Hepatitis B Virus Flares After Nucleot(s)ide Analogue Cessation Are Associated With Activation of Toll-Like Receptor Signaling Pathways

Samuel A L Hall; Gareth S Burns; Benjamin J Mooney; Rosemary Millen; Rachel Morris; Sara Vogrin; Vijaya Sundararajan; Dilip Ratnam; Miriam T Levy; John S Lubel; Amanda J Nicoll; Simone I Strasser; William Sievert; Paul V Desmond; Meng C Ngu; Peter Angus; Marie Sinclair; Christopher Meredith; Gail Matthews; Peter A Revill; Kathy Jackson; Margaret Littlejohn; Scott Bowden; Stephen A Locarnini; Alexander J Thompson; Kumar Visvanathan

doi:10.1093/infdis/jiac375

Hepatitis B Virus Flares After Nucleot(s)ide Analogue Cessation Are Associated With Activation of Toll-Like Receptor Signaling Pathways

J Infect Dis. 2022 Dec 28;227(1):123-132. doi: 10.1093/infdis/jiac375.

Authors

Samuel A L Hall^{1

2}, Gareth S Burns^{1

2}, Benjamin J Mooney², Rosemary Millen², Rachel Morris², Sara Vogrin², Vijaya Sundararajan³, Dilip Ratnam⁴, Miriam T Levy⁵, John S Lubel^{6

7}, Amanda J Nicoll⁸, Simone I Strasser^{9

10}, William Sievert^{4

11}, Paul V Desmond¹, Meng C Ngu¹², Peter Angus^{13

14}, Marie Sinclair¹³, Christopher Meredith¹⁵, Gail Matthews¹⁶, Peter A Revill¹⁷, Kathy Jackson¹⁷, Margaret Littlejohn¹⁷, Scott Bowden¹⁷, Stephen A Locarnini¹⁷, Alexander J Thompson^{1

2}, Kumar Visvanathan^{1

2}

Affiliations

¹ Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia.
² Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia.
³ The Department of Public Health, La Trobe University, Melbourne, Australia.
⁴ Gastroenterology and Hepatology Unit, Monash Health, Melbourne, Australia.
⁵ Gastroenterology Department of Liverpool Hospital, Sydney, Australia.
⁶ Department of Gastroenterology, Alfred Health, Melbourne, Australia.
⁷ Central Clinical School, Monash University, The Alfred Centre, Melbourne, Australia.
⁸ Gastroenterology Department of Eastern Health, Melbourne, Australia.
⁹ AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia.
¹⁰ Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
¹¹ Department of Medicine, Monash University, Melbourne, Australia.
¹² Gastroenterology Department of Concord Repatriation General Hospital, Sydney, Australia.
¹³ Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia.
¹⁴ Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia.
¹⁵ Gastroenterology Department of Bankstown-Lidcombe Hospital, Sydney, Australia.
¹⁶ Department of infectious Disease, St Vincent's Hospital Sydney, SydneyAustralia.
¹⁷ Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia.

PMID: 36108079
DOI: 10.1093/infdis/jiac375

Abstract

Background: We evaluated the patterns of peripheral Toll-like receptor (TLR) signaling activity and the expression of TLRs and natural killer (NK) cell activation in a cohort of patients experiencing severe hepatitis flares after stopping nucleot(s)ide analogues (NAs) therapy.

Methods: Samples were collected longitudinally from patients with chronic hepatitis B who were enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared with patients with normal alanine aminotransferase. Peripheral blood mononuclear cells (PBMCs) were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46, and triggering receptor expressed on myeloid cells 1 (TREM-1) on monocytes, NK, and NK-T cells was measured.

Results: Seventeen patients with severe reactivation hepatitis flares were compared to 12 nonflare patients. Hepatitis flares were associated with increased activity of TLR2-8 and TLR9 signaling in PBMCs at the time of peak flare compared to baseline. Hepatitis flares were also associated with (1) upregulation of TLR2 and (2) TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and nonflare patients.

Conclusions: Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signaling on peripheral monocytes and TLR2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares.

Keywords: cessation; entecavir; flare; hepatitis B virus; tenofovir.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / therapeutic use
Hepatitis B e Antigens
Hepatitis B virus
Hepatitis B, Chronic*
Humans
Natural Killer T-Cells*
Prospective Studies
Signal Transduction
Toll-Like Receptor 2
Toll-Like Receptors
Triggering Receptor Expressed on Myeloid Cells-1

Substances

Toll-Like Receptor 2
Triggering Receptor Expressed on Myeloid Cells-1
Toll-Like Receptors
Antiviral Agents
Hepatitis B e Antigens