New therapies for Hepatitis B ? The drug pipeline Prof. Dr. Dieter - PowerPoint PPT Presentation

AREVIR-GenaFor-Meeting- Köln; 29/30 th April 2016 New therapies for Hepatitis B ? The drug pipeline Prof. Dr. Dieter Glebe Institute of Medical Virology, National Reference Center for Hepatitis B and D Viruses, Justus Liebig University Giessen, Germany

What is hepatitis B?

Number of deaths/year from selected conditions, Global Burden of Disease Study 2010 and 2013 1.6 1.4 No. of deaths (millions) 1.2 1 2010 0.8 2013 0.6 0.4 0.2 0 HIV/AIDS Viral hepatitis Tuberculosis Malaria GBD 2013 Mortality and Causes of Death Study: Lancet 2014

Number of deaths/year from hepatitis B and C, Global Burden of Disease Study 1990, 2010 and 2013 900 1990 800 2010 700 No. of deaths (x1000) 2013 600 500 400 300 200 100 0 HBV HCV GBD Mortality and Causes of Death Study: Lancet 2014

Hepatitis-related mortality, 2013 1.45 million deaths from viral hepatitis per year 800 700 No. of deaths (x1000) 600 500 HCC 400 Cirrhosis 300 Acute 200 100 0 HAV HBV HCV HEV GBD 2013 Mortality and Causes of Death Study: Lancet 2014

Global burden of hepatitis B and C Statements of the World Hepatitis Summit September 2015 • The World Hepatitis Summit is a joint World Health Organization (WHO) and World Hepatitis Alliance (WHA) event that directly addresses the overwhelming global burden of viral hepatitis. The inaugural 2015 Summit was hosted by the Scottish Government. • The participants of the inaugural World Hepatitis Summit believe it is possible and essential to set as a goal the elimination of both hepatitis B and C as public health concerns.

What is hepatitis B?

Distribution of chronic HBV infection • ca. 30% of liver cirrhosis and 53% of hepatocellular carcinoma are HBV-dependent

What is hepatitis B?

How many persons need HBV treatment? Persons with history of ~2 billion HBV infection Persons with chronic HBV ~240 million infection (HBsAg pos) ~28-90 Persons with cirrhosis or million progressive disease (10%- 30%)

Hepatitis B Virus • HBV is highly infectious – Minimal infectious dose in chimpanzees 5-10 virions (vein injection, Tabuchi et al. 2008). • Chronic HBV patients can carry up to 10 9 virions/ml of blood (usually asymptomatic patients) – Often unrecognized – High risk for transmission of HBV • Minimal traces of blood are highly infectious – A blood spit (1µl) can contain 10 6 virions or enough virions to infect 100.000 chimps (theoretically). • Infectivity of HBV in dried blood spots is stable for at least one week (7 days, Bond et al., 1983).

Hepatitis B Virus Family Hepadnaviridae Virus Polymerase • Virions (ca. 45 nm diameter) Core Core • subviral particles SHBs • enveloped virion (lipids) MHBs • 3 envelope proteins • Polymerase und Core-Protein LHBs • Excess of subviral particles Subvirale Partikel • contains HBV-envelope proteins • Spherical/filamentous form Glebe & Bremer, Semin Liver Dis. 2013 May;33(2):103-12.

Hepatitis B Virus Family Hepadnaviridae Virus Polymerase • enveloped virion (ca. 45 nm) Core Core • subviral particle SHBs • genome: partial dsDNA (3.200 bp) MHBs • 4 overlapping ORFs LHBs • replicates via a reverse transcriptase (similar to HIV) Genom • strong liver-tropism • strong species-specificity • no direct cytopathogenic effects Glebe & Bremer, Semin Liver Dis. 2013 May;33(2):103-12.

Hepatitis B virus Glebe & Bremer, Semin Liver Dis. 2013 May;33(2):103-12.

HBV cure ? Zeisel et al., 2015

HBV cure ? Zeisel et al., 2015

HBV cure ? Zeisel et al., 2015

HBV cure ? Zeisel et al., 2015

HBV cure ? Zeisel et al., 2015

Replication cycle of hepatitis B virus Glebe und Bremer (2013)

HBV binding to cellular receptors Glebe & Bremer, Semin Liver Dis. 2013 May;33(2):103-12.

HBV binding to cellular receptors Glebe & Bremer, Semin Liver Dis. 2013 May;33(2):103-12.

NTCP: bile acid homeostasis cholesterol liver bile acids bile duct NTCP enterohepatic reabsorption of circulation of bile acids from bile acids the portal blood small intestine ASBT reabsorption of bile acids from the intestinal lumen

NTCP: structure and function • Na + -coupled bile acid transport • Stoichiometry: 1BA : 2Na + Taurocholic acid • 7/9 TMDs, N exo /C cyt • Core domain: TMDs 2-4, 7-9 • Panel domain: TMDs 1, 5, 6 ASBT NM 2 Na + Model from Noinaj and Buchanan (2014 Curr Opin Struct Biol 27:8) based on the crystal structures of ASBT Nm (Hu et al. 2011 Nature 478:408) and ASBT Yf (Zhou et al. 2014 Nature 505:569)

Replication cycle of hepatitis B virus cccDNA c ovalently c losed c ircular Glebe und Bremer (2013)

What is HBV cure ? Durantel & Zoulim, J. Hepatol. 2016 vol. 64, S117-S131.

What is HBV cure ? Durantel & Zoulim, J. Hepatol. 2016 vol. 64, S117-S131.

What is HBV cure ? Durantel & Zoulim, J. Hepatol. 2016 vol. 64, S117-S131.

What is HBV cure ? Durantel & Zoulim, J. Hepatol. 2016 vol. 64, S117-S131.

What is HBV cure ? Durantel & Zoulim, J. Hepatol. 2016 vol. 64, S117-S131.

Hepatitis B virus HBV envelope proteins Glebe & Bremer, Semin Liver Dis. 2013 May;33(2):103-12.

Antiviral intervention cccDNA c ovalently c losed Linear DNA c ircular Glebe und Bremer (2013)

Antiviral intervention Linearisation of cccDNA during integration cccDNA Sung et al. Nature Genetics 2012 44(7):765-770

Antiviral intervention Anti-viral HBsAg encoded von cccDNA • surrogate marker for  cccDNA Problems: secreted HBsAg-mutants • diagnostic escape  Nukleos(t)id analogs secretion block of HBsAg • intracellular accumulation of  HBsAg-mutants in ER ER-stress  apoptosis/pro-cancerogenic  Ground-glass hepatocytes  „Milchglashepatozyten“  Glebe und Bremer (2013)

Antiviral intervention Anti-viral HBsAg encoded von cccDNA • surrogate marker for  cccDNA Problems: secreted HBsAg-mutants • diagnostic escape  Nukleos(t)id analogs secretion block of HBsAg • intracellular accumulation of  HBsAg-mutants in ER ER-stress  apoptosis/pro-cancerogenic  Ground-glass hepatocytes  „Milchglashepatozyten“  Integration of cccDNA in • the cellular genome HBsAg-production from  integrated HBV genome Glebe und Bremer (2013)

Antiviral intervention Anti-viral Immune-system Entry Inhibitor Core assembly Inhibitor Transcriptions Inhibitor Glebe und Bremer (2013)

Antiviral intervention Anti-viral Immune-system Therapeutic Vaccination Core/S-antigen • Boost CD8 T-cells • Prime-boost immunization • adenovirus (woodchuck) Entry Inhibitor LT-beta receptor agonist mAk against LT-bR • Core assembly Stimulation of LT-bR • Inhibitor Induction APOBEC B/C • APOPEC interacts mit HBc • und cccDNA Transcriptions Orale TLR-7/8 agonists Inhibitor Innate immunity • Boost immune responses • TLR7 agonist induces • decrease of viral load, HBeAg und HBsAg in woodchucks und in chimps TLR8/TLR3 agonists show • antiviral effects in vitro Glebe und Bremer (2013)

Antiviral intervention

Antiviral intervention

AREVIR-GenaFor-Meeting- Köln; 29/30 th April 2016 Many thanks Prof. Dr. Dieter Glebe Institute of Medical Virology, National Reference Center for Hepatitis B and D Viruses, Justus Liebig University Giessen, Germany