clinical Trials Group (ACTG) protocols 384 and 5015, who were matched according to the CD4 cell count and plasma viral load at baseline, was performed using conditional logistic regression.

Results: Higher pretreatment concentrations of sTNFR-1, sCD27, sCD40L, and plasma IL-6 were associated with a new AIDS-defining illness or death in separate models adjusted for age, sex, hemoglobin, and the latest CD4 cell counts. In additional models that excluded case patients with opportunistic infections, sTNFR-1, sCD27, and sCD40L were each associated with a new AIDS-defining malignancy or death that developed at a median of 51 weeks after initiation of HAART, by which time the majority of subjects had a CD4 cell count of >200 cells/cm(3) and had achieved a plasma viral load of <50 copies/mL.

Conclusion: These data are compatible with a model in which these soluble inflammatory markers identify pathways that may contribute to the pathogenesis of HIV disease progression, pathways that might not be a direct consequence of ongoing HIV type 1 replication.

Figure 1

Kaplan-Meier plot depicting the onset of a CDC Category C clinical event or death among cases, by week after HAART-initiation.

Figure 2

Scatter/box plots of baseline immune activation markers among cases of opportunistic infection, and AIDS-associated malignancy or death, and their corresponding matched controls. The boxes encompass the upper and lower quartiles of the distribution of each variable, where the median value is represented by the line within each box. To facilitate comparisons between these markers, values of each variable were subtracted by their mean then divided by their standard deviation (z score). Trends and significant differences between cases and controls that were identified by multivariable models are indicated by the P-value for these differences.