Stopping NAs: Stop to flare as new concept for functional cure of - - PowerPoint PPT Presentation

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Stopping NAs: Stop to flare as new concept for functional cure of - - PowerPoint PPT Presentation

Feb 09, 2023 421 likes •630 views

Stopping NAs: Stop to flare as new concept for functional cure of chronic hepatitis B Franziska Rinker, Ph.D. in the group of Markus Cornberg Department of Gastroenterology, Hepatology and Endocrinology NA therapy in chronic HBV patients

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Stopping NAs: Stop to flare as new concept for functional cure of chronic hepatitis B

Franziska Rinker, Ph.D. in the group of Markus Cornberg Department of Gastroenterology, Hepatology and Endocrinology

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NA therapy in chronic HBV patients

1Chang et al., Hepatology 2010 2Marcellin et al., Lancet. 2013 3Hosaka et al., Hepatology 2013, Kwon and Lok, Antivir Ther 2011 4Kim et al., Gut. 2014 Aug;63(8):1325-32. Editorial: Cornberg et al., Gut. 2014 Aug;63(8):1208-9. 5Chevaliez et al., J Hepatol 2013; 58(4):676-83.

Glebe & Bremer, Semin Liver Dis. 2013

NA therapy

BL w48 w268 Regression of liver fibrosis/cirrhosis1,2 Potent suppression of viral replication Reduction of hepatocellular carcinoma incidences3

However, ...

HBsAg loss (clinical cure) is rare (0.33% per year with NA)4 and takes 30-143 years5

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Main drawback of NA therapy: cccDNA is not directly effected NAs

1 Fabien Zoulim and David Durantel, Cold Spring Harb Perspect, Med2015;5;a021501

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Stopping NA-therapy as a therapeutic concept?

  • 33 HBeAg negative patients with 4–5 yrs suppression on ADV

stopped therapy

 13 of 33 (39%) cleared HBsAg during a follow up of of 5.5 years !

Hadziyannis et al., Gastroenterology. 2012 Sep;143(3):629-36

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Study design

1.5-3 years at follow up: n=3 HBsAg negative (20%) n=2 anti-HBs positive

Höner zu Siederdissen, Rinker, et al., J Infect Dis. 2016 Age: 33-65 yrs 70% Gen D, 30% Gen B+C Fibroscan 5.3 – 11.4 kPa 46% HBsAg <1,000 IU/ml

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Prospective, randomized study confirms HBsAg decline after stopping TDF therapy

T Berg et al., O0119 EASL 2015

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Time point of virological relapse (VR) after treatment discontinuation

HBV DNA until peak viremia after treatment discontinuation

Reanalysis of Höner zu Siederdissen, Rinker, et al., J Infect Dis. 2016

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Late relapse after therapy stop with ETV compared to TDF

ETV TDF

>70% relapse < 10% relapse

Subjects without Viral Relapse (HBV-DNA ≤ 2000 IU/ml) after NA treatment interruption - Kaplan-Meier curves.

H Wedemeyer et al., ILC 2017; LBP-518

patients without viral relapse % patients without viral relapse %

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Study design

Age: 33-65 yrs 70% Gen D, 30% Gen B+C Fibroscan 5.3 – 11.4 kPa 46% HBsAg <1,000 IU/ml

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NK cell natural cytotoxicity is increased after therapy interruption

Zimmer, Rinker, et al., submitted 2017

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NK cell natural cytotoxicity is increased after therapy interruption

Zimmer, Rinker, et al., submitted 2017 Conditions:

  • K562 cells (natural cytotoxicity)
  • 721.221 wt cells (natural cytotoxicity)
  • 721.221 wt cells + Rituximab (ADCC)
  • IL-12+IL-18 (cytokine response)
  • IL-12+IL-18 + K562 (cytokine priming + natural cytotoxicity)
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NK cell multifunctionality is increased after therapy interruption

Zimmer, Rinker, et al., submitted 2017

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Stop of therapy changed the T cell phenotype

CD4+ T cells CD8+ T cells

Rinker, Zimmer, et al., manuscript in preparation 2017

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Patients with HBsAg loss showed an altered T cell phenotype

Rinker, Zimmer, et al., manuscript in preparation 2017

B

HBsAg loss HBsAg loss no HBsAg loss

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Increased T cell responses and multifunctionality after stop of therapy

Rinker, Zimmer, et al., manuscript in preparation 2017

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Increased T cell responses and multifunctionality after stop of therapy

SI>2 CD4+: 10/12 CD8+: 9/12

PBMC stimulated with overlapping peptides (HBV core, GenD)

Rinker, Zimmer, et al., manuscript in preparation 2017

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PD-L1 blockade could further augment T cell responses

Rinker, Zimmer, et al., manuscript in preparation 2017

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Summary – Stopping NA therapy

  • Treatment discontinuation in HBeAg-negative CHB is safe
  • It leads to virological relapse in most of the patients
  • Stop of therapy:

…. lead to induction of cytokines .... increased NK cell natural cytotoxicity …. changed the blood T cell phenotype …. induced HBV-specific T cell responses

Stopping therapy should be further investigated as a strategy to induce HBsAg decline or even HBsAg loss

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Acknowledgements

Hannover Medical School:

  • Prof. Dr. Markus Cornberg
  • Dr. Christoph Höner zu Siederdissen
  • Prof. Dr. Christine Falk
  • Prof. Dr. Michael P. Manns

Karolinska Institutet Stockholm:

  • Assoc. Prof. Niklas Björkström

Christine Zimmer