Optimal Management

of HBV:

A Partnership

Between

Primary Care and

Specialty Physicians

Primary Care

Specialist

Screening

Diagnostic testing
Identification of treatment

candidates

Initiation of treatment

On-treatment monitoring
Long-term follow-up for
disease activation
HCC screening

Vaccination

Hepatitis B:

An Important Disease

for Primary Care and

Specialty Physicians

Why Is HBV Relevant in

Primary Care?



High global impact

–

High prevalence in specific risk
groups

–

Risk of death/cancer



Effective prevention



Effective treatment

–

Improve liver disease outcomes

–

Decrease progression to cirrhosis
or HCC and improve survival

1. WHO. Hepatitis B. 2002. 2. Maynard JE, et al. In: Viral Hepatitis and
Liver Disease. New York: Alan R. Liss, Inc. 1988.
3. CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases. “The Pink
Book.” 8th ed. 4. CDC. MMWR. 2001;50:
RR-11.

Global Impact of HBV

A Significant Cause of

Worldwide Morbidity

and Mortality



>2 billion have been infected

1



4 million acute cases per year

1



1 million deaths per year

1



350 million chronic carriers

1

–

25% of carriers die from chronic active
hepatitis, cirrhosis, or liver cancer

1

–

Nearly 75% of chronic carriers are Asian

2



2nd most important carcinogen behind
tobacco

3



Causes 60%–80% of all primary liver cancer

1



HBV is 100 times more contagious than HIV

4

HBV

A Global Health Problem

1. WHO. Hepatitis B. 2002. 2. Custer B. et al. J Clin Gastroenterol.

2004;38(10 suppl):S158. 3. WHO/WPRO data.

HBsAg Prevalence (%)

1

<8: High

2–8: Intermediate

<2: Low

Country

HBsAg+ (%)

China

5.3–12

2

South
Korea

2.6–5.1

2

India

2.4–4.7

2

Taiwan

10–13.8

2

Viet Nam

5.7–10

2

Japan

4.4–13

3

Africa

5–19

2

Russia

1.4–8

2

Europe

0.3–12

2

HBV Disease Progression

Chronic

Infection

Cirrhosis

Death

Torresi J, et al. Gastroenterology. 2000;118:S83. Fattovich G, et al.

Hepatology. 1995;21:77.
Perrillo RP, et al. Hepatology. 2001;33:424.

Liver

Failure

Liver

Cancer

(HCC)

Liver

Transplanta

tion

Burden of HBV Infection

in the United States

New Acute Infections

per Year

1

73,000

Chronic

Infections

1

1,250,000

Deaths per

Year

1

5000

Liver Transplants

per Year

3

230

HCC per

Year

2

3100

1. CDC. HBV Disease Burden. 2005. 2. El-Serag HB, et al. Arch Intern Med.
2000;160:3227. 3. UNOS/OPTN.

Poor Survival in

HBV-Related Cirrhosis

1. Weissberg JI, et al. Ann Intern Med. 1984;101:613. 2. De Jongh FE, et al.
Gastroenterology. 1992;103:1630.

1

3

2

4

5

0

2
0

4
0

60

10
0

8
0

Cirrhosis

1

(n = 130)

Decompensated Cirrhosis

2

(n = 21)

14%

14%

55%

P

a

t

i

e

n

t

s

S

u

r

v

i

v

i

n

g

(

%

)

Years

0

HBV Is Preventable

Clinical-Epidemiologic

Correlations

Age of

Mode of

ESLD

HCC

Endemicity Location

Infection Transmission Chronicity

Risk

Risk

Low

N. America

Early

Percutaneous

Rare

Low

Low

W. Europe Adulthood

Sexual

High

Sub-Sahara

Birth

Perinatal

Likely

High

High

Far East

Toddler

Horizontal

CDC. MMWR. 1991;40(RR-13):1.

HBV Vaccine

Indications



Routine vaccination of infants

–

Regardless of mother’s HBsAg status

–

With HBIG for HBsAg positive mothers



Catch-up vaccination of children and

adolescents



Vaccination of adults with risk

factors for infection

–

High-risk sexual activity

–

Illegal injection drug use

–

Occupational exposure

–

Hemodialysis patients

–

Household contacts of infected

persons

HBIG = hepatitis B immune
globulin.

US Incidence of Viral

Hepatitis Infection Over

Time

CDC. Disease burden from viral hepatitis A, B, and C in the United
States. 2003.

Incidence of Hepatitis A, US

Incidence of Acute Hepatitis B, US

Incidence of Acute Hepatitis C, US

0

20

40

60

80

100

120

140

160

180

1990

1992

1994

1996

1998

2000

2002

2003

E

s

t

i

m

a

t

e

d

N

u

m

b

e

r

o

f

C

a

s

e

s

(

T

h

o

u

s

a

n

d

s

)

Year

1991

1993

1995

1997

1999

2001

HBV Vaccination

Effect on HCC Incidence and

Mortality*

Chang M-H, et al. N Engl J Med. 1997;336:1855.

*Nationwide vaccination in Taiwan, implemented 7/84

Incidence

0

0.2

0.4

0.6

0.8

1

1981–86

1986–90

1990–94

P

e

r

1

0

0

,

0

0

0

C

h

i

l

d

r

e

n

(

6

–

1

4

Y

e

a

r

s

)

0.7
0

0.57

0.36

P

e

r

1

0

0

,

0

0

0

C

h

i

l

d

r

e

n

(

6

–

1

4

Y

e

a

r

s

)

Mortality

0

0.2

0.4

0.6

0.8

1

1981–86

1986–90

1990–94

0.80

0.58

0.34

Screening for HBV

and Evaluating

Infected Patients

Who Should Be Screened?



Patients with abnormal ALT



Patients engaged in high-risk sexual behaviors



Injection drug users



Immigrants, refugees, or adoptees from areas of high

endemicity



Immunocompromised patients



Dialysis patients



Recipients of organ/tissue transplants or blood

transfusion



Household members or sexual partners of known HBV

carriers



Occupational exposure (healthcare workers, police, EMTs)



Inmates in long-term correctional facilities or residents

in institutions for the developmentally disabled



Pregnant women



Individuals infected with HCV or HIV

Adapted from CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases.
“The Pink Book.” 8th ed, 2005.
Lok ASF, et al. Hepatology. 2001;34:1225.

Lok ASF, et al. Hepatology. 2001;34:1225. Reprinted with permission of Wiley-
Liss, Inc, a subsidiary of John Wiley & Sons, Inc.

Prevalence of HBV Serologic

Markers in

Population Groups Who

Should Be Tested for HBV

Infection

Prevalence of HBV
Serologic Markers (%)
Population

HBsAg

Any Marker

Persons born in high endemic areas*

13 70–85

Men who have sex with men

6

35–80

Injection drug users

7

60–80

Dialysis patients

3–10

20–80

HIV infected patients

8–11

89–90

Pregnant females (USA)

0.4–1.5

Family/household and sexual contacts

3–6 30–60

*Africa; Southeast Asia, including China, Korea, Indonesia,
and the Philippines; the Middle East,
except Israel; South and Western Pacific Islands; the interior
Amazon River basin; and certain
parts of the Caribbean (Haiti and the Dominican Republic)

Screening Tests



HBsAg

–

If positive, indicates

infection



Anti-HBc

–

If positive, indicates HBV

exposure



Anti-HBs

–

If positive, indicates

immunity

Lok ASF, et al. Hepatology. 2001;34:1225. Tsai NCS, et al. Semin Liver
Dis. 2004;24(suppl 1):71.

History and Physical

Evaluation



Risk factors for coinfection



Alcohol use



Family history of HBV
infection and HCC



Physical findings of advanced
disease

–

Jaundice

–

Abdominal swelling

–

Upper GI bleeding

Assessment of

Liver Disease Severity



Liver disease activity, biochemical

–

ALT

–

AST



Liver function/synthetic testing

–

Albumin

–

Bilirubin

–

Prothrombin time (INR)



Ultrasonography: morphologic assessment

–

Liver size, contour, and

echogenicity

–

Splenomegaly

Lok ASF, et al. Hepatology 2001;34:1225. Tsai NCS, et al. Semin Liver Dis. 2004;24(suppl 1):71.
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87.

2nd-Phase Testing

in HBsAg+ Patients



Anti-HBc

–

IgG: if positive, indicates HBV exposure

–

IgM: if positive, indicates acute HBV



HBeAg

–

If positive, indicates active HBV replication

–

If negative



If HBV DNA negative, suggests HBV

replication is suppressed



If HBV DNA positive, most likely has

precore mutation



Anti-HBe



HBV DNA quantification

–

Quantitative level correlates with level of

HBV replication

Further Testing

for HBsAg+ Patients



HCV antibody in at-risk individuals



HIV antibody or RNA quantification
in
at-risk individuals



Consider screening for hepatitis
delta virus (HDV)
if adult-acquired HBV

–

Anti-HDV

–

Delta antigen

–

Delta RNA if any HDV testing is
available

Hepatitis Delta Virus (HDV)

Outcome

Clinical Scenario

 Risk of cirrhosis

and cancer

Chronic HDV/chronic HBV

 Risk of progressive

liver

disease

Acute HDV/chronic HBV

 Risk of acute

liver disease

Acute HDV/acute HBV

Who Are Treatment

Candidates?

Natural History of HBV

Infection

Inactiv

e

Carrier

<5%

HBeAg+

Chronic
Hepatit

is B

Adultho

od

Courtesy of W. Ray Kim, MD

Chen DS, et al . J. Gastroenterol Hep. 1993:8(5):470.
Seeff L, et al. N Engl J Med. 1987;316(16):965.

Immune

Toleran

ce

Cirrhosis

Early

Childho

od

>95%

HBeAg-

Chronic

Hepatitis B

Phases of Chronic HBV

Infection

*Precore mutant

†

Expert opinions vary as to this value

1IU = ~5 copies/mL

Lai CL, et al. Lancet. 2003:362:2089. Lok AS, et al. Gastroenterology.
2001;120:1828.

Immune Inactive HBeAg

HBeAg

Tolerant

HBsAg Positive

Negative

Phase

Carrier

CHB

CHB*

HBsAg

+

+

+

+

HBeAg

+

–

+

–

Anti-HBe

–

+

–

+

ALT

Normal

Normal





HBV DNA

>10

5

>10

4

<10

5

>10

4†

copies/mL copies/mL copies/mL copies/mL

HistologyNormal/Mild Inactive

Active

Active

HBV Disease Progression

Chronic

Infection

Cirrhosis

Death

1. Torresi J, et al. Gastroenterology. 2000;118:S83. 2. Fattovich G, et al. Hepatology. 1995;21:77.
3. Perrillo RP, et al. Hepatology. 2001;33:424.

5%–10%

1

Liver

Failure

30%

1

23% in 5 yr

2

Liver

Cancer

(HCC)

Chronic HBV is the

6th leading

indication of liver

transplantation in

the US

3

~5%

Liver

Transplanta

tion

Acute Flare

6% in 5 yr

2

HBeAg Negative Patients



HBeAg positive patients may

develop antibodies (anti-HBe)



When HBeAg is lost, 2 possible

scenarios

–

Inactive carrier (normal ALT,

low or negative HBV DNA level)

–

Precore mutant chronic HBV

(moderate

to high HBV DNA, elevated ALT)

Inactive Carriers



HBeAg negative, normal ALT,

low/negative

HBV DNA



“Healthy carriers” = oxymoron



All patients who are HBsAg

positive need ongoing monitoring

as part of management

–

Monitor for increased ALT or HBV

DNA every 6 months

–

Monitor for HCC in at-risk

groups

Sherman M. Semin Liver Dis. 2005;25:143.

Precore Mutant (HBeAg

Negative)

Chronic HBV



HBeAg negative, elevated ALT, moderate to

high HBV DNA



Usually result of mutation in precore or

basal core promoter regions of HBV



Potentially more severe and progressive

chronic disease



Longer, more aggressive (suppression of

HBV DNA) treatment needed



29% risk of adefovir resistance at 5 years

of therapy

1



Seen predominantly in genotypes B,C, and D

1. Borroto-Esoda K, et al. J Hepatol. 2006;44(Suppl 2):179.

HBV DNA and Prognosis

High viral load predicts



Progression of liver

disease

1



Cirrhosis

1



Cirrhosis-related

complications

2



HCC

1,3

–

Independent of HBeAg,

ALT,

and cirrhosis

3

1. Chen G, et al. Abstract 996. Presented at: AASLD 2004. 2. Yuan JH,
et al. J Viral Hepat. 2005;12:373.
3. Chen C-J, et al. JAMA. 2006;295:65.

Baseline HBV DNA Level and

Cumulative Incidence of

HCC

Entire Cohort

0

2

4

6

8

10

12

14

16

<300

300–<10

4

10

4

–<10

5

10

5

–<10

6

≥10

6

N = 3653, 13-year follow-up

C

u

m

u

l

a

t

i

v

e

I

n

c

i

d

e

n

c

e

o

f

H

C

C

(

%

)

Chen C-J, et al. JAMA. 2006;295:65.

HBV DNA (Copies/mL)

1.

3

1.3

7

3.5

7

12.17

14.89

1IU = ~5 copies/mL

Baseline HBV DNA Level and

Cumulative Incidence of HCC

Subgroup of Noncirrhotic HBeAg– Patients

with Normal ALT

0

2

4

6

8

10

12

14

16

<300

300–<10

4

10

4

–<10

5

10

5

–<10

6

≥10

6

N = 2925

C

u

m

u

l

a

t

i

v

e

I

n

c

i

d

e

n

c

e

o

f

H

C

C

(

%

)

Chen C-J, et al. JAMA. 2006;295:65.

HBV DNA (Copies/mL)

0.7

4

0.8

9

3.1

5

7.96

13.50

Baseline HBV DNA Level and
Relative Risk of Cirrhosis

Iloeje UH, et al, Gastroenterology. 2006;130:678.

0

10

<300

300–9.9x10

3

1.0–9.9x10

4

1.0–9.9x10

5

>10

5

N = 3582, 11-year follow-up

R

e

l

a

t

i

v

e

R

i

s

k

1

1.4

2.5

5.9

9.8

Adjusted for gender, age, smoking, alcohol consumption

HBV DNA (Copies/mL)

7
6

5

4

3

2

1

9

8

HBV DNA and Prognosis

Caveat

Low HBV DNA does not rule out risk



In HBeAg positive patients, HBV DNA
20,000 IU (<10

5

copies/mL) predicted better

histology

–

But 14.3% of patients with
HBV DNA 20,000 IU (<10

5

copies/mL) still

had fibrosis

1



In patients with cirrhosis, viral load was
the best predictor of complications

–

But even with HBV DNA 20,000 IU (<10

4

copies/mL) complications continued to
develop

2

1. Yuen MF, et al. Am J Gastroenterol. 2004;99:2031. 2. Yuan HJ, et al. J
Viral Hepat. 2005;12:373.

Candidacy for anti-HBV

Treatment

Principle

In general, a patient with chronic HBV is a
treatment candidate if there is evidence of



Liver disease (abnormal ALT) and



HBV replication (HBV DNA+)

When Do You Initiate

anti-HBV Therapy?



Parameters

–

HBV DNA levels >10

4-5

copies/mL

–

ALT levels >1–2 x ULN



Factors

–

HBeAg positive vs HBeAg

negative

–

Cirrhosis vs no cirrhosis

–

Compensated vs decompensated

disease

HBV DNA

HBeAg

(Copies/mL)

ALT

Management

+

>10

5

≤2 x ULN

Follow

+

>10

5

>2 x ULN

Treat

–

>10

5

>2 x ULN

Treat

–

–

≤2 x ULN

Follow

+/–

>10

5

Cirrhosis

If compensated, treat;

if decompensated*,

refer

for liver transplant

+/–

–

Cirrhosis

If compensated,

observe;

if decompensated*,

refer

for liver transplant

Which Patients Should Be

Treated?

AASLD Guidelines

1

1. Lok ASF, et al. Hepatology. 2004;39:857. Reprinted with permission of
Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc. 2. INTRON

®

A

(interferon alfa-2b) Product Information. Kenllworth, NJ: Schering
Corporation: 2004.
3. PEGASYS

®

(peginterferon alfa-2a) Product Information. Nutley, NJ: Hoffmann-

La Roche Inc.: 2004.

*Do not use interferon or peginterferon if the patient has
decompensated cirrhosis.

2,3

Specific treatment recommendations are

made elsewhere in this activity.

US Treatment Algorithm

Update

HBeAg Positive Compensated

Disease



No treatment



Monitor every 6–12 mo



Monitor every

3–12 mo

(immune

tolerant)



Consider

biopsy, if age

>35–40 y, and

treat if

significant

disease

Treat

HBeAg Positive

ALT

Elevated

ALT

Normal

HBV DNA

≥10

5

c/mL

HBV DNA

<10

5

c/mL

Courtesy of Emmet Keeffe, MD.
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.

US Treatment Algorithm Update

HBeAg Negative Compensated

Disease



No treatment



Monitor every 6–12 mo



Monitor ALT, or



Consider biopsy,

since ALT often

fluctuates, and

treat if

significant

disease



Long-term

treatment required



Treat



Long-

term

treatme

nt

require

d

HBeAg Negative

ALT

Elevated

ALT

Normal

HBV DNA

≥10

4

c/mL

HBV DNA

<10

4

c/mL

Courtesy of Emmet Keeffe, MD.
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.

May Choose to Treat or

Observe

Treat

HBV DNA

(PCR)

HBV DNA

<10

4

c/mL

HBV DNA

≥10

4

c/mL

US Treatment Algorithm Update

Compensated Cirrhosis

Courtesy of Emmet Keeffe, MD.
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.



Observe



Wait list for

transplant



Treat



Wait list for

transplant

HBV DNA

Detectable by PCR?

No

Ye

s

US Treatment Algorithm Update

Decompensated Cirrhosis

Courtesy of Emmet Keeffe, MD.
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.

Who May Not Need Referral

to a Specialist?

Noncirrhotic patients with

persistently normal ALT



Inactive carrier

–

HBeAg negative

–

DNA <10

4

–

Persistently normal ALT



Immune tolerant

–

HBeAg positive

–

Persistently normal ALT

Who Is Likely to Benefit

from Referral to a

Specialist?



HBeAg positive chronic hepatitis B

–

Abnormal ALT

–

DNA >10

5



HBeAg negative chronic hepatitis B

–

Abnormal ALT

–

HBV DNA may be variable



Cirrhosis

–

Regardless of HBeAg, DNA or ALT

status

*Upper limits of normal for a person with normal BMI, 17 for women
and 25 for men;

†

Treat any patient with cirrhosis who is NAT positive, refer to

specialist;

‡

Rule out fatty liver and other causes of CLD;

§

Consider

3–5 years. NAT = nucleic acid testing, such as PCR, bDNA or TMA.

Reprinted from Gish R. Clin Liver Dis. 2005;9:541, with permission
from Elsevier.

Management of Chronic HBV

Infection

ALT <17–25* U/L

ALT >17–25* U/L

DNA
<2000 IU/mL

Observe

†

Biopsy

‡

<10,0000 c/mL
DNA
>2000 IU/mL

Biopsy

Treat:

>10,000 c/mL

and treat ifeAg (+): >6 mo post Ag

seroC

active HBV

eAg (–): prolonged Rx

(at least 24 mo) beyond

NAT negative

§

(Consider

biopsy or use

noninvasive

testing to stage

disease)

Monitoring for Patients Not

Considered for Treatment



Check ALT every 3–6 months

–

If ALT is persistently

elevated, reevaluate for

treatment



HCC surveillance in relevant

population

Lok ASF, et al. Hepatology. 2001;34:1225. Lok ASF, et al. Hepatology. 2004;39:857.

Bruix J, Sherman M. Hepatology. 2005;42:1208. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.

HCC Surveillance Is Recommended for

the Following Groups of Patients (Level III)

Hepatitis B Carriers

Asian males ≥40 years
Asian females ≥50 years
All cirrhotic hepatitis B
carriers
Family history of HCC
Africans over age 20
For noncirrhotic hepatitis B
carriers not listed

above, the risk of HCC

varies depending on

the severity of the

underlying liver disease

and current and past

hepatic inflammatory

activity. Patients with

high HBV DNA

concentrations and those

with ongoing

hepatic inflammatory

activity remain at risk

for HCC.

Nonhepatitis B Cirrhosis

Hepatitis C
Alcoholic cirrhosis
Genetic hemochromatosis
Primary biliary cirrhosis
Although the following
groups have an

increased risk of HCC, no

recommendations

for or against surveillance

can be made

because a lack of data

precludes an

assessment of whether

surveillance would

be beneficial.

Alpha1-antitrypsin

deficiency

Nonalcoholic

steatohepatitis

Autoimmune hepatitis

1. Lok ASF, et al. Hepatology. 2001;34:1225. 2. Chevillotte G, et al. Gastroenterology. 1983;85:141.

3. Villa E, et al. Lancet. 1982;2:1243. 4. CDC. “The Pink Book.” 8th ed, 2005.

Counseling of

HBV-Infected Patients



Limit use of alcohol

1-3



Prevent transmission

1,4



Screen and vaccinate

sexual and

household contacts

1,4



Vaccinate against

hepatitis A

1

Treatment of

Hepatitis B

Primary Goal of anti-HBV Therapy

Preventing Cirrhosis, HCC, and Death

Durable Suppression

of HBV Replication

Treatment Goal

(Endpoints)



Remission of liver disease



Suppression of HBV



HBeAg positive HBV

–

Seroconversion



HBeAg negative HBV

–

Sustained suppression of
HBV DNA

Initial Therapy: What Are

the Therapeutic Options

and Considerations?



First-line therapy

–

Adefovir

–

Entecavir

–

Peginterferon alfa-2a



Lamivudine no longer considered

first-line therapy due to high

rate of resistance, except

in specific settings

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.

Peginterferon



Pegylated recombinant interferon alfa protein/immune
modulator



Subcutaneous injection, but less frequent than standard
interferon



Dual immunomodulatory and antiviral mode of action



Defined, finite treatment interval



High rate of HBeAg seroconversion in wild-type infection



High rate of HBV DNA suppression in precore mutant variant



High rate of HBsAg seroconversion



No reports of resistance mutations



Significant adverse events

–

Better than or similar to that when used to treat HCV

infection

Peginterferon

Considerations for Use



HBeAg positive

–

Response in genotype A better than B = C, better than D

1,2

–

ALT >80 IU/mL

2

–

HBV DNA <10

8

copies/mL

2

–

Compensated liver disease guidelines

3-6

–

Monoinfected

–

No psychiatric or medical contraindications



HBeAg negative

–

No specific genotype populations that benefit over others

7

–

Modest number of patients negative by PCR (20%) long term

7



Consider PEG IFN before nucleos(t)ide therapy due to defined
treatment intervals and
high HBeAg seroconversion rates



Should not be used in decompensated cirrhosis

8

1. Janssen HL, et al. Lancet. 2005;365:123. 2. Lau G, et al. N Engl J Med.

2005;352:2682. 3. Liaw YF, et al.

J Gastroenterol Hepatol. 2003;18:239. 4. De Franchis R, et al. J Hepatol.

2003;39:S3. 5. Lok AS, et al. Gastroenterology. 2001;120:1828. 6. Lok ASF, et

al. Hepatology. 2004;39:957. 7. Marcellin P, et al. Hepatology. 2005;42:580A.

8. PEGASYS® (peginterferon alfa-2a) Product Information. Nutley, NJ: Hoffmann-

La Roche Inc.: 2004.

Lamivudine



First oral nucleoside approved for
treatment of HBV



Cytidine nucleoside analog: inhibits
1st-strand DNA synthesis



Extensive database and publications

–

Half of patients who are HBeAg
positive undergo seroconversion by 5
years

1



Safety profile excellent except for
resistance



Risk of resistance is high (70%) at 4
years of therapy

2

–

Associated with flares and
decompensation

–

No longer a first-choice therapy due
to high rate of resistance

3

1. Guan R, et al. J Gastroenterol Hepatol. 2001;16(suppl):A60. 2. Lai CL, et
al. Clin Infect Dis. 2003;36:687. 3. Keeffe EB, et al. Clin Gatroenterol
Hepatol. 2006: In press.

Lai C-L, et al. Clin Infect Dis. 2003;36:687.

Lamivudine in CHB

Incidence of YMDD Mutants Over Time—

Integrated Phase 3 Data

0

20

40

60

80

100

Y

M

D

D

(

%

)

Year

1

24%

n =
426

Year

2

42%

n =

74

Year 3

53%

n =

58

Year 4

70%

n =

58

Adefovir



Adenosine nucleotide analog



First oral medication and first
nucleotide approved by regulatory
authorities for the treatment of HBV



Inhibits HBV DNA polymerase



Oral bioavailability not affected by food



No significant drug-drug interactions



Rare events of nephrotoxicity (overall
risk – low)



Effective against lamivudine-resistant
mutants



Long/indefinite duration

HEPSERA

®

Product Insert.

Safety of Adefovir

Dipivoxil

Over 4–5 Years



Resistance is 29% at 5 years of use in
HBeAg negative patients

1



Resistance is more likely if patients are
lamivudine resistant and switched to
adefovir

2



Renal safety

–

Infrequent (3%) increases in creatinine
≥0.5 mg/dL



Maximum value 1.5 mg/dL



Maximum increase 0.8 mg/dL

1. Borroto-Esoda K, et al. J Hepatol. 2006;44(Suppl 2):179.
2. Lee YS, et al. Hepatology. 2006;43:1385.
3. Hadziyannis S, et al. J Hepatol. 2006;44(Suppl 2):283.

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. 4.
Colonno RJ, et al. 56th AASLD. November 11–15, 2005. Poster 962.

Entecavir



Oral deoxyguanine nucleoside analog



Inhibits priming of HBV DNA polymerase, reverse
transcription of negative DNA strand from pregenomic RNA,
and synthesis of positive DNA strand



Superior efficacy to lamivudine

1-3



Comparable safety profiles except fewer ALT flares
compared with lamivudine

1-3



ETV-associated resistance

mutations were not observed in

nucleoside-naive, HBeAg positive, or negative studies

4



ETV-associated resistance mutations with rebound were
seen in 9%
of patients with previous lamivudine resistance during
second year
of therapy

4

ETV = entecavir.

Entecavir Phase 3 Studies

Histologic Endpoints–Primary

Efficacy Endpoint

Study 022*

HBeAg+

Study 027*

HBeAg–

Study 026

†

LVD-Refractory

ETV

0.5 mg

(n =

314)

LVD

100 mg

(n =

314)

ETV

0.5 mg

(n =

296)

LVD

100 mg

(n =

287)

ETV

1 mg

(n =

124)

LVD

100 mg

(n =

116)

Overall

histologic

improvement

72%

62%

70%

61%

55%

28%

Fibrosis no

worse

89%

82%

84%

79%

87%

70%

Necroinflammato

ry

>2-point

decrease

74%

64%

73%

64%

55%

32%

Ishak fibrosis

score

improvement

39%

35%

36%

38%

34%

16%

Primary analysis: only patients with evaluable baseline biopsy
included; missing/inadequate week-48 biopsy counted as failures.

*Treatment for 52 weeks up to 96 weeks for partial responders.

†

Treatment for 48 weeks for up to 96 weeks for partial

responders. ETV = entecavir; LVD = lamivudine.

FDA. Entecavir briefing document. February 10, 2005.

Entecavir Phase 3 Studies

Selected Secondary Efficacy

Endpoints

FDA. Entecavir briefing document. February 10, 2005.

*Treatment for 52 weeks up to 96 weeks for partial responders.

†

Treatment for 48 weeks for up to 96 weeks for partial

responders. ETV = entecavir; LVD = lamivudine.

Study 022*

HBeAg+

Study 027*

HBeAg–

Study 026

†

LVD-Refractory

ETV

0.5 mg

LVD

100 mg

ETV

0.5 mg

LVD

100 mg

ETV

1 mg

LVD

100 mg

HBV DNA PCR

<400 copies/mL

72%

42%

95%

77%

22%

1%

Log HBV DNA by

PCR (mean

change from

baseline)

-7.0

-5.5

-5.2

-4.7

-5.1

-0.5

HBeAg

seroconversion

21%

18%

NA

NA

8%

3%

ALT normalization

(<1 x ULN)

69%

61%

78%

71%

65%

17%

Current FDA-Approved

Nucleoside and Nucleotide

Treatment Options

(Not Head-to-Head Studies)

Lamivudine Adefovir

Entecavir
Resistance

~20%

~3%

~0%

Naive;

9% Lam-

R
E antigen seroconversion

~17%

~12%

~22%
Flares

Moderate

Low

Low

Viral suppression

4.5–5.5

3.5–5.5

5.2–7

(log reduction)
DNA negativity

32%–78%

21%–51%

69%–91%

Availability of long-term data 5 year

5 year

2 year
AEs

Rare

Rare

Rare

Lam-R = lamivudine resistance

Slide Courtesy of Robert G. Gish, MD.

Results Following

Suppression

of Viral Replication

Preventio

n of

Death,

Cirrhosis

, and HCC

Histologic

Improvement

Virologic

Response

Reduction

in:



HBV DNA



cccDNA

Serologic

Response



HBeAg loss



HBeAg

seroconversion



HBsAg loss and

seroconversion

Biochemical

and

Liver

Synthetic

Test

Improvement



ALT



Bilirubin,

INR,

Albumin

Summary



HBV infection is a worldwide epidemiologic
and clinical challenge



Screening at-risk individuals identifies
those with HBV infection



Pretreatment evaluation includes history,
physical exam,
and additional diagnostic testing



Candidates for anti-HBV treatment include
patients with active liver disease and high
levels of HBV replication



Refer HBsAg positive patients for treatment
with entecavir, adefovir, or peginterferon