Prof Eugene Schif

Diagnosis and Management
of Hepatitis at the Frontline

Chronic Hepatitis B

Patient Evaluation

and Clinical

Management

Prof Eugene R. Schif, M.D.

University of Miami, Florida,

USA

•

Incubation period:

Average 60–90

days

Range 45–180

days

•

Clinical illness (jaundice):

<5 yrs, <10%

>5 yrs, 30%–50%

•

Acute case-fatality rate: 0.5%–1%

•

Chronic infection:

<5 yrs, 30%–90%
>5 yrs, 2%–10%

•

Premature mortality from
chronic liver disease:

15%–25%

Hepatitis B – Clinical Features

Natural Course of CHB

HBeAg

Nuclear

Cytoplasm (++ ~)

(-)

(+++)

Membrane (++ ~)

HBsAg/preS

Membrane Cytoplasm (++ ~)

Cytoplasm (+++)

(+++)

Membrane (++ ~)

HLA-1

(-)

(++)

(++)

HBeAg

Nuclear

Cytoplasm (++ ~)

(-)

(+++)

Membrane (++ ~)

HBsAg/preS

Membrane Cytoplasm (++ ~)

Cytoplasm (+++)

(+++)

Membrane (++ ~)

HLA-1

(-)

(++)

(++)

Phase

Phase

Immune
Tolerance

Immune
Tolerance

Immune
Clearance

Immune
Clearance

Late/Residual

Late/Residual

Reactivation

Reactivation

Pre-C mutant

Pre-C mutant

HBV-DNA

HBV-DNA

HBeAg(+)

HBeAg(+)

anti-HBe(+)

anti-HBe(+)

HBsAg
Clearance

HBsAg
Clearance

ALT/Grading

ALT/Grading

HCC

HCC

Cirrhosis

Cirrhosis

20

20

40

40

60

60

Age

Age

Natural History of Chronic

Hepatitis B

•

Ranges from mild infection
(asymptomatic) to more severe chronic
liver disease

•

Fibrosis and subsequent cirrhosis

•

Liver failure

•

Hepatocellular carcinoma

•

Mortality

Healthy Liver

Liver Fibrosis

Cirrhosis

Liver Cancer

Natural History of Chronic HBV

Infection

Acute

Infection

Chronic

Chronic

Carrier

Carrier

Resolution

Resolution

30–50 Years

Chronic

Hepatitis

Stabilisatio

Stabilisatio

n

n

Progression

Progression

Cirrhosis

Compensated

Compensated

Cirrhosis

Cirrhosis

Liver

Cancer

Deat

h

Adapted from Feitelson, Lab Invest 1994

Decompensated

Decompensated

Cirrhosis

Cirrhosis

(Death)

(Death)

Chronic Hepatitis B: Definition

•

HBsAg+ for >6 months

•

Variable clinical course

•

Morbidity and mortality from chronic
necroinflammatory disease in liver

•

Disease progression is associated with
persistently high HBV replication

Predictors of Progression in

Chronic Hepatitis B

•

Bridging necrosis on liver biopsy

•

Persistence of HBeAg

•

Persistence of HBV DNA and elevated ALT
after HBeAg seroconversion (pre-core
mutation with HBeAg-negative CHB)

Predictors of Improved

Outcome in Chronic HBV

•

Loss of HBeAg

•

Associated with decreased viral replication

•

Improved survival

•

Persistently positive HBV DNA predicts pre-
core mutation and persistent chronic
hepatitis

•

Normalisation of ALT predicts better survival

•

Shorter duration of disease (age) predicts
survival

•

Extent of histologically-assessed liver damage
is also a predictor of survival

•

Mild

Raised ALT and/or AST only

•

More severe

Raised ALT/AST and raised

bilirubin

•

Severe, impending liver failure

Reduced albumin

Prolonged prothrombin time

Assessing Severity of Liver

Disease in Hepatitis B

Management of Chronic

Hepatitis B

•

Suppression of viral replication

•

Improvement in hepatic
necroinflammatory
disease

•

Reduction in long-term sequelae of
HBV-associated liver disease (cirrhosis,
hepatocellular carcinoma)

Goals of patient management

Antibodies to the

virus

•

Anti-HBc

•

Anti-HBe

•

Anti-HBs

Severity of liver

damage

•

Bilirubin

•

Albumin

•

Prothrombin time

Markers of the virus

•

HBV DNA

•

HBeAg

•

HBsAg

Markers of liver damage

•

ALT

•

AST

•

Bilirubin

Hepatitis B – Diagnostic

Tools

Never Been Exposed to Hepatitis

B

No viral markers

•

HBsAg

-

•

HBeAg

-

•

HBV DNA -

No immune
response to the
virus

•

Anti-HBc -

•

Anti-HBs -

•

Anti-HBe -

Sensitivity of HBV DNA Assays

Test

Method

Range of quantification

Dot blot

Rapid test

Abbott

Liquid hybridisation

Digene

RNA-DNA hybrid

Chiron

Branched DNA

Amplicor

Quantitative PCR

Monitor

10

6

10

5

10

3

10

2

10

4

Value of Serum HBV DNA

Assessment

•

Prognosis

•

Identification of viraemia irrespective of

HBeAg status

•

Therapy selection

•

Monitoring

–

Virological response to therapy

–

Disease progression

–

HBV replication after liver

transplantation

Acute Hepatitis

B

Full complement of
viral markers, all
present for
< 6 months

•

HBsAg

+

•

HBeAg

+

•

HBV DNA +

Some immune
response to the virus

•

Anti-HBc +

•

Anti-HBs -

•

Anti-HBe -

Evidence of acute
infection

•

Anti-HBc IgM

+

Acute Hepatitis B Virus Infection

with Recovery Typical Serologic

Course

Weeks after

exposure

Titer

Symptom
s

HBeAg

anti-HBe

Total anti-HBc

IgM anti-HBc

anti-HBs

HBsAg

0

4

8 12 16 20 24 28 32 36

52

100

Chronic Hepatitis B with

Evidence

of Viral Replication

Full complement of
viral markers, all
present for
>6 months

•

HBsAg

+

•

HBeAg

+

•

HBV DNA +

Some immune
response to the
virus

•

Anti-HBc +

•

Anti-HBs -

•

Anti-HBe -

No evidence of acute
infection

•

Anti-HBc IgM

-

Weeks after exposure

Titer

IgM anti-
HBc

Total anti-
HBc

HBsAg

Acute

(6

months)

HBeAg

Chronic

(years)

anti-HBe

0 4 8 12 16 20 24 28 32 36

52

Years

Progression to Chronic Hepatitis

B Virus Infection Typical

Serologic Course

Amrad Rapid Test

sAg/eAg positive

sAg positive

eAg positive

-ve

Test results

How to Monitor?

•

During therapy: ALT, HBeAg and or HBV-
DNA every 3 months

•

After therapy: ALT, HBeAg and or HBV-
DNA every 6 months

Possible Causes of ALT Rises

During Lamivudine Therapy

Hepatitis related

•

HBeAg seroconversion

•

Fluctuations in disease activity

Treatment related

•

Non compliance with medication

•

Emergence of YMDD variant HBV

Concomitant disease

•

Alcoholism

•

HAV, HCV infection

•

NASH

Does Emergence of YMDD

Variants Lead to Serum ALT

Elevations?

•

Reappearance of HBV (wild-type or
YMDD variant) may lead to a rise in
serum ALT which is usually
temporary and asymptomatic

•

Serum ALT rises accompanied by
evidence of hepatic decompensation
are rare

Serum ALT Elevations During

Treatment for 3 Years

Definition

LAM 100 mg (n=58)

n

%

2 x baseline ALT

22*

38

3 x baseline ALT

14

24

2 x baseline ALT & >500 ALT (U/L)

6

10

 2 x baseline ALT & >2 x ULN Bil &

 2 x baseline Bil

2

3

Leung et al., 1999

* 4 patients HBeAg-ve, HBeAb+ve and DNA-ve
6 patients HBeAg-ve, HBeAb+ve and DNA+ve

Management Options for Patients

with YMDD Variant and

Loss of Clinical Efficacy

0

10

20

30

40

50

60

70

80

Continue

Stop

Add

%

Survey of 110 European doctors, Vienna, March 2001

•

Continue lamivudine treatment

•

Stop lamivudine treatment

•

Additional antiviral agent - adefovir,

IFN

•

HBeAg seroconversion can still occur

•

Suppression of the wild-type virus is

maintained

•

Improvements in serum ALT and HBV DNA

are maintained in most patients

•

Histological improvement can be obtained

•

No significant increase in adverse events

Benefits of Continued Lamivudine

Therapy in Patients with

YMDD Variant CHB

Conclusions

•

In endemic areas, it is particularly important
for physicians to screen for HBV infection so
that treatment can be initiated before
advanced disease develops

•

An understanding of the serological
parameters of HBV and ALT elevations is
important in the management of
hepatitis B patients

•

Eradication of hepatitis B will come with
universal vaccination