CHRONIC HEPATITIS B

By:
PROF. DR Dr I DEWA NYOMAN WIBAWA SpPD-KGEH
Gastroentero-hepatology Div, Internal Medicine Dept, Udayana
Univ, Fac Of Medicine / Sanglah Hospital..
 CHRONIC HEPATITIS B
Histopathologycally characterized by necro-inflammation
& fibrosis in various degree and more than 6 months.

Classification (old):
Chronic persistent hepatitis (CPH)
Chronic lobular hepatitis (CLH)
Chronic active hapatitis (CAH)

New classification :
 CHRONIC HE PATITIS
AUTOIMMUNE AUTOIMMUNE TYPE 2
TYPE 1 (LUPOID) (LKM 1)

WILSON’S HEPATITIS
DISEASE
CHRONIC B±D
HEPATITIS

DRUGS HEPATITIS C

The spectrum of chronic hepatitis

Natural History and Diagnosis
Natural History of Chronic HBV Infection

Liver
Cancer
(HCC)

30% of
chronically
infected
individuals[2]
Acute Chronic Liver
Cirrhosis Death
Infection Infection Transplantation

 > 90% of infected

infants progress to
chronic disease[1]
Liver Failure
Chronic hepatitis B is
 < 5% of infected (Decompensation)
the 6th leading cause
immunocompetent
of liver transplantation
adults progress to 23% of patients decompensate within
in the US[4]
chronic disease[1] 5 yrs of developing cirrhosis[3]

1. CDC. HBV FAQs for health professionals. 2. T

orresi J, et al. Gastroenterology.2000;118(2 suppl 1):S83-S103. 3.
Fattovich G, et al. Hepatology.1995;21:77-82. 4. Seaberg EC, et al. Clin Transpl. 1998:17-37.
 Outcome of HBV Infection by Age of
Transmission

100 100
90%
Ch ro n ic In fectio n (% )

Predominantly
80 adult infection 80
in Western
Predominantly countries
60 neonatal infection 60
in Asia

40 40

25% to 30%
20 Chronic infection 20
Symptomatic infection
< 5%
0 0
Birth 1-6 Mo s 7-12 Mo s 1-4 Yrs Old er Ch ild ren
an d Ad u lts
StanfordAsian Liver Center. 2007 physician’s guide to hepatitis B: a silent killer.
Phases of Disease
 Stages of chronic HBV infection
Immune Immune Low replicative Reactivation
tolerance clearance phase phase
HBeAg + (wild) HBeAg - / anti-HBe + (PC/CP variants)
< >< >
>105 cp/ml
HBV-DNA <105 cp/ml
109-1010 cp/ml
107-108 cp/ml

ALT

Normal / moderate/severe CH Normal/mild CH moderate/severe CH

mild CH
cirrhosis Inactive cirrhosis cirrhosis

HBeAg + Inactive-carrier state HBeAg –

Chronic hepatitis Chronic hepatitis
 Phases of Chronic HBV Infection

HBeAg
Anti-HBe
HBV DNA

ALT

Immune clearance Reactivation

Immune Inactive
HBeAg-positive HBeAg-negative
tolerant carrier state
chronic hepatitis chronic hepatitis
0 20 40 60
Yrs
Yim HJ, et al. Hepatology. 2006;43:S173-S181.
 4 Phases of Chronic HBV Infection

 Immune-tolerance phase
- HBeAg positive; high HBV DNA (2 x 108-11 IU/mL); normal ALT
 HBeAg-positive chronic hepatitis (immune clearance)
- Intermediate to high HBV DNA (200,000 - 2 x 109 IU/mL); high or fluctuating
ALT; active inflammation on liver biopsy

 Inactive HBsAg carrier (low replication phase)

- HBeAg negative; low HBV DNA (< 2000 IU/mL); normal ALT
- HBsAg may become undetectable
 HBeAg-negative chronic hepatitis (reactivation phase)
- Intermediate to high HBV DNA (200,000 - 2 x 109 IU/mL); high or fluctuating
ALT; active inflammation on liver biopsy

Lok AS, et al. Hepatology. 2007;45:507-539.

Pungpapong S, et al. Mayo Clin Proc. 2007;82:967-975.
 Clinical Profiles of Chronic
HBV Infection

Immune HBeAg+ CHB Inactive HBeAg- CHB

Tolerant HBsAg Carrier (Precore Mutant)
HBsAg + + + +
HBeAg + + – –
Anti-HBe – – + +
ALT Normal  Normal 
> 20,000 IU/mL > 20,000 IU/mL < 200 IU/mL
> 2000 IU/mL
HBV DNA (> 105 (> 105 (< 103
(> 104 copies/mL*)
copies/mL) copies/mL) copies/mL)
*Expert opinions vary as to this value.
Histology Normal/mild Active Normal Active

Lai CL, et al. Lancet. 2003:362:2089. Lok AS, et al. Gastroenterology.

2001:120:1828.
Chronic Hepatitis B Disease Types

 HBeAg positive
- Also known as “wild type”
- Antibody to HBeAg negative
- HBV DNA > 20,000 IU/mL (> 105 copies/mL)
 HBeAg negative
- Also known as “precore mutant”
- Antibody to HBeAg positive
- HBV DNA > 2000 IU/mL (> 104 copies/mL)

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.

Chu CJ, et al. Gastroenterology. 2003;125:444-451.
 Differentiating HBeAg-Negative Chronic
Hepatitis B From Inactive Carrier State

Status HBeAg-Negative Disease Inactive Carrier

HBsAg positive  
Anti-HBe positive  
Anti-HBc positive  
HBV DNA Moderate, often fluctuating Low or undetectable; serum
levels; serum HBV DNA HBV DNA negative or
> 2000 IU/mL < 2000 IU/mL
ALT Elevated, Normal
often fluctuating levels

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

 Dynamic Nature of Carrier State

After spontaneous HBeAg seroconversion,

67% to 80% of carriers remain in inactive carrier phase

Immunotolerant Inactive carrier HBeAg-negative CHB

4% to 20% of inactive (Not healthy carrier) 10% to 20% have

carriers have reactivation after yrs of
reversion back to quiescence disease
HBeAg positive

Serial testing is necessary during the

“inactive carrier state”

LokAS, et al. Hepatology.2009;50:661-662.

 CLINICAL SYNDROME

 Most patients with are clinically asymptomatic.

 Some may have nonspecific symptoms such as
fatigue.
 In most instances, significant clinical symptoms will
develop only if liver disease progresses to
decompensated cirrhosis.
 In addition, extrahepatic manifestations may cause
symptoms.

Hepatology, A Clinical textbook 2014.

 CLINICAL SYNDROME

 physical exam will be normal in most instances.

 In advanced liver disease there may be clinical
signs of chronic liver disease such as
splenomegaly, spider angioma, caput medusae,
palmar erythema, testicular atrophy,
gynecomastia,etc.
 In patients with decompensated cirrhosis,
jaundice, ascites, peripheral edema, and
encephalopathy may be present.

Hepatology, A Clinical textbook 2014.

 Interpretation of Diagnostic Tests

Test HBsAg Anti-HBs Anti-HBc IgM HBV DNA

Anti-HBc
Acute infection, + - + + +
high infectivity
Recovery from - + + - -
infection
Immunization - + - - -
Chronic infection + - + - +/-
Unclear* - - + - -
*4 possibilities: 1) resolved infection (most likely), 2) false-positive anti-HBC, 3) “low level”
chronic infection, 4) resolving acute infection.
 Initial Testing in Patients Diagnosed
With Chronic HBV Infection

Testing for Patients Who Are HBsAg Positive[1]

Lab tests to assess liver disease: CBC, hepatic panel, and INR (prothrombin time)
Tests for HBV replication: HBeAg/anti-HBe, HBV DNA
Tests to rule out viral coinfections: anti-HCV, anti-HDV (in persons from countries
where HDV infection is common and in those with history of injection drug use),
and anti-HIV in those at risk
Tests for screening and surveillance for HCC: AFP and ultrasound as appropriate
Consider liver biopsy to grade and stage liver disease for patients who meet
criteria for chronic hepatitis

 Consider core and precore assays and testing for HBV genotype
 CDC guidelines recommend HIV testing in ALL chronic HBV patients[2]

1. Lok AS, et al. Hepatology. 2009;50:661-662.

2. Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.
TREATMENT
 GOALS OF TREATMENT

 Eliminate or significantly suppress HBV replication

 Prevent progression of liver disease to cirrhosis & liver
failure
 Prevention of HCC
 Improve survival
 Treatment endpoints
 Normalize ALT
 Decrease HBV DNA
 Induce HBeAg loss and seroconversion
 Improve histology
 Prevent and/or reverse decompensation

Keeffe et al., Clinical Gastroenterology and Hepatology 2004; 2:87-106.

Conjeevaram HS. J Hepatol. 2003;38:S90-S103
 Primary Goal of Hepatitis B Therapy:
Preventing Cirrhosis, HCC, and Death

Durable Suppression
of HBV Replication

Impact of viral suppression on liver disease outcomes

 Prolonged viral suppression is associated with
- Reduction in necroinflammation, fibrosis, and cirrhosis
- Reduction in decompensation
- Reduction in rates of HCC
- Reduction in mortality
 Treatment Goal for CHB

HBeAg positive CHB Signposts Goals of

treatment
Reduce Ant-HBe
Start serum
Normal HBeAg Sero- PCR HBsAg  Prevent
loss
Rx HBV DNA
ALT loss conversion negative
cirrhosis
 Prevent liver
failure
HBeAg negative CHB  Prevent HCC
 Improve
Start
Reduce
Normal PCR HBsAg survival
serum
Rx ALT negative loss
HBV DNA

Liver
inflammation and fibrosis
Treatment Options for Chronic HBV

Levamisole, Thymosin
Immunostimulants
+
TH
+ + TS
- Prednisone
+ TC

+ NK - Immunosuppressives

Interferon
+
-
- Nucleoside
1. Lamivudine
analogues 2. Adefovir
3. Telbivudin
4. Entecavir
5. Tenefovir
Treatment opportunity
Current Guideline Recommendations for First-
line Therapy

 Peginterferon alfa-2a
- Exceptions: pregnancy, chemotherapy
prophylaxis, decompensated cirrhosis
 Entecavir
 Tenofovir

EASL. J Hepatol. 2009;50:227-242.

Liaw YF, et al. Hepatol Int. 2008;2:263-283.
Lok AS, et al. Hepatology. 2009;50:661-662.
 Treatment Criteria for Chronic Hepatitis B

HBeAg + HBeAg-
Guideline HBV DNA ALT HBV DNA ALT
IU/mL U/L IU/mL U/L
NIH Consensus >2x ULN or ≥2x ULN or
>20,000 ≥20,000
Conference 2009a (+) biopsy (+) biopsy
EASL 2009b >2,000 > ULN >2,000 > ULN
US Algorithm >ULN or >ULN or
≥20,000 ≥2,000
2008c (+) biopsy (+) biopsy

APASL 2008d ≥20,000 >2x ULN ≥2,000 >2x ULN

>2x ULN or ≥2x ULN or

AASLD 2009e >20,000 ≥2,000
(+) biopsy (+) biopsy

aDegertekin B, Lok ASF. Hepatology 2009;49(S5):S129-S137.

bEuropean Association for the Study of the Liver J Hepatol 2009;50:227-242.
cKeeffe, EB et al. Clin Gastroenterol Hepatol 2008;6:1315-1341.
dYiaw Y-F et al. Hepatol Int 2008;2:263-283.
eLok ASF, McMahon BJ. Hepatology 2009; 45:507-539.
 Which drugs or strategy ?
 Recommendation 5: Patients can be treated:

IMMUNE-BASED THERAPY NUCLEOS/TIDEANALOGUE

1. Conventional IFN 5–10 MU 3 times 1. Entecavir 0.5 mg daily (I),
per week or 2. Adefovir 10 mg daily (I),
2. PegIFN-α2a 90–180 µg weekly (I), 3. eTlbivudine 600 mg daily (I), or
3. Thymosin α 1.6 mg 2 times per 4. Lamivudine 100 mg daily (I).
week can also be used (I).

Lamivudine is recommended if there is a concern regarding ensuing or

overt hepatic decompensation (II).
Entecavir and telbivudine may also be used in this situation (IV).

Liaw Y-F, et al. Hepatol Int (2008) 2:263–283

Who to Treat
 AASLD Guidelines for Chronic Hepatitis B
Treatment Initiation

HBeAg Positive HBeAg Negative

ALT < 1 x ULN ALT > 2 x ULN ALT < 1 x ULN ALT > 2 x ULN

Monitor patient HBV DNA HBV DNA HBV DNA

> 20,000 IU/mL < 2000 IU/mL ≥ 20,000 IU/mL

Treat if persistent Monitor patient Treat if persistent

ALT 1-2 x ULN ALT 1-2 x ULN

HBV DNA > 20,000 IU/mL HBV DNA

Consider biopsy if persistent 2000-20,000 IU/mL
or > 40 yrs; treat if needed Consider biopsy; treat if needed

Lok AS, et al. Hepatology. 2007;45:507-539.

 Treatment Criteria for Chronic Hepatitis B

 Recommended HBV DNA and ALT levels outlined in the following

table

HBeAg Positive HBeAg Negative

Liver Society
Guidelines* HBV DNA, ALT HBV DNA, ALT
IU/mL IU/mL
EASL 2009[1] > 2000 > ULN† > 2000 > ULN†
APASL 2008[2] ≥ 20,000 > 2 x ULN† ≥ 2000 > 2 x ULN†
> 2 x ULN‡ or ≥ 2 x ULN‡ or
AASLD 2009[3] > 20,000 ≥ 20,000**
(+) biopsy (+) biopsy

*Although ALT and HBV DNA are primary tests used to determine treatment candidacy, the levels of
elevation that warrant consideration of treatment are not universally agreed upon.
†Laboratory normal.
‡30 U/L for men and 19 U/L for women.

**In patients older than 40 yrs of age, 2000 IU/mL should be considered as a cutoff for treatment.

1. EASL. J Hepatol. 2009;50:227-242.

2. Liaw YF, et al. Hepatol Int. 2008;3:263-283.
3. Lok ASF, McMahon BJ. Hepatology. 2009;50:661-662.
What to Treat With
 Therapy for Chronic Hepatitis B: 2008

2008 and
1992 1998 2002 2005 2006 beyond…

IFN alfa LAM ADV ETV LdT TDF

Clevudine*
PegIFN alfa-2a
Combination Rx?
“The New Era”
Oral therapy

*not FDAapproved for the treatment of HBV

The First Branch Point in Choosing
What to Treat With

Decision to treat

IFN Nucleos(t)ide
(PegIFN alfa-2a) analogues
 Advantages and Disadvantages of
PegIFN

Pro Con
Finite course of therapy Subcutaneous administration
No resistance Adverse effects
HBeAg loss “catches up”
with
Higher rate of HBeAg loss in
> 1 year oral drugs;
1 year vs oral drugs
prolonged IFN use not
feasible
Potential for HBsAg clearance HBsAg clearance also occurs
with short duration therapy with oral agents
 When to Consider PegIFN

 Favorable predictors of response

 Genotype A or B > C or D
 Low HBV DNA
 High ALT
 Specific patient demographics
 Generally young people
○ Young woman wanting future pregnancy
 Absence of comorbidities
 Patient preference
 Concomitant HCV infection
Selecting Between Recommended First Line
Nucleos(t)ide and Interferon Therapy

Nucleos(t)ides Interferon-Based Therapy

Feature Pro Con Pro Con
Long term/
Administration Oral Finite duration Subcutaneous
indefinite
Low durable rates
Antiviral activity High
DNA suppression
Very low
Resistance No
resistance†
Rare renal tox
Adverse events Minimal Substantial*
with nucleotide
HBeAg loss and HBeAg loss  Lower rates vs Higher rates vs HBeAg loss ≠ HBV
clearance over time IFN nucles(t)ides DNA suppression
HBsAg loss and Higher and High rates (select Low rates in general
Low rates
clearance earlier events† populations) patient groups
May induce HIV
Other Anti HIV (TDF) resistance Anti HCV/HDV
(TDF/ETV)
*Prolonged treatment not feasible. † Newer vs older nucles(t)ides.
 Treatment of
HBeAg-Positive
Patients
Recommendations for Treatment Initiation in
HBeAg-Positive Patients

AASLD 2007[1] US Algorithm 2008[2] EASL 2009[3]

HBV DNA, IU/mL > 20,000 > 20,000 ≥ 2,000
ALT, x ULN* >2 >1 >1
Moderate/severe necroinflammation
Disease stage/grade
and/or significant fibrosis
ADV,† ETV, ETV, TDF, ETV, TDF,
First-line therapy
pegIFN pegIFN pegIFN

*Persistent (> 3-6 mos). †TDF not FDA approved at time of publication.

 Criteria for HBV DNA,AL

T and disease stage/grade must all be met

– If not, guidelines recommend monitoring and consideration of treatment based on individual’s age,
health status, and stage of infection/disease

1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-
1341. 3. EASL HBV Guidelines. J Hepatology. 2009;50:227-242.
 HBV Patients With Compensated
Disease in 2008: HBeAg Positive

HBeAg positive

HBV DNA HBV DNA

< 20,000 IU/mL ≥ 20,000 IU/mL

ALT
ALT normal
elevated
 No treatment
 Monitor every 6-12
months
 Treat to HBeAg
 Monitor ALT every 3-12 seroconversion
months (immune tolerant)  ETV, TDF, and pegIFN are
 Consider biopsy, if age is first-line options
> 35-40 years and treat if
significant disease

Keeffe EB, et al. DDW 2008. SP198. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.
 Treatment of
HBeAg-Negative
Patients
 Recommendations for Treatment Initiation in
HBeAg-Negative Patients
AASLD US Algorithm
EASL 2009[3]
2007[1] 2008[2]
HBV DNA, IU/mL > 20,000‡ > 2000 ≥ 2000
ALT, x ULN* 1 to > 2 >1 >1
Disease Moderate/severe necroinflammation
stage/grade and/or significant fibrosis
ADV,† ETV, ETV, TDF, ETV, TDF,
First-line therapy
pegIFN pegIFN pegIFN
*Persistent (> 3-6 mos). †TDF not FDA approved at time of publication. ‡ Consider liver biopsy if > 2000
IU/mL and treat if moderate/severe inflammation and/or fibrosis found.

 Criteria for HBV DNA,AL

T and disease stage/grade must all be met

– If not, guidelines recommend monitoring and consideration of treatment based on individual’s age, health status, and
stage of infection/disease

1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 3. EASL HBV
Guidelines. Journal of Hepatology. 2009;50:227-242.
 HBV Patients With Compensated
Disease in 2008: HBeAg Negative

HBeAg negative

HBV DNA HBV DNA

< 2000 IU/mL ≥ 2000 IU/mL

 No treatment ALT ALT

 Monitor every normal elevated
6-12 months

 Monitor ALT and  Treat long term

HBV DNA, or  ETV, TDF,
 Consider biopsy, or PegIFN are
since ALT often first-line options
fluctuates and treat if
significant disease

Keeffe EB, et al. DDW 2008. Abstract 198.