Interleukin 6 Blockade with Tocilizumab Diminishes Indices of Inflammation That Are Linked to Mortality in Treated Human Immunodeficiency Virus Infection

Nicholas T. Funderburg, Carey L. Shive, Zhengyi Chen, Curtis Tatsuoka, Emily R. Bowman, Chris T. Longenecker, Grace A. McComsey, Brian M. Clagett, Dominic Dorazio, Michael L. Freeman, Scott F. Sieg, Daniela Moisi, Donald D. Anthony, Jeffrey M. Jacobson, Sharon L. Stein, Leonard H. Calabrese, Alan Landay, Charles Flexner, Keith W. Crawford, Edmund V. CapparelliBenigno Rodriguez, Michael M. Lederman

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)272-279
Number of pages8
JournalClinical Infectious Diseases
Volume77
Issue number2
DOIs
StatePublished - Jul 15 2023
Externally publishedYes

Keywords

  • HIV-1
  • inflammation
  • interleukin-6
  • lipid profiling
  • tocilizumab

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

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