Hepatitis B Virus Flares following Nucleot(s)ide Analogue Cessation Are Associated with Activation of TLR Signalling Pathways.

Abstract

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. 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. 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. 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.