CHRONIC HEPATITIS B VIRUSProspects for Cure

Patrick T. F. KennedyReader in Hepatology & Consultant Hepatologist

Blizard Institute, Barts and The London SMD, QMUL, London

VIRAL HEPATITIS and CO-INFECTION with HIVBucharest, Romania, 6-7 October, 2016

350 million people worldwide

with CHB

80% of deaths in those infected at birth/early

childhood

25% of those infected in childhood develop

cirrhosis or HCC

>600,000 deaths per year

Chronic HBV Infection

Unmet challenges in HBV therapy

2

3

4

Strategies to achieve HBsAg loss and ‘cure’1

Defining treatment endpoints

Reducing the risk of HCC

Finite therapy options

Locarnini & Zoulim, Anitvir Ther 2010

Chronic HBV Infection

NUC target

Chronic HBV Infection

Locarnini & Zoulim, Anitvir Ther 2010

NUC target

Ideal therapytarget

Chronic HBV Infection

Locarnini & Zoulim, Anitvir Ther 2010

Natural history & disease phase

0

HBeAgAnti-HBe

HB

V D

NA/

HB

sAg

(log 1

0IU

/ml)

ALT (IU/L)

IMMUNE TOLERANT IMMUNE CLEARANCE IMMUNE CONTROL IMMUNE ESCAPE

ALT HBV DNA

Natural History & Disease Phase

adapted from Gill & Kennedy; Clin Med 2015

0

HBeAgAnti-HBe

HB

V D

NA/

HB

sAg

(log 1

0IU

/ml)

ALT (IU/L)

IMMUNE TOLERANT IMMUNE CLEARANCE IMMUNE CONTROL IMMUNE ESCAPE

ALT HBV DNA HBsAg

Natural History & Disease Phase

adapted from Gill & Kennedy; Clin Med 2015

Is our current understanding of natural history & disease phase

accurate?

Evidence of immune activity in the ‘immune tolerant’ disease phase

Kennedy/Bertoletti et al., Gastroenterology 2012

0

2

4

6

8

10

IT CA

Age (Years)

% C

D12

7lo

w P

D1+

CD

8 T

cel

ls

0 20 40 60 800

2

4

6

10

14

18P = .006

Age (Years)%

CD

127l

ow

PD

1+ C

D4

T c

ells

0 20 40 60 800

2

4

6

8P = .4383

Evidence of immune activity in the ‘immune tolerant’ disease phase

Kennedy/Bertoletti et al., Gastroenterology 2012

Evidence of liver damage in the ‘immune tolerant’ disease phase

Mason/Kennedy et al., Gastroenterology 2016

Nuclear core positive hepatocytes differentiate ‘immune tolerant’ disease

Mason/Kennedy et al., Gastroenterology 2016

Clonal hepatocyte expansion in ‘immune tolerant’ disease

Mason/Kennedy et al., Gastroenterology 2016

Redefining disease phase in CHB

Bertoletti & Kennedy, Cell & Mol.Immunol 2014

Immune Tolerance Immune Clearance

Non-Inflammatory Inflammatory

Treatment & management strategies

Current Treatment Regimes

Peg-IFN

NUCs

• Immunomodulatory agent• HBsAg decline or loss• Moderate rate of relapse• Finite therapy• Use of stopping rules

• Excellent viral suppression• Long term therapy• High barrier to resistance• Poor HBsAg reduction• ? Treatment endpoints

HBV Treatment regimesNucleos(t)ide Analogues (NUCs)

Marcellin et al, Lancet 2015; Chang, et al. Hepatology 2010

TENOFOVIR ENTECAVIR

Current therapies are non-curative

• Peg-IFN sustained immune control, but only in a minority of patients1

• HBeAg-negative & positive disease: – limited decline in HBsAg during NUC monotherapy2

• Long-term viral suppression is achieved, but sustained immune control following treatment cessation is limited3

1. EASL guidelines. J Hepatol 2012;57:167–85; 2. Zoutendijk R, et al. J Infect Dis 2011;204(3):415–8; 3. Hadziyannis SJ, et al. Gastroenterology 2012;143:629–36.

What are the available options…..

What are the available options…..

Sequential therapy strategies

Combination therapies

Discontinuation of NUCs

1

2

3

Sequential NUC Therapy

* p=

Sequential NUC Therapy

* p=

What are the available options…..

Sequential therapy strategies

Combination therapies

Discontinuation of NUCs

1

2

3

What are the available options…..

Sequential therapy strategies

Combination therapies

Discontinuation of NUCs

1

2

3

Can NUCs be discontinued after a period of consolidation therapy following HBeAg seroconversion?

HBeAg positive disease

Can NUCs be discontinued after a period of consolidation therapy following HBeAg seroconversion?

HBeAg positive disease

HBeAg negative disease

HBeAg Negative patientsVirally suppressed >24 months

No evidence of cirrhosis

4 weekly collection:Routine laboratory tests

PBMC

Immunoprofilingby CyTOF

mRNA expression By NanoString

by CyTOF

T cell phenotypingby flow cytometry

Ag-specific T cell analysisex vivo by CyTOFby flow cytometry

Ag-specific T cell analysis after in vitro expansion by Elispot

HBeAg negative diseaseImmune Profiling Study

Patient Profiles

on NUC off NUC

controllers: n = 2viral rebound: -hepatic flare: -

partial controllers: n = 11viral rebound: +hepatic flare: -

flare: n = 6viral rebound: +hepatic flare: +

Non-Flare Flare

Rivino*, Le Bert*, Gill*, et al., Manuscript in preparation* equal contribution

SFC

/105

cells

SFC

/105

cells

Increased frequency of HBV-specific T cell responses in ‘non-flare’ vs. flare patients prior to NUC discontinuation

* equal contribution Rivino*, Le Bert*, Gill*, et al., Manuscript in preparation

Novel Strategies for HBsAg loss

Bertoletti & Rivino, Curr Opin Infect Dis., 2014

Selective oral TLR Agonists in CHBTLR agonists enhance:•Production of IFN-γ and inflammatory cytokines like IL-12•Upregulation of costimulatory molecules such as CD80 and CD86•Induction of interferon stimulated genes

Gs-9620, an oral TLR7 agonist in development for chronic

viral hepatitis has demonstrated a potential for

induction of an antiviral response with an acceptable

adverse event profile

GS-9620, an Oral Agonist of Toll-Like Receptor-7, Induces Prolonged Suppression of Hepatitis B Virus in Chronically Infected Chimpanzees.Lanford et al Gastroenterology 2013

Gane et al, J Hepatol 2015Phase 1b safety, pharmacokinetics and pharmacodynamics of GS-9620

GS-4774 (Tarmogen)

Stubbs, et al. Nat Med 2001; Cereda, et al. Vaccine 2011; Francis et al Vaccine 2015

CD4+

CD8+

GS-4774

APC

M X Large S (env) Core His 6

GS-4774 Recombinant Antigen

C8F17 fluorocarbon chain

DensigenTM

• ~ 30-40 amino acids long peptides• CD4+/CD8+ T cell epitopes • Net positive charge/Hydrophobicity

Effective T cells control virus Exhausted T cells loose control of virus

CD8 T cells

Infected hepatocytes Infected hepatocytes

INF-γTNF-αIL-2

GranzymePerforin

?Checkpoint blockade

Reversal of T cell exhaustion

The goal of checkpoint inhibitors

Lessons from cancer checkpoint inhibitor trials: PD-1

APC

PD-1PD-L1

Exhausted T cell Re-invigorated T cell

CytotoxicityPD-1/-L1blockade

APC

Lessons from woodchuck hepadnaviral infection

• Boosting of T and B cell immunity• Sustained viral suppression and sAg seroconversion

Combining PD-1 blockade with therapeutic vaccination

Summary of future drug targets for HBV therapies

Summary• Better understanding & re-definition of disease phase in

CHB is central to better treatment outcomes

• Long term on-treatment viral suppression is standard ofcare – but suboptimal

• Strategies to target cccDNA & achieve global immunerestoration will be critical to delivering cure in CHB

ACKNOWLEDGEMENTSRoyal London Hospital

Louise Payaniandy, Jo Schulz, Sally Thomas, Deva Payaniandy,

William Tong

Dimitra Peppa, Lorenzo Micco, Harsimran D. Singh,

Mala K. Maini

Graham R.FosterJyoti Hansi

Upkar S. Gill

Samuel Litwin,Yan Zhou, Suraj Peri

William Mason

Fox Chase Cancer Centre

Blizard Institute, QMULRayne Institute, UCL Duke, NUS/SICS A* Star

Elena Sandalova, Juandy Jo, Laura Rivino, Nina Le Bert, Evan Newell,

Antonio Bertoletti

ILS, Kings College

Oltin Pop, Ivana CareyAlberto Quaglia

Dianummer 1Dianummer 2Dianummer 3Dianummer 4Dianummer 5Dianummer 6Dianummer 7Dianummer 8Dianummer 9Dianummer 10Dianummer 11Dianummer 12Dianummer 13Dianummer 14Dianummer 15Dianummer 16Dianummer 17Dianummer 18Dianummer 19Dianummer 20Dianummer 21Dianummer 22Dianummer 23Dianummer 24Dianummer 25Dianummer 26Dianummer 27Dianummer 28Dianummer 29Dianummer 30Dianummer 31Dianummer 32Dianummer 33Dianummer 34Dianummer 35Dianummer 36Selective oral TLR Agonists in CHB�GS-4774 (Tarmogen)�Dianummer 39Dianummer 40Dianummer 41Dianummer 42Dianummer 43Dianummer 44