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