Recent Advance of Chronic Hepatitis B Treatment

1
Recent Advance of Chronic Hepatitis B Treatment

• Ting-Tsung Chang, M.D.
• National Cheng Kung University Hospital

2

• Introduction
• Treatment of HBeAg () CHB
• Treatment of HBeAg (-) CHB
• Improvement in clinical outcome
• Emergence of drug resistant virus
• Summary

3
Prevalence of HBV and Incidence of Hepatocellular
Carcinoma (HCC)
World prevalence of HBV carriers
Annual incidence of primary HCC
HBsAg carriers prevalence lt2 27 gt8 Poorl
y documented
Cases/100,000 population 13 310 10150 Poorl
y documented
WHO 1999
4
Modes of Transmission
Child-to-child transmission
Perinatal/vertical
Hepatitis B
Unsafe injections and transfusions
Sexual contact
HBV is transmitted via contact with blood or body
fluids in the same way as HIV. However, HBV
is50100 times more infectious than HIV
WHO Fact Sheet 2000
5
HBV Virology

• Partially ds DNA genome, 42nm
• 4 genes HBsAg, HBcAg, HBV Pol/RT, X protein
• Serologic marker of HBV infection HBsAg
• Serologic markers of HBV replication HBeAg, HBV
  DNA, HBV Polymerase

6
Spectrum of Disease
Acute HBV infection
90 neonates
2530 children
lt10 adults
2
Chronic infection
1540
Progressive chronic hepatitis
Inactivecarrier state
Fulminant hepatic failure
Cirrhosis
HCC
Death
Decompensated cirrhosis
EASL Consensus Guidelines. J Hepatol 2003 Lok,
McMahon. Hepatology 2004 (AASLD Guidelines)
7
Stages of Chronic HBV Infection
Adapted from Fattovich. Sem Liver Dis 2003
8
Natural History of HBV Development of
HBeAg-negative CHB
HBeAg-positive
HBeAg-negative/ anti-HBe-positive
Brunetto. J Hepatol 1991
9
NIH Definition of Chronic Hepatitis B

• HBsAg positive (serum)
• HBV DNA gt 100,000 copies/mL or HBcAg in liver
• Elevated ALT for 6 months
• Liver histology showing chronic hepatitis (HAI 4)

10
Implications of HBeAg Seroconversion

• Usually (gt80) permanent suppression of HBV
  replication
• Loss of HBsAg possible
• Normalisation ALT reduced necroinflammatory
  change
• Functional improvement abolishes risk of liver
  failure or transplantation
• Effect on HCC risk 50 reduction

11
Long-term Follow-up of HBeAg Positive Patients
Cumulative survival without complications in 53
untreated patients
Clearance of HBeAg
1
0.8
Proportion of patients surviving
0.6
No clearance of HBeAg
0.4
0.2
0
12
24
36
48
60
72
84
96
0
Month
Niderau et al., NEJM 1996
12
NIH Definition of Inactive HBsAg Carrier

• Presence of HBsAg and anti-HBe in serum
• Serum HBV DNA lt 105 copies/ml
• Peristently normal serum ALT gt 6 months
• Liver histology (not essential) HAI grade lt 3

13
When is the Patient at Risk of Progressive
Disease and in Need of Treatment?

• Consider treatment if
• HBeAg-positive, HBV DNA gt105 cp/mL and ALT gt2 x
  ULN
• HBeAg-negative, HBV DNA gt105 cp/mL and ALT gt2 x
  ULN
• Monitor if
• HBeAg-positive, HBV DNA gt105 cp/mL, ALT 2 x ULN
• HBeAg-negative, HBV DNA gt105 cp/mL, ALT 2 x ULN
• No treatment required if
• HBeAg-negative, HBV DNA lt105 cp/mL, ALT 2 x
  ULN(if ALT gt12 x ULN, exclude other causes of
  liver disease)

Liver biopsy can be useful to aid the decision
on whether to treat
Lok, McMahon. Hepatology 2004 (AASLD Guidelines)
14
Treatment Options for CHB
a- IFN / Pegylated IFN
Immunomodulatory action
Antigen presenting cell
T helper cell
B cell
Cytotoxic T cell
Antiviral action
Natural killer cell
Nucleoside/ nucleotide analogues
Antiviral action
15
Antiviral Drugs for CHB
Adefovir Dipivoxil Bis(POM)-PMEA 2002
Lamivudine 3TC 1998



Entecavir 2005
16
Mechanism of Action of Antiviral Drugs
Antiviral drugs
Lai et al., J Med Virol 2000
17
Goals of Antiviral Treatment of CHB

• Sustained suppression of HBV replication
• ? serum HBV DNA to lt105 copies/ml
• HBeAg to anti-HBe seroconversion
• HBsAg to anti-HBs seroconversion
• Remission of liver disease
• Normalization of serum ALT levels
• ? necroinflammation in liver
• Improvement in clinical outcome
• ? risks of developing cirrhosis, liver failure
  and HCC
• ? survival

18

• Introduction
• Treatment of HBeAg () CHB
• Treatment of HBeAg (-) CHB
• Improvement in clinical outcome
• Emergence of drug resistant virus
• Summary

19
Median change from baseline in HBV DNA at Week 48
for HBeAg () CHB
0
-0.55 log
-
1
-
10
-
2
-
-
3
-
-3.52 log
10
Change in HBV DNA by PCR(log10 copies/mL)
-
4
-
-
5
-
-
5.46 log

10
-
6
-
p lt0.0001 for each comparison on-treatment
-
6.98 log
-
-
7
-
10






-
8
-
0
12
24
36
48
Week
On-treatment
Chang et al. NEJM 2005 Marcellin et al. NEJM 2003
20
Efficacy Endpoints at Week 48 after Antiviral
Treatment among HBeAg () CHB
Chang et al. NEJM 2005 Lau et al. NEJM 2005
Marcellin et al. NEJM 2003
21
Lamivudine Normalises Serum ALT
Lamivudine
Lamivudine Interferon
Placebo
Interferon a-2b

80
72
67
70
44
60
Patients ()
40
50
41
40
25
30
24
18
17
15
20
7
10
5
0
Lai
Dienstag
Tassopoulous
Schalm
Schiff
plt0.001 compared to placebo p0.007 compared
to interferon p0.005 compared to
lamivudine/interferon
22
HBeAg loss by baseline ALT at the end of
treatment
Perrillo et al 1998
23
Efficacy of 24-week IFN Treatment in eAg () CHB
at the end of 24-week follow-up (All Pegasys
Doses Grouped)

• HBeAg loss
• HBV DNA lt 500,000 copies/mL
• ALT normalization

Cooksley et al, J Viral Hepatitis 2003
24
HBV DNA Levels Over Time and HBeAg
Seroconversion at End of Follow-up
12
HBeAg Seroconversion Rates at End of Follow-up
Plt0.001
32
P0.023
27
19
n271
n271
n272
PEGASYS
PEGASYS LAM
LAM
Study week
Lau et al. AASLD 2004
all numbers shown are log10 reduction from
baseline
25
HBeAg Seroconversion Rates Over Time
On-treatment
Follow-up
32
27
27
Plt0.001
24
P0.023
19
20
HBeAg Seroconversion ()
PEGASYS placebo
PEGASYS lamivudine
lamivudine
Lau et al. AASLD 2004
Study week
26
HBeAg Seroconversion Increases in Patients with
Elevated ALT under Long Term Lamivudine (n58)
Treatment
ALT gt 1x ULN
ALT gt 2x ULN
80
73
65
59
Patients ()
60
49
42
47
38
37
40
40
27
29
20
22
18
12
0
1
2
3
4
0
Duration of therapy (years)
Chang et al.. Journal of Gastroenterology and
Hepatology 2004 19 127682
27
HBeAg Seroconversion Increases in Patients with
Elevated ALT under Long Term Lamivudine (n58)
and Adefovir dipivoxil (n288) Treatment
Lamivudine
80
59
Patients ()
60
49
37
40
27
20
0
0
1
2
3
4
Duration of therapy (years)
Chang et al.. Journal of Gastroenterology and
Hepatology 2004 19 127682
28
HBeAg Seroconversion Increases in Patients with
Elevated ALT under Long Term Lamivudine (n58)
and Adefovir dipivoxil (n288) Treatment
Lamivudine
80
59
Patients ()
60
49
37
40
43
27
29
20
12
0
0
1
2
3
4
Duration of therapy (years)
Chang et al.. Journal of Gastroenterology and
Hepatology 2004 19 127682
Marcellin et al. AASLD 2004 abst 1135
29
HBeAg Seroconversion Increases in Patients with
Elevated ALT under Long Term Lamivudine (n355)
and Entecavir (n354) Treatment
80
Patients ()
60
40
31
21
20
26
18
0
1
2
3
4
0
Duration of therapy (years)
Gish RG, Chang TT, et al. AASLD 2005
30
Durability of post-treatment response
HBeAg loss in different patient groups
100
87
86
81
80
68
60
Patients ()
40
20
20/23
37/43
21/26
21/31
0
Lamivudine Asian
Lamivudine Caucasian
Interferon
Spontaneous
Median Follow-up gt12 months
Korenman et al 1991
Schiffet al 1998
Loket al 1987
Guanet al 2000
31
Off-treatment Durability of HBeAg loss or
Seroconversion Among HBeAg CHB after
Discontinuation of Antiviral Treatment
Adefovir dipivoxil n75
Lamuvidne n67
Entecavir n74
HBeAg seroconversion Median duration off ADV
therapy 55 weeks (range 5-125) loss of HBeAg
and HBV DNA lt0.7 MEq/mL by bDNA 24 weeks follow
up
32

• Introduction
• Treatment of HBeAg () CHB
• Treatment of HBeAg (-) CHB
• Improvement in clinical outcome
• Emergence of drug resistant virus
• Summary

33
Median change from baseline in HBV DNA at Week 48
for HBeAg (-) CHB
p lt0.0001 for each comparison on-treatment
p lt0.0001 vs lamivudine HBV DNA assays by
COBAS PCR
On-treatment
Lai et al. NEJM 2005 Hadziyannis et al. NEJM 2003
34
Efficacy Endpoints at Week 48 after Antiviral
Treatment among HBeAg (-) CHB
77/ 121
17/ 59
19/ 57
207/ 296
63/ 123
254/325
296/325
175/287
84/166
0/61
354/ 494
361/ 494
Lai et al. NEJM 2005 Hadziyannis et al. NEJM
2005 Hadziyannis et al. NEJM 2003
35
HBeAg-negative CHB Mean HBV DNA Levels Over
Time
On-treatment
Follow-up
7
6
1.6
Mean HBV DNA (log10 cp/mL)
2.4
5
2.3
4
4.1
3
4.2
5.0
2
Study week
0
6
12
18
24
30
36
42
48
54
60
66
72
Change in HBV DNA from baseline
Marcellin et al. N Eng J Med 2004
36
HBeAg-negative CHB Combined 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. N Eng J Med 2004
37
Proportion of Patients with HBV DNA lt0.7 MEq/mL
and ALT lt1.25 x ULN Off-treatment
100
80
60
Proportion with HBV DNA lt0.7 MEq/mL and ALT lt1.25
x ULN ()
48
40
35
20
0
Weeks Off-Treatment
Treatment
ETV 0.5 mg Censored
LVD 100 mg Censored
Number at risk ETV 0.5 mg LVD 100 mg
259
245
245
243
240
234
233
227
219
204
196
178
157
126
0
220
107
103
100
96
92
90
87
80
1
213
199
173
155
102
ETV 85 x 48 41, LVD 78 x 35 27
38
Study 438 (0-96 weeks) Median Serum HBV DNA
LLQ 1000 copies/mL
39
Study 438 (0-96 weeks) Undetectable Serum HBV
DNA
100
PLB ADV (n60)
ADV ADV (n79)
90
ADV PLB (n40)
80
76
71
70
60
51
Patients ()
50
40
30
20
10
8
0
0
0
4
8
12
24
36
48
60
72
84
96
Weeks
LLQ 1000 copies/mL
40
Study 438 (0-96 weeks) ALT Normalization
100
90
80
80
76
70
72
60
Patients ()
50
40
32
30
29
20
10
0
0
4
8
12
24
36
48
60
72
84
96
Weeks
1ULN for males 43 IU/L, females 34 IU/L
41
ADV in HBeAg-ve CHBHBV DNA lt 1,000 copies/mL
HBsAg loss was observed in 4/125 (3.2) of
patients by Week 192 Kaplan Meier estimates
Hadzyannis et al J Hepatol 200542(suppl 2)178
42
ADV in HBeAg-ve CHBALT Normalization
Hadzyannis et al J Hepatol 200542(suppl 2)178
Kaplan Meier estimates
43
Proportion of Patients with Improved Ishak
Fibrosis Score (Year 4 and Year 5 Cohorts)
17/24 (71)
P0.005
11/24 (46)
12/22 (55)
8/24 (33)
7/22 (32)
Hadziyannis S, Tassopoulos N, Chang TT, et al.
AASLD 2005
44
Outcomes of Patients with Pretreatment Bridging
Fibrosis or Cirrhosis
Pretreatment Ishak Fibrosis Score Ishak Score Ishak Score End-of-Treatment Ishak Fibrosis Score
Pretreatment Ishak Fibrosis Score 1 year ADV 2 years ADV End-of-Treatment Ishak Fibrosis Score
4-Year Cohort (n5) 6 3 2
4-Year Cohort (n5) 6 2 2
4-Year Cohort (n5) 4 4 2
4-Year Cohort (n5) 6 6 5
4-Year Cohort (n5) 5 --- 6
5-Year Cohort (n7) 6 6 3 2
5-Year Cohort (n7) 5 5 --- 3
5-Year Cohort (n7) 5 3 --- 2
5-Year Cohort (n7) 4 1 --- 1
5-Year Cohort (n7) 4 3 3 3
5-Year Cohort (n7) 4 3 --- 3
5-Year Cohort (n7) 4 4 --- 4
96-week biopsies 1 year ADV treatment in Y4
cohort and 2 years ADV in Y5 cohort. Among 12
patients with bridging fibrosis or cirrhosis
pretreatment, after 4 or 5 years of ADV (1
received concomitant lamivudine).
7 improved 2 points
45
Regression of Fibrosis on ADV
1 year ADV Fibrosis 5/6
5 years ADV Fibrosis 3/6
Patient 1566 (year 5 cohort)
46

• Introduction
• Treatment of HBeAg () CHB
• Treatment of HBeAg (-) CHB
• Improvement in clinical outcome
• Emergence of drug resistant virus
• Summary

47
Actuarial Survival in end stage liver disease
Historical Comparisons
100
Lamivudine in decompensated CHB1
80
70
Patients surviving ()
60
55
Cirrhosis2
40
20
Decompensated cirrhosis3
14
1
3
2
4
5
0
Years
Perrillo et al 20011, Weissberg et al 19842, and
De Jongh et al 19923
48
Time to disease progression DB treatment and
off-treatment follow-up
Percentage with disease progression
21
Placebo
P0.001
9
Lamivudine
Time to disease progression (months)
Placebo (n215) ITT population Lamivudine
(n436) p0.001
Liaw et al. NEJM 20043511521-1531
49
Cumulative Survival

• Liver-related survival in main population (Long
  term LAM)
• Significant better than untreated
• Significant better than non-sustained reponders
  to IFN
• Similar to IFN sustained responders

50
Cumulative Major Events-Free Survival

• When the reversion of decompensation after ADV
  addition was taken into account, the major
  event-free survival of the main population
• Significantly better than untreated (p0.003)
• Better than IFN non-sustained responders (p0.02)
• Similar to IFN sustained responders (p0.65)

51

• Introduction
• Treatment of HBeAg () CHB
• Treatment of HBeAg (-) CHB
• Improvement in clinical outcome
• Emergence of drug resistant virus
• Summary

52
Identified Mutations Associated with Drug
Resistance
All ETV resistance require background YMDD
mutations
1 Allen et al. Hepatology 1998 271670-7 2 Gilead
data on file 3 Qi et al. J Hepatol 200440(suppl
1)20-1
4 Tenney et al. AAC 2004483498-507 5 Lai et al.
Hepatology 2003 38 262A
53
Cumulative Incidence of HBV Antiviral Resistance
with ADV or LAM Monotherapy
ADV (N236T/A181V)
LAM (M204V/I)b

70
67
Incidence of Resistance
53
41
29
18
18
11
3
0
Chang et al.. J Gastroenterol Hepatol 2004 19
127682 Locarnini et al J Hepatol 200542(suppl
2)17
54
GS 461 Efficacy resultsMedian change from
baseline serum HBV DNA
(n19)
(n19)
(n20)
Plt0.001 compared to LAM monotherapy
55
ETV-026 Lamivudine-Refractory HBeAg
CHBVirologic Response at Week 48
Patients ()
p lt0.0001 vs lamivudine
Sherman et al. Hepatology. 200440(suppl
1)A1152.
56
ETV-026 Lamivudine-Refractory HBeAg
CHBSecondary Endpoints
(HBV DNA lt0.7 Meq/mL and loss of HBeAg)
p lt0.0001 vs lamivudine
Sherman et al. Hepatology. 200440(suppl 1)A1152.
57
Summary of Viral Resistance Data (Week 48)
0
0
No rebounds due to resistance
No emerging ETVR or LVDR substitutions
Nucleoside Naïve (n 541)
58

• Introduction
• Treatment of HBeAg () CHB
• Treatment of HBeAg (-) CHB
• Improvement in clinical outcome
• Emergence of drug resistant virus
• Summary

59
Interferon a/ Pegylated Interferon for Treatment
of CHB Patients
Pros Cons
Short course (16-48 wk) Parenteral administration
30-40 HBeAg loss Expensive
5-10 HBsAg loss Many problem patients
No drug-resistant mutants Significant side effects
Immunomodulatory Dangerous in decompensated cirrhosis
Perrillo RP. Seminars in Liver Disease
20042423-29
60
Lamivudine, Adefovir dipivoxil and
Entecavirfor CHB Patients
Pros Cons
Orally available Long duration of treatment
Minimal side effects Drug-resistant mutants
Useful in decompensated cirrhosis and after liver transplantation Type of response differs from IFN (HBsAg loss rare)
Less expensive than IFN Postwithdrawal ALT flares (20-25)
Perrillo RP. Seminars in Liver Disease
20042423-29
61
Antiviral Treatment of HBeAg () mild-moderate
liver diseasePrimary aim prolonged viral
suppression
ALT gt 2 ULN and/or histology gt F1
Lamivudine/Adefovir/Entecavir
HBeAg seroconversion?
Yes
No
ALT normal?
Continue treatment for at least 6 months

• No
• Drug resistance ?
• Lamivudine ? Adefovir
• Adefovir Lamivudine
• Adefovir ? Lamivudine

Yes Continue therapy
62
Antiviral Treatment of HBeAg (-) mild-moderate
liver diseasePrimary aim prolonged viral
suppression
ALT gt 2 ULN and/or histology gt F1
Lamivudine/Adefovir/Entecavir
ALT normal?
Yes
No

• ALT?
• Drug resistance ?
• Lamivudine ? Adefovir
• Adefovir Lamivudine
• Adefovir ? Lamivudine

Continue treatment indefinitely
63
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