Changes in Inflammation but Not in T-Cell Activation Precede Non-AIDS-Defining Events in a Case-Control Study of Patients on Long-term Antiretroviral Therapy

Abstract

Background: We examined changes in soluble inflammatory cytokines and T-cell activation after antiretroviral therapy (ART) initiation in an AIDS Clinical Trials Group (ACTG) nested case-control study.

Methods: Cases were 143 human immunodeficiency virus (HIV)-infected adults who developed a non-AIDS event; 315 controls remained event-free. Specimens were tested pre-ART, year 1 post-ART, and at the visit preceding the event. Conditional logistic regression evaluated the associations of biomarker changes with non-AIDS events.

Results: Inflammatory and most activation biomarkers declined from pre-ART to year 1 for cases and controls. Subsequently, inflammatory biomarkers remained mostly stable in controls but not cases. Cellular activation markers generally declined for both cases and controls between year 1 and the pre-event sampling. Controls with greater pre-ART RNA levels or lower CD4+ levels had higher biomarker levels while also experiencing greater biomarker declines in the first year of ART. Changes in biomarkers to year 1 showed no significant associations with non-AIDS events. Cases, however, had significantly greater increases in all plasma biomarkers (but not cellular activation) from year 1 to the visit preceding the event.

Conclusions: Inflammation increases prior to non-AIDS events in treated HIV-infected adults. These biomarker changes may reflect subclinical disease processes or other alterations in the inflammatory environment that causally contribute to disease.

Clinical trials registration: NCT00001137.

Figure 1.

Changes of biomarkers. A, Changes of log₁₀-transformed soluble biomarkers from year 1 to the pre-event time. B, Changes of T-cell biomarkers from year 1 to the pre-event time. The box plots display the data distribution. Boxes represent the first quartile, median, and the third quartile. Median relative changes are given separately for cases and controls; statistical comparison is based on conditional logistic regression. P value from conditional logistic regression model comparing distributions between cases and controls. Abbreviations: CXCL10, interferon-γ inducible protein 10; IL-6, interleukin 6; sTNFR, soluble tumor necrosis factor receptors; CD14, soluble CD14.

Figure 2.

Correlations (P values) of pre–antiretroviral therapy (ART) factors with changes of biomarkers. Soluble and T-cell biomarkers from pre-ART to year 1 for the controls (A) and from pre-ART to year 1 for the cases (B). Negative correlations in red and positive in blue. Correlations (P value) if P < .05. Correlations comparisons used a Spearman rank test. Abbreviations: BMI, body mass index; CXCL10, interferon-γ inducible protein 10; HIV-1, human immunodeficiency virus type 1; IL-6, interleukin 6; sTNFR, soluble tumor necrosis factor receptors; CD14, soluble CD14.

Figure 3.

Odds ratios per interquartile range of having a non-AIDS-defining event for biomarker changes from pre–antiretroviral therapy to year 1. Adjusted analyses controlled for concurrent CD4⁺ T-cell count. *P = .01 to <.05; **P < .01. Abbreviations: CI, confidence interval; CXCL10, interferon inducible protein 10; IL-6, interleukin 6; IQR, interquartile range; OR, odds ratio; sTNFR, soluble tumor necrosis factor receptor.

Figure 4.

Odds ratios per interquartile range of having a non-AIDS-defining event for biomarker changes from year 1 to the pre-event time. Adjusted analyses controlled for concurrent CD4⁺ T-cell count. *P = .01 to <.05; **P < .01. Abbreviations: CXCL10, interferon inducible protein 10; IL-6, interleukin 6; IQR, interquartile range; sTNFR, soluble tumor necrosis factor receptor.