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 Capparelli; Benigno Rodriguez; Michael M Lederman

doi:10.1093/cid/ciad199

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

Clin Infect Dis. 2023 Jul 26;77(2):272-279. doi: 10.1093/cid/ciad199.

Authors

Nicholas T Funderburg¹, Carey L Shive^{2

3}, Zhengyi Chen⁴, Curtis Tatsuoka⁵, Emily R Bowman¹, Chris T Longenecker⁶, Grace A McComsey^{2

7}, Brian M Clagett², Dominic Dorazio², Michael L Freeman², Scott F Sieg², Daniela Moisi², Donald D Anthony^{2

3

8}, Jeffrey M Jacobson², Sharon L Stein⁹, Leonard H Calabrese¹⁰, Alan Landay¹¹, Charles Flexner^{12

13

14}, Keith W Crawford¹⁵, Edmund V Capparelli¹⁶, Benigno Rodriguez², Michael M Lederman²

Affiliations

¹ Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, Ohio State University, Columbus, Ohio, USA.
² Department of Medicine, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
³ Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, USA.
⁴ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
⁵ Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁶ Department of Medicine and Department of Global Health, University of Washington, Seattle, Washington, USA.
⁷ Department of Pediatrics, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
⁸ Rheumatology Section, MetroHealth Medical Center, Cleveland, Ohio, USA.
⁹ Department of Surgery, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
¹⁰ Immunology and Rheumatology, Cleveland Clinic, Cleveland, Ohio, USA.
¹¹ Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
¹² Divisions of Clinical Pharmacology and Infectious Diseases, School of Medicine and Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
¹³ Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁴ Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
¹⁵ Therapeutic Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
¹⁶ Clinical Pediatrics and Pharmacy, University of California, San Diego, La Jolla, California, USA.

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.

Keywords: HIV-1; inflammation; interleukin-6; lipid profiling; tocilizumab.

Publication types

Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cross-Over Studies
HIV Infections* / drug therapy
Humans
Inflammation / drug therapy
Interleukin-6* / metabolism
Lipids

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

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