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2 Peg-IFNa-2a (PEGASYS) in CHB Review of
Data Presented at the 40th Annual EASL meeting
1317 April 2005, Paris, France
George V. Papatheodoridis, MD Assistant
Professor in Medicine Gastroenterology 2nd
Academic Department of Medicine Hippokration
General Hospital, Athens, Greece Beirut, July
1st, 2005
3EASL Meeting, April 2005, Paris
- Abstracts on Pegasys in CHB
- Study 240 (HBeAg-positive CHB)
- GKK Lau et al. PEGASYS vs. PEGASYS plus
lamivudine vs. lamivudine in HBeAg-positive CHB
Effect of previous treatment and drug exposure on
sustained response - G Cooksley et al. Effect of genotype and other
baseline factors on response to PEGASYS in
HBeAg-positive CHB Results from a large,
randomised study - M Fried et al. Greater viral suppression with
lamivudine /- PEGASYS does not translate into
improved rates of sustained HBeAg seroconversion
results from a large, multinational study - T Piratvisuth et al. Effect of ALT flares on
efficacy and safety of PEGASYS, PEGASYS plus
lamivudine and lamivudine in HBeAg-positive CHB
4EASL Meeting, April 2005, Paris
- Abstracts on Pegasys in CHB (cont.)
- Study 241 (HBeAg-negative CHB)
- P Marcellin et al. Sustained response to PEGASYS
in HBeAg-negative CHB B. One-year follow-up data
from a large, randomised multinational study - P Farci et al. On-treatment predictors of
sustained biochemical and virological response in
patients with HBeAg-negative CHB treated with
PEGASYS - Studies 240 241
- S Hadziyannis et al. Sustained HBsAg
seroconversion in patients with chronic hepatitis
B treated with PEGASYS - Independent Study in HBeAg-negative CHB
- RM Ribeiro et al. Hepatitis B viral kinetics
under different approved antiviral treatment
regimens in HBeAg-negative patients with CHB
explain treatment antiviral mechanisms
5 Peginterferon Alfa-2a Alone, Lamivudine Alone,
and the Two in Combination in Patients with
HBeAg-Negative Chronic Hepatitis B Patrick
Marcellin, M.D., George K.K. Lau, M.D., Ferruccio
Bonino, M.D., Patrizia Farci, M.D., Stephanos
Hadziyannis, M.D., Rui Jin, M.D., Zhi-Meng Lu,
M.D., Teerha Piratvisuth, M.D., Georgios
Germanidis, M.D., Cihan Yurdaydin, M.D., Moises
Diago, M.D., Selim Gurel, M.D., Ming-Yang Lai,
M.D., Peter Button, M.Sc., Nigel Pluck, M.D., for
the Peginterferon Alfa-2a HBeAg-Negative Chronic
Hepatitis B Study Group
6Study Design
Patients with HBeAg-negative CHB were randomised
using a 111 ratio ITT population n537
End of Treatment 48 weeks
End of Follow-up 72 weeks
Randomised
PEGASYS 180 ?g qw oral placebo qd
24 weeks follow-up
PEGASYS 180 ?g qw lamivudine 100 mg qd
lamivudine 100 mg qd
0
24
48
72
Study weeks
7Key Inclusion Criteria
- HBsAg ve for ?6 months
- HBeAg ve, anti-HBe ve for ?6 months
- HBV DNA gt100,000 cp/mL
- (COBAS AMPLICOR HBV MONITOR)
- Serum ALT gt1 but ?10 x ULN at screening
- Less than 20 with serum ALT 12 x ULN
- Liver biopsy proven CHB
- Prominent necroinflammatory component
8Key Exclusion Criteria
- Decompensated liver disease
- Co-infection with HCV, HDV or HIV
- Anti-HBV therapy in 6 months prior to study
9Baseline Characteristics
Marcellin et al. NEJM 2004351120617
10Co-primary Endpoint - Normal ALT 24 Weeks After
End of Treatment (Week 72)
P0.004
60
59
Patients ()
44
n177
n179
n181
lamivudine
PEGASYS placebo
PEGASYS lamivudine
Marcellin et al. NEJM 2004351120617
11Co-primary Endpoint - HBV DNA Response 24 Weeks
After End of Treatment (Week 72)
P0.007
P0.849
P0.003
44
43
Patients ()
29
n177
n179
n181
PEGASYS placebo
PEGASYS lamivudine
lamivudine
HBV DNA response defined as lt20,000 cp/mL
Marcellin et al. NEJM 2004351120617
12HBV DNA lt400 copies/ml 24 Weeks After End of
Treatment (Week 72)
Plt0.001
P0.909
Plt0.001
20
19
Patients ()
7
n177
n179
n181
PEGASYS placebo
PEGASYS lamivudine
lamivudine
Marcellin et al. NEJM 2004351120617
13Combined Response 24 Weeks After End of
Treatment (Week 72)
38
36
Patients ()
23
n177
n179
n181
PEGASYS placebo
PEGASYS lamivudine
lamivudine
Combined response defined as ALT normalisation
and HBV DNA lt20,000 cp/mL
Marcellin et al. NEJM 2004351120617
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15Study Design
Patients with HBeAg-positive CHB were randomised
using a 111 ratio ITT population n814
End of Treatment 48 weeks
End of Follow-up 72 weeks
Randomised
PEGASYS 180 ?g qw oral placebo qd
24 weeks follow-up
PEGASYS 180 ?g qw lamivudine 100 mg qd
lamivudine 100 mg qd
0
24
48
72
Study weeks
16(No Transcript)
17(No Transcript)
18Baseline Characteristics
19HBeAg Seroconversion at End of Follow-up (Week
72) All Patients
Plt0.001
PNS
P0.023
32
27
Patients with HBeAg seroconversion ()
19
n271
n271
n272
PEGASYS placebo
PEGASYS lamivudine
lamivudine
20(No Transcript)
21Conclusions
- In both HBeAg-negative HBeAg-positive CHB
- PEGASYS monotherapy achieves significantly higher
response rates at 24 weeks post-treatment, as
compared with lamivudine monotherapy - The combination of PEGASYS lamivudine does not
improve response rates compared with PEGASYS
alone
22Conclusions
- No unexpected adverse events are observed with
PEGASYS, and the addition of lamivudine did not
alter the safety profile - The data support the use of PEGASYS asfirst-line
therapy in both patients with HBeAg-negative and
HBeAg-positive CHB
23Annual EASL Conference, April 2005, Paris
- Peginterferon Alfa-2a (40KD) (PEGASYS) vs.
Peginterferon alfa-2a Plus Lamivudine vs.
Lamivudine in HBeAg-positive Chronic HBV Effect
of Previous Treatment and Drug Exposure on
Sustained Response - GKK Lau, T Piratvisuth, K-X Luo, P Marcellin, S
Thongsawat, E Gane, MW Fried, G Cooksley, P
Button, Y-F Liaw - Abstract 31 (oral presentation)
-
24HBeAg Seroconversion at Week 72 in Patients with
Prior Exposure to Anti-HBV Therapy
PEGASYS placebo
Lamivudine
PEGASYS lamivudine
Plt0.001
P0.065
P0.009
P0.047
43
37
34
32
32
30
Patients with HBeAg seroconversion ()
27
25
19
17
16
13
n271
n271
n272
n31
n30
n24
n42
n32
n32
n57
n50
n64
Pts with prior exposure to lamivudine
All patients
Pts with prior anti-HBV therapy
Pts with prior exposure to conv. IFN?
P value for PEGASYS placebo vs lamivudine
includes lamivudine and conventional or
pegylated IFN
25HBeAg Seroconversion at End of Follow-up (Week
72) Effect of PEGASYS Exposure
33
28
Patients with HBeAg seroconversion ()
17/60
70/211
90 PEGASYS dose (7776 ?g)
lt90 PEGASYS dose (lt7776 ?g)
The bars represent 95 confidence intervals
26Effect of Previous Treatment on Sustained
Response Summary
- Prior treatment with lamivudine or interferon
does not substantially affect HBeAg
seroconversion rates - HBeAg seroconversion rates in patients without
prior anti-HBV therapy appear to be almost
identical to those seen in the overall population - HBeAg seroconversion rates are significantly
higher with PEGASYS alone than with lamivudine
monotherapy, irrespective of previous anti-HBV
therapy
27Effect of PEGASYS Drug Exposure on Sustained
Response Summary
- Drug exposure in the study was very high
- 78 of patients received 90 of the total
PEGASYS dose - A high rate (28) of HBeAg seroconversion was
achieved with PEGASYS even in patients who
received lt90 of the drug dose - Because of the relatively small number of
patients receiving lt90 of the PEGASYS dose, it
is difficult to determine an exposure/efficacy
relationship
28Annual EASL Conference, April 2005, Paris
- Effect of Genotype and Other Baseline Factors on
Response to Peginterferon Alfa-2a (40KD)
(PEGASYS) in HBeAg-positive Chronic Hepatitis B
Results from a Large, Randomised Study - G Cooksley, M Manns, GKK Lau, Y-F Liaw, P
Marcellin, W-C Chow, S Thongsawat, E Gane,
MW Fried, F Zahm - Abstract 71 (oral presentation)
29Factors Predictive of Response in HBeAg() CHB
- Common across conventional IFN?, lamivudine,
adefovir1,2 - High pretreatment ALT values
- For response to conventional IFN? and lamivudine1
- Low pretreatment serum HBV DNA levels
- High degree of necroinflammatory activity
- Infection as an adult
- For response to conventional IFN? only1, 36
- Genotype B (vs C)
- Genotype A (vs D)
1. EASL Consensus Statement J Hepatol 2003 (EASL
Guidelines) 2. Marcellin EASL 2002 3. Craxi J
Hepatol 2003 4. Erhardt Hepatology 2000 5. Hou
Hepatology 2001 6. Cooksley J Viral Hepat 2003
30HBeAg Seroconversion after 24 Weeks of
Follow-upBest Responses in Patients with High
Baseline ALT
PEGASYS placebo
PEGASYS lamivudine
lamivudine
41
37
Patients with HBeAg seroconversion ()
30
29
28
27
20
20
16
19/96
36/121
30/111
20/129
24/58
25/67
13/47
27/92
19/93
25 x ULN
gt5 x ULN
?2 x ULN
ALT
31HBeAg Seroconversion after 24 Weeks of
Follow-upBest Responses in Patients with Low
Baseline HBV DNA
HBeAg seroconversion 24 weeks after the end of
treatment
53
36
31
Patients ()
28
27
21
17
17
10
7/71
24/78
39/138
40/147
21/123
11/63
14/68
37/70
20/56
gt9.07 to 10.26 (2nd 3rd Quartiles)
gt10.26 (4th Quartile)
9.07 (1st Quartile)
HBV DNA (log10 cp/mL)
32Parameters Significantly Associated with
Sustained HBeAg Seroconversion (SR) in the MV
Analysis
- Treatment with PEGASYS
- 2-fold higher odds (chance) of SR than lamivudine
- ALT at baseline
- Chance of SR increased by 2.7-fold for each log10
ALT (IU/L) increase - Patients with ALT 500 IU/L had a 2.7-fold
higher chance of SR than those with an ALT 50
IU/L - HBV DNA at baseline
- Chance of SR increased by 20 for each log10
(copies/mL) decrease - HBeAg levels at baseline
- Chance of SR increased by 50 for each log10
(IU/mL) decrease
33HBeAg Seroconversion after 24 Weeks of Follow-up
(Week 72) Effect of HBV Genotype
52
Patients with HBeAg seroconversion ()
31
30
29
28
23
22
22
20
18
18
18
12/23
4/18
3/15
23/76
24/82
17/73
50/162
43/156
29/162
2/9
2/11
3/17
Genotype
34Summary (i)
- High ALT, low HBV DNA and low HBeAg levels at
baseline are strong independent predictors of
HBeAg seroconversion - Regardless of baseline ALT, HBV DNA or HBeAg
levels, rates of HBeAg seroconversion are higher
with PEGASYS than with lamivudine - Among patients with low HBV DNA levels (lt9 logs),
HBeAg seroconversion is achieved in gt50 of those
treated with PEGASYS alone - Among patients with ALT levels gt5 xULN, HBeAg
seroconversion is achieved in gt40 of those
treated with PEGASYS alone
35Summary (ii)
- HBeAg seroconversion rates with PEGASYS
monotherapy are substantially higher in patients
infected with genotype A compared with those
infected with genotypes B, C or D - More than half of the patients infected with
genotype A treated with PEGASYS achieve sustained
HBeAg seroconversion - Patients infected with HBV genotypes B and C
respond equally well to PEGASYS, in contrast to
what has been observed with conventional IFNa
36Annual EASL Conference, April 2005, Paris
Greater Viral Suppression with LAM /- PEGASYS
does not translate into Improved Rates of
Sustained HBeAg Seroconversion MW Fried, GKK
Lau, T Piratvisuth, K-X Luo, WC Chow, SW Paik,
WY Chang, R Flisiak, N Pluck, T Berg Abstract
488 (poster presentation)
37HBV DNA Levels On Treatment and HBeAg
Seroconversion at End of Follow-up
12
HBeAg Seroconversion Rates at End of Follow-up
On-treatment
Plt0.001
10
32
P0.023
27
8
Mean HBV DNA (log10 copies/mL)
19
6
4
n271
n271
n272
2
PEGASYS
PEGASYS LAM
LAM
0
6
12
18
24
30
36
42
48
54
60
66
72
Study week
all numbers shown are log10 reduction from
baseline
38HBV DNA suppression HBeAg seroconversionConclus
ions
- HBV-DNA suppression is greater with PEGASYSLAM
or LAM alone compared to PEGASYS monotherapy
(7.2, 5.8 and 4.5 mean log reduction at EOT) - However, HBeAg seroconversion 24 wks after EOT is
higher with PEGASYS (32) than with LAM (19) or
combination therapy (27) - The more potent HBV-DNA suppression does not
translate into improved HBeAg seroconversion
rates - The superior benefit seen with PEGASYS may be due
to its dual mode of action (antiviral
immunomodulatory)
39Annual EASL Conference, April 2005, Paris
Effect of ALT Flares on Efficacy and Safety of
PEGASYS /- Lamivudine, or Lamivudine alone in
HBeAg-positive CHB T Piratvisuth, K-X Luo, P
Marcellin, WY Chang, T Berg, R Flisiak, Y-C
Chao, SW Paik, S Thongsawat, P McCloud Abstract
523 (poster presentation)
40Marked ALT flares (maximum ALT) during therapy
(weeks 0-48)
PEGASYSplacebo (n271) PEGASYSlamivudine
(n271) Lamivudine (n271)
P0.037
18
Patients,
13
11
6
5
4
gt10 x ULN gt5 x baseline ALT
41Peak ALT during treatment and HBeAg
seroconversion 24 weeks after the end of
treatment (week 72)
42Marked ALT flares (maximum ALT) after therapy
(weeks 49-72)
PEGASYSplacebo (n271) PEGASYSlamivudine
(n271) Lamivudine (n271)
15
Patients,
13
12
11
11
7
gt10 x ULN gt5 x baseline ALT
43Liver decompensation in patients with
post-therapy (weeks 49-72) marked ALT flares
- Patients with
-
decompensation Outcome - PEGASYSplacebo 1
Resolved 1 - PEGASYSlamivudine 3
Resolved 3 - Lamivudine 4
Resolved 2 -
Death 1 -
OLT 1
44ALT flares safety-efficacy of therapy in
HBeAg()CHB Conclusions
- Marked on-treatment ALT elevations are generally
more frequent with PEGASYS monotherapy and are
more common in patients with HBeAg seroconversion
24 weeks after the end of treatment - In contrast, marked follow-up flares are
generally more frequent with lamivudine and may
lead to irreversible liver failure
45Annual EASL Conference, April 2005, Paris
- Sustained HBsAg seroconversion in patients with
chronic hepatitis B treated with peginterferon
alfa-2a (40KD) (PEGASYS) - S Hadziyannis, GKK Lau, P Marcellin, T
Piratvisuth, - G Cooksley, F Bonino, A Chuttaputti, M Diago, R
Jin, - N Pluck
- Abstract 491 (poster presentation)
46Objective
- To investigate the occurrence of HBsAg
seroconversion in 1,351 patients with
HBeAg-positive or HBeAg-negative CHB treated for
48 weeks with peginterferon alfa-2a (40KD)
(PEGASYS) alone, PEGASYS plus lamivudine or
lamivudine alone
47Methods
- Patients with HBeAg-positive (n814) or
HBeAg-negative (n537) CHB were treated in two
large, randomised, partially double-blind
multinational studies - All patients were positive for HBsAg and negative
for anti-HBs antibody at baseline - Patients were considered to have sustained HBsAg
seroconversion only if they were both HBsAg
negative and anti-HBs positive at 24 wks after
the end of treatment (wk 72)
48Sustained HBsAg seroconversion (24 weeks after
EOT in patients with HBeAg-positive CHB
49Sustained HBsAg Seroconversion According to
Ethnicity and Genotype
50HBsAg seroconversion in CHB -Conclusions
- HBsAg seroconversion can be achieved in patients
with HBeAg-positive or HBeAg-negative CHB treated
with a PEGASYS-containing regimen for 48 weeks - In contrast, HBsAg seroconversion is not observed
in patients treated with lamivudine monotherapy
for 48 weeks - HBsAg seroconversion rates are affected by
ethnicity and infecting HBV genotype. In patients
with HBeAg-positive CHB, the highest rates of
HBsAg seroconversion are observed in Caucasians
and in those infected with HBV genotype A
51EASL Meeting, April 2005, Paris
Hepatitis B Viral Kinetics under Different
Approved Antiviral Treatment Regimens in
HBeAg-negative Patients with CHB Explain
Treatment Antiviral Mechanisms RM Ribeiro, G
Germanidis, KA Powers, B Pellegrin, K
Arvanitakis, AS Perelson, JM Pawlotsky Abstract
526 (poster presentation)
52Aim - Methods
- Aim To assess early HBV kinetics in response to
treatments in HBeAg-negative CHB patients - 46 Greek pts with HBeAg(-)CHB prospectively
included - 48 weeks of treatment with
- IFN?-2a, 4.5 MU tiw (n 9)
- LAM 100 mg qd (n9)
- IFN?-2a LAM (n8)
- PEG-IFN?-2a, 180 µg/wk (n6)
- PEG-IFN?-2a LAM (n7)
- LAM Adefovir, 10 mg qd (n7)
- Analysis of HBV dynamics
53HBV Kinetics under Therapy - Results
- HBV DNA decrease over the first 48 hours differed
significantly by treatment regimen (p0.003),
with the largest decrease in the LAM group (-1.3
log10) and the smallest decrease in the
PEG-IFN?-2a group (-0.48 log) - Differences became less pronounced with time and,
at 1 month, all groups had similar viral decays
(between -2.9 and -3.5 log), except IFN?
monotherapy (-1.5 log)
54HBV Kinetics under Therapy Conclusions
- Nucleos(t)ide analogues (LAM or ADV) have better
initial antiviral efficacy than PEG-IFN?-2a in
HBeAg-negative CHB patients, but - This difference is lost upon treatment
continuation, probably because PEG-IFN?-2a
results in greater loss of infected cells,
a result in keeping with its
immunomodulatory properties
55Thank you very much for your attention