PTU-116 Functional immune restoration correlates with HBSAG decline and may predict treatment response on sequential NUC therapy in CHB

Abstract

Introduction Sequential/combined therapeutic approaches comprising Pegylated-Interferon (Peg-IFNα) and nucleot (s)ide analogues (NUC) are being given greater consideration as treatment strategies for chronic hepatitis B (CHB) to achieve HBsAg loss. We demonstrated boosting of NK cells in eAg- patients treated with Peg-IFNα (Micco et al , J. Hepatol , 2013), and postulated this effect could be maintained with sequential NUC therapy. Differential NK cell responses in patients receiving sequential NUCs were analysed and correlated with HBsAg response, to elucidate a possible treatment advantage with Peg-IFNα exposure. Method PBMC from 18eAg+ patients during Peg-IFNα therapy were utlised. 9/18 patients considered Peg-IFNα non-responders after 48-weeks therapy progressed to sequential NUCs and were followed until virally suppressed. Phenotypic and functional analysis of NK cell subsets was performed by multicolour flow-cytometry and findings correlated with on-therapy HBsAg changes. Results Peg-IFNα expanded CD56 bright NK cells by 3-fold (p = 0.0001) which was maintained on sequential therapy. NK cell receptor expression was analysed. All receptors, except NKG2C, were maintained on sequential NUCs, with marked augmentation in the expression of NKp30 and NKp46 on CD56 bright NK cells (p = 0.5 log 10 IU/ml) on sequential NUCs. We noted that only these patients showed the ability to increase the proportion of functional NK cells (IFNγ+&CD107 + ) on sequential NUCs. Additionally only these responders demonstrated a reduction in TRAIL expression on sequential NUCs, compared to those without HBsAg decline, who showed the reverse. Conclusion Restoration of NK cell cytotoxic/effector functions is seen on sequential therapy, but only in those patients with HBsAg decline. Lower expression of TRAIL also correlates with treatment response, in line with our finding that TRAIL+ NK cells can delete antiviral T-cells ( Peppa et al , JEM 2013 ). IFNγ, CD107 and TRAIL expression on NK cells may predict those patients who are likely to demonstrate HBsAg decline on sequential therapy. Thus we have identified a phenotype of TRAIL low IFNγ/CD107 hi NK cells which may act as a biomarker in predicting treatment response in this setting. Given these findings, the TRAIL pathway may be a potential future target in order to improve treatment outcomes in CHB. Disclosure of interest None Declared.