dr patrick kennedy - bhiva15/12/2014 1 in partnership with the royal london hospital, uk dr patrick...

15/12/2014

1

in partnership

with

The Royal London Hospital, UK

Dr Patrick Kennedy

Five Nations Conference on

HIV and Hepatitis

in partnership

with

COMPETING INTEREST OF FINANCIAL VALUE > £1,000

Statement

Acts in a consultant capacity for Gilead, BMS and Roche. He has also

acted as a speaker for Gilead, BMS and Roche.

Date: December 2015

The Royal London Hospital, UK

Dr Patrick Kennedy

15/12/2014

2

WILL HEPATITIS B BECOME A

CURABLE DISEASE?

Patrick T. F. KennedySenior Lecturer & Honorary Consultant Hepatologist

Barts and The London SMD, QMUL, London

FIVE NATIONS CONFERENCE - HIV & HEPATITIS

WHAT IS CURE?

•HBsAg loss approaches clinical cure – EASL

CPG 2012

•Durable HBsAg loss is the “gold standard”

endpoint of therapy in patients with CHB

•HBsAg loss – currently not achieved in majority

of cases

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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


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NUC therapy

target


NUC therapy

target

Ideal therapy

target

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• Understanding natural history of CHB

• Current treatment strategies

• Strategies for HBsAg loss and cure

OUTLINE

NATURAL HISTORY OF HBV

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‘Immunotolerant patients: HBeAg positive patients under 30

years of age with persistently normal ALT levels and a

high HBV DNA level, without any evidence of liver

disease and without a family history of HCC or cirrhosis,

do NOT require immediate liver biopsy or therapy’

EASL CPG 2012

IMMUNE TOLERANT DISEASE

EASL, Clinical Practice Guidelines, 2012

‘Immunotolerant patients: HBeAg positive patients under 30

years of age with persistently normal ALT levels and a

high HBV DNA level, without any evidence of liver

disease and without a family history of HCC or cirrhosis,

do NOT require immediate liver biopsy or therapy’

Unresolved issue: “Improve knowledge & prognosis of the

natural history and indications for treatment, particularly

in HBeAg positive immunotolerant patients)”

EASL CPG 2012

IMMUNE TOLERANT DISEASE

EASL, Clinical Practice Guidelines, 2012

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Representative patient: 26 yr old female

ALT 39, HBV DNA 8.59 log, HBsAg 4.01 log

Ishak fibrosis stage 3/6

Evidence of fibrosis in

‘immune tolerant’ patient

Kennedy et al, Gastroenterology 2012

0

2

4

6

8

10

IT CA<30 HC<30

%P

D-1

+ C

D8

T c

ell

s

P<0.001

P<0.001

0

2

4

6

8

10

IT CA<30 HC<30

% P

D-1

+ C

D4

T c

ell

s

P<0.001

P<0.001

Evidence of immune activity in

the ‘immune tolerant’ phase

Kennedy et al., Gastroenterology 2012

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Evidence of immune activity in


Kennedy et al., Gastroenterology 2012

Age (Years)

% C

D1

27

low

PD

1+

CD

8 T

ce

lls

0 20 40 60 80

0

2

4

6

10

14

18

P= .006

Age (Years)%

CD

12

7lo

w P

D1

+ C

D4

T c

ell

s0 20 40 60 80

0

2

4

6

8

P= .4383

Kennedy et al, Manuscript in preparation

0

500

1000

1500

2000

3000

4000

5000

IT 1 2 3 4 5 6 7 8 9

Age 15 17 18 18 21 22 28 29 30

Hepatocyte

clo

ne s

ize

Clonal hepatocyte expansion in


Kennedy et al., Manuscript in preparation

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Kennedy et al, Manuscript in preparation

Clonal hepatocyte expansion

in varying disease phase

0

5000

10000

15000

20000

25000

IT eAg+ IA eAg- IA HCC

Hepatocyte

clo

ne s

ize

Clonal hepatocyte expansion

In varying disease phase

Kennedy et al., Manuscript in preparation


RE-DEFINING DISEASE PHASE IN CHB

Bertoletti & Kennedy , Cell & Mol Immunol, 2014

Immune Tolerance Immune Clearance

Non-Inflammatory Inflammatory

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• Pegylated Interferon-α (PEG-IFN-α)

- Immunomodulatory agent

- Use in HBeAg positive and negative disease

- Finite therapy

- Limited success

- Use of ‘stopping rules’

CURRENT HBV TREATMENT REGIMES

CURRENT HBV TREATMENT REGIMES

• Nucleos(t)ide Analogues (NUCs)

- On treatment viral suppression

- TDF and ETV – high genetic barrier to resistance

- Little evidence of HBsAg reduction

- Treatment endpoint?

- Issues of cost & toxicity

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What do current therapies offer?

• HBeAg-negative patients:

– limited decline in HBsAg during NUC monotherapy2

• HBeAg-positive patients:

– HBsAg levels decrease slowly during NUC monotherapy2

• Although long-term viral suppression is achieved; immune

control following treatment cessation is limited3

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

of patients.

WHAT DO THESE CURRENT THERAPIES OFFER?

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.

Ishak fibrosis score

Missing

1

2

3

4

5

6

0

n=57

Patients(n)

10

20

30

40

50

60

Baseline Week 48 Long term†

0

† Up to 7 years

(range: 3–7 years)

median time: 280 weeks1*

*In the randomised controlled studies, patients received 0.5mg ETV. In the 901 rollover study, patients received 1mg ETV. Please refer to

the SmPC for further information on regimen.2

Improvement in Ishak Fibrosis score

with long term Entecavir

1. Adapted from Chang T-T, et al. Hepatology 2010;52:886–93. 2. the treatment Baraclude® (entecavir)

SmPC May 2011.

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12

HBeAg+

HBeAg-

⁄⁄

Low ALT

p =0.006

High ALT

p =0.02

⁄⁄

•Patients treated with ETV or TDF who achieved a Virologic Response (VR)

•No difference in HBsAg decline between treatment regimens

HBeAg-positive HBeAg-negative HBeAg-positive

High ALT

Years to 1log decline* 6.6 [1.7; 17.5] 8.0 [0.5; 14.9] 3.6 [1.3; 16.7]

Years to HBsAg loss* 36.4 [9.6; 98.3] 38.9 [1.3; 80.5] 19.5 [7.3; 99.9]

HBsAg decline in patients treated with ETV or TDF:

need for host immune response

Zoutendijk et al. J Infect Dis 2011

Complication-free survival

in compensated cirrhosis

*Kaplan–Meier estimates.

Months

Patients

at risk

HCC=17

HCC rate/year: 2.8%

Decompensation rate/year: 0%

155 153 149 145 135 125

86%

100%

HCC

Decompensation

115 105 92 58 20

Lampertico P, et al. AASLD 2012, Boston, MA. Poster 366. Available at http://www.natap.org/2012/AASLD/AASLD_41.htm [Accessed November 2012]

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STRATEGIES TO ACHIEVE HBsAG LOSS

*Kaplan–Meier estimates.

Months

HCC

Decompensation

Bertoletti & Rivino, Curr Opin Infect Dis., 2014

Peppa et al.,

PLoS Pathog. 2010

Boni et al.,

Gastroenterology 2012

Micco et al.,

J Hepatol. 2013

Boni et al.,

J. Virol 2007

Peppa et al.,

PLoS Pathog. 2010

Harnessing the immune response

Thimme & Dandri J Hepatol. 2013

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Boni et al.,

J. Virol 2007

Peppa et al.,

PLoS Pathog. 2010

Peppa et al.,

PLoS Pathog. 2010

Boni et al.,


Micco et al.,

J Hepatol. 2013



Peppa et al.,

PLoS Pathog. 2010

Boni et al.,


Micco et al.,

J Hepatol. 2013

Boni et al.,

J. Virol 2007

Peppa et al.,

PLoS Pathog. 2010



15/12/2014

15

Peppa et al.,

PLoS Pathog. 2010

Boni et al.,


Micco et al.,

J Hepatol. 2013

Boni et al.,

J. Virol 2007

Peppa et al.,

PLoS Pathog. 2010



Peppa et al.,

PLoS Pathog. 2010

Boni et al.,


Micco et al.,

J Hepatol. 2013

Boni et al.,

J. Virol 2007

Peppa et al.,

PLoS Pathog. 2010



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Sequential NUC therapy

following PEG-IFN exposure

Gill et al, submitted, 2014

ALT HBV DNA HBsAg IFNγ

AIMS & STUDY DESIGNNew treatment paradigms

Brouwer et al., EASL 2014, ARES Study

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• PEG-IFN add-on results in more viral decline



• PEG-IFN add-on leads to sustained response

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Future directions for HBV drug development

Immune modulation

• Toll-like receptors

agonists, e.g.

GS-9620

• Anti-PD-1 mAb,

e.g. BMS-936559

• CYT107

• GI13000

Zoulim F, et al. Antiviral Res 2012;96(2):256–9; HBF Drug Watch, Available at:

http://www.hepb.org/professionals/hbf_drug_watch.htm. Accessed 15 Aug 2013. Zoulim F, et al. Gastroenterology

2013;144:1342–4.

HBx

Endosome

rcDNA

cccDNA

Polymerase

pgRNA

Core

Surface

proteins

Entry inhibitors

• Lipopeptides, e.g.

Myrcludex-B

Inhibition of

cccDNA

formation

Inhibition of nucleocapsid

assembly, e.g. Bay 41-4109,

NVR1221

Polymerase

inhibitors

• Nucleoside

analogues, e.g.

emtricitabine,

amdoxovir,

MIV-210

• Non-nucleoside,

e.g. LB80380

Inhibitors of HBsAg

release, e.g. REP 9AC

RNA interference,

e.g. ARC-520

Development stage: preclinical, clinical

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Achieving cure in HBV

• Long term on treatment viral suppression is current

standard of care – but suboptimal

• Persistence of cccDNA in HBV is a barrier to cure

• Future therapies must target cccDNA & achieve global

immune restoration - to deliver a cure in CHB

Royal London Hospital

Louise Payaniandy, Jo Schulz

Deva Payaniandy

Dimitra Peppa

Harsimran D. Singh

Lorenzo Micco

Mala K. Maini

Upkar S. Gill

Jyoti Hansi

Sandhia Naik

Graham R. Foster

William Mason

Samuel Litwin

Fox Chase Cancer Centre

Blizard Institute, QMUL

Rayne Institute, UCL

Duke, NUS

Elena Sandalova,

Juandy Jo, Antony Chen,

Antonio Bertoletti

ACKNOWLEDGEMENTS

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in partnership

with

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