EASL Endorsed Hepatology Conference Proceedings on IFN and NUC Therapy

White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH

EASL endorsed conference “White nights of hepatology”
Saint-Petersburg, June 10-11, 2010

IFN therapy prospects
of chronic hepatitis B

K. ZHDANOV


25-year survival rates in untreated CHB

100
Inactive CHB
Survival probability

80

60 HBeAg-/HBV DNA+
or HBeAg reversion

40
HBeAg+ persistence
20

0
0 5 10 15 20 25
Time (years)
Fattovich et al. Gut 2008


HBsAg clearance – Improves survival

Survival in patients with and without HBsAg seroconversion
Retrospective study of 309 cirrhotic patients over mean follow-up of 5.7 years

100 With HBsAg
clearance
80
Survival (%)

P<0.001
60
No HBsAg
40 clearance

20

0 2 4 6 8 10 12 14
Time (years)
Fattovich et al. Am J Gastroenterol 1998


When should we treat?

Anti-HBe
HBV DNA

ALT

Immune Immune clearance Inactive Reactivation
tolerant HBeAg +ve CHB CHB HBeAg –ve CHB

?
Lok et al. Arch Intern Med 2006


Treatment options in CHB

IFN: immune stimulation and antiviral action
• Effect usually sustained off therapy/post-
treatment

Nucleos(t)ide analogs: antiviral action only
• Effect maintained on therapy unless resistance
• Effect may not be sustained off treatment


Effect of ETV treatment discontinuation
on viral load in CHB (HBeAg-)
Percentage of protocol-defined responders who had
achieved HBV DNA <300 copies/mL at Week 48

59%
ETV (n=257)
LVD (n=201)

14%
4% 5% 3% 5%

8 16 24
Follow-up weeks

Shouval D. et al. J Hepatol 50 (2009) 289-295

clinical undetectable
White Nights of Hepatology 2010, an EASL endorsed conference histological survival
Conference proceedings: www.elsevier.ru/WNH

remission HBV DNA improvement

ALT - N HBeAg HBsAg
seroconversion seroconversion

1980 1990 2000 2010

Peg-IFN alfa
IFN

ADV

ETV
LDT
LVD

TDF
18% (HBeAg+)
10-47% (HBeAg-)


IFN LONG-TERM OUTCOMES
HBeAg-positive: follow-up of 11 years

IFN Control
(n=233) (n=233)

18% 34%
Cirrhosis p = 0.041*

3% 13%
HCC p = 0.011*

98% 53%
Survival p = 0.003*

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


HBsAg clearance increases over time in
responders to IFN-based therapy
Patients with HBeAg seroconversion and undetectable HBV DNA
48 weeks post-treatment with IFN
90
80
80
Cumulative rate of HBsAg

70
60
clearance (%)

60

50
40
40

30

20

10

0
5 10 15
Years post treatment
Moucari et al. J Hepatol 2009


HBsAg clearance increases over time in
sustained responders to IFN

100
HBsAg-negative patients (%)

80
Sustained responders*
60
45%
40 IFN
All patients
20 18%

Treatment failures
0
0 12 24 36 48 60 72 84 96 108 120 Months

*ALT normal and HBV DNA undetectable <1pg/mL Lampertico et al. Hepatology 2003


1 year of PEG-IFN (± LAM) in HBeAg +ve CHB

HBeAg seroconversion
6 months
On-therapy
post-treatment
Janssen 25% 29%

Lau 27–24% 32–27%

Chan 38% 36%

Response is sustained post-treatment
Janssen et al. Lancet 2005; Lau et al. N Eng J Med 2005; Chan et al. Ann Intern Med 2005


Responders* to Peg-IFN α-2b therapy in
HBeAg-positive CHB: 3-year follow up

Patients treated with PEG-IFN ± LAM for 1 year
100

81%
80 77%
58%
Patients (%)

60

40
30%
20

0
HBeAg ALT HBV DNA HBsAg
cleared normal <10,000 cleared
cp/mL
*HBeAg loss at 6 months post-treatment Buster et al. Gastroenterology 2008


HBsAg clearance rate increases post-
treatment with PEGASYS (± lamivudine)

15 N=230
13 12%
HBsAg clearance (%)

11%
11
Patients with

9%
9

7 6%

5
3%
3

1
Years after EOT 1 2 3 4 5

HBeAg-negative patients Marcellin et al. APASL 2009


PEGASYS demonstrated sustained
immune control up to 5 years

88% of PEGASYS patients
who achieved HBV DNA
50
≤10,000 copies/mL
at Year 1 post-treatment
% patients with HBV DNA

40
maintained that response
31%
≤10,000 cp/mL

up to year 5 (N=36/41)
30

20
28% of PEGASYS patients
who achieved HBV DNA
10
≤10,000 copies/mL
at Year 1 post-treatment
N=72
0 cleared HBsAg at year 5
Post-treatment (N=20/72*)
* 54% of PEGASYS patients Y1
who achieved HBsAg clearance also
achieved HBsAg seroconversion Marcellin et al. AASLD 2009 poster


Efficacy of PEGASYS in patients who
failed prior treatment

HBeAg-positive/negative disease


Comparing PEGASYS with ADV in HBeAg-
positive LAM-resistant patients (China)
HBeAg-positive, LAM-resistant
(YMDD+), on lamivudine for ≥6
months and still on Rx, N=235

PEGASYS 180 µg N=155 Follow-up
LAM
100 mg

Adefovir 10 mg N=80
LAM
100 mg

0 12 24 48 72
Study Weeks

Randomization 2:1 Hou et al. AASLD 2008; Hou et al. APASL 2009


Better HBsAg decline with PEGASYS vs
ADV in patients who failed prior NAs

Mean reduction in HBsAg from baseline
LAM-YMDD mutation patients
0
-0.31 -0.35
Quantitative HBsAg

ADV
(N=80)
(log10 IU/mL)

-0.5
P<0.001

PEGASYS
-1 -0.75 (N=155)

-0.92

-1.5
BL 24 48
Weeks
Hou et al. AASLD 2008; Hou et al. APASL 2009


PEGASYS is superior to ADV in
patients with YMDD mutations

16 PEGASYS
P=0.045
14 13.6% Adefovir
12 11.6%
Patients (%)

10
8.8%
8
6

4 3.8%
3.2%
2 1.9%
0% 0%
0
HBeAg HBeAg HBsAg HBsAg
clearance seroconversion clearance seroconversion

Hou J et al. APASL 2009; EASL 2009


Potential ways to increase rates of
sustained immune control

1. Extending PEGASYS therapy

2. Combining PEGASYS with NAs


Extended treatment duration

N=49 HBeAg-positive patients treated for 96 weeks
• Week 48:
– HBeAg loss = 37% (18/49)
• Week 96:
– HBeAg loss increased to 53% (26/49); HBsAg cleared in 10%
(5/49)
60 53%
51%
HBeAg loss (%)

50
Cumulative

35% 37%
40
30%
30
18%
20
10
0
12 24 36 48 72 96
Weeks of PEGASYS treatment
Wu. APASL 2008


Extended treatment is associated with
better virologic response at week 72

Extension group Follow-up group

100% P=0.14
81%
80%

60% 53% P=0.043

38% P=0.23
40%
19%
20%
0% 0%
0%
HBV DNA HBeAg HBsAg clearance
undetectable seroconversion
Jiang et al. data on file


Italian PegBeLiver study:
Patients with HBeAg-negative disease

A
PEGASYS 180 µg Follow-up
HBeAg-negative

B
N=122

PEGASYS 180 µg PEGASYS 135 µg Follow-up

PEGASYS 180 µg plus
PEGASYS 135 µg Follow-up
LAM 100 mg
C
qHBsAg
0 48 96 144
Study Weeks

Randomization 2:2:1


HBsAg(-) HBsAg(-)
0% 9% (n=3)
+
6% (n=2)
<10IU/ml

n=51 n=52 n=51 n=52


Potential ways to increase rates of
sustained immune control

1. Extending PEGASYS therapy

2. Combining PEGASYS with NAs
• Sequential
PEGASYS +
• Concomitant ETV, ADV or TDF
• Nested


High rates of sustained immune control and
HBsAg clearance with PEGASYS + ADV

PEGASYS 180 μg/week + ADV 10 mg/d 48 weeks

HBeAg seroconversion
6 months post-treatment
10/28 36%
HBeAg-positive
patients (N=41) HBsAg clearance
up to 5 Y post-treatment*
4/28 14%

HBV DNA suppression
6 months post-treatment 14/30 47%
HBeAg-negative (<2,000 IU/mL)
patients (N=45)
HBsAg clearance
up to 5 Y post-treatment*
7/30 23%

*Patients who completed 6 months of
post-treatment follow up were followed for up to 5 years Takkenberg et al. AASLD 2009


Combination study: PEGASYS + nested ETV in
HBeAg-negative CHB
STUDY WEEK
BL 12 24 36 48 48 60 72 84 96 108 120 132 144

PEGASYS 180 µg sc/Wk
(GENOTYPES: B=30%; C=30%; D=30%, Other=10%)

A ENTECAVIR
FOLLOW UP PERIOD

placebo oral od

PEGASYS Duration Code break
HBeAg Negative

B ENTECAVIR
FOLLOW UP PERIOD

0.5mg oral od
N=400

C ENTECAVIR
PEGASYS 180 µg sc/Wk FOLLOW UP PERIOD

placebo oral od

D ENTECAVIR
PEGASYS 180 µg sc/Wk FOLLOW UP PERIOD

0.5mg oral od

RANDOMIZATION & DOUBLE BLIND 1ry END POINT: HBV DNA <10,000 copies/ml
ENTECAVIR TREATMENT ALLOCATION at 48 weeks post treatment

Planned 1st patient in for screening: July 2010
Planned 1st patient enrolled: September 2010


Switch study: UK

NA Follow up

NA 3Y

PEGASYS Follow up

3 years 0 48 weeks 144

Endpoints: 2 years post-treatment
• Sustained immune control (HBV DNA <10,000 copies/mL)
• Clearance of HBsAg

Parallel immunology/biomarkers substudy

Sustained immune control through IFN-based

therapy is the critical step towards HBsAg
clearance
Clinical benefit
(↓HCC/↓cirrhosis) &
improved survival

POST-TREATMENT
HBsAg clearance

SUSTAINED
IMMUNE
CONTROL*

*POST-TREATMENT
HBV DNA ≤10,000 copies/mL
ON-TREATMENT in HBeAg-negative disease
HBV DNA suppression
HBsAg decline


Treatment costs for PEGASYS vs NAs

40,000
Cumulative costs of treatment (US$)

30,000

NAs
20,000 PEGASYS

10,000

1 2 3 4 Years
Source: Costs of Antiviral Therapy of Chronic Hepatitis B,” an abstract by John B. Wong, M.D., Tufts New England Medical
Center, Boston, MA presented at the NIH Meeting; Management of Hepatitis B on April 7, 2006


CONCLUSIONS
1. Sustained immune control through IFN-based therapy in CHB
(HBeAg+ and HBeAg-) is the critical step towards HBsAg
clearance. Thus Peg-IFN can be used as first-line
monotherapies.
2. Peg-IFN is effective in NAs resistance and can be used in
patients who failed prior NAs.
3. HBV genotype has a poor individual predictive value and
currently, genotype alone should not override the choice of
treatment.
4. Extending Peg-IFN therapy improves SVR rate and HBsAg
clearance.
5. Combining Peg-IFN with NAs is potential way to increase rates
of sustained immune control.

EASL Endorsed Hepatology Conference Proceedings on IFN and NUC Therapy

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