학술논문
Interleukin 6 Blockade With Tocilizumab Diminishes Indices of Inflammation That Are Linked to Mortality in Treated Human Immunodeficiency Virus Infection.
Document Type
Article
Author
Funderburg, Nicholas T; Shive, Carey L; Chen, Zhengyi; Tatsuoka, Curtis; Bowman, Emily R; Longenecker, Chris T; McComsey, Grace A; Clagett, Brian M; Dorazio, Dominic; Freeman, Michael L; Sieg, Scott F; Moisi, Daniela; Anthony, Donald D; Jacobson, Jeffrey M; Stein, Sharon L; Calabrese, Leonard H; Landay, Alan; Flexner, Charles; Crawford, Keith W; Capparelli, Edmund V
Source
Subject
*LIPID analysis
*HIV infections
*INTERLEUKINS
*HIV-positive persons
*THERAPEUTICS
*C-reactive protein
*TOCILIZUMAB
*EFFECT sizes (Statistics)
*INFLAMMATION
*CELL receptors
*ANTIRETROVIRAL agents
*DISEASES
*RANDOMIZED controlled trials
*RISK assessment
*PLACEBOS
*TREATMENT effectiveness
*RESEARCH funding
*INFLAMMATORY mediators
*CROSSOVER trials
*STATISTICAL sampling
*T cells
*DRUG side effects
*COMORBIDITY
*PATIENT safety
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Language
ISSN
1058-4838
Abstract
Background People with human immunodeficiency virus (PWH) are at increased risk for comorbidities, and plasma interleukin 6 (IL-6) levels are among the most robust predictors of these outcomes. Tocilizumab (TCZ) blocks the receptor for IL-6, inhibiting functions of this cytokine. Methods This was a 40-week, placebo-controlled, crossover trial (NCT02049437) where PWH on stable antiretroviral therapy (ART) were randomized to receive 3 monthly doses of TCZ or matching placebo intravenously. Following a 10-week treatment period and a 12-week washout, participants were switched to the opposite treatment. The primary endpoints were safety and posttreatment levels of C-reactive protein (CRP) and CD4+ T-cell cycling. Secondary endpoints included changes in inflammatory indices and lipid levels. Results There were 9 treatment-related toxicities of grade 2 or greater during TCZ administration (mostly neutropenia) and 2 during placebo administration. Thirty-one of 34 participants completed the study and were included in a modified intent-to-treat analysis. TCZ reduced levels of CRP (median decrease, 1819.9 ng/mL, P <.0001; effect size, 0.87) and reduced inflammatory markers in PWH, including D-dimer, soluble CD14, and tumor necrosis factor receptors. T-cell cycling tended to decrease in all maturation subsets after TCZ administration, but was only significant among naive CD4 T cells. Lipid levels, including lipid classes that have been related to cardiovascular disease risk, increased during TCZ treatment. Conclusions TCZ is safe and decreases inflammation in PWH; IL-6 is a key driver of the inflammatory environment that predicts morbidity and mortality in ART-treated PWH. The clinical significance of lipid elevations during TCZ treatment requires further study. Clinical Trials Registration. NCT02049437. [ABSTRACT FROM AUTHOR]