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AASLD 2013: NUC to follow failed PegINF
TITLE: Sustained restoration of innate immune responses and sAg decline in sequential NUC therapy following failed Pegylated-Interferon-α therapy in Chronic Hepatitis B
AUTHORS (FIRST NAME, LAST NAME): Upkar S. Gill1, Dimitra Peppa2, Lorenzo Micco2, Graham R. Foster1, Mala K. Maini2, Patrick T. Kennedy1
Institutional Author(s):
INSTITUTIONS (ALL): 1. Hepatology Unit, Centre for Digestive Diseases, Blizard Institute, Barts and The London, School of Medicine & Dentistry, QMUL, London, United Kingdom.
2. Division of Infection & Immunity, UCL, London, United Kingdom.
ABSTRACT BODY: INTRODUCTION: Treatment strategies in Chronic Hepatitis B (CHB) are rapidly evolving and greater consideration is being given to combination/sequential therapies. Recently a Pegylated-Interferon-α (PEG-IFN-α) switch strategy following viral suppression with a nucleos(t)ide analogue (NUC) was demonstrably superior to NUC monotherapy in sAg reduction and loss. The mechanism underpinning this effect remains ill defined. We have demonstrated boosting of NK cell responses in eAg-negative patients treated with PEG-IFN-α whereas long-term NUC’s have been shown to restore T-cell responses. We tested whether it would be possible to combine these two complementary effects by investigating whether augmented NK cell responses can be maintained on sequential NUC therapy, following PEG-IFN-α failure.
PATIENTS & METHODS: PBMC’s from 18 eAg-positive patients during PEG-IFN-α therapy were utilised. 8/18 patients, considered PEG-IFN-α non-responders after 48 weeks therapy, progressed to sequential NUC therapy and were followed until viral suppression was achieved. Phenotypic and functional analysis of NK cell subsets was performed by multicolour flow cytometry. Changes in immune responses were correlated with simultaneous measurements of ALT, HBV DNA and sAg titres.
RESULTS: PEG-IFN-α treatment expanded the CD56bright NK cell population by a mean of 3-fold (p=0.0001). Expression of the C-type lectin receptors (NKG2A, NKG2C, NKG2D) and natural cytotoxicity receptors (NKp30, NKp44, NKp46) were analysed. A 2-fold increase in NKp30 and a 1.5-fold increase in NKp46 expression on CD56bright NK cells was noted during PEG-IFN-α (p=0.03 and 0.04 respectively), sustained on sequential NUC therapy; whilst no significant change was detected in the C-type lectin receptors or NKp44 expression. An increase in the expression of IFN-γ producing CD56bright NK cells, during PEG-IFN-α therapy (p=0.05) was sustained on sequential NUC therapy; a functional restoration not achieved with NUC’s alone. These changes were associated with a sAg decline of 1.22 logIU/ml from baseline (p=0.05).
CONCLUSIONS: PEG-IFN-α expanded the CD56bright NK cell subset; NK cell expression of NKp30, NKp46 and IFN-γ production was augmented and sustained on sequential NUC therapy, correlating with a greater reduction in sAg levels compared to PEG-IFN-α alone or NUC monotherapy. Thus PEG-IFN-α in non-responders induces sustained innate boosting which is maintained on sequential NUC therapy, in association with sAg decline. Further work is needed to establish whether this priming effect is also present when early PEG-IFN-α stopping rules are applied.
AUTHORS (FIRST NAME, LAST NAME): Upkar S. Gill1, Dimitra Peppa2, Lorenzo Micco2, Graham R. Foster1, Mala K. Maini2, Patrick T. Kennedy1
Institutional Author(s):
INSTITUTIONS (ALL): 1. Hepatology Unit, Centre for Digestive Diseases, Blizard Institute, Barts and The London, School of Medicine & Dentistry, QMUL, London, United Kingdom.
2. Division of Infection & Immunity, UCL, London, United Kingdom.
ABSTRACT BODY: INTRODUCTION: Treatment strategies in Chronic Hepatitis B (CHB) are rapidly evolving and greater consideration is being given to combination/sequential therapies. Recently a Pegylated-Interferon-α (PEG-IFN-α) switch strategy following viral suppression with a nucleos(t)ide analogue (NUC) was demonstrably superior to NUC monotherapy in sAg reduction and loss. The mechanism underpinning this effect remains ill defined. We have demonstrated boosting of NK cell responses in eAg-negative patients treated with PEG-IFN-α whereas long-term NUC’s have been shown to restore T-cell responses. We tested whether it would be possible to combine these two complementary effects by investigating whether augmented NK cell responses can be maintained on sequential NUC therapy, following PEG-IFN-α failure.
PATIENTS & METHODS: PBMC’s from 18 eAg-positive patients during PEG-IFN-α therapy were utilised. 8/18 patients, considered PEG-IFN-α non-responders after 48 weeks therapy, progressed to sequential NUC therapy and were followed until viral suppression was achieved. Phenotypic and functional analysis of NK cell subsets was performed by multicolour flow cytometry. Changes in immune responses were correlated with simultaneous measurements of ALT, HBV DNA and sAg titres.
RESULTS: PEG-IFN-α treatment expanded the CD56bright NK cell population by a mean of 3-fold (p=0.0001). Expression of the C-type lectin receptors (NKG2A, NKG2C, NKG2D) and natural cytotoxicity receptors (NKp30, NKp44, NKp46) were analysed. A 2-fold increase in NKp30 and a 1.5-fold increase in NKp46 expression on CD56bright NK cells was noted during PEG-IFN-α (p=0.03 and 0.04 respectively), sustained on sequential NUC therapy; whilst no significant change was detected in the C-type lectin receptors or NKp44 expression. An increase in the expression of IFN-γ producing CD56bright NK cells, during PEG-IFN-α therapy (p=0.05) was sustained on sequential NUC therapy; a functional restoration not achieved with NUC’s alone. These changes were associated with a sAg decline of 1.22 logIU/ml from baseline (p=0.05).
CONCLUSIONS: PEG-IFN-α expanded the CD56bright NK cell subset; NK cell expression of NKp30, NKp46 and IFN-γ production was augmented and sustained on sequential NUC therapy, correlating with a greater reduction in sAg levels compared to PEG-IFN-α alone or NUC monotherapy. Thus PEG-IFN-α in non-responders induces sustained innate boosting which is maintained on sequential NUC therapy, in association with sAg decline. Further work is needed to establish whether this priming effect is also present when early PEG-IFN-α stopping rules are applied.
I don't have any more information. This is an abstract to be presented in the coming AASLD Liver meeting in November. There may be more information at the meeting, a full paper may or may not be published later on.
Please note this is a very small study. Hopefully we can gain more understanding about the interplay between NUC and Interefron sequential treatments from studies like this and arrive at a treatment scheme that will benefit us all.
Please note this is a very small study. Hopefully we can gain more understanding about the interplay between NUC and Interefron sequential treatments from studies like this and arrive at a treatment scheme that will benefit us all.
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