A Personalized Interferon Therapy for
Chronic Hepatitis B
Jia-Horng Kao MD, Ph D
Graduate Institute of Clinical Medicine,
Hepatitis Research Center,
Department of Internal Medicine,
National Taiwan University College of
Medicine and Hospital
October 30, 2012
Kao 2012
Outline
• Update on the disease
• Current status of antiviral
treatment
• Pegylated interferon
– Predictors
• Personalized medicine
– Risk calculator
– Individualized therapy
Kao 2012
Hepatitis B virus (HBV)
• A DNA virus (3.2 kb): S, C, P and X genes
• Replicate via an RNA intermediate (Pregenomic
RNA)
• Reversely transcribed into HBV DNA by virusencoded polymerase (error prone RT activity)
– Variation rate: 1.4-3.5x10-5/site/year
• The reverse transcription step accounts for the
majority of point mutations and deletions or
insertions observed in HBV genome
– Genotype / subgenotype
– Recombinant
– Variant / mutant
– Quasispecies
Kao 2012
Hepatitis B: a global health problem
• > 350 million people are chronic HBV
carriers worldwide
• The world’s 10th leading cause of death
• Chronic HBV infection is endemic in the
African and Asian-Pacific regions
(HBsAg prevalence > 8%)
• Usually acquired perinatally or in early
childhood
• Adverse sequelae may develop (hepatic
decompensation, cirrhosis or HCC)
– 25-40% of HBV carriers die prematurely of
end-stage liver disease
Kao 2012
Natural history of perinatally acquired chronic
20-30%
HBV infection
Immune
Tolerance
Immune
Clearance
(HBeAg+ CHB)
HBeAg+
Low Replication
Phase
(Inactive-carrier state)
Reactivation
Phase
(HBeAg- CHB)
HBeAg-/anti-HBe+ (precore/core promoter mutants)
> 2000 IU/mL
HBV DNA
>2x
107
< 2000 IU/mL
IU/mL
> 2 x 104 IU/mL
ALT
Normal/minimal
change/mild CH
Moderate/severe CH
2-6%/yr
Cirrhosis
Normal/mild
CH/moderate
fibrosis
Inactive cirrhosis
Modified from Lok et al. Hepatology 2007;45:507-539 and
Pungpapong et al. Mayo Clin Proc 2007;82:967-975.
Moderate/severe CH
8-10 %/yr
Cirrhosis
Kao 2012
Annual rates of progression during chronic
HBV infection
30-40%
Chronic HBV infection
Chronic hepatitis B
<1.0%
60-70%
Inactive carrier state
2-6% for HBeAg(+) hepatitis B
8-10% for HBeAg(-) hepatitis B
<0.2%
Compensated cirrhosis
2-3%
3-5%
Decompensated
cirrhosis
7-8%
Hepatocellular
Carcinoma
20-50%
20-50%
Fattovich et al. 2004.
Death
Kao 2012
Factors associated with disease progression
in HBV carriers
Viral
Host
Environment
Persistent presence
of HBeAg
Male gender
Increasing age
Heavy drinking
Persistently high
HBV-DNA level
Recurrent ALT
flare
HBV genotype C >
genotype B
Persistently
increased ALT
levels
Core promoter
mutations and Pre-S
deletion*
Cigarette
smoking*
Aflatoxin*
HCV, HDV, or HIV
coinfection
Cirrhosis*
Diabetes*
*Factors shown to be associated with an increases risk of HCC only. Abbreviations: ALT,
alanine aminotransferase; HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma
Modified from Kwon and Lok. Nat. Rev Gastroenterol Hepatol 2011; 8: 275–284.
Kao 2012
Clinical significance of qHBsAg in natural
history of CHB
Kao 2012
HBV DNA, HBsAg and ALT levels during
different phases of CHB
Janssen et al. Gut 2012.
Kao 2012
Identification of inactive infection using
HBsAg and HBV DNA levels
Analysis of 209 HBV genotype D patients
Prediction of:
Inactive infection
HBsAg levels
HBV DNA levels
<1000 IU/mL plus
<2000 IU/mL
PPV
87.9%
NPV
96.7%
•
Confirmed in other studies in genotype D (Manesis AASLD
2010)
•
Confirmed in other genotypes (Martinot-Peignoux APASL
2011)
Brunetto et al. Gastroenterology 2010; Manesis et al. AASLD 2010;
Martinot-Peignoux APASL 2011
Kao 2012
Proposed algorithm to categorize risk of
disease progression and management in Asian
HBeAg-negative patients
N=1068 Taiwanese HBeAg-negative patients with HBV DNA <2000 IU/mL
followed up for mean duration of 13 years
Demonstrated the clinical utility of HBsAg levels for defining carriers at
minimal risk and actionable information for the physician
Follow up (months)
according to risk
≥2000 IU/mL
High risk
AsianHBeAg(-)
HBeAg(-)
Asian
HBV
carriers
HBV carriers
HBV DNA
Abnormal
Intermediate
risk
<2000 IU/mL
ALT
Normal
≤3 mo or treat
≥1000 IU/mL
Low risk
3–6 mo
6–12 mo
HBsAg
Minimal risk
12 mo
<1000 IU/mL
Tseng et al. Hepatology 2012
Kao 2012
qHBsAg can predict spontaneous HBsAg
loss in HBV carriers
• Serum HBsAg level <100 IU/ml at 1 year postHBeAg seroconversion can predict HBsAg loss
within 6 years1
• HBsAg <10 IU/ml is the strongest predictor of
HBsAg loss in HBeAg-negative patients who
have HBV DNA <2000 IU/ml2
• Decreasing HBsAg level (<200 IU/ml or a
decrease of 1 log 10 IU/ml) can predict HBsAg
seroclearance in inactive CHB patients3
1. Tseng, Kao et al. Gastroenterology 2011
2. Tseng, Kao et al. Hepatology 2012
3. Chen YC, et al. Clin Gastroenterol Hepatol 2011
Kao 2012
qHBsAg can predict HCC risk in HBV
carriers
Can we refine our risk stratification?
REVEAL-HBV study: N=3653
Cumulative incidence of HCC (%)
16
14.9%
Baseline HBV-DNA (copies/mL)
≥ 106
105–<106  >20,000 IU/ml
104–<105  >2000 IU/ml
300–<104
<300
14
12
10
8
12.2%
Does HBV DNA
full picture?
6
provide the
4
3.6%
2
1.4%
1.3%
0
0
1
2
3
4
5
6
7
8 9
Years of follow-up
10 11 12
13
Chen et al. JAMA 2006
• HBsAg > 1000 IU/ml could predict HCC risk in HBeAgnegative patients, especially in those who have HBV
DNA <2000 IU/ml4,5
1. Tseng and Kao et al. Gastroenterology 2012
2. Chen et al. AASLD 2011 Abstract 1095
Kao 2012
HBsAg level is an important risk factor in
patients with low HBV DNA level (<2000
IU/mL)
ERADICATE-B (2688 HBV carriers)
5-fold risk increase
by univariate analysis
Tseng, Kao. Gastroenterology 2012; Chan HL. Gastroenterology 2012
Kao 2012
Kao 2012
Outline
• Update on the disease
• Current status of antiviral
treatment
• Pegylated interferon
– Predictors
• Personalized medicine
– Risk calculator
– Individualized therapy
Kao 2012
Goal of treatment for CHB
Short-term vs. Long-term
Initial
response
Durable
response
Anti-HBe
gain
HBeAg(+)
patients
HBeAg
loss
Prevent
complications
Prolong survival
HBV DNA
undetectable
ALT
normalization
TIME
Initiation of
treatment
Primary aim of treatment:
Permanently suppress HBV replication
Liaw et al. Asia Pacific Consensus Statement 2008. Hepatol Int 2008.
Kao 2012
Treatment landscape of CHB: 2012
Generic Name
Trade Name
Manufacturer
Date Approved
for Hepatitis B
Interferon alfa
INTRON® A
ROFERON ®
Schering
Hoffman LaRoche
1991
Lamivudine
ZEFFIX®
GlaxoSmithKline
1998
Adefovir dipivoxil
HEPSERA™
GlaxoSmithKline
2002
Entecavir
BARACLUDE™
Bristol-Myers
Squibb
2005
Peginterferon
alfa-2a
PEGASYS®
Hoffman LaRoche
2005
Telbivudine
SEBIVO™
Novartis
2006
Tenofovir
VIREAD™
Gilead Sciences
2008
Kao 2012
Treatment strategies of CHB
INTERFERON
NAs
Sustained remission
Maintained remission
=
Low viremia
=
No viremia
ALT normalization
ALT normalization
Immune control,
no further need for
antiviral drugs
No immune control,
continued need for
antiviral drugs
Kao 2012
Outline
• Update on the disease
• Current status of antiviral
treatment
• Pegylated interferon
– Predictors
• Personalized medicine
Kao 2012
Immunopathogenesis of HBV infection
Innate Immune
System
Adaptive Immune
System
Macrophage
NK
NKT
CD8
CD4
Cytokines
B
cell
Ig
IFNγ
TNFα
NonCytolytic
Cytokines
Hepatocyte
Clearance
Ganem D. NEJM 2004;350:11118-29.
Edward D. Gastroenterology 2001;120:1000-8.
Direct
cytotoxicity
Cytolytic
Apoptosis
Kao 2012
Immunopathology of chronic HBV infection
Immune
response
Viral
replication
CD8+
HBV
Immune tolerance
Clearance phase
Chronic hepatitis
Seroconversion
Remission
CD8+
HBV
HBV
CD8+
Guidotti Science 1999; Guo J Virol 2000; Kakimi J Exp Med 2000; Zhu J Virol 2001
Kao 2012
IFN/Peg-IFN, dual mode of action
-The only approved immunomodulatory agent
IFN
Direct antiviral
effect
•2‘,5‘-oligoadenylate synthetase
induction leading to viral
cleavage
•IFN-inducible human MxA
protein-> breakdown viral RNA
Modulation of
immune responses
•MHC class I protein display
enhanced
•activation of CTL and NK cells
Kao 2012
PEG-IFN treated HBeAg+ CHB
patients: T cell response and T-regs
HBcAg-induced proliferation
Responders
Non-responders
Responders
Non-responders
16
12
8
4
0
0
8
52
78
% T reg of CD4+ cells
20
Stimulation index
Percentage regulatory T cells
*
4
3
*
2
*
1
0
0
Time (weeks)
Tang, et al. J Hepatol 2005; Sprengers, et al. Antiviral Therapy 2007.
8
52
78
Time (weeks)
Kao 2012
Outline
• Update on the disease
• Current status of antiviral
treatment
• Pegylated interferon
– Predictors
• Personalized medicine
– Risk calculator
– Individualized therapy
Kao 2012
Responder to standard IFN therapy
•
•
•
•
•
Younger age (short duration of infection)
•
•
High ALT (> 5x ULN)
•
•
Genotype A or B
Female gender
Child bearing age
Compensated liver disease
HBeAg-positive
– Low baseline HBeAg level and early HBeAg suppression
Low baseline HBV DNA (<109 copies/ml) and more
profound suppression of HBV DNA during therapy
Significant necro-inflammatory activity
Kao JH. Hepatol Res 2007;37:S47-S54.
Kao 2012
Pegylated interferon alpha:
Baseline predictors
• In HBeAg-positive CHB, predictors
of anti-HBe seroconversion are low
viral load (< 2x108 IU/mL), high
serum ALT levels (> 2-5 times ULN),
HBV genotype (A and B) and high
activity scores on liver biopsy (at
least A2)
• In HBeAg-negative CHB, no strong
pre-treatment predictors of VR
EASL Clinical Practice Guidelines: Management of Chronic Hepatitis B 2012.
Kao 2012
Best response to Peg IFN- in Asian patients
with high baseline ALT and low HBV DNA
HBeAg seroconversion 24 weeks after the end of treatment
≤10 log10 HBV DNA
>10 log10 HBV DNA
60
Patients (%)
52%
40
36%
32%
28%
22%
20
12%
0
18/56
2/17
< 2 × ULN
10/45
22/61
> 2 - < 5 × ULN
13/25
8/29
> 5 × ULN
ALT
Cooksley et al. Shanghai Hong Kong International Liver Congress 2006.
Kao 2012
HBV genotype and IFN response
Kao JH et al, J Hepatol 2000; Liu & Kao, Liver Int 2005
Kao 2012
Effect of HBV genotype on rate of HBeAg
seroconversionin HBeAg+ve CHB pts with
pegIFN therapy
After (a) Janssen et al and (b) Lau et al-
Kao 2012
Kao 2012
Meta-analysis of 721 HBeAg+ patients
receiving 1yr-Peg-IFN: Prediction by BL factors
Genotype
ALT
DNA
Nomogram
Buster et al, Gastroenterology
2009;137:2002
Kao 2012
NEPTUNE: Similar high rate of HBeAg
seroconversion for genotypes B and C
HBeAg seroconversion for patient treated with 180 µg PEGASYS
for 48 weeks Genotype B (N=45) or C patients (N=67)
Response 6 months
post-treatment (%)
60
50
42%
40
39%
30
20
10
0
19/45
26/67
B
C
Genotype
Genotype B and C patients respond equally well to PEGASYS
Xie et al. APASL 2011 Poster 97
Liaw et al. Hepatology 2011
Kao 2012
Response rates are highest with
180 µg/week for 48 weeks in genotype B
24%
34% 29%
HBV DNA <2,000 IU/mL
Response 6 months
post-treatment (%)
Response 6 months
post-treatment (%)
HBeAg seroconversion
42%
90 mg/24 180 mg/24 90 mg/48 180 mg/48
n=45
n=49
n=47
n=45
Response 6 months
post-treatment (%)
ALT normalization
Liaw et al. Hepatology 2011
47%
12%
19%
90 mg/24 180 mg/24
n=49
n=47
24%
90 mg/48 180 mg/48
n=45
n=45
64%
53%
45%
37%
90 mg/24
n=49
180 mg/24 90 mg/48 180 mg/48
n=45
n=47
n=45
Kao 2012
Response rates are highest with
180 µg/week for 48 weeks in genotype C
HBV DNA <2000 IU/mL
Response 6 months
post-treatment (%)
Response 6 months
post-treatment (%)
HBeAg seroconversion
39%
10%
16%
24%
90 mg/24 180 mg/24 90 mg/48 180 mg/48
n=70
n=76
n=68
n=67
21%
11%
90 mg/24
n=70
25%
7%
180 mg/24 90 mg/48 180 mg/48
n=76
n=68
n=67
Response 6 months
post-treatment (%)
ALT normalization
Liaw et al. Hepatology 2011
49%
29%
90 mg/24
n=70
35%
24%
180 mg/24 90 mg/48 180 mg/48
n=67
n=76
n=68
Kao 2012
HBV genotype Ba genomic background
and response to IFN therapy
 Is there any IFN sensitivity-determining region
in HBV genome?
 Full-length viral genomic comparison between HBVs
obtained from IFN-R and IFN-NR
 18 HBV genotype Ba pts, 24-wk IFN therapy
 10 IFN-Rs vs. 8 IFN-NRs; comparison of paired genomes in
IFN-NRs
 Findings:
 Pretreatment full-length viral nucleotide consensus sequence
identical between Rs and NRs.
 Genetic complexity of HBV quasispecies also comparable
between Rs and NRs.
 Conclusion: An IFN sensitivity-determining region
might not exist within genome of HBV genotype Ba.
Liu CJ et al, Antivir Ther 2004;9:895
Kao 2012
Baseline viral factors affecting Tx outcomes
in HBeAg+ pts with 6M Peg-IFN alfa-2a
(N=115)
HBeAg SC+ VL< 20,000IU/mL
Combined response at 6M off therapy
HBeAg seroconversion at 6M off therapy
P=0.004
45%
P=0.125
36.7%
40%
35%
45%
P=0.086
29.4%
23.4%
40%
35.9%
P=0.469
30%
25%
40.9%
P=0.731
27.9%
25.0%
30%
22.4%
21.1%
20%
16.9%
P=0.412
21.6%
P=0.567
20%
15.6%
16.7%
15%
10%
10%
5%
5%
0%
0%
ALT
>5x
ULN
B
C
Genotype
W
M
PC
W
M
BCP
<7
≧7
Log HBV-DNA
(copeis/mL)
Tseng TC, Kao JH, et al. Antiviral Therapy 2011.
29.6%
P=0.403
25%
15%
2-5x
ULN
P=0.014
35%
P=0.013
30.8%
23.3%
20.9%
16.5%
11.8%
11.3%
2-5x
ULN
ALT
>5x
ULN
B
C
Genotype
W
M
PC
W
M
BCP
<7
≧7
Log HBV-DNA
(copeis/mL)
Kao 2012
Results
• HBeAg seroconversion and combined response
rates were 26.1% and 18.3%, respectively.
Multivariate analysis
 BCP mutation (OR: 8.13, 95% CI: 2.02-32.65) was
associated with a higher sustained HBeAg
seroconversion rate;
 BCP mutation (OR: 9.28, 95% CI: 1.92-44.99) and
viral load < 2x106 IU/mL (OR: 4.78, 95% CI: 1.3716.69) were associated with a higher combined
response rate.
Tseng TC, Kao JH, et al. Antiviral Therapy 2011.
Kao 2012
Baseline viral factors affecting Tx outcomes
in HBeAg+ pts with 6M Peg-IFN alfa-2a
(N=115)
* Viral load, high is ≥2x106 IU/ml; low is <2x106 IU/ml.
Tseng TC, Kao JH, et al. Antiviral Therapy 2011.
Kao 2012
Pegylated interferon alpha:
On-treatment predictors
•
•
•
•
ALT level
HBV DNA level
HBeAg level
HBsAg titer
Kao 2012
On-treatment ALT flares are indicative
of enhanced immune response
ALT flares during Peg IFN are
associated with host immune response
12
10
8
8
6
6
4
4
2
2
0
0
0
8
16
24
32
40
48
56
64
72
78
ALT
Flink et al. Gut 2005.
12
Peg IFN treatment
10
20
Log H BV DNA
10
ALT (x ULN)
25
8
15
6
10
4
5
Log H BV DNA
12
Peg IFN treatment
ALT (x ULN)
14
ALT flares after Peg IFN
therapy are virus induced
2
0
0
0
8
16
24
32
40
48
56
64
72
78
HBV DNA
Kao 2012
On-treatment ALT flares predict response
to Peg IFN therapy
Peg IFN--2b
Peg IFN--2a
Patients achieving response* (%)
100
90
80
70
58%
60
44%
50
40
30
20
20%
10
0%
0
Host
induced
N=24
Virus
induced
N=25
Flink et al. Gut 2005; Piratvisuth et al. ILC 2006.
Host
induced
N=18
Virus
induced
N=10
Kao 2012
HBeAg seroconversion
at wk 72
Quantitative HBeAg at weeks 12 and 24
relationship to HBeAg seroconversion
*
HBeAg (PEIU/ml)
Fried, et al. Hepatology. 2008;47:428-434.
*P=0.059
Kao 2012
Prediction of response to PEGASYS:
HBeAg vs. HBV DNA
Mean HBeAg (PEIU/mL)
Mean HBV DNA (log cp/mL)
Week 24:
HBeAg >100 U/mL: NPV 96%
HBV DNA > 9 log: NPV 86%
HBeAg is a better negative predictor of response than HBV DNA
Fried et al, Hepatology 2008.
Kao 2012
HBsAg level at week 12 is associated
with 6 months post-treatment response
51% of patients with HBsAg <1500 IU/mL at week 12
achieved HBeAg seroconversion 6 months post-treatment
HBsAg level (IU/mL)
60
HBeAg seroconversion
(% patients)
HBeAg seroconversion
(% patients)
60
50
40
30
29.7
20
10
0
Overall
1500–20,000
<1500
50
51
40
29
30
>20,000
HBsAg clearance =
10% pts overall
18% pts with HBeAg
seroconversion
16
20
10
0
<1500
HBeAg-positive patients
Proportion of patients 21%
Lau et al. AASLD 2008; Lau et al. APASL 2009 Poster 083
1500–20,000
>20,000
HBsAg (IU/ml)
55%
24%
Kao 2012
NEPTUNE: On-Treatment HBsAg Level as
Marker of Response to PegIFN
• HBeAg-positive patients: pegIFN alfa-2a 180 µg/wk for 48 wks
– HBsAg analyzed at baseline and every 12 wks
HBsAg levels (IU/mL) at Wk 24
HBsAg levels (IU/mL) at Wk 12
< 1500
(n = 31)
< 1501-20,000
(n = 62)
19%
Response 6 Mos
Posttreatment (%)
100
80
60
40
P < .0001
58
42
27%
< 1500
(n = 46)
P = .0004
52
0
0
HBeAg
HBV DNA
Seroconversion < 2000
IU/mL
Gane E, et al. EASL 2011. Abstract 69.
P = .2866
10
0 0
HBsAg
Clearance
> 20,000
(n = 16)
14%
40%
60
P = .0003
57
40
35
54%
31
< 1501-20,000
(n = 52)
100
80
20
0
> 20,000
(n = 21)
P = .0015
54
19
20
0
HBeAg
HBV DNA
Seroconversion < 2000
IU/mL
0
0
46%
P = .3819
7
0 0
HBsAg
Clearance
Kao 2012
NEPTUNE: On-Treatment HBsAg as Marker
of Response to PegIFN
HBeAg Seroconversion
6 Mos Posttreatment (%)
•
HBsAg < 20,000 IU/mL identified as
key marker of response
HBsAg > 20,000 IU/mL at Week 12 or
24 predicts lack of HBeAg
seroconversion
– Negative predictive value: 100%
100
Week 12
Week 24
80
60
47
45
40
20
0
0
0
(n = 93)
(n = 21)
(n = 98)
(n = 16)
< 20,000 > 20,000 < 20,000 > 20,000
•
Combination of ALT level and
HBsAg decline improves positive
predictive value
HBsAg Levels at Week 12
< 1500 IU/mL
1500-20,000 IU/mL
> 20,000 IU/mL
100
HBeAg Seroconversion
6 Mos Posttreatment (%)
•
80
68
60
40
46
45
31
20
0
0
0
1-2 x ULN
> 2 x ULN
ALT
HBsAg (IU/mL)
Gane E, et al. EASL 2011. Abstract 69.
Kao 2012
Practical application of response-guided
therapy (RGT) of Peg-IFN by HBsAg levels
Identify responders (PPV)
Identify non-responders (NPV)


Week 12/24:
HBeAg-positive e+
HBsAg <20,000 IU/mL
HBeAg-negative
e-
>10% decline in HBsAg (Week 24 for
GT D)
Week 12/24:
HBeAg-positive
e+
HBsAg >20,000 IU/mL
HBeAg-negative (GT D)
e-
No decline in HBsAg and <2 log decline
in HBV DNA
Kao 2012
Summary: Prediction of response to
Peginterferon
• Individualize therapy in patients
based on on-treatment HBsAg levels
• Alternatively, serum HBV DNA or
HBeAg can be used
• ALT flare during therapy predicts a
better response
Kao 2012
Role of host genomics/genetics?
Kao 2012
IFN antiviral and signaling pathways
Hypothesis: Variations of host genes may account,
in part, for response to IFN therapy
Kao 2012
Host genomic background and response
to IFN therapy
• In the candidate gene approach, we ever selected
genes in the IFN pathway involved in antiviral and
signaling activities and sequenced 22 single
nucleotide polymorphisms (SNPs) of 82 patients.
• We identified 2 SNPs in the antiviral pathway that
may influence IFN response: one SNP in the
regulatory region of the eIF-2 alpha gene; the
other in the MxA gene promoter.
King et al, Hepatology 2002;36:1416
Kao 2012
Genetic Mapping of IL28A, IL28B, and IL29 (IFN λ
Family)
Balagopal A, et al. Gastroenterology 2010;139:1865-76
Kao 2012
Does IL28B GT Predict HBsAg Clearance?
HBeAg-Positive Population
–
65% Asian, 29% white
–
HBV GT: 47% C, 20% B, 13% A, 13% D
IL28B genotyping at SNPs rs12980275
and rs12979860
–
Only rs12980275 reported
–
AA/AG/GG nomenclature with this SNP
essentially equivalent to common CC/CT/TT
nomenclature with rs12979860
•
Median follow-up: 173 wks (IQR: 108-356)
•
IL28B independently predicted HBeAg
seroconversion and HBsAg seroclearance
*Adjusted for HBV genotype and baseline ALT and
HBV DNA
Sonneveld MJ, et al. EASL 2011. Abstract 71.
100
Cumulative Probability of
HBeAg Seroconversion
•
HBeAg-positive patients treated with IFN
(n = 14) or pegIFN alfa-2a or 2b ± LAM (n
= 191)
80
AA genotype
60
P = .018
40
AG/GG genotype
20
0
0
10
HBsAg Seroclearance
•
HR for AA vs AG/GG*: 2.14 (1.14-4.31)
48
96 144 192 240 288 336
Wks
HR for AA vs AG/GG: 3.47 (1.04-13.48)
8
AA genotype
6
P = .042
4
2
AG/GG genotype
0
0
48
96 144 192 240 288 336
Wks
Kao 2012
Does IL28B GT Predict HBsAg Clearance?
Primarily HBeAg-Negative Population
• HBsAg-positive patients
treated with IFN or pegIFN for
12-24 mos (N = 151)
• Response defined as HBsAg
loss and anti-HBs
seroconversion
– Mean posttreatment follow-up:
24 mos (range: 12-52)
• No significant association
observed
Mangia A, et al. EASL 2011. Abstract 1331.
100
IL28B Distribution (%)
– 127 HBeAg negative
– 24 HBeAg positive
– All white, HBV genotype D
IL28B Genotype and
HBsAg Clearance
80
60
CC
CT
TT
P = .28
50
47
44
40
35
18
20
6
0
HBsAg No HBsAg
Clearance Clearance
Kao 2012
IL28B genotypes and HBeAg SC in CHB
patients with Peg-IFN in Europe and Asia
Lampertico et al. Gut 2012.
Kao 2012
• Rs 8099917
Nature Genetics 2009.
Kao 2012
Impact of Host and Viral Factors on HBeAg+
CHB Patients Receiving Peg-IFN Therapy
Tseng TC, Kao JH, et al. Antiviral Therapy 2011.
Kao 2012
GWAS may be helpful
 Most common liver diseases are multifactorial (complex) diseases
 Essentials
 Large patient cohort with clear phenotypes
 Phenotypes correlated with genome-wide
markers by genetic linkage analyses
 Potentials
 Understand pathogenesis
 Provide a framework for the development
of "personalized" strategies for prediction,
early prevention and therapy
Kao 2012
Outline
• Update on the disease
• Current status of antiviral
treatment
• Pegylated interferon
– Predictors
• Personalized medicine
– Risk calculator
– Individualized therapy
Kao 2012
Risk calculator for HBV-HCC
Nomogram for REVEAL Model 3
Yang et al. JCO 2010;28:2437-2444
Kao 2012
REACH-B: Cumulative Risk Scores and
Projected HCC Risk
Risk predictor
Gender
Female
Male
Age
30-34
35-39
40-44
45-49
50-54
55-59
60-65
ALT, U/L
<15
15-44
≥45
HBeAg
Negative
Positive
HBV DNA level, copies/mL
<300 (Undetectable)
300-9999
10000-99999
100000-999999
106
Risk score
0
2
0
1
2
3
4
5
6
0
1
2
0
2
0
0
3
5
4
Cumulative
risk score
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3rd
At
year
0.0%
0.0%
0.0%
0.0%
0.0%
0.1%
0.1%
0.2%
0.3%
0.5%
0.9%
1.4%
2.3%
3.7%
6.0%
9.6%
15.2%
23.6%
HCC risk
At 5th
year
0.0%
0.0%
0.0%
0.1%
0.1%
0.2%
0.3%
0.5%
0.8%
1.2%
2.0%
3.3%
5.3%
8.5%
13.6%
21.3%
32.4%
47.4%
At 10th
year
0.0%
0.1%
0.1%
0.2%
0.3%
0.5%
0.7%
1.2%
2.0%
3.2%
5.2%
8.4%
13.4%
21.0%
32.0%
46.8%
64.4%
81.6%
Yang HI, et al. Lancet Oncol 2011;12:568–574. Kao 2012
Yang et al. Lancet Oncology 2011.
Kao 2012
Outline
• Update on the disease
• Current status of antiviral
treatment
• Pegylated interferon
– Predictors
• Personalized medicine
– Risk calculator
– Individualized therapy
Kao 2012
Hypothetical algorithm for
personalized interferon therapy of CHB
Lin and Kao. EOP 2011.
Kao 2012
Personalized medicine of HBV Therapy
NR
NR
30%
Ontreatment
adjustment
40%
Withdrawal
10%
Relapse
NR
Withdrawal
Relapse
Case
selection by
baseline
host/viral
factors
Withdrawal
Relapse
New
strategies
SVR
10-20%
> 70%
SVR
SVR
50-60%
30-40%
Past
Present
Identify
AErelated
SNPs New
treatment
strategy
Future Kao 2012
Advancing Hepatology in New Era:
Milestones and Perspectives
Kao 2012