Professor George KK Lau The University of Hong Kong Hong Kong SAR, China HBeAg-positive chronic hepatitis B: why do I treat my patients with pegylated.

Professor George KK Lau

The University of Hong Kong

Hong Kong SAR, China

HBeAg-positive chronic hepatitis B: why do I treat my patients with

pegylated interferon

Yang et al. NEJM 2002

12

10

8

6

4

2

0

Per

cen

t cu

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lati

ve i

nci

den

ce

0 1 2 3 4 5 6 7 8 9 10

Year

HBsAg+, HBeAg+

HBsAg+, HBeAg–

HBsAg–, HBeAg–

Positivity for HBeAg is Associated withan Increased Risk of HCC – Taiwanese Data

Hsu. Hepatology 2007.

Spontaneous HBeAg Seroconversion Confers Favorable Long-term Outcomes

Timing is important: earlier seroconversion is associated with

reduced risk of cirrhosis

Chu & Liaw 2007

Longitudinal study of 240 patients with normal ALT at baseline* Hazard ratio for progression to cirrhosis for each decade without HBeAg seroconversion

Hazard ratio* = 3.4(95% CI 1.4–8.2)

35

30

25

20

15

10

5

0<30 30-39 40-49 ≥50

Age of HBeAg seroconversion (years)

% o

f p

atie

nts

wit

h c

irrh

osi

s

IFN -treatedpatients(n=233)

Matched untreated controls(n=233)

Cirrhosis18%

p = 0.041*

34%

HCC3%

p = 0.011*

13%

Survival98%

p = 0.003*

53%

Lin et al. EASL 2005 and J Hepatol 2007*p vs control

Follow-up: mean 11 years (median 6.6 years; range: 1.1 to 16.5 years)

Long-term Outcome of IFN Treatment inHBeAg-positive CHB: 11-year Follow-up

Sung et al Aliment Pharmacol Ther 2008

Twelve studies (n = 2742) enrolling patients treated by IFN vs. controlshowed that the risk of HCC after treatment was reduced by 34% (RR: 0.66, 95% CI: 0.48–0.89).

Meta-analysis: Effect of IFN treatment on HCC

Favourable long-term outcome following HBeAg seroconversion

HBeAg seroconversion

Disease remission

HBsAg loss/seroconversion

Prevention of HCC

Increased survival

Hoofnagle Ann Intern Med 1981; Fattovich Hepatology 1986;Di Bisceglie Gastroenterology 1987;

Niederau NEJM 1996; Chu Gastroenterology 2002; van Zonneveld Hepatology 2004

HBeAg loss

Registered treatment of CHB-2009Immune therapy (finite)

Conventional IFN-Pegylated IFN-2a

Anti-viral (life-long)

Lamivudine

Adefovir dipivoxil

Entecavir

Telbuvidine

Clevudine (Korea)

Tenofovir (EU and FDA)

Sustained remission (~30-40%)

=

Maintained remission

=

Low viraemia Low viraemia

ALT normalisation ALT normalisation

Immune control,

no antiviral drugs

Continued need for

antiviral drugs

What are the response rates with longer-term treatment with NAs?

0

10

20

30

40

50

60

70

80

LAM ADV ETV LdT

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

HB

eAg

res

po

nse

(%

)

2125

2932

36

12

48

21

31

39

30

22

Years of treatment

PEGASYSoff-treatment

1

32

48

NAs on-treatment

24wk

48wk

Resistance Profiles of antiviral agents

Genotypic resistance to adefovir2

HBeAg(-) HBeAg(-)

0 311

18

29

0

20

40

60

80

100

1 2 3 4 5Year of treatment

of

resi

sta

nce

(%

)

Cu

mu

lati

ve p

rob

abil

ity

Genotypic resistance to lamivudine1

HBeAg(+) HBeAg(+)

23

4655

7165

0

20

40

60

80

100

1 2 3 4 5

Pre

vale

nce

of

resi

stan

ce (

%)

Year of treatment

1. Lok AS, et al. Gastroenterology. 2003;125:1714-22. 2. Borroto-Esoda K. J Hepatol. 2006;44(suppl 2):S179-80 (Poster 483). 3. Standrigg DN, et al. J Hepatol. 2006;44(suppl 2):S191 (Poster 514). 4. Lai CL, et al. Hepatology. 2006;44(4 suppl 1):222A (Oral 91). 5. Colonno et al. J Hepatol 2007;46(suppl 1):S293 (oral 781).

HBeAg(+) and (-) patientsHBeAg(+) and (-) patients

Nucleoside naiveNucleoside naiveLamivudine refractoryLamivudine refractory

Viral rebound with genotypic resistance to entecavir5

0

20

40

60

80

100

1 2 3 4Year of treatment

Cu

mu

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Res

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nce

(%

)

<1 <1

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50

20

40

60

80

100

Year of treatment

Cu

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ce

of

res

ista

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e (

%)

HBeAg(+)HBeAg(+) HBeAg(-)HBeAg(-)

Viral rebound with genotypic resistance to telbivudine3,4

4

22

39

1 2 3 4 5<1 <1 <1

15

Peginterferon alfa-2b (12KD) 100 g qw* + oral placebo

* PEG-IFN-2b (12KD) dose reduced to 50 g qw after 32 weeks

Janssen et al Lancet 2005

Peginterferon alfa-2b (12KD) 100 g qw*+ lamivudine 100 mg od

Peginterferon alfa-2b (12KD) in HBeAg-positive CHB

Patients with HBeAg-positive CHB were randomised using a 1:1 ratio

ITT population: n=266

0 52 78Study weeks

26 weekfollow-up

End of Treatment(52 weeks)

End of Follow-up(78 weeks)

Off-label Product Use

0

20

40

60

HBeAg Loss

29%35%

Pat

ien

ts (

%)

End of Treatment(Week 52)

End of Follow-up(Week 78)

44%

P=0.01

36%

P=0.91

Peginterferon alfa-2b (12KD) + placebo

Peginterferon alfa-2b (12KD) + lamivudine

Janssen et al Lancet 2005

Relapse at wk 78 : 5/40 (13%) Vs 22/57 (39%), p=0.005 Janssen et al Gut 2007

Long-Term Follow-Up of Peginterferon andLamivudine Combination Treatment in

HBeAg-Positive CHB

Chan LY Hepatology 2005

0

10

20

30

40

HBeAg Seroconversion* in Asian Patients (6 Months Post-treatment)

31%

19%

Pa

tie

nts

(%

)

PEGASYS+ placebo

PEGASYS+ lamivudine

Lamivudine

29%

n=238 n=238 n=232

NS P=0.02

P=0.005

Overall population: HBeAg seroconversion 32% in PEGASYS monotherapy arm

*HBeAg loss and presence of anti-HBe ABs

59/69 14/103

1. Lau et al. N Engl J Med 2005; 2. Lau et al. EASL 2006

HBeAg Seroconversion Long-term Roll-over Study: 1 Year Analysis

• 173 patients from the PEGASYS mono therapy arm entered the long-term study (63% of original study): 69 responders and 103 non responders

86% of initial respondersmaintained response

after 1 year

0

10

20

30

40

32%

Pa

tient

s (%

)

87/271

50

Initial study1

24 weeks post-treatmentLong-term study2

48 weeks post-treatment

14% of initial non-responders developed a late response 6–12

months post-treatment

42% Overall response

HBsAg need to be cleared before the development of cirrhosis

Population Status at Clearance

No. of cases

Mean age (yr)

Outcome

Caucasian1 Cirrhosis 32 44 22%

Asian2 Cirrhosis 29 54 17%

No cirrhosis 189 43 2.1%*

*only in those with HCV/HDV co-infection

1Fattovich et al Am J Gastro 1998; 2Liaw et al Gastroenterology 2002

Direct antivirals Interferon-based

Patient/physician preferenceConsider risk of drug resistance

Length of treatmentSide effects

Immunocompetent

Compensated liver disease

Younger patients

NA-failures/resistant

Immunosuppressed

Advanced liver disease

IFN/PEG-IFN non-responders

High ALT

Low HBV DNA

Liver lesions

NA treatment should not be prescribed until the PATIENT understands that they CANNOT be stopped

abruptly for any reason

NA treatment should not be prescribed until the PATIENT understands that they CANNOT be stopped

abruptly for any reason

Who should be treated with what?

NAsLong-term maintenance (years)

Risk of resistance, and cross-resistance – monitor closely

Use in combination?

Prescribe responsibly

Optimising response in HBeAg-positive CHB through immune control

PEGASYSShort-term, finite duration (48 wks)

Long-term benefit in ~1/3 pts

HBsAg seroconversion achievable

No resistance

Prior exposure to NAs not a barrier to tx

For patients who do not respond or for whom IFN contraindicatedwe need to know how to use NAs appropriately

!

Summary: Treatment Algorithm to Improve Clinical Outcomes

1st choice Aiming for sustained remission

Using a treatment of finite durationeg pegylated or conventional IFN

Sustainedremission

yes

no*

2nd choice Maintained remission

Using a treatment of indefinite duration

eg nucleos(t)ide analogues

*or IFN contraindicated / not tolerated

SurvivalLau GK, Marion P Hepatol Int 2008