George LAU

Hepatitis B e antigen positive patients:Why do I treat my patient with pegylated

interferon?2nd Hepatitis Paris conference

George KK Lau, M.D.

The University of Hong Kong

What do we want to achieve in treating HBeAg+ CHB patients?

HBeAg seroconversion

Disease remission (↓ HBV DNA; ↓ ALT)

HBsAg loss/seroconversion

Prevention of HCC and cirrhosis

Increased survival

Hoofnagle et al. Ann Intern Med 1981; Fattovich et al. Hepatology 1986; Di Bisceglie et al. Gastroenterology 1987; Niederau et al. NEJM 1996; Chu et al. Gastroenterology 2002; van Zonneveld et al. Hepatology 2004

HBeAg loss

Why is serological clearance of HBeAgHBsAg important?

HBsAg HBeAg ALT Relative Risk-- -- normal 1 (23/71,105 person-yr)

-- -- elevated 5.4

+ -- normal 10.3

+ -- elevated 29.3

+ + normal 61.3

+ + elevated 109

Yang et al., NEJM 2002

Study of HBV progression and HCC in 11,893 men in Taiwan

Registered treatment of chronic hepatitis B-2007

Immune therapy (finite)

Conventional IFN-Pegylated IFN-2a

Anti-viral (life-long)

Lamivudine

Adefovir dipivoxil

Entecavir

LdT

Clevudine (Korea)

Immune control,

no antiviral drugs

Continued need for

antiviral drugs

Aim for sustained remission Suppression of viral replication ? Immune recovery

Peg-IFN 2a Peg-IFN 2b

Cooksley 2003 Lau 2005 Janssen 2005 Chan 2005

Comparator arm

IFN LAM LAM+ pIFN

LAM+pIFN LAM vs. pIFN + LAM

Peginterferon- trials on HBeAg positive CHB

Hui et al Semin Liv Disease 2006

PEGASYS in CHB: Phase III Study Designs

HBeAg-positive CHB – ITT population: n=814

Lamivudine 100 mg qd

PEGASYS 180 g qw + lamivudine 100 mg qd

PEGASYS 180 g qw + oral placebo qd

0 24 48

24 weekfollow-up

72Study weeks

RandomisedEnd of Treatment

48 weeksEnd of Follow-up

72 weeks

Lau et al. NEJM 2005

HBV DNA Levels Over Time plus HBeAg Seroconversion at End of Follow-up

12

*all numbers shown are log10 reduction from baseline

On-treatment Follow-up

Mea

n H

BV

DN

A (

log

10 c

op

ies/

mL

)

2

4

6

8

10

0 6 12 18 24 30 36 42 48 54 60 66 72

-4.5*

-5.8*

-2.0

-7.2*

-2.6

-2.4

32%

27%

19%

P=0.023

P<0.001

HBeAg Seroconversion Rates at End of Follow-up

PEGASYS

n=271 n=271 n=272

PEGASYS+ LAM

LAM

Study week

HBV DNA Suppression in Patients Achieving HBeAg Seroconversion

On-treatment Follow-up

Study week

Mea

n H

BV

DN

A (

log

10 c

op

ies/

mL

)

3.3

0

2

4

6

8

10

12

0 6 12 18 24 30 36 42 48 54 60 66 72

10,000 cp/mL

patients with HBeAg seroconversion maintained DNA levels <10,000 cp/mL

Fried et al. EASL 2005

0

5

10

15

20

1.37

12.17

3.57

14.89

1.30

Incidence of Hepatocellular Carcinoma (HCC) by HBV DNA Level

Chen et al. JAMA 2006

Cu

mu

lati

ve In

cid

enc

e o

f H

CC

(%

)*

≥106104–105<104PCR negative

Level of HBV DNA (cp/mL)

*at the end of the 19th year of follow-up

105–106

21

1820

24

27

22

25

0

5

10

15

20

25

30

354 355 272 271 271 136 130

69% 38% 40% 69% 25% 10% 33%

Chang NEJM 2006 Lau NEJM 2005

(%)

Janssen Lancet 2005

ETV LAM Peg-2a + LAM

LAM Peg-2a Peg-2b + LAM

Peg-2b

No

DNA <400cp/ml

HB

eAg

ser

oco

nve

rsio

n

at e

nd

of

trea

tmen

t (%

)End of Treatment HBeAg seroconversion in Relation to

Extent of HBV DNA Suppression

Serological clearance of HBsAg with current treatment (~1 yr)

% Lam1 ADV2 LdT3 ETV4 Pegasys5

Adoptive immune transfer6

HBeAg 18 12 25* 21 32 -

HBsAg 0 0 0 0 3 65

*HBeAg loss

Spontaneous HBsAg clearance in Chinese-0.1-0.8%/yr

1Lai et al NEJM 1998, 2Marcellin et al NEJM 2003, 3Poynard et al. J Hepatol 2004, 4Chang et al. Hepatology 2004, 5Lau et al. NEJM 2005, 6 Lau et al Gastroenterology 2002

0

10

20

30

40

50

60

70

80

1 2 3 4 5

Pat

ien

ts w

ith

H

BeA

g s

ero

con

vers

ion

(%

)

Lamivudine1

1. Lok et al Gastroenterology 2004; 2. Marcellin et al AASLD 2004

Adefovir2

Years

16% 17%23%

28%35%

12%NA NA

NA = not available

On-therapy Response to Long-term Nucleos(t)ide Analog Therapy in HBeAg-positive CHB

29%

43%

845 a.a.

Terminal protein Pol/RT RNaseH

A B C ED

1 183 349 692

YMDD

V173L

L180M M204I/V

GVGLSPFLLA

I(G) II(F)

(rt1) (rt 344)

Identified Mutations Associated with Drug Resistance

LAM1 / FTC2

ETV *4 T184A/G/I/S S202G/I M250V

ADV 3 A181V N236T

LdT 5

M204I

* All ETV resistance require background YMDD mutations

1 Allen MI, et al. Hepatology 1998; 27:1670-16772 Gilead data on file

3 Qi X, et al. J Hepatol 2004, 40 (suppl 1): 20-214 Tenney et al. AAC. 2004:48:3498-5075 Lai CL, et al. Hepatology 2003; 38: 262A6 Soriano V et al, AASLD 2004

spacer

Duration of Lamivudine-ResistantDuration of Lamivudine-ResistantMutations (Years)Mutations (Years)

% o

f P

atie

nts

wit

h

% o

f P

atie

nts

wit

h

Hep

atit

is F

lare

Hep

atit

is F

lare

100100

7575

5050

2525

00 Not Not <1 <1 1–2 1–2 2–3 2–3 3–4 3–4 >4>4

detecteddetected

3–5 x ULN3–5 x ULN

n = 998n = 998

Long-Term Safety of Lamivudine in HBeAg Positive CHB

Hepatitis Flares

• Hepatitis flares(ALT >3 x ULN) more frequent in patients with lamivudine resistance (P < .005)

• Hepatitis flares increased with duration of lamivudine resistance (P < .001)

5–10 x ULN 5–10 x ULN

>10 x ULN>10 x ULN

Lok ASF, et al. Gastroenterology. 2003;125:1714.

HBeAg Relapse Following Lamivudine and IFN

Cu

mu

lati

ve %

rel

apse

of

HB

eAg

sero

con

vers

ion

0 26 52 78 104 130 156

10

20

30

40

50

60

70

80

90

100

Time (weeks) after the end of therapy

LAM

IFN

van Nunen et al. Gut 2003

Cumulative rate of relapse in patients who had achieved HBeAg seroconversion by end of treatment

54%

32%

Adverse Events experienced in Chronic HBeAg+ patients

PEGASYS® + placebo

(n=271)

PEGASYS® + lamivudine

(n=271)

lamivudine

(n=272)

At least 1 adverse event 240 (89%) 240 (89%) 152 (56%)

Pyrexia 133 (49%) 148 (55%) 12 (4%)

Fatigue 99 (37%) 99 (37%) 36 (13%)

Headache 76 (28%) 81 (30%) 27 (10%)

Myalgia 70 (26%) 77 (28%) 8 (3%)

Alopecia 55 (20%) 78 (29%) 6 (2%)

Injection site reaction 30 (11%) 15 (6%) 0 (0%)

Dizziness 25 (9%) 32 (12%) 11 (4%)

Urinary tract infections 21 (8%) 15 (6%) 29 (11%)

* AEs with an incidence of >10% in one treatment arm during treatment and up to 8 weeks post-therapy

Long-term Follow-up Study: 1-year Analysis

* Lau et al. NEJM 2005; Marcellin et al. NEJM 2004

** 1-year analysis of patients from initial study who completed 6-month follow-up

Lamivudine 100 mg qd

PEGASYS 180 μg qw + 100 mg lam qd

PEGASYS 180 μg qw + placebo qd

48 weeks

12 monthspost-EOT(week 96)

5 yearspost-EOT

**

Initial study*

EOT(week 48)

6 monthspost EOT(week 72)

Long-term study

0

10

20

30

40

50

40%

39%

HBeAg Seroconversion: 40% of Asian Patients Achieved Sustained Responses 1 year Post-treatment

31%

Pa

tie

nts

ac

hie

vin

g

HB

eA

g s

ero

co

nve

rsio

n (

%)

n=238 n=58/150 n=60/150

Week 48 Week 72 Week 96Time point

Lau et al. Shanghai Hong Kong Liver Congress 2006

Initial study Entered long-term study

Over 80% of patients with responses 6 months post-treatment sustained these responses 1 year post-treatment

(83%)

Late responders

Sustained responders

38

23

0

31

23

1

10

31

0

21 23

99

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

>100'000

10'001 to 100'000

401 to10'000

<=400

No HBeAg

Seroconversion

(n=67)

HBV DNA Levels 1 Year Post-treatment According to Type of Response

HBV DNA 1 year post-treatment

(copies/ml)

Sustained HBeAg

Seroconversion

(n=53)

Late HBeAg

Seroconversion

(n=13)

Study FU (yrs)

Number of patients Comments

IFN Control

Niederau NEJM 1996

4.2 103 53 IFN induced serological clearance of HBeAg has improved clinical outcome

Lin JVH 1999

7.0 67 34 IFN increase HBV clearance, reduces HCC, and prolongs survival

Fattovich Hepatol 1997

7.2 40 50 IFN-induced disease remission associated with improved survival in HBeAg-positive patients with compensated cirrhosis

Lin J Hepatol 2007

6.8 233 233 IFN-induced HBeAg seroconversion reduces liver cirrhosis and cancer

Long-term follow-up on CHB patients with active hepatitis or advance fibrosis/cirrhosis Rx with IFN-based therapy

Lau GK. J Hepatol 2007

Nucleos(t)ide analogues Immunomodulatory

Oral administration Subcutaneous

Potent HBV DNA suppression Less potent HBV DNA suppression

Not imunomodulatory Antiviral and immunomodulatory

Few side effects Frequent side effects

Risk of resistance development No resistance

HBsAg seroconversion rare HBsAg seroconversion more common

Long-term therapy – potential for drug fatigue

Finite therapy duration

Pros and cons of available treatment options

Significant* Baseline Predictors of Response 24 Weeks Post-treatment

VariableHBeAg-negative

(combined response**)

HBeAg-positive

(HBeAg seroconversion)

PEGASYS treatment (vs. lam) Age (young > old) Gender (female > male) Ethnicity Bodyweight Baseline ALT (high > low) Baseline HBV DNA (low > high) Baseline HBeAg (low > high) na Genotype

*P<0.05 by MV analysis; **ALT normalisation and HBV DNA <20,000 cp/mL Roche data on file

HBsAg-seroconversion by Genotype

1 Flink, Am J Gastroenterol 2006; 2 Hadziyannis, EASL 2005

PEG-IFN α-2b 1

0

3

6

9

12

15

A n=47

5%

8%

0%

Bn=12

C n=21

D n=51

1815%

Per

cen

tag

e o

f p

atie

nts

(%

) 21

24

HBV genotype

PEG-IFN α-2a 2

22%

0

3

6

9

12

15

A n=23

2%0% 0%

Bn=76

C n=162

D n=9

18

Per

cen

tag

e o

f p

atie

nts

(%

) 21

24

HBV genotype

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

Survival