Hepatitis B is a Treatable Disease!

Harry L.A. Janssen

Dept. of Gastroenterology & Hepatology

Erasmus University Medical Center

Rotterdam The Netherlands

Hepatitis Summit Brussels

October 2010

Prevalence of Hepatitis BRole of Immigration in Europe

China

8 - 10%

The Netherlands

0.2 - 0.3%

Annelot David

Acuteinfection

Asymptomaticcarrier

Resolution

30–50 years

ChronicHepatitis

Stabilization

Cirrhosis

Compensated

HCC

Decompensation

Death

Transplantation

HBV Disease: Silent Killer

Hepatitis Bunder-diagnosed and under-treated

Tested Active

• Inflammation (ALT) 94% 28%

• Viral Load 68% 27%

• Treatment - 4%

Kim, Hepatology 2004

Hepatitis B: 1990

A preventable

disease!

Treatment of Hepatitis B 1990-2010

1957Discoveryinterferon

1991Interferon alfa-2b

licensed

1999Lamivudine (3TC)

licensed

1991Discovery

lamivudine (3TC)

1990Discovery

PMEA

2003Adefovir dipivoxil (PMEA prodrug)

licensed

1998Discoveryentecavir

2006Entecavirlicensed

2007Telbivudine

licensed

2001Discoverytelbivudine

2005Peginterferon alfa-2aPeginterferon alfa-2b*

licensed

2008Tenofovirlicensed

* Specific countries onlyAdapted from: ClinicalCareOptions.com

Goals for treatment

• Long-term clinical goals

– Keep patient healthy for as long as possible

– Prevent hepatic decompensation

– Prevent progression to cirrhosis and liver cancer

– Prolong survival

Fung S, Lok ASF. Clinical Gastroenterol Hepatol. 2004;2(10):839–848

Phases Of Infection

Immunotolerant

Phase

HBeAg

Immuno-active

Phase

Immune control

Phase

HBeAg-negative

Chronic Hepatitis

HBV DNA

Anti-HBe

ALT

Treatment indicated Treatment indicated

What end points are used?

• HBeAg seroconversion

• Suppression in HBV DNA levels

• Histological improvement

• ALT normalization

• HBsAg seroconversion

• Studies have linked high HBV DNA levels with

increased risk of:

– Development of HCC and cirrhosis

– Disease progressionKeeffe EB, et al. Clin Gastroenterol Hepatol 2006, 4: 936-62. The EASL Jury. J Hepatol. 2003; 39:S3–S25

Chen CJ, et al. JAMA 2006; 295:65–73. Iloeje UH, et al. Gastroenterology 2006; 130:678–686

Treatment Options

Antivirals

Lamivudine

Adefovir

Entecavir

Telbivudine

Emtricitabine

Immuno-modulators

IFNα

Peg IFN

Nx cytokines

Vaccine therapy

Treatment combinations

T-cel HBV

Concepts of Treatment Goals in Hepatitis B

Maintained response

=

Continued need for antiviral drugs

VIRAL CONTROL

Nucleos(t)ideAnalogues

Sustained response

=

No need for antiviral drugs

IMMUNE CONTROL

PegylatedInterferon

Concepts of Treatment Goals in Hepatitis B

Maintained response

=

Continued need for antiviral drugs

VIRAL CONTROL

Nucleos(t)ideAnalogues

Sustained response

=

No need for antiviral drugs

IMMUNE CONTROL

PegylatedInterferon

Response to PEG-IFN 6 months

post treatment

Pa

tie

nts

(%

)

Lau, NEJM 2005; Janssen, Lancet 2005; Marcellin, NEJM 2004.

Treatment duration 48 weeks

HBeAg

negative

ALT

normal

HBV DNA

<10,000

copies/ml

HBsAg

negative

0

10

20

30

40

50

60

70

80

90

100

Pe

rce

nta

ge

of

init

ial re

sp

on

de

rs (

%)

81%78%

58%

30%

45%

HBV DNA

<400

copies/ml

Buster et al. , Gastroenterology 2008

Follow-up of PEG-IFN α-2b in HBeAg (+) CHB:

3 years post-treatment among HBeAg responders

n=64

IFN-2b Treatment is Associated

with Prolonged Survival

Years

v Zonneveld et al. Hepatology 2004

151050

1.0

0.8

0.6

0.4

0.2

0

Cirrhosis at baseline No cirrhosis at baseline

151050

1.0

0.8

0.6

0.4

0.2

0

Responders

Non-responders

Proportion of patients surviving

Years

Concepts of Treatment Goals in Hepatitis B

Maintained response

=

Continued need for antiviral drugs

VIRAL CONTROL

Nucleos(t)ideAnalogues

Sustained response

=

No need for antiviral drugs

IMMUNE CONTROL

PegylatedInterferon

Regression of

disease

Improved

liver histology

Uncontrolled

viral replication

No/ineffective

treatment

Fibrosis

Cirrhosis/

HCC

Adherence

+

Antiviral

potency

High genetic

barrier to

resistance

+

Favourable

safety profile

Improving the long-term health of HBV patients

with NA rests on these pillars

Resistance rates through 6 years among

nucleos(t)ide-naïve patients

LVD1

ETV*5,6

LdT†2,3

ADV‡1

TDF4

Year 3

1.2%

0%

55%

11%

Year 4

1.2%

–

0%

71%

18%

Year 2

<1%

0%§

46%

3%

25%

Year 1

<1%

0%

23%

0%

5%

Year 5

–

–

80%

29%

1.2%

72 Weeks

–

Year 6

1.2%

Drug

Generation

1st

2nd

3rd

Chang TT et al. Hepatology 2010;51:422–30.

Pro

po

rtio

n o

f p

ati

en

ts w

ith

HB

V D

NA

<30

0 c

op

ies/m

L (

%)

55%

Year 1

83%

Year 2

89%

Year 3

n =

Year 4

91%

80/146 116/140 116/131 98/108

Year 5

88/94†

94%

0

20

40

60

80

100

HBeAg(+) ETV long-term cohort (ETV-022ETV-901)

Entecavir 5-year efficacy data

Tenofovir 3-year efficacy data

91

100

14

83

95

68

9799

0

10

20

30

40

50

60

70

80

90

100

Week 481 Week 1442 Week 481 Week 1443

Pro

po

rtio

n o

f p

ati

en

ts (

%)

ADV–TDF

TDF–TDF

HBeAg(+) HBeAg (–)

HBV DNA undetectable <400 copies/mL

p<0.001

p<0.001

84 141 117 241 110 223160 82

Adapted from 1. Marcellin P et al. N Engl J Med 2008;359:2442–55. 2. Heathcote EJ et al. 60th AASLD Oct 30–Nov 3, 2009; Boston, USA. Poster 483. Available at

http://www.natap.org/2009/AASLD/AASLD_35.htm. (Accessed April 2010). 3. Marcellin P et al. 60th AASLD Oct 30–Nov 3, 2009, Boston, USA. Poster 481. Available at

http://www.natap.org/2009/AASLD/AASLD_36.htm (Accessed April 2010).

Liaw et al. NEJM 2004; 351:1521

Patients with CHB and cirrhosis or advanced fibrosis

Antiviral treatment delays

disease progression

25

20

15

10

5

0

6 12 18 24 30 36

21%

9%

(n=198)

(n=417)

(n=385)

(n=173)

(n=43)

(n=122)

p=0.001

Placebo

(n=215)

ITT population

Time to disease progression (months)

0

Lamivudine

(n=436)

Pati

en

ts (

%)

Who Should be Treated and With What?PEG-IFN or Nucleoside Analogues?

Benefits

Risks

Patient’s age

Host genetics

HBV genotype

Patient’s preference

Co-morbid illness

Costs

Likelihood of sustained response

Severity of liver disease

Side effects

Drug resistance

Balancing the facts

Conclusions

• Major improvement in HBV therapy in last decades!

• Choice of therapy depends on individual patient characteristics: PEG-IFN in selected proportion of patients

• Choose most potent NA with highest genetic barrier

• Therapy with NA may be indefinite in many patients

• More than 95% of HBV in remission with current drugs

Issues for the Future

Safety & efficacy of longterm therapy

Response prediction: individualized therapy

Role of combination therapy

How to induce long-term cure (HBsAg loss)

New agents with different sites of action

Hepatitis B: 2010

A treatable

disease!