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

AREVIR-GenaFor-Meeting- Köln; 29/30th April 2016

• Prof. Dr. Dieter Glebe

Institute of Medical Virology, National Reference Center for Hepatitis B and D Viruses, Justus Liebig University Giessen, Germany

New therapies for Hepatitis B ? The drug pipeline

What is hepatitis B?

Number of deaths/year from selected conditions, Global Burden of Disease Study 2010 and 2013

1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 HIV/AIDS Viral hepatitis Tuberculosis Malaria

• No. of deaths (millions)

2010 2013

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

900 800 700 600 500 400 300 200 100 HBV HCV

• No. of deaths (x1000)

1990 2010 2013

GBD Mortality and Causes of Death Study: Lancet 2014

Hepatitis-related mortality, 2013

800 700 600 500 400 300 200 100 HAV HBV HCV HEV

• No. of deaths (x1000)

HCC Cirrhosis Acute

GBD 2013 Mortality and Causes of Death Study: Lancet 2014

1.45 million deaths from viral hepatitis per year

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. Global burden of hepatitis B and C

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?

~2 billion

~240 million ~28-90 million

Persons with history of HBV infection Persons with chronic HBV infection (HBsAg pos) Persons with cirrhosis or progressive disease (10%- 30%)

• 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 109 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 106 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

Hepatitis B Virus

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

Family Hepadnaviridae

• Virions (ca. 45 nm diameter)
• subviral particles
• enveloped virion (lipids)
• 3 envelope proteins
• Polymerase und Core-Protein
• Excess of subviral particles
• contains HBV-envelope proteins
• Spherical/filamentous form

Polymerase Core SHBs MHBs LHBs Virus Subvirale Partikel Core

Hepatitis B Virus

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

Family Hepadnaviridae

• enveloped virion (ca. 45 nm)
• subviral particle
• genome: partial dsDNA (3.200

bp)

• 4 overlapping ORFs
• replicates via a reverse

transcriptase (similar to HIV)

• strong liver-tropism
• strong species-specificity
• no direct cytopathogenic effects

Genom Polymerase Core SHBs MHBs LHBs Virus Core

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

Glebe und Bremer (2013)

Replication cycle of hepatitis B virus

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

HBV binding to cellular receptors

HBV binding to cellular receptors

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

bile acids

liver small intestine bile duct

cholesterol

enterohepatic circulation of bile acids

ASBT

reabsorption of bile acids from the intestinal lumen

NTCP

reabsorption of bile acids from the portal blood

NTCP: bile acid homeostasis

ASBTNM Taurocholic acid 2 Na+

• Na+-coupled bile acid transport
• Stoichiometry: 1BA : 2Na+
• 7/9 TMDs, Nexo/Ccyt
• Core domain: TMDs 2-4, 7-9
• Panel domain: TMDs 1, 5, 6

Model from Noinaj and Buchanan (2014 Curr Opin Struct Biol 27:8) based on the crystal structures of ASBTNm (Hu et al. 2011 Nature 478:408) and ASBTYf (Zhou et al. 2014 Nature 505:569)

NTCP: structure and function

Glebe und Bremer (2013)

Replication cycle of hepatitis B virus

cccDNA

covalently closed circular

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

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

HBV envelope proteins

Glebe und Bremer (2013)

Antiviral intervention

cccDNA

covalently closed circular Linear DNA

Sung et al. Nature Genetics 2012 44(7):765-770

Antiviral intervention

cccDNA

Linearisation

• f cccDNA

during integration

Glebe und Bremer (2013)

Antiviral intervention

Anti-viral

Nukleos(t)id analogs HBsAg

• encoded von cccDNA
• surrogate marker for

cccDNA Problems:

• secreted HBsAg-mutants
• diagnostic escape
• 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

Nukleos(t)id analogs HBsAg

• encoded von cccDNA
• surrogate marker for

cccDNA Problems:

• secreted HBsAg-mutants
• diagnostic escape
• 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

Entry Inhibitor

Therapeutic Vaccination

• Core/S-antigen
• Boost CD8 T-cells
• Prime-boost immunization

adenovirus (woodchuck)

Core assembly Inhibitor Transcriptions Inhibitor

Orale TLR-7/8 agonists

• 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 LT-beta receptor agonist

• mAk against LT-bR
• Stimulation of LT-bR
• Induction APOBEC B/C
• APOPEC interacts mit HBc

und cccDNA

Antiviral intervention

Antiviral intervention

AREVIR-GenaFor-Meeting- Köln; 29/30th April 2016

• Prof. Dr. Dieter Glebe

Institute of Medical Virology, National Reference Center for Hepatitis B and D Viruses, Justus Liebig University Giessen, Germany

Many thanks