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
mu
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
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
lati
ve P
rob
abil
ity
of
Res
ista
nce
(%
)
<1 <1
10 16
50
20
40
60
80
100
Year of treatment
Cu
mu
lati
ve
in
cid
en
ce
of
res
ista
nc
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