1
1
Updated Approaches
Updated Approaches
for Treating Hepatitis B
for Treating Hepatitis B
1
1
Updated Approaches
Updated Approaches
for Treating Hepatitis B
for Treating Hepatitis B
2
2
Whom to Treat
Whom to Treat
3
3
Liver disease (raised ALT level)
HBV replication (high levels of HBV DNA)
Candidates for Anti-HBV
Candidates for Anti-HBV
Treatment
Treatment
In general, a patient with chronic HBV is a
In general, a patient with chronic HBV is a
treatment candidate if there is evidence of
treatment candidate if there is evidence of
4
4
Undetectable
serum
HBV DNA
HBeAg loss
or
seroconversion
HBsAg
clearance
Treatment
endpoints
Decreased HAI
and fibrosis
Normal ALT
cccDNA
clearance
Treatment Endpoints in
Treatment Endpoints in
Chronic Hepatitis B
Chronic Hepatitis B
5
5
AASLD Guidelines: 2007
AASLD Guidelines: 2007
Update
Update
6
6
HBV DNA
HBeAg(PCR; IU/mL)
ALT
Management
+
>20,000
≤2 x ULN
Observe; biopsy if >40 y, ALT ≥2 x ULN,
or family history of HCC; treat if
moderate/
severe inflammation, significant fibrosis,
or ALT becomes elevated
+
>20,000
>2 x ULN
Treat immediately if icteric/clinical
decompensation; otherwise, observe 3–6
mo,
consider biopsy; treat if no HBeAg loss
–
>20,000
>2 x ULN
Treat
–
>2000
1–>2 x ULN
Consider biopsy; treat if
moderate/severe
inflammation or significant fibrosis
–
≤2000
≤ ULN
Observe; treat if HBV DNA or ALT
become elevated
+/–
Detectable
Cirrhosis
If compensated, treat if HBV DNA
>2000 IU/mL or ALT elevated; if
decompensated, refer for liver
transplant
+/–
Undetectable Cirrhosis
If compensated, observe; if
decompensated,
refer for liver transplant
Which Patients Should Be
Which Patients Should Be
Treated?
Treated?
AASLD Guidelines—2007 Update
AASLD Guidelines—2007 Update
Lok ASF, et al. Hepatology. 2007;45:507. Reprinted with permission of Wiley-Liss, Inc, a
subsidiary of John Wiley & Sons, Inc.
7
7
2007 AASLD Treatment
2007 AASLD Treatment
Guidelines on CHB for
Guidelines on CHB for
Patients Without Cirrhosis
Patients Without Cirrhosis
HBeAg
+
ALT <1 x ULN
ALT 1–2 x ULN
ALT >2 x ULN
Q 3–6 mo ALT
Q 6–12 mo HBeAg
Q 3 mo ALT
Q 6 mo HBeAg
Consider biopsy if
persistent or age
>40
Rx as needed
Q 1–3 mo ALT, HBeAg
Treat if persistent
Liver bx optional
Immediate Rx if
jaundice or
decompensation
Lok ASF, et al. Hepatology. 2007;45:507. Reprinted with permission of Wiley-Liss, Inc, a
subsidiary of John Wiley & Sons, Inc.
8
8
2007 AASLD Treatment
2007 AASLD Treatment
Guidelines on CHB for
Guidelines on CHB for
Patients Without Cirrhosis
Patients Without Cirrhosis
HBeAg –
ALT ≥ 2 x ULN
HBV DNA ≥ 20,000
IU/mL
ALT 1–2 x ULN
HBV DNA 2000-20,000
IU/mL
ALT < 1 x ULN
HBV DNA <2000
IU/mL
Treat if persistent,
Liver biopsy
optional
Q 3 mo ALT & HBV
DNA
Consider biopsy if
persistent
Rx as needed
Q 1–3 mo ALT x 3
Then Q 6–12 mo if
ALT still <1 x ULN
Lok ASF, et al. Hepatology. 2007;45:507. Reprinted with permission of Wiley-Liss, Inc, a
subsidiary of John Wiley & Sons, Inc.
9
9
Cirrhosis
Avoid use of IFN
or PEG IFN in
patients with
cirrhosis due to
risk of IFN-related
flares of
hepatitis.
Avoid use of IFN
or PEG IFN in
patients with
cirrhosis due to
risk of IFN-related
flares of
hepatitis.
Compensated
Decompensated
Refer for
liver transplant
Observe
Lok ASF, et al. Hepatology. 2007;45:507.
2007 AASLD Treatment
2007 AASLD Treatment
Guidelines
Guidelines
for Patients with Cirrhosis
for Patients with Cirrhosis
HBV DNA detectable
Compensated Decompensated
HBV DNA undetectable
HBV DNA
>2000 IU/mL
HBV DNA
<2000 IU/mL
Treat.
Adefovir or
entecavir
preferred
Consider
treatment if
ALT elevated.
Adefovir or
entecavir
preferred
Coordinate with
transplant center.
Treat.
Lamivudine/adefovir,
telbivudine/adefovir,
or entecavir preferred
10
10
Lok ASF, et al. Hepatology. 2007;45:507.
2007 AASLD Guidelines for
2007 AASLD Guidelines for
CHB
CHB
Treatment Recommendations
Treatment Recommendations
If criteria for treatment candidacy are met, treat with
If criteria for treatment candidacy are met, treat with
any of the approved 6 antiviral agents
any of the approved 6 antiviral agents
However, PEG IFN, adefovir, or entecavir are preferred
However, PEG IFN, adefovir, or entecavir are preferred
If cirrhosis, avoid IFN or PEG IFN
If cirrhosis, avoid IFN or PEG IFN
–
Adefovir or entecavir preferred for compensated
Adefovir or entecavir preferred for compensated
cirrhosis
cirrhosis
–
Lamivudine/adefovir combination preferred for
Lamivudine/adefovir combination preferred for
decompensated cirrhosis
decompensated cirrhosis
Telbivudine/adefovir or entecavir possible
Telbivudine/adefovir or entecavir possible
options but data lacking
options but data lacking
Refer all decompensated patients for liver
Refer all decompensated patients for liver
transplant
transplant
11
11
US Treatment Algorithm
US Treatment Algorithm
Updated Recommendations
Updated Recommendations
2006
2006
12
12
US Treatment Algorithm
US Treatment Algorithm
Update
Update
HBeAg Positive Without Cirrhosis
HBeAg Positive Without Cirrhosis
No treatment
Monitor every 6–12 months
Monitor every
3–12 months
(immune
tolerant)
Consider
biopsy, if age
>35–40 years;
treat if
significant
disease
Treat
ALT
elevated
ALT
normal
HBV DNA
≥20,000 IU
HBV DNA
<20,000 IU
ADV = adefovir; ETV = entecavir; PEG IFN =
pegylated interferon.
Keeffe EB, et al. Clin Gastroenterol Hepatol.
2006;4:936.
1 IU = 5.6 copies/mL
ADV, ETV,
or
PEG IFN
alfa-2a
1st-line
Telbivudine is FDA approved since
Telbivudine is FDA approved since
publication
publication
of guidelines and is a viable option.
of guidelines and is a viable option.
Telbivudine is FDA approved since
Telbivudine is FDA approved since
publication
publication
of guidelines and is a viable option.
of guidelines and is a viable option.
HBeAg positive
13
13
US Treatment Algorithm
US Treatment Algorithm
Update
Update
HBeAg Negative Without Cirrhosis
HBeAg Negative Without Cirrhosis
No treatment
Monitor every
6–12 months
Monitor ALT, or
Consider biopsy,
since ALT often
fluctuates; treat if
significant disease
Long-term treatment
required
Treat
Long-term
treatment
required for
oral agents
HBeAg
negative
ALT
elevated
ALT
normal
HBV DNA
≥2000 IU
HBV DNA
<2000 IU
Keeffe EB, et al. Clin Gastroenterol Hepatol.
2006;4:936.
ADV, ETV, or
PEG IFN alfa-
2a
1st-line
1 IU = 5.6 copies/mL
Telbivudine is FDA approved since
Telbivudine is FDA approved since
publication of guidelines and is a
publication of guidelines and is a
viable option
viable option
Telbivudine is FDA approved since
Telbivudine is FDA approved since
publication of guidelines and is a
publication of guidelines and is a
viable option
viable option
14
14
May choose to treat or
observe
Treat
HBV DNA
(PCR)
HBV DNA
<2000 IU
HBV DNA
≥2000 IU
US Treatment Algorithm
US Treatment Algorithm
Update
Update
Compensated Cirrhosis
Compensated Cirrhosis
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936.
Long-term treatment
recommended
ADV, ETV 1st-line
Consider combination therapy
1 IU = 5.6 copies/mL
Telbivudine is FDA approved since
Telbivudine is FDA approved since
publication of guidelines and is a viable
publication of guidelines and is a viable
option.
option.
Telbivudine is FDA approved since
Telbivudine is FDA approved since
publication of guidelines and is a viable
publication of guidelines and is a viable
option.
option.
15
15
Consider
treatment
(long-term
required)
Wait list for
transplant
HBV DNA <200 or
≥200 IU
US Treatment Algorithm
US Treatment Algorithm
Update
Update
Decompensated Cirrhosis
Decompensated Cirrhosis
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936.
Combination therapy with
LAM/ADV or possibly ETV
preferred
PEG IFN alfa-2a contraindicated
1 IU = 5.6 copies/mL
16
16
Treatment Options for
Treatment Options for
Chronic Hepatitis B Virus
Chronic Hepatitis B Virus
Infection
Infection
17
17
Current Therapeutic Options
Current Therapeutic Options
FDA-approved medications
FDA-approved medications
–
Adefovir dipivoxil (Hepsera
Adefovir dipivoxil (Hepsera
®
®
)
)
–
Interferon alfa-2b (Intron A
Interferon alfa-2b (Intron A
®
®
)
)
–
Entecavir (Baraclude
Entecavir (Baraclude
®
®
)
)
–
Lamivudine (Epivir
Lamivudine (Epivir
®
®
)
)
–
Peginterferon alfa-2a (Pegasys
Peginterferon alfa-2a (Pegasys
®
®
)
)
–
Telbivudine (Tyzeka
Telbivudine (Tyzeka
TM
TM
)
)
Medications approved for HIV infection, also active
Medications approved for HIV infection, also active
against HBV infection
against HBV infection
–
Tenofovir (Viread
Tenofovir (Viread
®
®
)
)
–
Emtricitabine (Emtriva
Emtricitabine (Emtriva
®
®
)
)
–
Emtricitabine/tenofovir (Truvada
Emtricitabine/tenofovir (Truvada
TM
TM
)
)
18
18
Factors to Consider in
Factors to Consider in
Initiating
Initiating
Anti-HBV Therapy
Anti-HBV Therapy
HBV DNA levels
HBV DNA levels
ALT levels
ALT levels
HBeAg status
HBeAg status
Cirrhosis vs no cirrhosis
Cirrhosis vs no cirrhosis
Compensated vs decompensated
Compensated vs decompensated
disease
disease
19
19
Lamivudine
Lamivudine
20
20
P
a
ti
e
n
ts
w
it
h
H
B
e
A
g
P
a
ti
e
n
ts
w
it
h
H
B
e
A
g
S
e
ro
c
o
n
v
e
rs
io
n
(
%
)
S
e
ro
c
o
n
v
e
rs
io
n
(
%
)
Duration of Therapy (Years)
Duration of Therapy (Years)
YMDD variant (n = 40 at year 5)
YMDD variant (n = 40 at year 5)
Non-YMDD variant (n = 18 at year 5)
Non-YMDD variant (n = 18 at year 5)
Total (n = 58)
Total (n = 58)
22
22
29
29
40
40
47
47
50
50
0
0
20
20
40
40
60
60
80
80
100
100
1
1
1
1
2
2
1
1
3
3
1
1
4
4
1
1
5
5
2
2
Lamivudine in HBeAg Positive CHB
Lamivudine in HBeAg Positive CHB
5-Year Asian Trial: HBeAg Seroconversion and YMDDm
5-Year Asian Trial: HBeAg Seroconversion and YMDDm
CHB = chronic hepatitis B.
1. Chang TT, et al. J Gastroenterol Hepatol. 2004;19:1276. 2. Guan R, et al. J Gastroenterol
Hepatol.
2001;16(suppl):A60. Adapted from Chang TT, el al. J Gastroenterol Hepatol. 2004;19:1276, with
permission from Blackwell Scientific Publications.
21
21
P
a
ti
e
n
ts
w
it
h
H
B
e
A
g
P
a
ti
e
n
ts
w
it
h
H
B
e
A
g
S
e
ro
c
o
n
v
e
rs
io
n
(
%
)
S
e
ro
c
o
n
v
e
rs
io
n
(
%
)
YMDD variant (n = 40 at year 5)
YMDD variant (n = 40 at year 5)
Non-YMDD variant (n = 18 at year 5)
Non-YMDD variant (n = 18 at year 5)
Total (n = 58)
Total (n = 58)
47
47
53
53
68
68
74
74
78
78
22
22
29
29
40
40
47
47
50
50
0
0
20
20
40
40
60
60
80
80
100
100
1
1
1
1
2
2
1
1
3
3
1
1
4
4
1
1
5
5
2
2
Lamivudine in HBeAg Positive CHB
Lamivudine in HBeAg Positive CHB
5-Year Asian Trial: HBeAg Seroconversion and YMDDm
5-Year Asian Trial: HBeAg Seroconversion and YMDDm
Duration of Therapy (Years)
Duration of Therapy (Years)
1. Chang TT, et al. J Gastroenterol Hepatol. 2004;19:1276. 2. Guan R, et al. J Gastroenterol
Hepatol.
2001;16(suppl):A60. Adapted from Chang TT, el al. J Gastroenterol Hepatol. 2004;19:1276, with
permission from Blackwell Scientific Publications.
22
22
P
a
ti
e
n
ts
w
it
h
H
B
e
A
g
P
a
ti
e
n
ts
w
it
h
H
B
e
A
g
S
e
ro
c
o
n
v
e
rs
io
n
(
%
)
S
e
ro
c
o
n
v
e
rs
io
n
(
%
)
YMDD variant (n = 40 at year 5)
YMDD variant (n = 40 at year 5)
Non-YMDD variant (n = 18 at year 5)
Non-YMDD variant (n = 18 at year 5)
Total (n = 58)
Total (n = 58)
10
10
18
18
26
26
33
33
38
38
47
47
53
53
68
68
74
74
78
78
22
22
29
29
47
47
50
50
0
0
20
20
40
40
60
60
80
80
100
100
1
1
1
1
2
2
1
1
3
3
1
1
4
4
1
1
5
5
2
2
Lamivudine in HBeAg Positive CHB
Lamivudine in HBeAg Positive CHB
5-Year Asian Trial: HBeAg Seroconversion and YMDDm
5-Year Asian Trial: HBeAg Seroconversion and YMDDm
40
40
Duration of Therapy (Years)
Duration of Therapy (Years)
1. Chang TT, et al. J Gastroenterol Hepatol. 2004;19:1276. 2. Guan R, et al. J Gastroenterol
Hepatol.
2001;16(suppl):A60. Adapted from Chang TT, el al. J Gastroenterol Hepatol. 2004;19:1276, with
permission from Blackwell Scientific Publications.
23
23
Adefovir
Adefovir
24
24
Adefovir in HBeAg Positive
Adefovir in HBeAg Positive
CHB
CHB
Virologic, Serologic, and Biochemical
Virologic, Serologic, and Biochemical
Response Over Time
Response Over Time
P
e
rc
e
n
ta
g
P
e
rc
e
n
ta
g
e
e
Marcellin P, et al. DDW; May 14-19, 2005. Poster M931. Reprinted with
permission from Dr. Patrick Marcellin.
Serum HBV DNA
Serum HBV DNA
<1000 copies/mL
<1000 copies/mL
29
29
40
40
48
48
0
0
10
10
20
20
30
30
40
40
50
50
60
60
70
70
80
80
90
90
48
48
96
96
144
144
Week:
Week:
ALT
ALT
Normalization
Normalization
63
63
73
73
80
80
48
48
96
96
144
144
14
14
33
33
46
46
HBeAg
HBeAg
Seroconversion
Seroconversion
48
48
96
96
144
144
Week 48 (n = 171)
Week 48 (n = 171)
Week 96 (n = 85)
Week 96 (n = 85)
Week 144 (n = 65)
Week 144 (n = 65)
25
25
Hadziyannis SJ, et al. Gastroenterology. 2006;131:1743.
Adefovir in HBeAg Negative
Adefovir in HBeAg Negative
CHB
CHB
Study Design
Study Design
Primary endpoint = histologic
Primary endpoint = histologic
improvement
improvement
Week 144
Week 144
liver biopsy
liver biopsy
(optional)
(optional)
185 HBeAg-
185 HBeAg-
negative
negative
patients
patients
randomized
randomized
Adefovir 10
mg/d
(n = 80)
Placebo
(n = 62)
Adefovir 10
mg/d
(n = 60)
Adefovir 10 mg/d
(n = 60 at wk 96; n = 55
at wk 144 and wk 240)
Week 0
Week 0
Placebo
(n = 40)
Adefovir group
Adefovir group
re-randomized
re-randomized
Adefovir 10 mg/d
(n = 80 at wk 96; n = 70
at wk 144 and wk 240)
Week 48
Week 48
liver
liver
biopsy
biopsy
Week 96
Week 96
liver
liver
biopsy
biopsy
(optional)
(optional)
Adefovir 10
mg/d
(n = 123)
Week 240
Week 240
Double-
Double-
blind
blind
Double-
Double-
blind
blind
Open-
Open-
label
label
Open-
Open-
label
label
26
26
Adefovir in HBeAg Negative
Adefovir in HBeAg Negative
CHB
CHB
Virologic and Biochemical Response
Virologic and Biochemical Response
Over Time
Over Time
P
e
rc
e
n
ta
g
e
P
e
rc
e
n
ta
g
e
Serum HBV DNA
Serum HBV DNA
<1000 Copies/mL
<1000 Copies/mL
72
72
80
80
77
77
0
0
10
10
20
20
30
30
40
40
50
50
60
60
70
70
80
80
90
90
48
48
96
96
144
144
Week:
Week:
ALT
ALT
Normalization
Normalization
75
75
74
74
71
71
48
48
96
96
144
144
73
73
192
192
73
73
192
192
240
240
240
240
Hadziyannis SJ, et al. Gastroenterology. 2006;131:1743.
67
67
69
69
27
27
Adefovir for HBeAg Negative
Adefovir for HBeAg Negative
CHB
CHB
5-Year Data: Fibrosis Scores
5-Year Data: Fibrosis Scores
Adefovir-adefovir group
Placebo-adefovir group
0
10
20
30
40
50
60
70
80
48
192
240
Weeks on Adefovir Dipivoxil
%
o
f
P
a
ti
e
n
ts
w
it
h
Im
p
ro
v
e
m
e
n
t
in
F
ib
ro
s
is
*
100
35%
40%
55%
71%
8/23
†
8/20
‡
12/22
17/24
*Improvement in fibrosis is at least a 1-point decrease in Ishak Fibrosis Score compared with
adefovir dipivoxil baseline.
†
These 23 patients at week 48 all had liver biopsies after 240 weeks of adefovir dipivoxil. Of 113
patients treated with adefovir dipivoxil in the double-blind phase of the study with biopsies at 48
weeks, 34% had improvement in fibrosis.
‡
13 of these patients had biopsies after 192 weeks of adefovir dipivoxil.
Hadziyannis SJ, et al. Gastroenterology. 2006;131:1743. Reprinted with permission Elsevier Inc.
28
28
Adefovir
Adefovir
Summary
Summary
1st oral medication and 1st nucleotide
1st oral medication and 1st nucleotide
approved by regulatory authorities for
approved by regulatory authorities for
the treatment of HBV
the treatment of HBV
Intermediate potency
Intermediate potency
Oral bioavailability not affected by food
Oral bioavailability not affected by food
No significant drug-drug interactions
No significant drug-drug interactions
Rare events of nephrotoxicity
Rare events of nephrotoxicity
Effective against lamivudine-resistant
Effective against lamivudine-resistant
mutants
mutants
29
29
Entecavir
Entecavir
30
30
Entecavir vs Lamivudine in
Entecavir vs Lamivudine in
Nucleoside-Naive HBeAg
Nucleoside-Naive HBeAg
Positive CHB
Positive CHB
Primary and Secondary Endpoints at
Primary and Secondary Endpoints at
Week 48
Week 48
Entecavir 0.5 mg QD (n =
Entecavir 0.5 mg QD (n =
354)
354)
Lamivudine 100 mg QD (n =
Lamivudine 100 mg QD (n =
355)
355)
Histologic
Histologic
Improvement
Improvement
(n = 314 with
(n = 314 with
evaluable histology
evaluable histology
in each group)
in each group)
72
72
62
62
0
10
20
30
40
50
60
70
80
P = NS
21
21
18
18
0
5
10
15
20
25
HBeAg Seroconversion
HBeAg Seroconversion
68
68
60
60
ALT Normalization
ALT Normalization
(<1 x ULN)
(<1 x ULN)
0
10
20
30
40
50
60
70
80
90
P < .01
P = .02
Chang TT, et al. N Engl J Med. 2006;354:1001.
P
a
ti
e
n
ts
(
%
)
P
a
ti
e
n
ts
(
%
)
P
a
ti
e
n
ts
(
%
)
P
a
ti
e
n
ts
(
%
)
P
a
ti
e
n
ts
(
%
)
P
a
ti
e
n
ts
(
%
)
31
31
P
a
ti
e
n
ts
A
c
h
ie
v
in
g
R
e
s
p
o
n
s
e
P
a
ti
e
n
ts
A
c
h
ie
v
in
g
R
e
s
p
o
n
s
e
(%
)
(%
)
36
36
0
0
1
1
0
0
2
2
3
3
0
0
4
4
5
5
0
0
6
6
7
7
8
8
1
1
0
0
20
20
3
3
0
0
40
40
5
5
0
0
60
60
70
70
80
80
Entecavir vs Lamivudine in
Entecavir vs Lamivudine in
Nucleoside-Naive HBeAg
Nucleoside-Naive HBeAg
Positive CHB
Positive CHB
Virologic Response at Week 48
Virologic Response at Week 48
67
67
HBV DNA < 300 Copies/mL
HBV DNA < 300 Copies/mL
(PCR)
(PCR)
Entecavir (ETV) 0.5 mg QD (n =
Entecavir (ETV) 0.5 mg QD (n =
354)
354)
Lamivudine (LAM) 100 mg QD (n =
Lamivudine (LAM) 100 mg QD (n =
355)
355)
P <
P <
.001
.001
Chang TT, et al. N Engl J Med. 2006;354:1001.
-6.9
-6.9
0
0
-1
-1
-2
-2
-3
-3
-4
-4
-5
-5
-6
-6
-7
-7
-5.4
-5.4
H
B
V
D
N
A
b
y
P
C
R
,
C
h
a
n
g
e
a
t
H
B
V
D
N
A
b
y
P
C
R
,
C
h
a
n
g
e
a
t
W
e
e
k
4
8
(
lo
g
W
e
e
k
4
8
(
lo
g
c
o
p
ie
s
/m
L
)
c
o
p
ie
s
/m
L
)
32
32
Entecavir vs Lamivudine in
Entecavir vs Lamivudine in
Lamivudine-Refractory HBeAg
Lamivudine-Refractory HBeAg
Positive CHB
Positive CHB
Co-primary Endpoints Through Week 48
Co-primary Endpoints Through Week 48
Entecavir (ETV) 1.0 mg QD (n =
Entecavir (ETV) 1.0 mg QD (n =
141)
141)
Lamivudine (LAM) 100 mg QD (n =
Lamivudine (LAM) 100 mg QD (n =
145)
145)
Sherman M, et al. Gastroenterology.
2006;130:2039.
Histologic
Histologic
Improveme
Improveme
nt*
nt*
Composite
Composite
Endpoint
Endpoint
†
†
55
55
28
28
55
55
4
4
0
10
20
30
40
50
60
70
80
90
100
P
P
< .0001
< .0001
P
P
< .0001
< .0001
*n = 124 and n = 116 with evaluable histology for ETV and LAM,
respectively.
†
HBV DNA <0.7 MEq/mL and ALT <1.25 x ULN.
P
a
ti
e
n
ts
A
c
h
ie
v
in
g
R
e
s
p
o
n
s
e
P
a
ti
e
n
ts
A
c
h
ie
v
in
g
R
e
s
p
o
n
s
e
(%
)
(%
)
-5.11
-5.11
0
0
-1
-1
-2
-2
-3
-3
-4
-4
-5
-5
-6
-6
-7
-7
-0.48
-0.48
H
B
V
D
N
A
b
y
P
C
R
,
C
h
a
n
g
e
H
B
V
D
N
A
b
y
P
C
R
,
C
h
a
n
g
e
a
t
W
e
e
k
4
8
(
lo
g
a
t
W
e
e
k
4
8
(
lo
g
c
o
p
ie
s
/m
L
c
o
p
ie
s
/m
L
)
)
33
33
HBV DNA
HBV DNA
<300
<300
Copies/mL
Copies/mL
19
19
1
1
ALT
ALT
Normalization
Normalization
(<1.25 x ULN)
(<1.25 x ULN)
61
61
15
15
0
0
10
10
20
20
30
30
40
40
50
50
60
60
70
70
80
80
90
90
100
100
P
P
= .06
= .06
8
8
3
3
Entecavir vs Lamivudine in
Entecavir vs Lamivudine in
Lamivudine-Refractory HBeAg
Lamivudine-Refractory HBeAg
Positive CHB
Positive CHB
Secondary Endpoints Through Week 48
Secondary Endpoints Through Week 48
Entecavir 1.0 mg QD (n =
Entecavir 1.0 mg QD (n =
141)
141)
Lamivudine 100 mg QD (n =
Lamivudine 100 mg QD (n =
145)
145)
HBeAg
HBeAg
Seroconversi
Seroconversi
on
on
P
P
< .0001
< .0001
P
P
< .0001
< .0001
Sherman M, et al. Gastroenterology.
2006;130:2039.
P
a
ti
e
n
ts
A
c
h
ie
v
in
g
R
e
s
p
o
n
s
e
P
a
ti
e
n
ts
A
c
h
ie
v
in
g
R
e
s
p
o
n
s
e
(%
)
(%
)
34
34
Entecavir vs Lamivudine in
Entecavir vs Lamivudine in
Nucleoside-Naive HBeAg
Nucleoside-Naive HBeAg
Negative CHB
Negative CHB
Primary and Secondary Endpoints at
Primary and Secondary Endpoints at
Week 48
Week 48
P
P
= .01
= .01
Histologic
Histologic
Improvement
Improvement
70
70
61
61
0
0
10
10
20
20
n = 296 for ETV and n = 287 for
n = 296 for ETV and n = 287 for
LAM
LAM
with evaluable baseline histology
with evaluable baseline histology
30
30
40
40
50
50
60
60
70
70
80
80
Lamivudine 100 mg QD (n =
Lamivudine 100 mg QD (n =
313)
313)
Entecavir 0.5 mg QD (n =
Entecavir 0.5 mg QD (n =
325)
325)
Lai C-L, et al. N Engl J Med. 2006;354:1011.
P
a
ti
e
n
ts
A
c
h
ie
v
in
g
R
e
s
p
o
n
s
e
P
a
ti
e
n
ts
A
c
h
ie
v
in
g
R
e
s
p
o
n
s
e
(%
)
(%
)
-5.0
-5.0
0
0
-1
-1
-2
-2
-3
-3
-4
-4
-5
-5
-6
-6
-7
-7
-4.5
-4.5
H
B
V
D
N
A
b
y
P
C
R
,
C
h
a
n
g
e
a
t
H
B
V
D
N
A
b
y
P
C
R
,
C
h
a
n
g
e
a
t
W
e
e
k
4
8
(
lo
g
W
e
e
k
4
8
(
lo
g
c
o
p
ie
s
/m
L
)
c
o
p
ie
s
/m
L
)
Noncompleter = failure analysis
Noncompleter = failure analysis
n = 314 for ETV and n = 287
n = 314 for ETV and n = 287
for LAM with week 48 results
for LAM with week 48 results
35
35
Entecavir vs Lamivudine in
Entecavir vs Lamivudine in
Nucleoside-Naive HBeAg
Nucleoside-Naive HBeAg
Negative CHB
Negative CHB
Secondary Endpoints at Week 48
Secondary Endpoints at Week 48
Entecavir 0.5 mg QD (n =
Entecavir 0.5 mg QD (n =
325)
325)
Lamivudine 100 mg QD (n =
Lamivudine 100 mg QD (n =
313)
313)
Lai C-L, et al. N Engl J Med.
2006;354:1011.
90%
90%
72%
72%
0
0
20
20
40
40
60
60
80
80
100
100
HBV DNA < 400 Copies/mL (PCR)
HBV DNA < 400 Copies/mL (PCR)
P
P
< .001
< .001
P
a
ti
e
n
ts
A
c
h
ie
v
in
g
P
a
ti
e
n
ts
A
c
h
ie
v
in
g
R
e
s
p
o
n
s
e
(
%
)
R
e
s
p
o
n
s
e
(
%
)
ALT
ALT
Normalization
Normalization
(<1.0 x ULN)
(<1.0 x ULN)
78
78
%
%
71%
71%
0
0
10
10
20
20
30
30
40
40
50
50
60
60
70
70
80
80
90
90
P
a
ti
e
n
ts
A
c
h
ie
v
in
g
P
a
ti
e
n
ts
A
c
h
ie
v
in
g
R
e
s
p
o
n
s
e
(
%
)
R
e
s
p
o
n
s
e
(
%
)
P
P
= .045
= .045
36
36
On-Treatment ALT Flares
On-Treatment ALT Flares
Entecavir vs Lamivudine
Entecavir vs Lamivudine
1. Yurdaydin C, et al. 40th EASL; April 13-17, 2005. Abstract 540. 2. Lai C-L, et al. N
Engl J Med. 2006;354:1011.
P
a
ti
e
n
ts
w
it
h
A
LT
F
la
re
P
a
ti
e
n
ts
w
it
h
A
LT
F
la
re
(%
)
(%
)
HBeAg Positive
HBeAg Positive
Lamivudine-Refractory
Lamivudine-Refractory
1
1
HBeAg Positive
HBeAg Positive
Treatment-
Treatment-
Naive
Naive
1
1
0.5
0.5
0
0
2
2
4
4
6
6
8
8
10
10
12
12
14
14
3
3
6
6
<1
<1
11
11
HBeAg Negative
HBeAg Negative
2
2
<1
<1
2
2
Note: Tx duration was 48 weeks for all
studies.
Entecavir 0.5 mg QD (n =
Entecavir 0.5 mg QD (n =
325)
325)
Lamivudine 100 mg QD (n =
Lamivudine 100 mg QD (n =
313)
313)
37
37
1. Shouval D, et al. 40th EASL; April 13-17, 2005. Abstract 529. 2. Lurie Y, et al. 40th
EASL;
April 13-17, 2005. Abstract 509. 3. Thomas HC, et al. 40th EASL; April 13-17, 2005.
Abstract 530.
Entecavir vs Lamivudine in
Entecavir vs Lamivudine in
Nucleoside-Naive HBeAg+/–
Nucleoside-Naive HBeAg+/–
CHB Trials
CHB Trials
Analyses of Combined Data
Analyses of Combined Data
Entecavir was superior to lamivudine in terms of
Entecavir was superior to lamivudine in terms of
histologic and virologic endpoints
histologic and virologic endpoints
1-3
1-3
–
Superiority was independent of baseline
Superiority was independent of baseline
demographic factors
demographic factors
1
1
–
Superiority was independent of baseline ALT
Superiority was independent of baseline ALT
levels and HBV genotypes
levels and HBV genotypes
2
2
Patients who achieved HBV DNA < 400 copies/mL
Patients who achieved HBV DNA < 400 copies/mL
and ALT
and ALT
< 1 x ULN were more likely to have histologic
< 1 x ULN were more likely to have histologic
response
response
3
3
38
38
1. Chang TT, et al. Hepatology. 2004;40:193A. 2. Sherman M, et al. Hepatology.
2004;40:664A.
3. Shouval D, et al. Hepatology. 2004;40:728A.
Entecavir vs Lamivudine
Entecavir vs Lamivudine
Summary
Summary
Entecavir was superior to lamivudine
Entecavir was superior to lamivudine
1-3
1-3
–
Histologic improvement
Histologic improvement
–
Reduction in HBV DNA levels
Reduction in HBV DNA levels
–
Normalization of ALT
Normalization of ALT
Entecavir and lamivudine had
Entecavir and lamivudine had
comparable safety profiles except for
comparable safety profiles except for
flares
flares
1-3
1-3
39
39
Peginterferon
Peginterferon
40
40
*P < .05 vs lamivudine
†
P < .01 vs lamivudine
‡
P < .001 vs
lamivudine
PEG IFN alfa-2a +/–
PEG IFN alfa-2a +/–
Lamivudine
Lamivudine
in HBeAg Positive CHB
in HBeAg Positive CHB
Response at Week 72
Response at Week 72
41
†
39
†
28
P
a
ti
e
n
ts
(
%
)
P
a
ti
e
n
ts
(
%
)
32
‡
27*
19
32* 34
†
22
0
0
10
10
20
20
30
30
40
40
50
50
60
60
70
70
80
80
90
90
100
100
HBeAg
HBeAg
Seroconversion
Seroconversion
1
1
HBV DNA < 100,000
HBV DNA < 100,000
Copies/mL
Copies/mL
1
1
ALT Normalization
ALT Normalization
1
1
PEG IFN
PEG IFN
alfa-2a
alfa-2a
(n = 271)
(n = 271)
PEG IFN
PEG IFN
alfa-2a
alfa-2a
+ lamivudine (n =
+ lamivudine (n =
271)
271)
Lamivudine (n = 272)
Lamivudine (n = 272)
1. Lau GKK, et al. N Engl J Med. 2005;352:268. 2. Fried MW, et al. 40th EASL; April 13–17, 2005. Abstract
488.
•
Increased HBV DNA suppression did not translate into improved HBeAg
Increased HBV DNA suppression did not translate into improved HBeAg
seroconversion
seroconversion
2
2
•
Increased HBV DNA suppression with combination therapy resulted in a lower
Increased HBV DNA suppression with combination therapy resulted in a lower
incidence of
incidence of
YMDD mutation than seen with lamivudine alone
YMDD mutation than seen with lamivudine alone
2
2
41
41
PEG
PEG
IFN
IFN
-
-
2a
2a
43
43
LAM
LAM
29
29
P
P
= .007
= .007
PEG IFN
PEG IFN
-2a
-2a
+ LAM
+ LAM
44
44
0
0
20
20
40
40
60
60
80
80
100
100
P
P
= .004
= .004
59
59
PEG
PEG
IFN
IFN
-
-
2a
2a
44
44
LAM
LAM
60
60
PEG IFN
PEG IFN
-2a
-2a
+ LAM
+ LAM
HBV DNA <20,000 Copies/mL
HBV DNA <20,000 Copies/mL
ALT Normalization
ALT Normalization
PEG
PEG
IFN alfa-2a +/– Lamivudine
IFN alfa-2a +/– Lamivudine
in HBeAg Negative CHB
in HBeAg Negative CHB
Posttreatment Responses (Week 72)
Posttreatment Responses (Week 72)
PEG IFN
PEG IFN
-2a
-2a
(n = 177)
(n = 177)
PEG IFN
PEG IFN
-2a
-2a
+ lamivudine
+ lamivudine
(n =
(n =
179)
179)
Lamivudine
Lamivudine
(n =
(n =
181)
181)
0
0
20
20
40
40
60
60
80
80
100
100
Reprinted from Marcellin P, et al. N Engl J Med. 2004;351:1206, with permission. Copyright
2004 Massachusetts Medical Society. All rights reserved.
P
a
ti
e
n
ts
(
%
)
P
a
ti
e
n
ts
(
%
)
P
a
ti
e
n
ts
(
%
)
P
a
ti
e
n
ts
(
%
)
42
42
PEG IFN alfa-2a +/– Lamivudine in
PEG IFN alfa-2a +/– Lamivudine in
HBeAg Negative CHB
HBeAg Negative CHB
Change in HBV DNA from Baseline
Change in HBV DNA from Baseline
PEG IFN
PEG IFN
-2a
-2a
(n =
(n =
177)
177)
PEG IFN
PEG IFN
-2a + lamivudine
-2a + lamivudine
(n
(n
= 179)
= 179)
Lamivudine
Lamivudine
(n =
(n =
181)
181)
On-treatment
On-treatment
Follow-up
Follow-up
M
e
a
n
H
B
V
D
N
A
M
e
a
n
H
B
V
D
N
A
(L
o
g
(L
o
g
1
0
1
0
C
o
p
ie
s
/m
L
)
C
o
p
ie
s
/m
L
)
2
3
4
5
6
7
Baseline 4
12 18 24 30 36 42 48
5
6
60
68 72
–
–
4
4
.
.
1
1
–
–
4.2
4.2
–
–
1
1
.
.
6
6
–
–
2
2
.
.
4
4
–
–
2
2
.
.
3
3
Week
Week
–
–
5.0
5.0
No. of patients
Peginterferon alfa-2a plus placebo
177 175 174176 176 174 174 170 164 166165 158 162 158145 165
Peginterferon alfa-2a plus lamivudine
179 174 176176 175 173 171 170 168 165169 161 163 164152 170
Lamivudine
181 179 181180 180 180 179 178 177 174162 159 160 150146 154
64
5
2
8
8
1
0
Reprinted from Marcellin P, et al. N Engl J Med. 2004;351:1206, with permission. Copyright
2004 Massachusetts Medical Society. All rights reserved.
43
43
Lau GKK, et al. N Engl J Med. 2005;352:2682. Marcellin P, et al. N Engl J Med.
2004;351:1206.
PEG + IFN alfa-2a /–
PEG + IFN alfa-2a /–
Lamivudine
Lamivudine
Adverse Events in HBeAg Positive
Adverse Events in HBeAg Positive
and
and
HBeAg NegativeTrials
HBeAg NegativeTrials
Withdrawals due to drug-related
Withdrawals due to drug-related
adverse events were low across all
adverse events were low across all
groups
groups
No new adverse events were reported
No new adverse events were reported
Addition of lamivudine did not alter
Addition of lamivudine did not alter
adverse events profile of peginterferon
adverse events profile of peginterferon
44
44
Peginterferon
Peginterferon
Summary
Summary
Defined treatment interval
Defined treatment interval
High rate of HBeAg seroconversion in
High rate of HBeAg seroconversion in
wild-type infection
wild-type infection
High rate of HBV DNA suppression in
High rate of HBV DNA suppression in
precore-mutant variant
precore-mutant variant
High rate of HBsAg seroconversion
High rate of HBsAg seroconversion
Significant adverse events profile
Significant adverse events profile
–
Better than or similar to that when
Better than or similar to that when
used to treat HCV infection
used to treat HCV infection
45
45
Telbivudine
Telbivudine
46
46
N = 687
Telbivudine (600 mg/d)
Telbivudine (600 mg/d)
2 years
2 years
Lamivudine (100 mg/d)
2 years
N = 680
Primary analysis
Final
analysis
Week 52
Week 104
Randomization
(1:1)
Lai C-L, et al. 57th AASLD 2006. Abstract 91. Reprinted with permission from Wiley-Liss,
Inc, a subsidiary of John Wiley & Son, Inc.
The GLOBE Study Design
The GLOBE Study Design
Entry criteria
Entry criteria
Chronic hepatitis B with compensated liver disease
Chronic hepatitis B with compensated liver disease
HBeAg positive (n = 921) or negative (n = 446)
HBeAg positive (n = 921) or negative (n = 446)
Serum HBV DNA > 10
Serum HBV DNA > 10
6
6
copies/mL by COBAS PCR
copies/mL by COBAS PCR
ALT ≥ 1.3 x ULN and <10 x ULN
ALT ≥ 1.3 x ULN and <10 x ULN
47
47
GLOBE Study Efficacy
GLOBE Study Efficacy
Results
Results
HBeAg Positive ITT Population
HBeAg Positive ITT Population
Telbivudine
(n = 458)
Lamivudine
(n = 463)
Week 52
Week 52
Week 104
Week 104
Week 52
Week 52
Week 104
Week 104
Therapeutic response (%)
75
75
64
64
67
67
48
48
HBV DNA ↓ from baseline
(mean log
10
)
-6.5
-6.5
-
-
5.7
5.7
-5.5
-5.5
-
-
4.4
4.4
HBV DNA nondetectable
by PCR (%)
60
60
56
56
40
40
39
39
ALT normalization (%)
77
70
75
62
HBeAg loss (%)
26
35
23
29
HBeAg seroconversion
(%)
22
30
21
25
Color
Color
designates P < .05, telbivudine vs lamivudine at week 104
Lai C-L, et al. 57th AASLD 2006. Abstract 91. Reprinted with permission from Wiley-Liss,
Inc, a subsidiary of John Wiley & Son, Inc.
48
48
Telbivudine
(n = 222)
Lamivudine
(n = 224)
Week 52
Week 104
Week 52
Week 104
Therapeutic response
(%)
75
78
77
66
HBV DNA ↓ from
baseline (mean log
10
)
-5.2
-5.2
-
-
5.0
5.0
-4.4
-4.4
-
-
4.2
4.2
HBV DNA nondetectable
by PCR (%)
88
88
82
82
71
71
57
57
ALT normalization (%)
74
78
79
70
Color
Color
designates P < .05, telbivudine vs lamivudine at week 104
GLOBE Study Efficacy
GLOBE Study Efficacy
Results
Results
HBeAg Negative ITT Population
HBeAg Negative ITT Population
Lai C-L, et al. 57th AASLD 2006. Abstract 91. Reprinted with permission from Wiley-Liss,
Inc, a subsidiary of John Wiley & Son, Inc.
49
49
Comparison of Approved
Comparison of Approved
Antiviral Therapies for CHB
Antiviral Therapies for CHB
IFN
Lamivudi
ne
Adefovir
Enteca
vir
Telbivudi
ne
PEG
IFN
Loss of serum
HBV DNA
HBeAg+
HBeAg–
37%
60%–70%
40%–44%
60%–73%
21%
51%
67%
90%
60%
88%
25%
63%
HBeAg
seroconversion
in HBeAg+
18% difference over
placebo
16%–21%
12%
21%
22%
27%–
32%
Loss of HBsAg in
HBeAg+
7.8%
<1%
0
2%
0
3%
Normalization of
ALT
HBeAg+
HBeAg–
23% difference over
placebo
60%–70%
41%–75%
60%–79%
48%
72%
68%
78%
77%
74%
39%
38%
Histologic
improvement
HBeAg+
HBeAg–
NA
NA
49%–56%
60%–66%
53%
64%
72%
70%
65%
67%
38%
48%
Side effects
Many
Negligible
Potential
nephrotoxi
city
Negligibl
e
Negligible
Many
Drug resistance
—
~20%, y 1
~70%, y 5
None, y 1
~29%, y 5
<1% up
to y 2
~25% up
to y 2
—
Not direct comparison trials. NA = not available.
Lok AS, et al. Hepatology. 2007;45:507. Reprinted with permission of Wiley-Liss, Inc, a
subsidiary of John Wiley & Sons, Inc.
50
50
Resistance to
Resistance to
Antiviral Agents
Antiviral Agents
51
51
Ben-Ari Z, et al. Am J Gastroenterol. 2003;98:151. Hoffman C, et al (eds). HIV Medicine
2006. Available at: www.HIVMedicine.com. Adapted from Locarnini S, et al. Antiviral Ther.
2004;9:679, with permission.
Antiviral Drug Resistance
Antiviral Drug Resistance
Genotypic resistance
Genotypic resistance
–
Emergence of novel
Emergence of novel
substitutions in the
substitutions in the
presence of agent
presence of agent
Phenotypic resistance
Phenotypic resistance
–
Decrease in
Decrease in
susceptibility level
susceptibility level
compared with a
compared with a
reference strain,
reference strain,
usually expressed as
usually expressed as
“fold change”
“fold change”
Viral breakthrough or
Viral breakthrough or
rebound
rebound
–
Confirmed increase in
Confirmed increase in
plasma HBV DNA ≥1
plasma HBV DNA ≥1
log
log
10
10
IU/mL from nadir
IU/mL from nadir
52
52
The Language of Treatment
The Language of Treatment
Failure
Failure
“Refractory” ≠ “Resistant”
“Refractory” ≠ “Resistant”
Treatment Refractory
Primary treatment failure
—
Failure to reduce
HBV DNA by ≥1 log
10
IU/mL within 3 months
—
Inadequate potency
—
A priori viral resistance
—
Noncompliance
—
Poor absorption
Treatment-Emergent Resistance
Secondary treatment failure
—
Caused by mutation(s) in
the DNA polymerase gene
—
Viral breakthrough
occurs with ≥1 log
10
IU/mL rise in HBV DNA
compared with nadir
in patients with an
initial treatment effect
—
Confirmed on
2 assessments at a
1-month interval
Locarnini S, et al. Antiviral Ther. 2004;9:679, with
permission.
53
53
Terminal protein
Spacer
Reverse transcriptase
RNase H
F G
A
C
D E
B
1
344
YM
DD
M
20
4V
or
I
M2
04
I
A181V
or T
N236TK241E
K318Q
V1
73
L
L
18
0M
M250
S202
T184
I169
Lamivudine-resistant mutations
Adefovir-resistant mutations
Entecavir-resistant mutations
(requires pre-existing M204I/V
mutation)
Telbivudine-resistant mutations
Mutations in the HBV
Mutations in the HBV
Genome Lead to Resistance
Genome Lead to Resistance
to Antiviral Therapies
to Antiviral Therapies
Courtesy of Dr. K. Kowdley.
54
54
Development of Antiviral
Development of Antiviral
Resistance Is
Resistance Is
Associated with Depth of Viral
Associated with Depth of Viral
Suppression
Suppression
Minimal Level of HBV DNA (Copies/mL)
*P < .001 vs the <10
1.7
group
Patients received lamivudine daily for >1 year
Ide T, et al. Am J Gastroenterol. 2003;98:2048.
100
75
50
25
0
100*
40*
0
<10
1.7
(n = 8)
10
1.7–2.5
(n = 5)
≥
10
2.6
(n = 11)
P
a
ti
e
n
ts
w
it
h
Y
M
D
D
M
u
ta
ti
o
n
s
(
%
)
55
55
4 Years of Therapy with
4 Years of Therapy with
Lamivudine
Lamivudine
(100 mg/d) for HBeAg
(100 mg/d) for HBeAg
Negative CHB
Negative CHB
P
a
ti
e
n
ts
(
%
)
Months
n = 23
n = 78
n = 45
n = 94
89
66
60
39
8
34
40
59
0
100
3–12
24
36
48
HBV DNA < 1000 copies/mL
Viral breakthrough
Gaia S, et al. Aliment Pharmacol Ther.
2004;20:281.
75
50
25
56
56
Adefovir Resistance Over 5
Adefovir Resistance Over 5
Years in HBeAg Negative CHB
Years in HBeAg Negative CHB
0
5
10
15
20
25
30
35
40
45
50
Year 1
Year 2
Year 3
Year 4
Year 5
Genotypic resistance (M)
Virologic resistance (VR) = M + virologic rebound
Clinical resistance (M + VR + ALT > 1 x ULN)
C
u
m
u
la
ti
v
e
P
ro
b
a
b
il
it
ie
s
(
%
)
C
a
lc
u
la
te
d
b
y
L
if
e
-T
a
b
le
A
n
a
ly
s
is
3 3
2
11
8
6
18
0
14
1
0
11
0
20
29
Hadziyannis SJ, et al. Gastroenterology. 2006;131:1743.
0
57
57
Colonno RJ, et al. 57th AASLD; October 27-31, 2006. Abstract 110. Reprinted with
permission from Wiley-Liss, Inc, a subsidiary of John Wiley & Son, Inc.
Entecavir Has Low Rate of
Entecavir Has Low Rate of
Resistance
Resistance
3-Year Treatment Data
3-Year Treatment Data
Only 1.1% cumulative rate of resistance over
Only 1.1% cumulative rate of resistance over
3 years in treatment-naive patients
3 years in treatment-naive patients
–
2 out of 3 patients did not have entecavir-
2 out of 3 patients did not have entecavir-
resistance mutations (ETVr)
resistance mutations (ETVr)
M204I/V mutations appear to be prerequisite
M204I/V mutations appear to be prerequisite
to development of ETVr
to development of ETVr
Virologic rebound was observed in 14 of 68
Virologic rebound was observed in 14 of 68
(20.6%) lamivudine-refractory patients treated
(20.6%) lamivudine-refractory patients treated
with entecavir
with entecavir
–
10 of the 11 rebounds analyzed showed
10 of the 11 rebounds analyzed showed
ETVr
ETVr
58
58
HBeAg Positive
HBeAg Negative
Analytic
Method
Telbivudi
ne
Lamivudi
ne
Telbivudi
ne
Lamivudi
ne
Per protocol
17.8%
30.1%
7.3%
16.6%
1 log above
nadir
21.6%
35.0%
8.6%
21.9%
Less resistance for telbivudine in all pairwise comparisons, P < .001
Lai C-L, et al. 57th AASLD; October 27-31, 2006. Abstract 91. Reprinted with permission
from
Wiley-Liss, Inc, a subsidiary of John Wiley & Son, Inc.
GLOBE Study of Telbivudine
GLOBE Study of Telbivudine
Cumulative Resistance at Year 2
Cumulative Resistance at Year 2
2 virologic breakthrough analyses; ITT population
2 virologic breakthrough analyses; ITT population
–
Per protocol: HBV DNA returns to >5 log, or
Per protocol: HBV DNA returns to >5 log, or
within 1 log of baseline
within 1 log of baseline
–
1 log above nadir
1 log above nadir
Resistance = breakthrough with resistance
Resistance = breakthrough with resistance
mutations
mutations
59
59
Lai C-L, et al. 57th AASLD; October 27-31, 2006. Abstract 91. Reprinted with
permission from Wiley-Liss, Inc, a subsidiary of John Wiley & Son, Inc.
GLOBE Study of Telbivudine
GLOBE Study of Telbivudine
Additional Resistance Findings
Additional Resistance Findings
Week 24 viral load predicts telbivudine resistance at
Week 24 viral load predicts telbivudine resistance at
year 2
year 2
80% of resistance from patients with viral load
80% of resistance from patients with viral load
>3 logs at week 24
>3 logs at week 24
–
Minimal resistance when PCR negative at week
Minimal resistance when PCR negative at week
24: 2% for HBeAg negative, 4% for HBeAg positive
24: 2% for HBeAg negative, 4% for HBeAg positive
No breakthrough with telbivudine in 1st 24 weeks
No breakthrough with telbivudine in 1st 24 weeks
M204I substitution in HBV Pol OR wild-type sequence
M204I substitution in HBV Pol OR wild-type sequence
has been found in all telbivudine patients with
has been found in all telbivudine patients with
confirmed virologic breakthrough
confirmed virologic breakthrough
–
Some M204I breakthrough patients have
Some M204I breakthrough patients have
secondary mutations of uncertain significance (no
secondary mutations of uncertain significance (no
breakthrough with these mutations alone)
breakthrough with these mutations alone)
60
60
Management of Antiviral-Resistant
HBV
Lamivudine resistance
Add adefovir or tenofovir
Stop lamivudine, switch to
emtricitabine/tenofovir*
Stop lamivudine, switch to entecavir
(pre-existing lamivudine-resistant
mutation predisposes to entecavir
resistance)
†
Adefovir resistance
Add lamivudine
†
Stop adefovir, switch to
emtricitabine/tenofovir*
Switch to or add entecavir*
†
Entecavir resistance
Switch to or add adefovir or tenofovir*
Telbivudine resistance
‡
Add adefovir or tenofovir
Stop telbivudine, switch to
emtricitabine/tenofovir
Stop telbivudine, switch to entecavir (pre-
existing telbivudine-resistant mutation
predisposes to entecavir resistance)
*
In HIV-coinfected persons; scanty in vivo data in non–HIV-infected persons.
†
Durability of viral suppression unknown, especially in patients with prior lamivudine
resistance.
‡
Clinical data not available.
Lok ASF, et al. Hepatology. 2007;45:507. Reprinted with permission of Wiley-Liss, Inc, a
subsidiary of John Wiley & Sons, Inc.
61
61
Conclusions and
Conclusions and
Clinical Recommendations
Clinical Recommendations
62
62
Deciding Whom to Treat
Deciding Whom to Treat
Anyone meeting AASLD Guidelines
Anyone meeting AASLD Guidelines
Modify using US Treatment Algorithm
Modify using US Treatment Algorithm
Although biopsy is not needed in most cases, it
Although biopsy is not needed in most cases, it
can be helpful in patients with mildly to
can be helpful in patients with mildly to
moderately elevated ALT and low HBV DNA
moderately elevated ALT and low HBV DNA
levels
levels
1
1
Confirm that patient is in “stable” state before
Confirm that patient is in “stable” state before
initiating treatment
initiating treatment
–
Repeatedly HBV DNA positive
Repeatedly HBV DNA positive
–
Stable HBeAg, HBeAb status
Stable HBeAg, HBeAb status
Able and willing to adhere to therapy
Able and willing to adhere to therapy
1. Lok ASF, et al. Hepatology. 2007;45:507.
63
63
Deciding How to Treat
Deciding How to Treat
First-line therapy: PEG IFN, adefovir, or entecavir
First-line therapy: PEG IFN, adefovir, or entecavir
preferred
preferred
–
Lamivudine and telbivudine have higher rates of
Lamivudine and telbivudine have higher rates of
resistance, especially for long-term treatment
resistance, especially for long-term treatment
For lamivudine resistance: combination therapy
For lamivudine resistance: combination therapy
preferred over monotherapy with adefovir or
preferred over monotherapy with adefovir or
entecavir
entecavir
Monitor on treatment; response unlikely if
Monitor on treatment; response unlikely if
–
HBV DNA >10
HBV DNA >10
4
4
after 12 weeks of lamivudine
after 12 weeks of lamivudine
–
HBV DNA >10
HBV DNA >10
6
6
after 12 months of adefovir
after 12 months of adefovir
–
No response to telbivudine at 6 months
No response to telbivudine at 6 months
64
64
Criteria to Guide Choice of
Criteria to Guide Choice of
Therapy
Therapy
Anticipated duration of therapy
Anticipated duration of therapy
–
Resistance profile important for oral agents
Resistance profile important for oral agents
–
Long-term treatment needed if HBeAg
Long-term treatment needed if HBeAg
negative
negative
Baseline viral load
Baseline viral load
–
Seroconversion unlikely with IFN if HBV DNA
Seroconversion unlikely with IFN if HBV DNA
>10
>10
8
8
Genotype
Genotype
–
Superior response to PEG IFN with genotype A
Superior response to PEG IFN with genotype A
Histology
Histology
–
PEG IFN to be avoided in cirrhotic patients
PEG IFN to be avoided in cirrhotic patients
65
65
1. Bruix J, et al. Hepatology. 2005;42:1208.
Monitoring Patients While
Monitoring Patients While
on Treatment
on Treatment
Assess serum HBV DNA and ALT levels every
Assess serum HBV DNA and ALT levels every
3–6 months for
3–6 months for
–
Response to therapy
Response to therapy
–
Potential development of resistance to antiviral
Potential development of resistance to antiviral
therapies
therapies
Assess HBeAg status in HBeAg positive patients
Assess HBeAg status in HBeAg positive patients
Initiate screening for HCC in high-risk patients
Initiate screening for HCC in high-risk patients
1
1
–
Asian men ≥40 years/women ≥50 years,
Asian men ≥40 years/women ≥50 years,
Africans >20 years, cirrhotics, those with family
Africans >20 years, cirrhotics, those with family
history of HCC, high HBV DNA, active hepatic
history of HCC, high HBV DNA, active hepatic
inflammation
inflammation
–
Ultrasound examination every 6–12 months
Ultrasound examination every 6–12 months