A Personalized Interferon Therapy for Chronic Hepatitis B

1
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
2
Outline

• Update on the disease
• Current status of antiviral treatment
• Pegylated interferon
• Predictors
• Personalized medicine
• Risk calculator
• Individualized therapy

3
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
  virus-encoded 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

4
Hepatitis B a global health problem

• gt 350 million people are chronic HBV carriers
  worldwide
• The worlds 10th leading cause of death
• Chronic HBV infection is endemic in the African
  and Asian-Pacific regions (HBsAg prevalence gt
  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

5
Natural history of perinatally acquired chronic
HBV infection
20-30
Modified from Lok et al. Hepatology
200745507-539 and Pungpapong et al. Mayo Clin
Proc 200782967-975.
6
Annual rates of progression during chronic HBV
infection
Chronic HBV infection
60-70
30-40
lt1.0
Inactive carrier state
Chronic hepatitis B
2-6 for HBeAg() hepatitis B 8-10 for HBeAg(-)
hepatitis B
lt0.2
2-3
Compensated cirrhosis
3-5
Hepatocellular Carcinoma
Decompensated cirrhosis
7-8
20-50
20-50
Death
Fattovich et al. 2004.
7
Factors associated with disease progression in
HBV carriers
Viral Persistent presence of HBeAg Persistently
high HBV-DNA level HBV genotype C gt genotype
B Core promoter mutations and Pre-S deletion
Host Male gender Increasing age Recurrent ALT
flare Persistently increased ALT
levels Cirrhosis Diabetes
Environment Heavy drinking Cigarette
smoking Aflatoxin HCV, HDV, or HIV coinfection
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 275284.
8
Clinical significance of qHBsAg in natural
history of CHB
9
HBV DNA, HBsAg and ALT levels during different
phases of CHB
Janssen et al. Gut 2012.
10
Identification of inactive infection using HBsAg
and HBV DNA levels
Analysis of 209 HBV genotype D patients
Prediction of Inactive infection
HBsAg levelsHBV DNA levels lt1000 IU/mL pluslt2000 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
11
Proposed algorithm to categorize risk of disease
progression and management in Asian
HBeAg-negative patients
N1068 Taiwanese HBeAg-negative patients with HBV
DNA lt2000 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
3 mo or treat
Abnormal
36 mo
1000 IU/mL
Asian HBeAg(-) HBV carriers
HBV DNA
612 mo
ALT
lt2000 IU/mL
Normal
HBsAg
12 mo
lt1000 IU/mL
Tseng et al. Hepatology 2012
12
qHBsAg can predict spontaneous HBsAg loss in HBV
carriers

• Serum HBsAg level lt100 IU/ml at 1 year post-HBeAg
  seroconversion can predict HBsAg loss within 6
  years1
• HBsAg lt10 IU/ml is the strongest predictor of
  HBsAg loss in HBeAg-negative patients who have
  HBV DNA lt2000 IU/ml2
• Decreasing HBsAg level (lt200 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

13
qHBsAg can predict HCC risk in HBV carriers

• HBsAg gt 1000 IU/ml could predict HCC risk in
  HBeAg-negative patients, especially in those who
  have HBV DNA lt2000 IU/ml4,5

1. Tseng and Kao et al. Gastroenterology
2012 2. Chen et al. AASLD 2011 Abstract 1095
14
HBsAg level is an important risk factor in
patients with low HBV DNA level (lt2000 IU/mL)
ERADICATE-B (2688 HBV carriers)
5-fold risk increase by univariate analysis
Tseng, Kao. Gastroenterology 2012 Chan HL.
Gastroenterology 2012
15
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16
Outline

• Update on the disease
• Current status of antiviral treatment
• Pegylated interferon
• Predictors
• Personalized medicine
• Risk calculator
• Individualized therapy

17
Goal of treatment for CHB Short-term vs.
Long-term
Durable response
Initial response
Anti-HBegain
HBeAg()patients
HBeAgloss
Prevent complications Prolong survival
HBV DNAundetectable
ALTnormalization
TIME
Primary aim of treatment Permanently suppress
HBV replication
Initiation of treatment
Liaw et al. Asia Pacific Consensus Statement
2008. Hepatol Int 2008.
18
Treatment landscape of CHB 2012
Generic Name Trade Name Manufacturer Date Approved for Hepatitis B
Interferon alfa INTRON A ROFERON Schering Hoffman La-Roche 1991
Lamivudine ZEFFIX GlaxoSmithKline 1998
Adefovir dipivoxil HEPSERA GlaxoSmithKline 2002
Entecavir BARACLUDE Bristol-Myers Squibb 2005
Peginterferon alfa-2a PEGASYS Hoffman La-Roche 2005
Telbivudine SEBIVO Novartis 2006
Tenofovir VIREAD Gilead Sciences 2008
19
Treatment strategies of CHB
NAs
INTERFERON
Sustained remission Maintained remission
Low viremia No viremia
ALT normalization ALT normalization
Immune control,no further need forantiviral drugs No immune control, continued need forantiviral drugs
20
Outline

• Update on the disease
• Current status of antiviral treatment
• Pegylated interferon
• Predictors
• Personalized medicine

21
Immunopathogenesis of HBV infection
Innate Immune System
Adaptive Immune System
Ganem D. NEJM 200435011118-29. Edward D.
Gastroenterology 20011201000-8.
22
Immunopathology of chronic HBV infection
Viral replication
Immune response
CD8
HBV
Immune tolerance
CD8
HBV
Clearance phase Chronic hepatitis
HBV
Seroconversion Remission
CD8
Guidotti Science 1999 Guo J Virol 2000 Kakimi J
Exp Med 2000 Zhu J Virol 2001
23
IFN/Peg-IFN, dual mode of action -The only
approved immunomodulatory agent
IFN?
Direct antiviral effect
Modulation of immune responses

• MHC class I protein display enhanced
• activation of CTL and NK cells

• 2,5-oligoadenylate synthetase induction leading
  to viral cleavage
• IFN?-inducible human MxA protein-gt breakdown
  viral RNA

24
PEG-IFN? treated HBeAg CHB patients T cell
response and T-regs
Tang, et al. J Hepatol 2005 Sprengers, et al.
Antiviral Therapy 2007.
25
Outline

• Update on the disease
• Current status of antiviral treatment
• Pegylated interferon
• Predictors
• Personalized medicine
• Risk calculator
• Individualized therapy

26
Responder to standard IFN therapy

• Younger age (short duration of infection)
• Female gender
• Child bearing age
• Compensated liver disease
• HBeAg-positive
• Low baseline HBeAg level and early HBeAg
  suppression
• High ALT (gt 5x ULN)
• Low baseline HBV DNA (lt109 copies/ml) and more
  profound suppression of HBV DNA during therapy
• Genotype A or B
• Significant necro-inflammatory activity

Kao JH. Hepatol Res 200737S47-S54.
27

• Pegylated interferon alpha
• Baseline predictors
• In HBeAg-positive CHB, predictors of anti-HBe
  seroconversion are low viral load (lt 2x108
  IU/mL), high serum ALT levels (gt 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.
28
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
52
36
32
28
Patients ()
22
12
8/29
2/17
10/45
18/56
22/61
13/25
lt 2 ULN
gt 2 - lt 5 ULN
gt 5 ULN
ALT
Cooksley et al. Shanghai Hong Kong International
Liver Congress 2006.
29
HBV genotype and IFN response
Kao JH et al, J Hepatol 2000 Liu Kao, Liver
Int 2005
30
Effect of HBV genotype on rate of HBeAg
seroconversionin HBeAgve CHB pts with pegIFN
therapy
After (a) Janssen et al and (b) Lau et al-
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32
Meta-analysis of 721 HBeAg patients receiving
1yr-Peg-IFN Prediction by BL factors
Genotype ALT DNA
Nomogram
Buster et al, Gastroenterology 20091372002
33
NEPTUNE Similar high rate of HBeAg
seroconversion for genotypes B and C
Liaw et al. Hepatology 2011
34

Response rates are highest with180 µg/week for
48 weeks in genotype B
HBeAg seroconversion
HBV DNA lt2,000 IU/mL
47
42
34
Response 6 monthspost-treatment ()
Response 6 monthspost-treatment ()
29
24
24
19
12
180 mg/48n45
90 mg/48n45
90 mg/24n49
180 mg/24n47
90 mg/48n45
90 mg/24n49
180 mg/24n47
180 mg/48n45
ALT normalization
64
53
45
37
Response 6 monthspost-treatment ()
90 mg/24n49
180 mg/24n47
90 mg/48n45
180 mg/48n45
Liaw et al. Hepatology 2011
35

Response rates are highest with180 µg/week for
48 weeks in genotype C
HBeAg seroconversion
HBV DNA lt2000 IU/mL
39
Response 6 monthspost-treatment ()
Response 6 monthspost-treatment ()
25
21
24
16
11
7
10
90 mg/24n70
180 mg/24n76
90 mg/48n68
180 mg/48n67
90 mg/24n70
180 mg/24n76
90 mg/48n68
180 mg/48n67
ALT normalization
49
35
29
Response 6 monthspost-treatment ()
24
90 mg/24n70
180 mg/24n76
90 mg/48n68
180 mg/48n67
Liaw et al. Hepatology 2011
36
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 20049895
37
Baseline viral factors affecting Tx outcomes in
HBeAg pts with 6M Peg-IFN alfa-2a (N115)
HBeAg SC VLlt 20,000IU/mL
Tseng TC, Kao JH, et al. Antiviral Therapy 2011.
38
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 lt 2x106 IU/mL (OR 4.78, 95 CI
  1.37-16.69) were associated with a higher
  combined response rate.

Tseng TC, Kao JH, et al. Antiviral Therapy 2011.
39
Baseline viral factors affecting Tx outcomes in
HBeAg pts with 6M Peg-IFN alfa-2a (N115)
Viral load, high is 2x106 IU/ml low is lt2x106
IU/ml.
Tseng TC, Kao JH, et al. Antiviral Therapy 2011.
40
Pegylated interferon alphaOn-treatment
predictors

• ALT level
• HBV DNA level
• HBeAg level
• HBsAg titer

41
On-treatment ALT flares are indicative of
enhanced immune response
ALT flares during Peg IFN are associated with
host immune response
ALT flares after Peg IFNtherapy are virus induced
12
12
Peg IFN treatment
Peg IFN treatment
14
25
12
10
10
20
10
8
8
15
8
Log H BV DNA
ALT (x ULN)
Log H BV DNA
ALT (x ULN)
6
6
6
10
4
4
4
2
2
0
0
0
0
0
8
16
24
32
40
48
64
72
78
56
0
8
16
24
32
40
48
64
72
78
56
ALT HBV DNA
Flink et al. Gut 2005.
42
On-treatment ALT flares predict response to Peg
IFN therapy
Peg IFN-?-2b
Peg IFN-?-2a
100
90
80
70
58
60
44
Patients achieving response ()
50
40
30
20
20
10
0
0
Hostinduced N24
Virus inducedN25
HostinducedN18
Virus inducedN10
Flink et al. Gut 2005 Piratvisuth et al. ILC
2006.
43
Quantitative HBeAg at weeks 12 and
24relationship to HBeAg seroconversion
HBeAg seroconversion at wk 72

HBeAg (PEIU/ml)
P0.059
Fried, et al. Hepatology. 200847428-434.
44
Prediction of response to PEGASYS HBeAg vs. HBV
DNA
Mean HBeAg (PEIU/mL)
Mean HBV DNA (log cp/mL)
Week 24 HBeAg gt100 U/mL NPV 96 HBV DNA gt 9
log NPV 86
HBeAg is a better negative predictor of response
than HBV DNA
Fried et al, Hepatology 2008.
45
HBsAg level at week 12 is associated with 6
months post-treatment response
51 of patients with HBsAg lt1500 IU/mL at week 12
achieved HBeAg seroconversion 6 months
post-treatment
HBsAg level (IU/mL)
lt1500
150020,000
gt20,000
HBsAg clearance 10 pts overall 18 pts with
HBeAg seroconversion
HBeAg-positive patients
55
21
24
Proportion of patients
Lau et al. AASLD 2008 Lau et al. APASL 2009
Poster 083
46
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
lt 1500(n 46)
lt 1501-20,000 (n 52)
gt 20,000 (n 16)
lt 1500(n 31)
lt 1501-20,000(n 62)
gt 20,000(n 21)
14
100
19
100
27
40
80
80
P lt .0001
P .0003
46
54
P .0015
P .0004
57
58
60
60
54
Response 6 Mos Posttreatment ()
52
42
35
40
40
31
P .3819
19
P .2866
20
20
10
7
0
0
0
0
0
0
0
0
0
0
HBeAg Seroconversion
HBV DNA lt 2000 IU/mL
HBsAg Clearance
HBeAg Seroconversion
HBV DNA lt 2000 IU/mL
HBsAg Clearance
Gane E, et al. EASL 2011. Abstract 69.
47
NEPTUNE On-Treatment HBsAg as Marker of Response
to PegIFN

• HBsAg lt 20,000 IU/mL identified as key marker of
  response
• HBsAg gt 20,000 IU/mL at Week 12 or 24 predicts
  lack of HBeAg seroconversion
• Negative predictive value 100

• Combination of ALT level and HBsAg decline
  improves positive predictive value

HBsAg Levels at Week 12
lt 1500 IU/mL
1500-20,000 IU/mL
Week 12
Week 24
100
100
gt 20,000 IU/mL
80
80
68
60
60
HBeAg Seroconversion 6 Mos Posttreatment ()
HBeAg Seroconversion 6 Mos Posttreatment ()
47
46
45
45
40
40
31
20
20
0
0
0
0
0
0
1-2 x ULN
gt 2 x ULN
(n 93) lt 20,000
(n 21) gt 20,000
(n 98) lt 20,000
(n 16) gt 20,000
ALT
HBsAg (IU/mL)
Gane E, et al. EASL 2011. Abstract 69.
48
Practical application of response-guided therapy
(RGT) of Peg-IFN by HBsAg levels
Identify non-responders (NPV)
Identify responders (PPV)
?
?
Week 12/24 HBeAg-positive HBsAg lt20,000
IU/mL HBeAg-negative gt10 decline in HBsAg (Week
24 for GT D)
Week 12/24 HBeAg-positive HBsAg gt20,000
IU/mL HBeAg-negative (GT D) No decline in HBsAg
and lt2 log decline in HBV DNA
e
e
e-
e-
49
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

50
Role of host genomics/genetics?
51
IFN antiviral and signaling pathways
Hypothesis Variations of host genes may account,
in part, for response to IFN therapy
52
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 2002361416
53
Genetic Mapping of IL28A, IL28B, and IL29 (IFN ?
Family)
Balagopal A, et al. Gastroenterology
20101391865-76
54
Does IL28B GT Predict HBsAg Clearance?
HBeAg-Positive Population
HR for AA vs AG/GG 2.14 (1.14-4.31)

• HBeAg-positive patients treated with IFN (n 14)
  or pegIFN alfa-2a or 2b LAM (n 191)
• 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

100
80
AA genotype
60
P .018
Cumulative Probability of HBeAg Seroconversion
40
AG/GG genotype
20
0
0
48
96
144
192
240
288
336
Wks
10
HR for AA vs AG/GG 3.47 (1.04-13.48)
8
AA genotype
6
HBsAg Seroclearance
P .042
4
2
AG/GG genotype
Adjusted for HBV genotype and baseline ALT and
HBV DNA
0
0
48
96
144
192
240
288
336
Wks
Sonneveld MJ, et al. EASL 2011. Abstract 71.
55
Does IL28B GT Predict HBsAg Clearance? Primarily
HBeAg-Negative Population

• HBsAg-positive patients treated with IFN or
  pegIFN for 12-24 mos (N 151)
• 127 HBeAg negative
• 24 HBeAg positive
• All white, HBV genotype D
• Response defined as HBsAg loss and anti-HBs
  seroconversion
• Mean posttreatment follow-up 24 mos (range
  12-52)
• No significant association observed

IL28B Genotype and HBsAg Clearance
100
CC
CT
80
TT
P .28
60
50
47
IL28B Distribution ()
44
40
35
18
20
6
0
HBsAg Clearance
No HBsAg Clearance
Mangia A, et al. EASL 2011. Abstract 1331.
56
IL28B genotypes and HBeAg SC in CHB patients with
Peg-IFN in Europe and Asia
Lampertico et al. Gut 2012.
57

• Rs 8099917

Nature Genetics 2009.
58
Impact of Host and Viral Factors on HBeAg CHB
Patients Receiving Peg-IFN Therapy
Tseng TC, Kao JH, et al. Antiviral Therapy 2011.
59
GWAS may be helpful

• Most common liver diseases are multi-factorial
  (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

60
Outline

• Update on the disease
• Current status of antiviral treatment
• Pegylated interferon
• Predictors
• Personalized medicine
• Risk calculator
• Individualized therapy

61
Risk calculator for HBV-HCC Nomogram for REVEAL
Model 3
Yang et al. JCO 2010282437-2444
62
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63
Yang et al. Lancet Oncology 2011.
64
Outline

• Update on the disease
• Current status of antiviral treatment
• Pegylated interferon
• Predictors
• Personalized medicine
• Risk calculator
• Individualized therapy

65
Hypothetical algorithm for personalized
interferon therapy of CHB
Lin and Kao. EOP 2011.
66
Personalized medicine of HBV Therapy
NR
On-treatment adjustment
NR 30
Withdrawal
NR 40
Relapse
Withdrawal
Case selection by baseline host/viral factors
New strategies
Withdrawal 10
Relapse
Relapse 10-20
SVR gt 70
Identify AE-related SNPs
SVR 50-60
SVR 30-40
New treatment strategy
Past
Present
Future
67
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