Dataset Information

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

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.

SUBMITTER: Funderburg NT

PROVIDER: S-EPMC10371305 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Funderburg Nicholas T NT Shive Carey L CL Chen Zhengyi Z Tatsuoka Curtis C Bowman Emily R ER Longenecker Chris T CT McComsey Grace A GA Clagett Brian M BM Dorazio Dominic D Freeman Michael L ML Sieg Scott F SF Moisi Daniela D Anthony Donald D DD Jacobson Jeffrey M JM Stein Sharon L SL Calabrese Leonard H LH Landay Alan A Flexner Charles C Crawford Keith W KW Capparelli Edmund V EV Rodriguez Benigno B Lederman Michael M MM

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20230701 2

<h4>Background</h4>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.<h4>Methods</h4>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 intrave ...[more]

PMID: 37011013

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Project description:BackgroundAllergic conjunctivitis (AC) is one of the reported potential risk factors of progression in keratoconus patients after corneal cross-linking surgery; however, the causal relationship is still inconclusive. Recent studies have indicated that various inflammatory cytokines play a vital role in the development of primary keratoconus. It is still unclear whether these inflammatory mediators also trigger CXL failures. This study aimed to investigate the impact of AC on the rabbit corneas after trans-epithelial corneal cross-linking (TCXL).MethodsA total of six rabbits were kept untreated as the normal control (NC) group. A total of 18 rabbits were treated by TCXL and divided into three groups (six in each group), namely, no treatment (TCXL group); induction of AC (TCXL + AC group); and induction of AC plus topical prednisolone acetate (TCXL + AC + PA group), according to additional treatment. AC was induced by topical application of ovalbumin after intraperitoneal pre-sensitization with ovalbumin. Rabbits were evaluated by slit lamp, in vivo laser scanning confocal microscopy, anterior segment optical coherence tomography, and measurement of corneal biomechanics. The cornea specimens were collected for the transmission electron microscope, the collagenase I digestion test, and PCR assay for TNF-α, IL-6, IL-1β, matrix metalloproteinase 9 (MMP-9), lysyl oxidase (LOX), and tissue inhibitor of metalloproteinases 1 (TIMP-1) on the day (D) 28.ResultsOn D28, the TNF-α, IL-6, IL-1β, MMP-9, and LOX levels were significantly increased while the TIMP-1 was decreased in the TCXL + AC group when compared with the TCXL and TCXL + AC + PA groups. In vivo confocal microscopy revealed that at a depth of 150-210 μm, a trabecular patterned hyperdense structure surrounded by elongated needle-like processes could be observed in the TCXL and TCXL + AC + PA groups, but hardly seen in the TCXL + AC group. The demarcation lines were indistinct and blurred in the TCXL + AC group. An electron microscope demonstrated less interlacing fibril lamellae and higher interfibrillar spacing in the TCXL + AC group. The stability of corneal biomechanics and resistance to collagenase were decreased in the TCXL + AC group.ConclusionThe corneal microstructures induced by TCXL and biomechanical stability were diminished in rabbits with AC but could be maintained by topical anti-inflammatory treatment. Our results supported the causal relationship between altered cytokine profiles and corneal microstructure after primary corneal cross-linking.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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