1 interferon-induced immune response and antiviral therapy ahn( 安 ), sang hoon( 相勳 ), md, phd...

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

5

Overview of Anti-Viral Immune Responses

10

100

Immune activation

Coordinated activation of innate and adaptive response is necessary for HBV control

1

10

100

2 4 6 8 10 12 14 16 18

Viri

ons

10

6/m

l

Absence of viral replication and

innate immunity

Activation of innate and adaptive

immunity

Presence of adaptive immunity

(Thelp, CTL, B)

Time post-infection (weeks)

HBV

Resolution

Adapted from Bertoletti et al. J Gen Virol 2006

2 4 6 8 10 12 14 16 18

1

Persistence

Absence of viral replication and

innate immunity

Weak activation of innate immunity

Weak/Absent adaptive immunity

(Thelp, CTL, B)

Time post-infection (weeks)

HBV

Tolerance

Hepatocyte

Rehermann & Nascimbeni. Nature Rev Immunol 2005; Bertoletti & Gehring. J Gen Virol 2006

NK(T)

DC

Uptake viral

particles/antigens

Type I IFN

(IFN)

Viral replication

activation

CytotoxicityIFN /TNF: viral replication

Y

BY

YAnti-HBe, HBc, HBs

Y

Y

Hepatocyte

lysis

Viral replication

neutralization

Innate immunity Adaptive immunity

CD4+

CD8+

Immune response to hepatitis B


Overview


The mode of action of IFN is dual

IFN

Modulation of immune responses

Interferon alfa

• Antiviral effect of type I IFN

No direct effect on viral replication

Induction of IFN-stimulated genes via Jak-Stat pathway: non-virus-specific

Sen et al Ann Rev Microbial 2001

• Fewer HBV nucleocapsids secreted by IFN-treated HBV infected hepatocytes through induction of hepatocellular genes

Chisari et al J Virol 2000; Weiland et al PNAS 2005; Bonvin et al Hepatology 2006

• Immunomodulatory effect of type I IFN

Promotes T cell proliferation, prevents T cell apoptosis, stimulates NK cell activation and DC maturation

Stetson and Medzhitov Immunity 2006

Type-I IFN induction and effector phase

Modified: Haller, Kochs and Weber, Virology 2006

virus

IFN-

RIG-I / MDA-5

TBK-1 IKKIFN-

Cardif (IPS-1) TRIF

TLR3

dsRNAdsRNA

IRF-3 -3

Induction Phase

IFN-

IFN-

IFN-

ISGISRE

IFNAR

JAK-1 / TYK-2

STAT-1 -2

IRF-9

ISGF-3

Effector Phase antiviral effect

dsRNA

IFN-/

IRF-7 -3

ADAR

PKROAS

p56

Induction of antiviral state through gene activation prevents infection of new cells

STAT: JAK-Signal Transducers and Activators of Transcription

Immune response induced by IFN therapy

12

T helper cell

DC: Antigenpresenting

cell

B cell

Hepatocyte

HBV replication

HBV

Natural killer cell

Cytotoxic T cell

Interferon-alfa

1. Induction of antiviral state

prevents infection of new cells

2. Immuno-modulatory action

Destruction ofinfected cells

Induction of antiviral state through gene activation prevents infection of new cells

cccDNAcccDNA persists

in liver


Overview





Discovery of HBVDiscovery of HBV

Barush S Blumberg, M.D., Ph.D.The Nobel Prize in Physiology and Medicine 1976

1960 NIH : Double diffusion in agar gel (Ouchterlony) method to detect antibodies in multiply transfused patients

1963 Au-antigen from hemophiliacs (Mt. Sinai Hospital in New York)

“ Why did precipitin band has developed between the serum of hemophilia patients in NY and that of an aborigine from Australia?”

1967 Association between Au and acute hepatitis (Ann Int Med 1967;66:924-931)

Subsequent study found the Australian Antigen to be the HBs antigen.

16

HBsAg: Back to the Future?HBsAg: Back to the Future?

• Qualitative HBsAg: – Diagnostic Tool for HBV Infection – Prognostic Marker for Disease Resolution

• Quantitative HBsAg:– Reflect of the Natural History– Predictor of Sustained Response in IFN-Based

Therapy– Guide to Optimize Treatment Duration with NUC

Moucari et al. Expert Rev Anti-infect Ther. 2009

PEG-IFN therapy in HBeAg (+) CHB

17

NEPTUNE Study: in HBeAg-positive patients (n=524)

Treatment Group APEG-IFN α-2a 90 g/week

Treatment Group CPEG-IFN α-2a 90 g/week

Treatment Group DPEG-IFN α-2a 180 g/week

Screening Days -35 to -1

0 24Weeks

48

Primary endpoint6 months post-treatment

72

Randomization Primary endpoint6 months post-treatment

Stratified bygenotype and

ALT level

Treatment Group BPEG-IFN α-2a 180 g/week

Follow up

Follow up

Further Follow up

Further Follow up

Follow up

Follow up

34% genotype B, 51% genotype C

e+

36.2%

Highest HBeAg seroconversion rate in the 180 µg/week for 48 weeks group

90 µg/week24 weeks

n=142

180 µg/week24 weeks

n=140

90 µg/week48 weeks

n=132

180 µg/week48 weeks

n=130

HB

eAg

ser

oco

nve

rsio

n 6

mo

nth

sp

ost

-tre

atm

ent

(%)

14.1%

22.9%25.8%

LIAW HEPATOLOGY 2011

e+

90 g/24n=142

Res

po

nse

6 m

on

ths

po

st-t

reat

men

t (

%)

11% 11%

23%30%

180 g/24n=140

90 g/48n=132

180 g/48n=130

90 g/24n=142

Res

po

nse

6 m

on

ths

po

st-t

reat

men

t (

%)

22% 21%

33%42%

180 g/24n=140

90 g/48n=132

180 g/48n=130

90 g/24n=142

Res

po

nse

6 m

on

ths

po

st-t

reat

men

t (

%)

30% 31%

43%

52%

180 g/24n=140

90 g/48n=132

180 g/48n=130

Secondary endpoint results are consistent with the primary efficacy endpoints

HBV DNA <2000 IU/mL HBV DNA <20,000 IU/mL

ALT normalization

LIAW HEPATOLOGY 2011

e+

Lower HBsAg levels at week 12 are associated with post-treatment response

HBsAg levels (IU/mL)

<1500 (n=31) 1501–20,000 (n=62) >20,000 (n=21)

P<0.0001P=0.0004

P=0.2866

18/31 26/62 16/31 19/62 3/31

e+

Patients with HBsAg >20,000 IU/mL do not achieve a post-treatment response

HBsAg (IU/mL) HBsAg (IU/mL)

PEG-IFN α-2a 180 g/week, 48 wksLIAW HEPATOLOGY 2011

e+

Conclusion of The NEPTUNE study

• 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

“Early stopping rule” can be applied.

CHB: chronic hepatitis B

HBeAg: hepatitis B ‘e’ antigen

HBsAg: hepatitis B surface antigen

Response-Guided Therapy (RGT) Response-Guided Therapy (RGT) using HBsAg levelsusing HBsAg levels

Week 12:

HBeAg-positive

HBsAg <20,000 IU/mL

HBeAg-negative

>10% decline in HBsAg(Week 24 for geno D)

Identify responders (PPV)Identify responders (PPV) Identify non-responders (NPV)Identify non-responders (NPV)

e-

e+

Week 12:

HBeAg+

HBsAg >20,000 IU/mL

HBeAg- (geno D)

No decline in HBsAg +

< 2log decline in HBV DNA

e-

e+


Overview





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.

HBV genotype C2 in KOREA

Ahn SH et al.J Med Virol 2010

Variables

HBeAg (+) P

value

HBeAg (-) P

value24 weeks(n=90)

48 weeks (n=259)

24 weeks(n=16)

48 weeks (n=74)

Male, n(%) 48 (53.3) 141 (54.4) NS 10 (62.5) 46 (62.2) NS

Age (years) 37.8±9.0 37.4±8.8 NS 41.5±9.4 41.9±9.5 NS

Baseline HBV-DNA

(mean ± SD)6.96±1.61 6.63±1.53 NS 5.41±1.45 5.43±1.46 NS

Baseline ALT(mean ± SD)

183.5±196.0 173.6±172.51 NS 150.5±115.0 153.6±116.2 NS

Baseline characteristics of patients (N=439)

Response, n (%)24 weeks treatment

(n=64)48 weeks treatment

(n=242) P-value

VR (HBV-DNA <2000 IU/mL) 11 (17.2) 113 (46.7) 0.001

CVR (HBV-DNA < 60 IU/mL) 2 (3.1) 11 (4.5) NS

HBeAg seroconversion 11 (17.2) 75 (23.7) 0.028

ALT normalization 28 (45.2) 172 (76.8) 0.006

HBsAg loss 0 (0) 2 (0.8) NS

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


Overview





Potential Ways to Increase Response Rates to PEGASYS

PEG-IFN weekly

qHBsAg testing + HBV-DNA

Future RGT Therapy : PEG-IFN +/- NAsFuture RGT Therapy : PEG-IFN +/- NAs

Stop or Extension?Sequential or Add PEG-IFN?

NUC

NUC

PEG-IFN weekly

PEG-IFN weekly

NUC

PEG-IFN weekly

continue? extension?

OSST study designOSST study design

ETV 0.5mg qd

(N=200)

Switch to PEGASYS 180 µg qw 48W(n=100)

ETV0.5 mg qd

8W

HBV DNA <103 cp/mL

qHBeAg < 100 PEIU/mL

1–3 years

ETV 0.5 mg qd 48W(n=100)

Randomized, Open label, multi-center study

Endpoints: HBeAg clearance/seroconversion, HBsAg clearance

Randomization 1:1AASLD 2011

China

HBsAg loss and seroconversion HBsAg loss and seroconversion at Week 48at Week 48

13%

0

P < 0.05

7/53

6%

3/53 0

Pat

ient

s (%

)

PEGASYS (N=53)

ETV (N=49)

WEEK 48

1 cleared at week 12,3 at week 24,

1 at week 36and 2 at week 48

EXCEL ML22266 (RGT study) Design EXCEL ML22266 (RGT study) Design

36 720 2412

Early response = qHBsAg <1500 IU/ml & HBV DNA <105 at 24w

PEGASYS 24 wks

PEGASYS 48 wks Slow Responders

PEGASYS 24 wks

48

Randomization 1:1:1

Early Responders

PEGASYS 24 wks

F/U 24w

F/U 24w

PEGASYS 48 wks

ADV 36 wks

F/U 24w

F/U 24w

28 6496 120

N=66 (25%)

N=195

China

HBeAg loss and seroconversion statusHBeAg loss and seroconversion statusat Week 24at Week 24

Pat

ient

s (%

)

n=66

n=195

5.6%

25.80%

17/ 66 11/195 17/ 66 11/195

WEEK 24

25.80%

5.6%

Early responders

Slow responders

Summary

• PEG-IFN is one of the first line drugs for CHB.

Absence of resistance

Dual mode of action – antiviral and immuno-modulatory effects

Higher rates of HBeAg and HBsAg seroconversion

Finite duration

Sustained off-treatment response (~30-40%)

• However, frequent adverse effect and modest HBV DNA suppression remain unsolved yet.

• Furthermore, responses vary widely according to several predictors such as viral burdens and HBV genotype.

49

Future perspectives

• Taken together, PEG-IFN should only be considered for patients with a high chance of response.

• Baseline and on-treatment viral markers to identify the "good" responder early have been under investigation, avoiding unnecessary treatment.

• Furthermore, combination therapy with a high genetic barrier drug (ETV or TDF) to suppress HBV DNA more effectively is an appealing approach.

Thank youThank you

1 interferon-induced immune response and antiviral therapy ahn( 安 ), sang hoon( 相勳 ), md, phd...

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