Hepatitis B Virus Flares following Nucleot(s)ide Analogue Cessation Are Associated with Activation of TLR Signalling Pathways
Samuel Al Hall 1 2 , Gareth S Burns 3 4 , Benjamin J Mooney 4 , Rosemary Millen 4 , Rachel Morris 4 , Sara Vogrin 4 , Vijaya Sundararajan 5 , Dilip Ratnam 6 , Miriam T Levy 7 , John S Lubel 8 9 , Amanda J Nicoll 10 , Simone I Strasser 11 12 , William Sievert 6 13 , Paul V Desmond 3 , Meng C Ngu 14 , Peter Angus 15 16 , Marie Sinclair 15 , Christopher Meredith 17 , Gail Matthews 18 , Peter A Revill 19 , Kathy Jackson 19 , Margaret Littlejohn 19 , Scott Bowden 19 , Stephen A Locarnini 19 , Alexander J Thompson 3 4 , Kumar Visvanathan 3 4
Affiliations
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
Gastroenterology Department of St Vincent's Hospital Melbourne Melbourne, Australia.
4
Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia.
5
The Department of Public Health, La Trobe University Melbourne, Australia.
6
Gastroenterology & Hepatology Unit, Monash Health Melbourne, Australia.
7
Gastroenterology Department of Liverpool Hospital Sydney, Australia.
8
Department of Gastroenterology, Alfred Health Melbourne, Australia.
9
Central Clinical School, Monash University, The Alfred Centre Melbourne, Australia.
10
Gastroenterology Department of Eastern Health Melbourne, Australia.
11
AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital Sydney, Australia.
12
University of Sydney Sydney, Australia.
13
Monash University Melbourne, Australia.
14
Gastroenterology Department of Concord Repatriation General Hospital Sydney, Australia.
15
Department of Gastroenterology & Hepatology, Austin Health Melbourne, Australia.
16
University of Melbourne Melbourne, Australia.
17
Gastroenterology Department of Bankstown-Lidcombe Hospital Sydney, Australia.
18
Department of infectious Disease, St Vincent's Hospital Sydney Sydney Australia.
19
Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute Melbourne, Australia.
PMID: 36108079 DOI: 10.1093/infdis/jiac375
Abstract
Background and aims: We evaluated the patterns of peripheral TLR signalling activity and the expression of TLRs and NK cell activation in a cohort of patients experiencing severe hepatitis flares after stopping NA therapy.
Methods: Samples were collected longitudinally from CHB patients enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared to patients with normal ALT. PBMC were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46 and TREM-1 on monocytes, NK and NK-T cells was measured.
Results: 17 patients with severe reactivation hepatitis flares were compared to 12 non-flare patients. Hepatitis flares were associated with increased activity of TLR 2-8 and TLR 9 signalling in PBMC at the time of peak flare compared to baseline. Hepatitis flares were also associated with upregulation of TLR2, and TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and non-flare patients.
Conclusion: Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signalling on peripheral monocytes and TLR-2 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.