1 Interferon-induced immune response and antiviral therapy Ahn( 安 ), Sang Hoon( 安安 ), MD, PhD Department of Internal Medicine Institute of Gastroenterology Yonsei University College of Medicine Brain Korea 21 Project for Medical Science Liver Cirrhosis Clinical Research Center Seoul, Korea
51
Embed
1 Interferon-induced immune response and antiviral therapy Ahn( 安 ), Sang Hoon( 相勳 ), MD, PhD Department of Internal Medicine Institute of Gastroenterology.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
1
Interferon-induced immune response and antiviral therapy
Ahn(安 ), Sang Hoon(相勳 ), MD, PhD
Department of Internal MedicineInstitute of GastroenterologyYonsei University College of MedicineBrain Korea 21 Project for Medical ScienceLiver Cirrhosis Clinical Research CenterSeoul, Korea
Sang Hoon Ahn has received unrestricted research grant from Bristol-Myers Squibb, Gilead Sciences and Hofmann-La Roche.
Prof. Ahn has acted as an advisor and lecturer for Bayer, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hofmann-La Roche, HANDOK, Merck, Novartis/Idenix and Otsuka Pharmaceuticals.
Sang Hoon Ahn, M.D., Ph.D.
Yonsei Universtiy College of Medicine,
Seoul, Republic of Korea
Conflict of Interest relevant to my presentation
Immune Response to HBVImmune Response to HBV
Overview
Immunological Properties of InterferonImmunological Properties of Interferon
Peg-interferon Therapy in CHBPeg-interferon Therapy in CHB
A Real World Data in KoreaA Real World Data in Korea
Future Perspective on PEG-IFN TherapyFuture Perspective on PEG-IFN Therapy
Immune Response to HBVImmune Response to HBV
Overview
Immunological Properties of InterferonImmunological Properties of Interferon
Peg-interferon Therapy in CHBPeg-interferon Therapy in CHB
A Real World Data in KoreaA Real World Data in Korea
Future Perspective on PEG-IFN TherapyFuture Perspective on PEG-IFN Therapy
5
Overview of Anti-Viral Immune Responses
10
100
Immune activation
Coordinated activation of innate and adaptive response is necessary for HBV control
• The NEPTUNE study data confirm that compared with lower doses and shorter durations, the licensed dose of 180 µg and duration for 48 weeks of PEG-IFN α-2a is the most efficacious and beneficial treatment regimen for CHB patients
• HBsAg >20,000 IU/mL at weeks 12 or 24 ofPEG-IFNα-2a therapy is a potential stopping rule having been validated in two individual studies
• Patients with on-treatment HBsAg <20,000 IU/mL should be encouraged to complete therapy
• The higher dose and longer duration of PEG-IFNα-2a is well tolerated and does not compromise adherence/compliance.
e+
PEG-IFN therapy in HBeAg (-) CHB
24
PEGASYS in HBeAg-negative CHB
1. Marcellin et al. N Engl J Med 20042. Marcellin et al. Gastroenterology 20093. Marcellin et al. APASL and EASL 2009
EOT: end of treatmentHBeAg: hepatitis B ‘e’ antigenITT: intent to treat
Lamivudine 100 mg qd
PEGASYS 180 µg qw+ lamivudine 100 mg qd
PEGASYS 180 µg qw+ placebo qd
Initial study1
EOT(week 48)
Post treatment(6 months)
Long-term study2,3
Post-treatment (5 years)
e-
Baseline
ITT population: N=537 Modified ITT population (PEG+LAM): N=230
552 patients with HBeAg-negative CHB randomized using a 1:1:1 ratio
Treatment period
PEGASYS drives a robust HBsAg decline – an early sign of treatment success
Marcellin et al. APASL 2010
LamivudineN=44
PEGASYSN=59
PEGASYS + lamivudine (N=61)
Mea
n de
clin
e fr
om b
asel
ine
(lo
g 10
IU/m
L)
Decline in HBsAg levels over time with a 48-week course of PEGASYS therapy
Time (weeks)
e-
0
-1.5
0 12 24 36 48 60 72
-1.0
-0.5
HBsAg: hepatitis B surface antigen
PEGASYS delivers sustained immune control in 31% of HBeAg-negative patients
Marcellin et al. APASL 2010CHB: chronic hepatitis B; EOT: end of treatment;
HBeAg: hepatitis B ‘e’ antigen; HBV DNA: HBV viral DNA
72/2300
10
20
30
40
31%
Pat
ient
s w
ith H
BV
DN
A
≤10,
000
copi
es/m
L (%
)
50
Post-treatment (1 year)
e-
230 patients with HBeAg-negative CHB treated with PEGASYS ± lamivudine
88% of PEGASYS patients who achieved HBV DNA ≤10,000 copies/mLat Year 1 post-treatment maintained that response up to year 5 (N=36/41*)
11/230
5%
1
14/230
6%
2
20/230
9%
3
25/230
11%
4
28/230
12%
5
Follow up (years)
0
2
4
6
8
10
12
14
PEGASYS delivers efficacy that keeps increasing post-treatment
Marcellin et al. EASL 2009CHB: chronic hepatitis B
Pat
ient
s w
ith H
BsA
g c
lear
ance
(%
)
230 patients with HBeAg-negative CHB treated with PEGASYS ± lamivudine
230 patients with HBeAg-negative CHB treated with PEGASYS ± lamivudine*
HBsAg decline is significantly associated with sustained immune control
Marcellin et al. APASL 2010* Based on 120 patients with available HBsAg data at all time points
HB
V D
NA
≤10
,000
cop
ies/
mL
1 ye
ar p
ost-
trea
tmen
t (%
)
HBsAg decline from baseline≥10% <10%
P=0.0005
25/530
10
47%50
30
11/67
16%20
40
HB
V D
NA
≤10
,000
cop
ies/
mL
1 ye
ar p
ost-
trea
tmen
t (%
)
HBsAg decline from baseline
P=0.0078
29/670
10
43%50
30
7/53
13%20
40
≥10% <10%
Week 12 Week 24
An ‘early’ stopping rule for PEGASYS An ‘early’ stopping rule for PEGASYS based on HBsAg and HBV DNA levelsbased on HBsAg and HBV DNA levels
• Combining HBsAg and HBV DNA at week 12 predicts response
– Combining on-treatment declines in HBsAg and HBV DNA provided the best model for predicting response• Cut-off for HBsAg: any decline
• Cut-off for HBV DNA: 2 log10 copies/mL.
SR : an HBsAg decline andan HBV DNA decline 2 log copies/mL at week 12 versus the baseline.
Rijckborst et al. Hepatology 2010
e-
Summary of Peg-IFN Therapy in HBeAg(–) CHB
• HBeAg-negative CHB PEGASYS delivers sustained immune control, which is
highly durable
Sustained immune control with PEGASYS is associated with high rates of HBsAg clearance post-treatment
HBsAg clearance increases post-treatment after a finite course of PEGASYS therapy
Immunological Properties of InterferonImmunological Properties of Interferon
Peg-interferon Therapy in CHBPeg-interferon Therapy in CHB
A Real World Data in KoreaA Real World Data in Korea
Future Perspective on PEG-IFN TherapyFuture Perspective on PEG-IFN Therapy
Young Eun Chon1, Dong Joon Kim2, Sang Gyune Kim3, In Hee Kim4, Si Hyun Bae5, Seong Gyu Hwang6, Jeong Heo7, Jeong Won Jang8, Byung Seok Lee9, Hyung Joon Kim10, Dae Won Jun11, Gang Mo Kim12, Woo Jin Chung13, Moon Seok Choi14, Jae Young Jang15, Hyung Joon Yim16, Won Young Tak17, Ki Tae Yoon18, Jun Yong Park1, Ki Tae Suk2, Hyun Woong Lee10, and Byoung Kuk Jang13 and Sang Hoon Ahn1
18 Liver clinics from tertiary Korean hospital
Supported by unrestricted grant from Hofmann-La Roche
Observational, Multi-Center, Cohort Study Evaluating the Antiviral Efficacy, Safety, and Tolerability in Korean patients with Chronic Hepatitis B (CHB) receiving pegylated Interferon-alpha 2a (Pegasys®): TRACES STUDY
Geographic Distribution of HBV GenotypesGeographic Distribution of HBV Genotypes
Kim BK, Revill P, Ahn SH. Antivir Ther. 2011;16:1169-1186.
ALL of VR, HBeAg seroconversion, ALT normalization.
5 (7.8) 40 (16.5) 0.003
ALL of CVR, HBeAg seroconversion, ALT normalization.
2 (3.1) 8 (3.3) NS
Response Rates in HBe-positive patients at PT 6
Response, n (%)24 weeks treatment
(n= 16)48 weeks treatment
(n=74) P-value
VR (HBV-DNA <2000 IU/mL) 13 (81.2) 65 (87.8) NS
CVR (HBV-DNA < 60 IU/mL) 8 (50.0) 45 (60.8) NS
ALT normalization 6 (37.5) 45 (67.2) 0.039
HBsAg loss 0 (0) 1 (1.4) NS
ALL of VR, ALT normalization. 4 (25.0) 35 (47.3) NS
ALL of CVR, ALT normalization. 3 (18.7) 30 (40.5) NS
Response Rates in HBe-negative patients at ET
HB
eAg
sero
conv
ersi
on
%
17.2%
23.7%
P=0.012 P=0.028
Viro
logi
cal
resp
onse
44.4%
17.2%
46.7%
%P=0.005 P=0.001
48 weeks of PEG-IFNa-2a treatment was superior to 24 weeks regimen
in HBeAg-positive patients
e+
40
Virologic Response and ALT normalization at ET
81.2%
87.8%
37.5%
67.2%
%P=NS
P=0.039
24 weeks regimen48 weeks regimen
e-
• PEG-IFNa-2a showed substantial treatment response and good tolerability.
• In HBeAg-positive CHB, the 48 weeks-treatment of PEG-IFNa-2a was more efficacious with similar safety profiles than 24 weeks treatment.
• Compared to the NEPTUNE study, virologic response was higher but serologic response was lower in Korean CHB patients treated for 48 weeks of 180 µg PEG-IFN α-2a
Conclusion of Korean study
Immune Response to HBVImmune Response to HBV
Overview
Immunological Properties of InterferonImmunological Properties of Interferon
Peg-interferon Therapy in CHBPeg-interferon Therapy in CHB
A Real World Data in KoreaA Real World Data in Korea
Future Perspective on PEG-IFN TherapyFuture Perspective on PEG-IFN Therapy
Potential Ways to Increase Response Rates to PEGASYS