New Developments in HBV
Treatment

CCO Independent Conference Coverage

of the 2005 Annual Meeting of the European Association for the
Study of Liver*

This program is supported by an unrestricted
educational grant from

*CCO is an independent medical education
company that provides state-of-the-art medical
information to healthcare professionals through
conference coverage and other educational
programs.

April 13-17, 2005
Paris, France

clinicaloptions.com

New Developments in HBV Treatment

About These Slides



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and attribution not be changed. Users are asked

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

These slides may not be published or posted

online without permission from Clinical Care

Options.



We are grateful to Daniel Shouval, MD, Hadassah

University Hospital, Jerusalem, Israel, who aided

in the content creation of these slides.

Disclaimer

The materials published on the Clinical Care Options Web site reflect the views of the

authors, not those of Clinical Care Options, LLC, the CME providers, or the companies

providing educational grants. The materials may discuss uses and dosages for

therapeutic products that have not been approved by the United States Food and Drug

Administration. A qualified healthcare professional should be consulted before using

any therapeutic product discussed. Readers should verify all information and data

before treating patients or using any therapies described in these materials.

Predictors of

Liver Disease Progression

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New Developments in HBV Treatment

REVEAL: Baseline HBV DNA
and Liver Disease Progression



REVEAL: prospective, multicenter, observational
cohort study

1991-1992: 7 Taiwanese townships

Individuals aged 30-65 years eligible

(N = 89,293)

HCC Analysis

HBsAg+ with BL HBV DNA

(n = 3851)

2004: 43,993 PYs follow-

up

176 HCC patients (4.5%)

HCC-free individuals enrolled

(n = 23,820)

Cirrhosis Analysis

(n = 3774)

2004: 42,115 PYs follow-

up

395 cirrhotic patients

(10.5%)

Excluded if cirrhotic within 6 months

Chen, et al. EASL 2005. Abstract 35.

Chen, et al. EASL 2005. Abstract 476.

Iloeje, et al. EASL 2005. Abstract 496.

clinicaloptions.com

New Developments in HBV Treatment

REVEAL: Relationship Between
Baseline Viral Load and
Cirrhosis



Baseline HBV DNA predicted progression to cirrhosis

–

Relationship independent of HBeAg status

Chen, et al. EASL 2005. Abstract 35.

Serum HBV DNA
(copies/mL)

Total

Patients

Cases of

Cirrhosis

Adjusted RR*

(95% CI)

P Value

HBeAg-Negative Patients

< 10

4

2132

104

1.0 (reference)

--

≥ 10

4

to < 10

5

631

55

1.9 (1.4 - 2.7)

< .001

≥ 10

5

451

96

4.9 (3.7 – 6.4)

< .001

HBeAg-Positive Patients

< 10

4

22

2

2.6 (0.6 – 10.5)

NS

≥ 10

4

to < 10

5

18

3

6.2 (1.9 – 19.5)

< .01

≥ 10

5

520

135

8.6 (6.6 – 11.2)

< .001

* Adjusted for gender, age, anti-HCV levels, smoking, and alcohol use.
NS, not significant

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New Developments in HBV Treatment

REVEAL: Relationship Between
Baseline HBV DNA Levels and
HCC



HCC incidence increased with increasing HBV baseline
viral load

–

HBV levels independent predictor of HCC in multivariate
analysis

Chen, et al. EASL 2005. Abstract 35.

HBV DNA
(copies/mL)

< 300

300 to <

10

3

1.0-9.9 x

10

4

1.0-9.9 x

10

5

≥ 1.1 x

10

6

Adjusted RR
(95% CI)

1.0

(ref)

0.9

(0.5-1.9)

2.4

(1.3-4.5)

7.2

(4.0-12.9)

11.6

(6.7-19.9)

P Value

--

NS

< .005

< .001

< .001

0

200

400

600

800

1000

1200

1400

145

113

315

952

1150

H

C

C

I

n

c

id

e

n

c

e

R

a

te

P

e

r

1

0

0

,0

0

0

clinicaloptions.com

New Developments in HBV Treatment

REVEAL: Relationship Between
Persistent Viremia and HCC
Incidence



Persistent HBV levels associated with greater risk of
HCC

–

Examined in those with levels ≥ 10

4

copies/mL at baseline (n =

1376)

Chen, et al. EASL 2005. Abstract 35.

Baseline HBV DNA,
copies/mL

< 10

4

≥ 10

5

≥ 10

5

≥ 10

5

Follow-up HBV DNA,
copies/mL

--

< 10

4

10

4

to < 10

5

≥ 10

5

Adjusted RR
(95% CI)

1.0

(reference)

3.6

(1.7-7.6)

6.9

(3.4-13.8)

9.1

(5.8-14.1)

P Value

--

< .001

< .001

< .001

0

2.0 x 10

3

4.0 x 10

3

6.0 x 10

3

8.0 x 10

3

1.0 x 10

4

1.2 x 10

4

1473

5882

8730

10,108

H

C

C

I

n

c

id

e

n

c

e

R

a

te

P

e

r

1

0

0

,0

0

0

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New Developments in HBV Treatment

REVEAL: Risk Factors for HCC



Several independent HCC risk factors identified in

multivariate analysis

–

Cigarette smoking had no significant effect

Chen, et al. EASL 2005. Abstract 35.

Risk Factor

Adjusted RR (95% CI)

P Value

Elevated baseline HBV DNA
 ≥ 10

5

copies/mL

 10

4

to < 10

5

copies/mL

6.4 (4.1-10.1)

2.5 (1.5-4.3 )

< .001

< .01

HBeAg-positive status

2.3 (1.6-3.3)

< .001

Male gender

2.1 (1.4-3.2)

< .01

ALT ≥ 1 x ULN

1.7 (1.2-2.6)

< .01

Alcohol use

1.6 (1.1-2.3)

< .05

Older age

1.10 (1.08-1.12)

< .01

ALT, alanine aminotransferase; RR, risk ratio; ULN, upper limit of normal

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New Developments in HBV Treatment

REVEAL: Summary of Key
Conclusions



Higher HBV DNA levels at baseline associated with
an increased risk of cirrhosis and hepatocellular
carcinoma



Continued viremia associated with an increased
risk for HCC



Elevated HBV DNA strongest predictor of HCC risk
in multivariate analysis

Issues for Transplant

Patients

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New Developments in HBV Treatment

HBV DNA Testing in Organ,
Tissue, and Cell Donors



11,155 samples organ, tissue and cell donors tested

–

Serologic markers evaluated: HBsAg, anti-HBc, anti-HBs



626 (5.6%) positive for

≥ 1 of 3 HBV serum markers



HBV DNA identified in

–

Most HBsAg-positive samples, mean = 2.0-3.3 IU/mL

–

1 cornea, 2 organ donors with 3 positive seromarkers

–

Corneas prone to false-negative and false-positive results

–

3.8% of organ donors, 9.5% of cornea donors positive for

anti-HBc

–

HBV-seronegative donors, prevalence, 0.07%

–

Confirmed in 1 of 8 brain-dead organ donors initially positive

Challine, et al. EASL 2005. Abstract 14.

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New Developments in HBV Treatment

HBV DNA Testing in Organ,
Tissue, and Cell Donors:
Conclusions



HBV-DNA detectable in most HBsAg+ donors

–

Usually low-level viremia



Presence of anti-HBc (alone) in donors associated with
HBV viremia in 3.8% to 9.5% of subjects



Systematic donor HBV DNA testing may be considered for
improving prevention of transplantation-transmitted HBV

–

However, prevalence of HBV DNA and level of viremia in
seronegative donors in Europe are low

–

Risk reduction of HBV transmission following HBV DNA
testing in seronegative organ donors remains to be proven



Post mortem HBsAg testing in cornea donors unreliable

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New Developments in HBV Treatment

Adefovir Treatment for LAM-
Resistant Patients Awaiting
Transplantation



226 patients with lamivudine-resistant HBV awaiting

OLT

–

Median MELD score, 12

–

CPT score ≥ 7, 60%



Adefovir 10 mg/day given in addition to ongoing

lamivudine



Median 96-week survival, 78%

–

Transplant no longer needed in 52% of patients at study

close

Schiff, et al. EASL 2005. Abstract 7.

Clinical Indicator

Week 24

Week 48

Week 96

Undetectable serum HBV DNA (< 1000

copies/mL), %

---

59

65

ALT normalization, %

---

77

77

CPT parameters, %

 CPT B

 CPT C

 Albumin normalization

 Bilirubin normalization

 Prothrombin time normalization

50

64

---

---

---

63

88

76

60

84

---

---

90

56

100

Mean MELD change

-2.8

-3.8

-5.1

Treatment with Adefovir

for Chronic Hepatitis B

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New Developments in HBV Treatment

Adefovir Treatment in HBeAg-
Positive Patients

Marcellin, et al. EASL 2005. Abstract 73.

Week 48

Open-label

phase

Adefovir 10

mg/day

(n = 171)

Significant

intermittent dosing

HBeAg(+)

Patients

(N = 338)

Placebo

(n = 167)

Week 96

Week 0

Open-label for

up to Week 144

Placebo

(n = 71)

Adefovir 10

mg/day

(n = 85)

Adefovir 10

mg/day

(n = 138)

Adefovir 10

mg/day

(n = 65)

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New Developments in HBV Treatment

Adefovir Treatment in HBeAg-
Positive Patients



Viral and biochemical response increased yearly with

adefovir

–

48% with undetectable HBV DNA at 3 years

–

80% with normal ALT at 3 years



HBeAg seroconversion

–

14% at 1 year and 46% at 3 years in adefovir group

–

HBeAg loss in 53% of patients at 3 years

Marcellin, et al. EASL 2005. Abstract 73.

Outcome, %

Response to Adefovir

Year 1

Year 2

Year 3

HBV DNA < 1000 copies/mL

29

40

48

ALT normalized

63

73

80

HBeAg seroconversion

14

33

46

HBeAg loss

23

46

53

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New Developments in HBV Treatment

Adefovir ± Lamivudine for
Lamivudine-Resistant, HBeAg-
Negative Patients



Patients on lamivudine added adefovir or switched to
adefovir monotherapy

Koskinas, et al. EASL 2005. Abstract 501.

HBeAg(-) patients

with lamivudine

resistance

(N = 50)

Adefovir dipivoxil 10 mg/day

(n = 28)

Adefovir dipivoxil 10 mg/day

+ Lamivudine 100 mg/day

(n = 22)

Week

48

Randomization

Week

0

24 weeks
follow-up

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New Developments in HBV Treatment

Adefovir ± Lamivudine for
Lamivudine- Resistant, HBeAg-
Negative Patients



Best virologic responses with adefovir + lamivudine

–

Adefovir also effective (undetectable HBV DNA at Wk 48,

46%)

–

ALT normalization similar between groups

Koskinas, et al. EASL 2005. Abstract 501.

-3

-2

-1

0

Week 24

Week 48

M

e

a

n

C

h

a

n

g

e

i

n

H

B

V

D

N

A

f

ro

m

B

a

s

e

li

n

e

,

lo

g

1

0

c

o

p

ie

s

/m

L

Adefovir + Lamivudine

Adefovir

-1.85

-2.31

-2.44

-2.80

P = .015

P = .020

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New Developments in HBV Treatment

Analysis of Adefovir Resistance
in Chronic Hepatitis B Patients



Pooled data from 5
studies



Development of
resistance

–

22 patients over 4 years

–

Only with ADV monotherapy



Higher HBV DNA
predictive of ADV
resistance

–

Analysis in HBeAg(-)
patients



Two resistance mutations



N236T

–

LAM susceptibility ↓ 2-fold in
vitro

–

Undetectable HBV DNA in 5
of 8 patients
adding/switching to LAM
within 1 year



A181V

–

LAM susceptibility ↓ 14-fold
in vitro

–

2-3 log

10

HBV DNA reduction

after > 6 months LAM + ADV

Locarnini, et al. EASL 2005. Abstract 36.

Week 48 HBV DNA
(log

10

copies/mL)

Week 144

Adefovir

Resistance, %

< 3

4

3-6

26

> 6

67

Treatment With Entecavir

for Chronic Hepatitis B

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New Developments in HBV Treatment

ETV-022: Sustained Response
After Treatment with Entecavir



ETV-022: International, randomized, double-blind,

phase 3 trial

Treatment-naive

patients positive

for HBeAg

(N = 709)

Entecavir
0.5 mg/day

(n = 354)

Lamivudine

100 mg/day

(n = 355)

1:1

Randomization

Week 0

Week 48

Liver biopsy

Off

treatment*

(n = 141)

*HBeAg-negative patients with HBV DNA < 0.7 MEq/mL by bDNA at Week 48 stopped treatment

Week 72

Current Analysis

(n = 74)

(n = 67)

Gish, et al. EASL 2005. Abstract 490.

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New Developments in HBV Treatment

ETV-022: Sustained Response
After Treatment with Entecavir



Greater sustained response 24 weeks post-treatment with

entecavir

–

Superior suppression of viral load

–

Superior sustained ALT normalization



Response by Week 24 on treatment predicted sustained

response off treatment

–

89% vs 76% for those not responding by Week 24 on

treatment

–

Early relapse more common in patients previously taking

lamivudine

Sustained Response Endpoint, %

Entecavir

(n = 74)

Lamivudine

(n = 67)

ALT < 1.25 x ULN

76

58

HBV DNA < 0.7 mEq/mL by bDNA, HBeAg loss

82

73

ALT < 1.25 x ULN, HBV DNA < 0.7 mEq/mL, HBeAg loss

73

57

bDNA, branched DNA assay; ULN, upper limit of normal

Gish, et al. EASL 2005. Abstract 490.

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New Developments in HBV Treatment

ETV Efficacy and Resistance in
Nucleoside-Naive Patients



Pooled data from HBeAg+/-,
nucleoside-naive patients



↓Wk 48 viral load for
entecavir

–

HBV DNA < 300 copies/mL, 81%



Viral genotyping: 76
emerging genetic changes

–

None found in > 0.6% of pts

–

No ↓ in entecavir sensitivity



Virologic rebound in 11 ETV-
treated patients, < 2%

Colonno, et al. EASL 2005. Abstract 478.

Percent of Subjects *

* Circle size corresponds to percentage of

patients. Each column of circles adds up to 100%.

n =

Entecavir

Lamivudine

10

3

300-999

< 300

10

9

10

10

≥10

11

10

4

10

8

10

7

10

6

10

5

81%

57%

H

B

V

D

N

A

,

c

o

p

ie

s

/m

L

676

Wk

0

0

48

48

655 665 621

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New Developments in HBV Treatment

Analysis of Entecavir Efficacy
and Resistance in LAM-
Refractory Patients



Pooled data of studies

comparing ETV and LAM



HBV DNA < 300 copies/mL

at Wk 48 with entecavir,

22%



5 entecavir patients with

HBV rebound

–

2 attributable to emergent

entecavir resistance

–

T184S/A or S202G



ETV resistance mutations in

6% of LAM-refractory ETV-

unexposed patients

Colonno, et al. EASL 2005. Abstract 478.

Percent of Subjects *

n
=

Wk

Entecavir

Lamivudine

10

3

300-999

<300

10

9

10

10

≥10

11

10

4

10

8

10

7

10

6

10

5

H

B

V

D

N

A

(

C

o

p

ie

s

/m

L

)

6%

22%

<1%

2%

* Circle size corresponds to percentage of

patients. Each column of circles adds up to 100%.

0

24 48 0 24 48

18

3

17

6

17

1

19

0

17

9

15

7

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New Developments in HBV Treatment

Mechanisms for Resistance:
Relationships Between LAM and
ETV



Entecavir and lamivudine have similar binding

sites on reverse transcriptase gene

Mechanism 1



Resistance mutations M204V and L180M reduce

size of binding pocket for both drugs



Mutations to residues T184 and S202 further

preclude entecavir entry into binding site

Mechanism 2



M250V mutations could alter drug binding or chain

termination mechanism created by entecavir

Colonno, et al. EASL 2005. Abstract 478.

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New Developments in HBV Treatment

Literature Review: Entecavir vs
Adefovir vs Lamivudine



26 articles included after 2-stage qualifying review

Dienstag, et al. EASL 2005. Abstract 481.

Response

ETV >

LAM

ETV =

LAM

ETV >

ADV

ETV =

ADV

LAM > ADV

LAM =

ADV

HBeAg-positive patients

Histology

improved

x

x

x

NI diminished

x

x

x

Fibrosis

diminished

x

x

x

Undetectable VL

x

x

x

ALT normalized

x

x

x

Anti-HBe

x

x

x

HBeAg-negative patients

Histology

improved

x

x

x

NI diminished

x

x

x

Fibrosis

diminished

x

x

x

Undetectable VL

x

x

x

ALT normalized

x

x

x

NI, necroinflammation; VL, viral load

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New Developments in HBV Treatment

Overview of Efficacy with
Current Treatments for
Hepatitis B



HBV DNA comparison at Yr 1

–

Mean drop, log

10

copies/mL

–

Entecavir, 5.20-6.98

–

Lamivudine, 4.66-5.46

–

Adefovir, 3.57-3.65



HBeAg seroconversion at Yr 1

–

Entecavir, 21%

–

Lamivudine, 18%

–

Adefovir, 12%



ALT normalization at Yr 1

Entecavir Trial AI463022.

Marcellin et al. New Engl J Med. 2003; 348:808-16.

We are grateful to Michael Manns, MD for synthesis of the data.

0

20

40

60

80

100

HBeAg +

Patients

HBeAg -

Patients

U

n

d

e

te

c

ta

b

le

H

B

V

D

N

A

(<

4

0

0

c

o

p

ie

s

/m

L

)

a

t

1

Y

r,

%

Adefovir Entecavir Lamivudine

21

51

69

91

38

73

0

20

40

60

80

100

HBeAg +

Patients

HBeAg -

Patients

A

LT

N

o

rm

a

li

z

a

ti

o

n

a

t

1

Y

r,

%

Adefovir Entecavir Lamivudine

48

68

60

72

78

71

Potential New Agents for

the Treatment of Hepatitis

B

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New Developments in HBV Treatment

Agents for Chronic HBV
Infection



Approved Antiviral Agents

–

Lamivudine

–

Adefovir

–

Interferon alfa

–

Entecavir (newly approved)



New Experimental Agents

–

Pegylated interferons

–

LB80380: LB80317 prodrug

–

Pradefovir: PME prodrug

–

Valtorcitabine: LdC prodrug



Further Experimental

Agents

–

Tenofovir

–

Clevudine

–

Telbivudine (LdT)

–

Emtricitabine



Combination therapy

–

Experimental

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New Developments in HBV Treatment

Predicting Response to
Peginterferon

Cooksley, et al. EASL 2005. Abstract 71.

Fried, et al. EASL 2005. Abstract 488.

HBeAg-positive patients

with chronic hepatitis B

(N = 814)

Peginterferon alfa-2a 180 µg/week

+ Placebo

(n = 271)

Peginterferon alfa-2a 180 µg/week

+ Lamivudine 100 mg/day

(n = 271)

Lamivudine 100 mg/day

(n = 272)

Week 48

YMDD Analysis

24 weeks
follow-up

Randomized

1:1:1

Week 72

Seroconversio

n Analysis

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New Developments in HBV Treatment

HBeAg Seroconversion Rates
According to Baseline
Characteristics



Highest seroconversion for

↑

ALT,

↓

viral load,

↓

HBeAg at

baseline

[1]

–

Superior seroconversion rates with PEG-based treatment

independent of previous treatment with interferon or

lamivudine

[2]

Cooksley, et al. EASL 2005. Abstract 71.

Lau, et al. EASL 2005. Abstract 31.

Baseline Variable

HBeAg Seroconversion Rate, n (%)

Peginterferon +

Placebo

(n = 271)

Peginterferon +

Lamivudine

(n = 271)

Lamivudine

(n = 272)

ALT, x ULN

 < 2

 2-5

 > 5

27/92 (29)

36/121 (30)

24/58 (41)

19/93 (20)

30/111 (27)

25/67 (37)

19/96 (20)

20/129 (16)

13/47 (28)

HBV DNA, log

10

copies/mL

 < 9.07

 9.07-10.26

 > 10.26

37/70 (53)

39/138 (28)

11/63 (17)

20/56 (36)

40/147 (27)

14/68 (21)

24/78 (31)

21/123 (17)

7/71 (10)

HBeAg, IU/mL

 < 30.69

 30.69-1294.04

 > 1294.04

35/65 (54)

35/135 (26)

16/67 (24)

24/64 (38)

30/133 (23)

20/73 (27)

27/73 (37)

16/135 (12)

7/61 (11)

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New Developments in HBV Treatment

LAM ± PEG: Viral Suppression
and HBeAg Seroconversion



Sustained HBeAg seroconversion rates highest with PEG

–

PEG alone,

32%

vs

PEG + LAM, 27%

vs

LAM alone, 19%



HBeAg seroconversion correlated with greater viral

suppression

–

Highest rates of suppression in patients on PEG + LAM

regardless of HBeAg status



Development of YMDD mutations by treatment end

significantly lower with PEG + LAM vs LAM monotherapy

–

11% vs 35%, respectively (P < .001)

Fried, et al. EASL 2005. Abstract 488.

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New Developments in HBV Treatment

HBeAg Seroconversion Rates
According to Genotype



> 50% response with PEG monotherapy in genotype A

patients

[1]



Similar seroconversion rates in genotypes B and C



Data similar to recently published report

[2]

–

Also higher rates with genotype B

HBV
Genotype

HBeAg Seroconversion Rate, n (%)

Peginterferon +

Placebo

(n = 271)

Peginterferon +

Lamivudine

(n = 271)

Lamivudine

(n = 272)

A

12/23 (52)

4/18 (22)

3/15 (20)

B

23/76 (30)

24/82 (29)

17/73 (23)

C

50/162 (31)

43/156 (28)

26/162 (18)

D

2/9 (22)

2/11 (18)

3/17 (18)

1. Cooksley, et al. EASL 2005. Abstract 71.

2. Janssen, et al. Lancet. 2005;365:123-129.

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New Developments in HBV Treatment

Sustained HBsAg
Seroconversion with
Peginterferon Therapy



Combined data from 2 large, randomized, multinational

trials

–

48 weeks therapy, 24 weeks follow-up (N = 1351)

–

Peginterferon alfa-2a 180 µg/wk

–

HBeAg(+), n = 271

–

HBeAg(-), n = 177

–

Lamivudine 100 mg/day

–

HBeAg(+), n = 272

–

HBeAg(-), n = 181

–

Peginterferon alfa-2a 180 µg/wk + Lamivudine 100 mg/day

–

HBeAg(+), n = 271

–

HBeAg(-), n = 179



HBsAg seroconversion evaluated at Week 72

–

24 weeks post-treatment

Hadziyannis, et al. EASL 2005. Abstract 491.

Marcellin, et al. NEJM. 2005; 351:1206-1217.

Cooksley, et al. EASL 2005. Abstract 71.

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New Developments in HBV Treatment

Sustained HBsAg
Seroconversion with
Peginterferon Therapy at Week
72



HBeAg-positive patients

–

Sustained seroconversion

superior in PEG-treated pts

–

No HBsAg seroconversion

in those without HBeAg

seroconversion



HBeAg-negative patients

–

Sustained seroconversion

superior in PEG-treated pts

–

Combined response:

–

ALT normalization and

HBV DNA < 20,000

copies/mL

Hadziyannis, et al. EASL 2005. Abstract 491.

0

5

10

15

20

25

Total

Pts with HBeAg

seroconversion

H

B

s

A

g

S

e

ro

c

o

n

v

e

rs

io

n

,

%

3%

3%

0%

8%

11%

0%

P = .

004 vs

LAM

H

B

s

A

g

S

e

ro

c

o

n

v

e

rs

io

n

,

%

0

5

10

15

20

2
5

Total

Combined

response

No combined

response

3%

2%

0%

6%

4%

0%

< 1%

0%

0%

PEG

PEG + LAM

LAM

P = .

03 vs

LAM

PEG

PEG + LAM

LAM

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New Developments in HBV Treatment

Chronic Hepatitis Treatment
With Peginterferon alfa-2b +
Adefovir



GS 01-522: single-center, open-label pilot study

–

Week 48 interim analysis

Wursthorn, et al. EASL 2005. Abstract 76.

Adefovir 10 mg/day +

Peginterferon alfa-2b 1.5

µg/kg/wk

Adefovir 10 mg/day

Week 0

Week 48

Week 144

Liver Biopsy

Liver Biopsy

Current Analysis

Planned

Chronic

hepatitis B

patients

(N = 26)

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New Developments in HBV Treatment

Chronic Hepatitis B Treatment
With Peginterferon alfa-2b +
Adefovir



Virology, serology, and

histology improved at Wk 48



Virologic outcomes

–

HBV DNA < 100 copies/mL,

52%

–

Mean drop in cccDNA, 2.2 log

10

copies/mL



ALT improvement, 84%

–

ALT normalization, 48%



Histologic improvement,

64%



Combination therapy

partially restored CD4+ T

cell response



Serologic response with

combined therapy

–

HBsAg seroconversion, 16%

–

HBeAg seroconversion,

38%

–

HBeAg loss, 23%



HBsAg seroconverters

tended to have:

–

Higher baseline ALT

–

Higher on-treatment ALT



Serum HBsAg change

correlated with cccDNA

change (P < .01)

Wursthorn, et al. EASL 2005. Abstract 76.

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New Developments in HBV Treatment

LB80380 for Lamivudine-
Resistant HBV



Phase 2, international, open-label, dose-escalation

study



LB80317 prodrug LB80380 (ANA380)

–

Phosphonate guanosine nucleotide analogue with anti-HBV

activity



40 patients with YMDD mutation recruited to 3 dosing

arms

–

Started at 30 mg/day, escalated to 60 mg and 90 mg once

daily

–

4 weeks LB80380 + lamivudine; 8 weeks LB80380 alone

–

12-week follow-up period

Lai, et al. EASL 2005. Abstract 72.

Week 12 Response

LB80380

30 mg

(n = 13)

60 mg

(n = 13)

90 mg

(n = 14)

ALT normalization, n

3

2

5

HBV DNA ↓ from baseline, log

10

copies/mL

-2.8

-3.2

-3.9

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New Developments in HBV Treatment

Pradefovir (Remofovir) for
Chronic Hepatitis B



Randomized, double-blind, multicenter, phase 1
study

Lau, et al. EASL 2005. Abstract 74.

Patients with chronic

compensated HBV

HBV DNA > 200

copies/mL

(N = 40)

Randomized

1:1:1:1:1

Day 28

Pradefovir 5 mg/day

(n = 8)

Pradefovir 10 mg/day

(n = 8)

Pradefovir 30 mg/day

(n = 8)

Pradefovir 60 mg/day

(n = 8)

Placebo

(n = 8)

12-week follow-up

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New Developments in HBV Treatment

Pradefovir for Chronic Hepatitis
B:
Interim Analysis of Phase 1
study



Dose-related HBV DNA decrease

–

2 log

10

decrease in 5-mg group

–

3 log

10

decrease in 60-mg group



Pharmacokinetics

–

Pradefovir mean half-life shorter (4-14 hrs) than PMEA (29-39 hrs)

–

Dose-related linear increase in AUC

0-24h

and C

max



Safety

–

No serious adverse events discontinuations, or dosage modifications

–

No significant renal effects

–

ALT flares in 2 patients for unknown reasons

–

Not associated with change in serum viral concentration or

HBeAg loss

Lau, et al. EASL 2005. Abstract 74.

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New Developments in HBV Treatment

Valtorcitabine for Chronic
Hepatitis B



57 HBeAg(+) pts given

placebo or Val-LdC

prodrugs

–

28 d Val-LdC/12 wk follow-

up



Greater HBV DNA reductions

with increasing doses

–

Emax modeling

–

Up to 900 mg/day



Optimal viral reduction with

900 mg/day 3’ monovalyl-

LdC

–

Mean HBV DNA change,

-3.04 log

10

copies/mL



Safety of valtorcitabine

prodrugs similar to placebo



No treatment-related

adverse events

Lim, et al. EASL 2005. Abstract 34.

Drug Administered

(mg/day)

Patients

Placebo

8

3', 5'-divalyl-LdC



50



100



200



400

6
6
6
6

3'-monovalyl-LdC



300



600



900



1200

7
6
6
6

LdC, L-deoxycitadine

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New Developments in HBV Treatment

Summary of Selected New
Agents
for Chronic Hepatitis B

Peginterferon

LB80380

(ANA380)

Pradefovi

r
(Remofovi

r)

Valorcitabine

-LdC

Drug

class

Interferon alfa 2a /2b

Nucleoside

analogue

Nucleotide

analogue

Novel nucleoside

Dosing

Injection

Oral

Daily oral

Daily oral

Current

analysis

Phase 1 to 3 for PEG alfa 2a.

Only pilot study on PEG alfa

2b.

Phase 2, dose-

finding, open-label

Phase 1,

placebo

Phase 1/2,

placebo, dose-

finding

Patients

HBeAg+/-

LAM-resistant;

HBeAg+, HBsAg+

HBeAg+/-

HBeAg+

Treatmen

t

Up to 48 wks

4 wks + LAM, then

8 wks as mono

4 wks

4 wks

Follow-up 48-72 wks

12 wks

12 wks

12 wks

Outcome

Good HBeAg seroconversion;

no advantage of combination

with nucleoside analogue

90mg/d:↓3.9 log

10

60 mg/d:
↓3.0 log

10

900 mg/d: ↓3.04

log

10

Safety

↓YMDD w/ PEG + LAM vs LAM No drug-related

AEs

↓ Renal

tox

No drug-related

AEs

Other

Best response: ↑ALT,↓HBV

DNA, ↓HBeAg at BL

ALT normalized in

some patients

Favorable

kinetics

Monovalyl-LdC

preferred

ADV, adefovir; AEs, adverse events; ALT, alanine aminotransferase; LAM,
lamivudine; NRTI, nucleoside reverse transcriptase inhibitor; Val-LdC,
valtorcitabine

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New Developments in HBV Treatment

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

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