Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment

Abstract

Background: Defining the association of non-AIDS-defining events with inflammation and immune activation among human immunodeficiency virus (HIV)-infected persons with antiretroviral therapy (ART)-associated virological suppression is critical to identifying interventions to decrease the occurrence of these events.

Methods: We conducted a case-control study of HIV-infected subjects who had achieved virological suppression within 1 year after ART initiation. Cases were patients who experienced non-AIDS-defining events, defined as myocardial infarction, stroke, non-AIDS-defining cancer, non-AIDS-defining serious bacterial infection, or death. Controls were matched to cases on the basis of age, sex, pre-ART CD4(+) T-cell count, and ART regimen. Peripheral blood mononuclear cells and plasma specimens obtained at the visit before ART initiation (hereafter, baseline), the visit approximately 1 year after ART initiation (hereafter, year 1), and the visit immediately preceding the non-AIDS-defining event (hereafter, pre-event) were analyzed for activated CD4(+) and CD8(+) T cells, plasma interleukin 6 (IL-6) level, soluble tumor necrosis factor receptor I (sTNFR-I) level, sTNFR-II level, soluble CD14 level, kynurenine-to-tryptophan (KT) ratio, and D-dimer level. Conditional logistic regression analysis was used to study the association between biomarkers and outcomes, with adjustment for potential confounders.

Results: Higher IL-6 level, sTNFR-I level, sTNFR-II level, KT ratio, and D-dimer level at year 1 were associated with the occurrence of a non-AIDS-defining event. Significant associations were also seen between non-AIDS-defining events and values of these biomarkers in specimens obtained at baseline and the pre-event time points. Effects remained significant after control for confounders. T-cell activation was not significantly related to outcomes.

Conclusions: Interventional trials to decrease the incidence of non-AIDS-defining events among HIV-infected persons with virological suppression should consider targeting the pathways represented by these soluble markers. Clinical Trials Registration. NCT00001137.

Keywords: ART; HIV; Non-AIDS morbidity; immune activation; inflammation.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Timing of non–AIDS-defining events in relation to time in years after antiretroviral therapy (ART) initiation. Fatal cases are indicated by solid black circles. Abbreviations: MI, myocardial infarction; SBI, serious bacterial infection.

Figure 2.

Median levels of soluble markers of inflammation and coagulation between cases (open circle) and controls (x) in specimens obtained at the visit before antiretroviral therapy (ART) initiation (baseline), the visit approximately 1 year after ART initiation (year 1), and the visit immediately preceding the non–AIDS-defining event (pre-event). Abbreviations: IL-6, interleukin 6; IP-10, interferon γ–inducible protein 10; sTNFR, soluble tumor necrosis factor receptor.

Figure 3.

Biomarker levels in specimens obtained at the visit before antiretroviral therapy initiation (baseline) and odds ratios (ORs) of having a non–AIDS-defining event. Adjusted analyses controlled for log10 baseline human immunodeficiency virus RNA load. *P = .01 to <.05; **P < .01. Abbreviations: IL-6, interleukin 6; IP-10, interferon γ–inducible protein 10; IQR, interquartile range; KT, kynurenine to tryptophan; MI, myocardial infarction; sTNFR, soluble tumor necrosis factor receptor.

Figure 4.

Biomarker levels in specimens obtained at the visit approximately 1 year after ART initiation (year 1) and odds ratios (ORs) of having a non–AIDS-defining event. Adjusted analyses controlled for concurrent CD4+ T-cell count. *P = .01 to <.05; **P < .01. Abbreviations: IL-6, interleukin 6; IP-10, interferon γ–inducible protein 10; IQR, interquartile range; KT, kynurenine to tryptophan; MI, myocardial infarction; sTNFR, soluble tumor necrosis factor receptor.

Figure 5.

Biomarker levels in specimens obtained at the visit immediately preceding the non–AIDS-defining event (pre-event) and odds ratios (ORs) of having a non–AIDS-defining event. Adjusted analyses controlled for concurrent CD4+ T-cell count. *P = .01 to <.05; **P < .01. Abbreviations: IL-6, interleukin 6; IP-10, interferon γ–inducible protein 10; IQR, interquartile range; KT, kynurenine to tryptophan; MI, myocardial infarction; sTNFR, soluble tumor necrosis factor receptor.

Figure 6.

Median levels of T-cell markers of activation and senescence between cases (open circle) and controls (x) in specimens obtained at the visit before antiretroviral therapy (ART) initiation (baseline), the visit approximately 1 year after ART initiation (year 1), and the visit immediately preceding the non–AIDS-defining event (pre-event).