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The path towards the cure of HBV infection
Fabien Zoulim
Hepatology Department, Hospices Civils de Lyon
INSERM U1052, Cancer Research Center of Lyon
Lyon University, France
• 240 million CHB worldwide
• 1.7 million CHB treated worldwide
• Hepatocellular Carcinoma (HCC) : 2nd cause of cancer death worldwide
Chronic Hepatitis B (CHB) - a global health problemfrom viral suppression to cure
Elimination of HBV infection and HBV-related diseaes
HBV susceptible
Acute HBV
Chronic HBV
Cirrhosis/HCC
Vaccine
Universal precautions
Antiviral
treatment
Current treatments: virus suppression and sustained disease control
Liaw YF et al, N Engl J Med. 2004; Chang et al, Hepatology 2010; Marcellin et al, Lancet 2013;
Hosaka et al, Hepatology 2013; Kim et al, Cancer 2015; Papatheodoridis et al, J Hepatol 2015
Decreased inflammation/fibrosis
Decreased progression
Reversal of fibrosis
Decreased progression
Decreased incidence
but not eliminated
NUCs
Virus suppression
HBsAg loss rate
Max 10% after 5 years
UNTREATED
Liver
Blood
Rc-DNA
HBsAg
ccc-DNA
HBV-DNA
Normal Cirrhosis Hepatocellular
carcinoma
From viral suppression to cure
Liver
Blood
Rc-DNA
HBsAg
ccc-DNA
NUCs
Normal Cirrhosis Hepatocellular
carcinoma
Risk of HCC reduced
(after 5 yrs)
but not eliminated
Liver
Blood
ccc-DNA Liver
Blood
NMEs NMEs“Cure”
Direct Antiviral Agents
Immunomodulatory
strategies
Normal Cirrhosis Hepatocellular
carcinoma
Definition of HBV cure: what do we want to achieve ?
Therapy
HB
V D
NA
ch
an
ge
fro
m b
as
eli
ne (
log
10
c/m
L)
0.0
-1.0
-2.0
-3.0
-4.0
+1.0
Time
HBsAg
HBV DNA
cccDNA
SERUM
LIVER
+/- Anti-HBsAb
Lok et al, Hepatology / J Hepatol joint publication, in press; Testoni et al, Sem Liver Dis, in press.
Partial Cure
Functional
Cure
Complete Cure
Sterilizing
Cure
Virus
Suppression
Mechanisms of viral persistence
cccDNA reservoir
Antigenic load
Liver tolerance
Defective CD8+ response
Defective B cell response
Inefficient innate response
HBV persistence Defective immune responsesLocarnini, S. & Zoulim, F. et al. (2016) Global strategies are required to cure and eliminate HBV infectionNat. Rev. Gastroenterol. Hepatol.
Vaccine therapy
Check-point
inhibitors
TLR agonistsBlockade
of immune-
suppressive
cytokines
Chimeric antigen
Receptors (CAR)
Antiviral cytokines
Entry inhibitors
Core modulators
Targeting cccDNA
Polymerase
inhibitors
RNA
interference
Egress Inhibitors
Core modulators
Targeting
HBx
Testoni and Zoulim, Hepatology 2015
Persistence of intrahepatic viral DNA synthesisand cccDNA during Tenofovir therapy
(HIV-HBV cohort)
Boyd et al, J Hepatol 2016
New round of infection and/or replenishment of the cccDNA pool occur
despite « viral suppression »
Zoulim, et al, Clin Gastroenterol
Hepatol 2013
Lucifora et al, Science 2014
Belloni et al, JCI 2012
Koeniger etal, PNAS 2014
Durantel&Zoulim, J Hepatol 2016
cccDNA loss
cccDNA silencing
cccDNA
degradation
cccDNA
formation
Targeting cccDNA, the viral minichromosome
cccDNA
repleneshiment
cccDNA
repleneshiment
Billioud et al, Antiviral Res 2011; Klumpp K et al, PNAS 2015; Venkatakrishnan B et al, J Virol 2016
Targeting the HBV capsid with capsidassembly modulators
Phase 1b clinical trial: CpAM NVR 3-778 reduces serum HBV DNA and RNA
Pre-clinical evaluation in hepatocyte culture and chimeric mouse models
Serum HBV DNA: mean 1.7 log reduction (600 mg BID)
Serum HBV RNA: mean 0.86 log reduction (600 mg BID)
Cohort I: 600 mg BIDDecrease of circulating HBV RNA
contained in viral particles
Yuen M-F, et al. AASLD 2015, San Francisco. #LB-10
Combination trials with
NUCs and/or PegIFN
HBsAg targeting strategies
• HBsAg clearance an endpoint of therapy
• Decline in HBsAg levels may restore the antiviral activity of
exhausted T cells
• Several strategies in evaluation
- RNA interference (SiRNA): « gene silencing »
- Nucleic acid polymers (NAPs): HBsAg release
- HBs antibodies
SiRNA ARC-520 produces deep and durable knockdown of viral antigens and DNA in a phase II study
Yuen M-F, et al. AASLD 2015, San Francisco. #LB-9
S promoter X promoter Precore, core
promoters
Integrated HBV DNAS mRNA
S protein ARC-520 siRNAs
Host
chromosome
cccDNA
HBsAg reduction in ETV naive
patients with a single 4 mg dose
(cohort 7)
Will this result in restoration of immune
responses ?
Impact of integrated sequences on siRNA efficacy
Restoration of antiviral immunity
Bertoletti A, Gehring AJ (2013) Immune Therapeutic Strategies in Chronic Hepatitis B Virus Infection: Virus or
Inflammation Control?. PLoS Pathog
Gane et al, EASL ILC Amsterdam 2017 PS-044
A Phase 1 study evaluating anti-PD-1 treatment with or without GS-4774
in HBeAg negative chronic hepatitis B patients
Immune modulation
• Toll-like receptors agonists
• Anti-PD-1 mAb
• Vaccine therapy
• Redirection of T cells
RNA
interference
NUCs“Polymerase inhibitors”
Targeting
cccDNA
Entry inhibitors
CpAMs
“Capsid inhibitors”
plasma
membrane
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
HBV Virion
~10 ng/ml
HBV Sphere
~100 g/ml
HBV Filament
~1 g/ml
LHBsAg
HBsAg
MHBsAg
~1%
~90%
~10%
~5%
~85%
~10%
~10%
~80%
~10%
HIGH
COPY #
LOW
COPY #
Inhibitors
of HBsAg
release “exhaustion”
“high antigen
load” PD-1
CD8+
T cell
Dysfunctional
T-cell response Insufficient
B-cell response
B cell
The main targets & drug discovery efforts
Revill, Zoulim et al, Nature Reviews Gastro & Hepatol 2016 ; Levrero et al, Current Opinion Virology, 2016
Antivirals
Therapy
HB
V D
NA
ch
an
ge
fro
m b
as
eli
ne (
log
10
c/m
L)
0.0
-1.0
-2.0
-3.0
-4.0
+1.0
Time
HBV cure - New treatment concepts – Will we need combination of DAA and immune therapy ?
HBsAgHBVDNA
cccDNA
Immune
restoration
SERUM
LIVER
NUCCapsid
SiRNA
Ag loadTLR
agonist
Tx
Vaccine
Check
point
inhibitorsAnti-HBsAb
Testoni et al, Liver International 2017
• Collaboration between Academia, Industry and Stakeholders
• International HBV cure programs
HBV cure:An attainable goal within the next decade !
• Created in September 2016 by ANRS, Doherty Institute,
and The International HBV Conference.
• Aim#1: to support the discovery of a safe, affordable,
scalable and effective cure, available to all persons living
with CHB.
• Aim#2: to create an international, independent, research-
based and patient-centered forum in order to coordinate,
promote and foster collaborative partnerships working
towards a cure for HBV.
The International Coalition for the Eradication of HBV
ICE-HBV
www.ICE-HBV.org
www.ICE-HBV.org
Governing Board
Chairs: P Revill & F Zoulim
Scientific Working Group
Stakeholders Consulting
Group
Chairs: U Protzer, T Block,
V Miller
Virology
M Dandri
& H Guo
Immunology
A Ghering & R Thimme
Innovative Tools
J Hu & F Lu
Clinical SciencesH Janssen, P Lampertico, SG Lim
PartnersSponsors
What are we doing?
• Define research priorities to achieve a cure of HBV
infection and produce a position paper on a research
roadmap, similar to papers published in the HIV field
(Deeks et al. Nat. Med. 2016)
• Foster international collaborations on specific projects:• cccDNA assay standardization with ANRS and DZIF
• HBV cure mathematical modelling with Stanford
• Promote HBV cure initiatives to increase awareness and
funding for HBV research worldwide.• Contacts with NIAID, NCI, EU, etc.
• World Hepatitis Summit, Sao Paulo
www.ICE-HBV.org
Acknowledgements
Hepatology Unit INSERM U1052 Collaborations
David Durantel
Barbara Testoni
Julie Lucifora
Bernd Stadelmeyer
Guada Martinez
Maelle Locatelli
Fleur Chapus
Aurore Inchauspé
Maud Michelet
Judith Fresquet
C. Caux, Lyon CRCL
FL. Cosset, Lyon CIRI
K. Lacombe, Paris
F Carrat, Paris
C Ferrari, Parma
P Lampertico, Milan
A Craxi, Palermo
JP Quivy, Institut Curie
U Protzer, Munich
M Dandri, Hamburg
S Locarnini, Melbourne
XX Zhang, Shanghai
Marc Bonin
Thomas Lahlali
Lucyna Cova
Romain Parent
Anna Salvetti
Birke Bartosch
Eve Pecheur
Boyan Grigorov
Christophe Combet
François Bailly
Samir Benmaklouf
Marie Ecochard
Kerstin Hartig
Fanny Lebossé
Massimo Levrero
Marianne Maynard
Christian Trépo
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