SPOTLIGHT ON HEPATITIS B

LIMUEL ANTHONY ABROGENA, MD, DFM

Name of Speaker
AMOSUP Chapter Name
Seamen’s Hospital
Date and Public Health
Ateneo School of Medicine

CME Grant given by HI-Eisai Pharmaceutical, Inc.

 OBJECTIVES
• Discuss the burden of hepatitis B

• Apply the biopsychosocial approach in a

family with Chronic Hepatitis B
> diagnosis & classification
> medical interventions
> non-pharmacological interventions
> psychosocial interventions
The Global Impact of HBV Disease
 Almost 1/3 of the world’s population live in an
area with high HBV prevalence
2 billion with evidence of
HBV infection
15–25% die of
cirrhosis or
liver cancer

300–400 million with

chronic HBV

World population
6 billion
Source: WHO, CDC
 Prevalence of HBV: Global Estimates

HBsAg
Positive, %
Taiwan 10.0-13.8
Vietnam 5.7-10.0
China 5.3-12.0
Africa 5.0-19.0

HBsAg Prevalence Philippines 5.0-16.0

Thailand 4.6-8.0
Japan 4.4-13.0
High (≥ 8%)
Indonesia 4.0
Intermediate (2% to 8%)
South
2.6-5.1
Low (< 2%) Korea

Mast EE, et al. MMWR Recomm Rep. 2006;55:1-33. India 2.4-4.7

Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158-S168. Russia 1.4-8.0
US 0.2-0.5
 Chronic Hepatitis B
• Chronic necroinflammatory disease of the
liver caused by persistence of hepatitis B virus
> HBeAg positive
> HBeAg negative

AASLD Practice Guidelines 2009

 Chronic Hepatitis B
• Diagnostic Criteria
1. HBsAg positive > 6 months
2. Serum HBV DNA 20,000 IU/ml
3. lower values 2,000-20,000 IU/ml are seen in
HBeAg-negative CHB
4. Persistent or intermittent elevation in ALT levels
5. Liver biopsy with moderate or severe
necroinflammation
AASLD Practice Guidelines 2009
 Hepatitis B: Diagnostic Markers
•Anti-HBc IgM
HBsAg
- marker of acute infection
-General marker of infection
• Anti-HBc IgG
- past or chronic infection
HBVDNA
-Indicates active replication of
virus (more accurate than
HBeAg especially in cases of
escape mutants)
- used mainly for monitoring
Anti-Hbe HBeAg
response to therapy
- virus no longer replicating -indicates active replication
of the virus (infectiveness)
AntiHbs
- documents recovery
and/or immunity to HBV
infection
SEROLOGIC PATTERNS IN HEPATITIS B
INFECTION
HBsAg Anti-HBs Anti-HBc HBeAg Anti-Hbe Interpretation
+ - IgM + - Acute hepatitis B
Chronic hepatitis B with
+ - IgG + - active viral replication
Chronic hepatitis B with
+ - IgG - + LOW viral replication

- + IgG - +/- Recovery from hepatitis

B (immunity)

- + ---- - - Vaccination (immunity)

- - IgG - - False-positive;
Infection in remote past
COSTS of LABORATORY WORK-UPS
ALT – Php 180-P220

HEPATITIS PROFILE
HBsAg – Php 230 - Php 250
antiHBs – Php 300 - Php 350
HBeAg – Php 330 - Php 750
anti-Hbe - Php 330 - Php 350

HBVDNA – Php 4500 – Php 10,000

 Screening for CHB infection
HBsAg

Positive Negative

HBeAg Anti-HBs
Anti Hbe
AntiHBc/total Positive Negative
or IgG
HBeAg + ALT HBeAg -
AntiHBe - AntiHBe + Vaccinate

Immune to
HBVDNA HBV

Classify phase of CHB based on

result (see table)
Phases of Chronic Hepatitis B
Infection

5 log or 105 copies/mL

or 100,000 copies/ml=
20,000 IU/ml or 2 x
104 IU/ml

1 IU/ml=5copies/ml
Phases of Chronic Hepatitis B
Infection
Phases of Chronic Hepatitis B
Infection

 ALT levels
normal
 Asymptomatic
 Absent/minimal
inflammation
Phases of Chronic Hepatitis B
Infection
Phases of Chronic Hepatitis B
Infection

 Body no longer able

to “tolerate”
 ALT levels elevated
 Liver necrosis and
inflammation
Phases of Chronic Hepatitis B
Infection
Phases of Chronic Hepatitis B
Infection

 ALT levels return to

normal
 HBV DNA
undetectable
 Minimal
necroinflammation
Phases of Chronic Hepatitis B
Infection
 Phases of Chronic Hepatitis B Infection
IMMUNE IMMUNE INACTIVE REACTIVATION/
PHASE TOLERANCE CLEARANCE/ CARRIER HBeAg (-) CHB
HBeAg(+) CHB
HBsAg POSITIVE POSITIVE POSITIVE POSITIVE
HBeAg POSITIVE POSITIVE NEGATIVE NEGATIVE
AntiHbe NEGATIVE NEGATIVE INITIALLY, POSITIVE POSITIVE
THEN POSITIVE AS
PHASE ENDS

HBVDNA >20,000 > 20,000, <2000 >2000

FLUCTUATING
ALT NORMAL FLUCTUATING/ NORMAL FLUCTUATING/
RAISED RAISED

LIVER MINIMAL VARIABLE MINIMAL MOD TO SEVERE

HISTO INFLAMMATION INFLAMMATION INFLAMMATION HEPATITIS, SOME
BUT MAY HAVE MAY HAVE
CIRRHOSIS CIRRHOSIS
 Initial testing in patients diagnosed with
chronic HBV Infection
• Lab tests to assess liver disease:
CBC, liver profile and INR (prothrombin time)
• Tests for HBV replication:
HBeAg/anti-Hbe, HBV DNA
• Tests to rule out viral co-infections:
anti-HCV, anti-HIV in those at risk
• Tests for screening and surveillance for HCC:
AFP and ultrasound as appropriate
1. Lok, AS, et al. Hepatology. 2009; 50:661-662.
2. Weinbaum CM, et al. MMWR Recomm Rep . 2008; 57(RR-8):1-20.
 Candidates for HBV Screening
(AASLD Guidelines)
• Persons born in high and
intermediate endemic areas
(≥ 2% prevalence)
• US-born children of immigrants
from high endemic areas (≥ 8%;
only if not vaccinated as infants
in the US)
• Household and sexual contacts
of HBV carriers
• Persons who have injected drugs
• Persons with multiple sexual
partners or history of STDs
Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.
Lok AS, et al. Hepatology. 2009;50:661-662.
• Men who have sex with men
• Inmates of correctional facilities
• Individuals with chronically
elevated ALT/AST
• Individuals infected with HIV or
HCV
• Patients undergoing dialysis
• Patients undergoing
immunosuppressive therapy
• All pregnant individual
• Infants born to HBV carrier
mothers
MANAGEMENT OF CHRONIC
HEPATITIS B INFECTION
 Management of Phases of Chronic Hepatitis B Infection
IMMUNE IMMUNE CLEARANCE/ INACTIVE REACTIVATION/
PHASE TOLERANCE HBeAg(+) CHB CARRIER HBeAg (-) CHB
HBsAg POSITIVE POSITIVE POSITIVE POSITIVE

HBeAG POSITIVE POSITIVE NEGATIVE NEGATIVE

AntiHbe NEGATIVE NEGATIVE INITIALLY, THEN POSITIVE POSITIVE

POSITIVE AS PHASE ENDS

HBVDNA >20,000 > 20,000, FLUCTUATING <2000 >2000

ALT NORMAL FLUCTUATING/ NORMAL FLUCTUATING/

RAISED RAISED

LIVER HISTO MINIMAL VARIABLE INFLAMMATION MINIMAL MOD TO SEVERE

INFLAMMATION INFLAMMATION BUT HEPATITIS, SOME MAY
MAY HAVE HAVE CIRRHOSIS
CIRRHOSIS

Candidate for
therapy
NO YES NO YES
AASLD Treatment Recommendations
for Chronic Hepatitis B

Treatment Categories

HbeAg Positive

HBeAg Negative
 Treatment Candidacy for
HBeAg-Positive Patients (AASLD)

HBsAg Positive

HBeAg Positive

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

HBV DNA > 20,000 IU/mL HBV DNA > 20,000 IU/mL HBV DNA > 20,000 IU/mL

Q 3-6 mos ALT Q 3 mos ALT Q 1-3 mos ALT, HBeAg

Q 6-12 mos HBeAg Q 6 mos HBeAg Treat if persistent
Consider biopsy if Liver biopsy optional
persistent or age > 40 Immediate treatment if
Treatment as needed jaundice or decompensated
IMMUNE TOLERANCE IMMUNE CLEARANCE
Lok AS, McMahon BJ. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ,
www.aasld.org. Copyright@2009. American Association for the Study of Liver Diseases, Reproduced with permission
of the American Association for the Study of Liver Diseases.
Treatment Candidacy for HBeAg-Negative
Patients (AASLD)

HBsAg Positive

HBeAg Negative

ALT < 1 x ULN ALT 1-2 x ULN ALT ≥ 2 x ULN

HBV DNA < 2000 IU/mL HBV DNA 2000-20,000 IU/mL HBV DNA ≥ 20,000 IU/mL

Q 3 mos ALT x 3, Q 3 mos ALT and HBV DNA Treat if persistent

then Q 6-12 mos if Consider biopsy if persistent Liver biopsy optional
ALT still < 1 X ULN Treatment as needed
INACTIVE CARRIER REACTIVATION
Lok AS, McMahon BJ. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ,
www.aasld.org. Copyright@2009. American Association for the Study of Liver Diseases, Reproduced with permission
of the American Association for the Study of Liver Diseases.
Hepatitis B Treatment : Goals and Benefits
PRIMARY ENDPOINT
Prevention of long-term negative clinical
outcomes by durable suppression of HBV DNA

 Cirrhosis
 Hepatic decompensation or liver failure
 Hepatocellular carcinoma (HCC)
 Death
Hepatitis B Treatment : Goals and Benefits
SECONDARY ENDPOINT
– Decrease or normalize serum ALT

– Improve liver histology

– Induce HBeAg loss or seroconversion in HBeAg-

positive disease

– Induce HBsAg loss or seroconversion (very rare)

Hepatitis B Treatment : Goals and Benefits

Chronic HBV infection cannot

currently be completely
eliminated or “cured”.

Treatment is often long term or

lifelong.
 Current treatment options for CHB

INTERFERONS NUCLEOS(T)IDE ANALOGUES

• Interferon • Adefovir dipivoxil

• Tenofovir*
• Pegylated • Lamivudine
IFN-alpha • Entecavir
• Telbivudine
• Clevudine†
*not available for CHB treatment in Asia
†only available in Korea and Philippines
Current treatment options for CHB
• Major factors affecting therapeutic choices:
 Efficacy
 Tolerability and safety
(adverse events: interferons)
 Resistance (antivirals)

 Clinical status
(interferons contraindicated in decompensated cirrhosis)
 Cost
Comparison PegIFN vs Nucleos(t)ide Analogues
Nucleos(t)ide
PeGIFN
Analogues
Course of Finite Indefinite
treatment

Route of SQ PO
administration
Resistance No resistance Potential for drug
resistance
Indication Contraindicated in patients with ETV approved for patients
decompensated cirrhosis, in with decompensated
pregnancy, with acute hepatitis disease
B, and who are
immunosuppressed
Adverse Effects Frequent Less frequent
*Particularly for HBeAg-positive patients with genotype A infection.
†Risk of lactic acidosis higher in patients with advanced liver disease. [2-3]

1. Buster EH, et al. Gastroenterology. 2008;135:459-467. 2. Entecavir [package insert]. 2010.

3. Tenofovir [package insert]. 2010.
Adapted from Ganem and Prince 2004 NEJM
 Differentiated Mechanism of Action from
Other Approved HBV Products
Clevudine (L-FMAU)
Thymidine analog , A potent inhibitor against HBV

cccDNA : template for the synthesis of all viral transcripts involved in

viral protein production and replication
Current treatment options for CHB
• Interferon
• Pegylated
IFN-alpha • LAMIVUDINE:
NUCLEOS(T)IDE ANALOGUES – Associated with the HIGHEST rate of
resistance
• Adefovir dipivoxil
• Tenofovir*
• Lamivudine • ENTECAVIR:
• Entecavir – Associated with the LOWEST rate of
resistance
• Telbivudine
• Clevudine†

*not available for CHB treatment in Asia

†only available in Korea and Philippines
 Forty-eight weeks treatment with
clevudine 30mg qd vs entecavir 0.5mg qd
for chronic hepatitis B infection:
a double-blind randomized study
CLEVUDINE ENTECAVIR p-value
HBeAg (+) patients
(N=62) (N=59)
Viral suppression 5.65 log10 copies/ml 5.73 log10 copies/ml NS
(median reduction)

HBVDNA 68% 71% NS

(below 12 IU per ml)

HBeAg 22% 20% NS

seroconversion

ALT Normalization 80% 86% NS

Lau, KK & Leung, N. The Korean J of Hep 2010;16:315-320
Cumulative Rates of Resistance with Oral Agents in
Nucleos(t)ide-Naïve Patients

Drug YL1 YL2 YL3 YL4 YL5 YL6

Generation
1st LAM

24% 38% 49% 67% 70%

ADV
0% 3% 11% 18% 29%
2nd
TBV
4% 17%

ETV
0.2% 0.5% 1.2% 1.2% 1.2% 1.2%
3rd
EASL HBV Guidelines. J Hepatol. 2009; 50:227-242.
CLV
0% 0% Tenny DJ, et al. EASL 2009. Abstract 20.
Marcellin, P. et al. AASLD 2009. Abstract 481.
 Recommended Dosing of Anti-HBV Agents
Recommended Dosing
Agent Route
Adult Children
Interferon 6 MU/m2 3 x per wk
SQ 5 MU daily or 10 MU 3 x per wk
alpha (max: 10 MU)
Peginterferon
SQ 180 µg/wk Not approved
alpha-2a

Tenofovir PO 300 mg QD* Not approved

Adefovir PO 10 mg QD* Not approved‡

3 mg/kg/day
Lamivudine PO 100 mg QD*†
(max: 100 mg/day)
• 0.5 mg QD (no previous LAM)
Entecavir PO • 1.0 mg QD (if refr/resist to Not approved
LAM)*
Telbivudine PO 600 mg QD* Not approved
Clevudine PO 30 mg QD Not approved
 Therapeutic Signposts for Chronic Hepatitis B

HBeAg-positive CHB Signposts Goals of Tx

Start Reduce Normal HBeAg Anti-HBe HBsAg

•Prevent
HBV DNA ALT loss seroconversion loss/SC
Rx
cirrhosis
~25% 0
liver failure
HCC
HBeAg-negative CHB
9% seroconversion in 5 year
•Improve
Start Reduce Normal HBV DNA HBsAg
Rx HBV DNA ALT undetectable loss/SC survival
PCR
negative

Liver
inflammation and fibrosis

Adapted from Naoumov N et al. (EASL 2006). J Hepatol 2006; 44 (2 Suppl): S276–S277.
 When to refer to an HBV Expert?
• Seek advice in the following situations

– Treatment-experienced patients
– Patients with advanced disease stage,
especially decompensated cirrhosis
– Concern for antiviral resistance
– Patients with HIV or HCV co-infection
– Pregnant women
– Children
– Any time you have concerns about how best to
manage a patient
PSYCHOSOCIAL
MANAGEMENT
How will you respond
when given the
following situations?
 On disclosure
You have
Hepatitis B How did I
get it?
 MODE OF TRANSMISSION
• ALL forms of sexual intercourse
• Materno-fetal/child transmission
• Intravenous drug use with needle
sharing
• Inadvertent needle stick injury with
used needle
• Infected blood contact with mucus
membranes
• Infection via infected blood, blood
products or transplanted organs
 When educating
Either you
It can be
abstain or use
sexually
barrier We can’t have
transmitted
protection sex anymore?!
 PREVENTION
Persons who are HBsAg-positive
• Advise sexual contacts to be vaccinated
• Use barrier protection during sexual intercourse if partner is not
vaccinated or naturally immune
• Do not share toothbrushes or razors
• Cover open cuts and scratches
• Clean blood spills with detergent or bleach
• Do not donate blood, organs, or sperm
Children and adults who are HBsAg-positive
• Can participate in all activities, including contact sports
• Should not be excluded from daycare or school participation, and
should not be isolated from other children
• Can share food and utensils and kiss others
 Discussing vaccination
I am pregnant.
Should I be My eldest child
vaccinated? has not been
Will my baby be vaccinated, should
protected? he be vaccinated?

Should I still
be
vaccinated?
Persons who have already been infected
with HBV will receive no benefit from
vaccination

Adapted from: A Comprehensive Immunization Strategy to Eliminate Transmission of Hepatitis B Virus

Infection in the US: Recommendations of the Advisory Committee on Immunization Practices. Part I:
Immunization of Infants, Children and Adolescents. MMWR 2005;54 (No. RR-16)
Hepatitis B Vaccination: recommendation
for infants born to HBsAg (+) mothers
ACIP 2012

 Administer Hepatitis B vaccine and

hepatitis B immune globulin (HBIG)
0.5 ml within 12 hours of birth
 HEPATITIS B IMMUNEGLOBULIN
• Acute Exposure to Blood Containing HBsAg
IM 0.06 mL/kg as soon as possible after exposure and within 24 h
plus hepatitis B vaccine series, if possible. For persons who refuse
hepatitis vaccine or who are known nonresponders to vaccine, a
second dose of HBIG should be given 1 month after the first dose.

• Sexual Exposure to an HBsAg-Positive Person Adults

IM 0.06 mL/kg within 14 days of last sexual contact. Also give
hepatitis B vaccine.

• Household Exposure to Persons With Acute HBV Infection

Infants younger than 12 months of age.
IM 0.5 mL. HBIG may be administered at the same time as, or up to 1
month preceding, hepatitis B vaccination.
Hepatitis B Vaccination: recommendation
for infants born to HBsAg (+) mothers
ACIP 2012

 Ideal dosing schedule for Hepa B

vaccine:
* 0 - 1 - 6 months
 Minimum interval between doses after the birth dose :
dose 1 and dose 2 : 1 month – confers 90% immunity
 3rd dose: can be given at 4 months after the 1st dose but
the infant should be at least 6 months old – confers
prolonged immunity
 Hepatitis B Vaccination:
recommendation for infants born to
HBsAg (+) mothers

AFTER VACCINATION OF INFANT:

Test antibody to HBsAg (anti-HBs) 1 to 2 months after

completion of at least 3 doses of the
Hepatitis B vaccine series
 usually at age 9 through 18 months
(generally at the next well-child visit)
ACIP 2012
 Hepatitis B Vaccination:
recommendation for infants born to
mothers with UNKNOWN HBsAg status

within 12 hours of birth administer:

for infants weighing ≥ 2,000 grams

 HepB vaccine

for infants weighing <2,000 grams

 HepB vaccine plus HBIG ACIP 2012
 Who Should Be Vaccinated for HBV?
CDC. Hepatitis B FAQs for Health Professionals.

Infants
 At birth
Children
 Who were not vaccinated as infants
At-Risk Adults
 Travelers to regions of intermediate/high endemicity
 Susceptible sex partners and household contacts of HBsAg-positive
persons
 Persons seeking evaluation or treatment for an STD
 Persons with behavioral or occupational exposures
 Persons with end-stage renal disease, chronic liver disease, or HIV
infection
 Residents/staff in certain settings with clients with known HBV risk
factors
Routine Schedule of HepB Vaccination
• VACCINATION- What should have been done:
Routine schedule: (0-1-6)

1st dose (at birth)

2nd dose (1-2 months)

3rd dose (6-18 months)

 CATCH UP Vaccination
• VACCINATION – start as soon as possible
Catch-up schedule:

1st dose (start anytime)

2nd dose (1-2 months after 1st dose)

3rd dose (2 months after the 2nd dose)

------ at least 16 weeks from 1st dose
CDC Pink Book 12th ed, May 2012
 When giving prognosis
This can lead to
cirrhosis or Am I going to
hepatocellular die soon? What
carcinoma will happen to
my family ?
 Possible Complications of
Chronic Hepatitis B Infections
Hepatitis B: PROGRESSION OF INFECTION
 Phases of Chronic Hepatitis B: PROGNOSIS

IMMUNE TOLERANCE IMMUNE INACTIVE REACTIVATION

CLEARANCE CARRIER
HBeAg (-) CHB

Low risk of Associated with Low risk of High risk of

progression to hepatic flares cirrhosis & progression to
advanced liver HCC advanced liver
disease HBsAg loss disease
majority will of 1% /yr
eventually 10-20% may
progress to have
immune clearance reactivation
Dealing with problems of living

I can’t get the

job I applied
for!? If I cant
work anymore…
Dealing with concerns
of daily living
 Price Comparison of Drugs for Hepatitis B

* Price per tablet/capsule based on Mercury Drugstore prices as of August 2012.

 Price Comparison of Drugs for Hepatitis B

Interferon alpha- P2,000 x 3 doses/wk x 48 wks

= P288,000

Pegylated interferon alpha – P10000/injection x

48 wks = P480,000

* Price per tablet/capsule based on Mercury Drugstore prices as of August 2012.

EMPLOYMENT
ISSUES
 A HBV+ job applicant
may transmit the infection
• Risk of transmission depends on type
of occupation and infectivity
– Occupations classified into 3 categories
• According to exposure risk
– Infectivity divided into 2 categories
• According to HBV-DNA level

HSP Guidelines on the Evaluation of the Hepatitis B Surface

Antigen Positive Worker for Employment
 Categories of Occupations
Category 1 Category 3
Category 2
(HIGH RISK) (LOW RISK)
HEALTH CARE HEALTH CARE •NON-HEALTH CARE
WORKERS (HCWs) WORKERS who do WORKER
who perform NOT perform
EXPOSURE-PRONE exposure prone All other occupations that
PROCEDURES (EPP’s) procedures (EPPs) do not fall into Categories
1 or 2
COMMERCIAL SEX
WORKERS

Guidelines on the Evaluation of the HBsAg-Positive Workers for Employment

Revisions made during the Consensus Meeting held January 26, 2008
Risk of transmission of HBV in relation to
exposure risk & infectivity
Category 1 Category 3
INFECTIVITY Category 2
(HIGH RISK) (LOW RISK)

HIGH HIGH RISK OF

(HBV DNA TRANSMISSION LOW RISK OF NEGLIGIBLE
>2000 IU/ml) TRANSMISSION RISK OF
TRANSMISSION

LOW LOW RISK OF

(HBV DNA TRANSMISSION
<2000 IU/ml)

Guidelines on the Evaluation of the HBsAg-Positive Workers for Employment

Revisions made during the Consensus Meeting held January 26, 2008
 Pre-employment Clearance

• Diagnosis:

• Type of occupation:

• Risk of transmission:

• Recommendation:

• Plan for treatment and monitoring:

 Pre-employment Clearance
• Diagnosis: Phase of CHB infection
• Type of occupation: Category
• Risk of transmission: Low or high risk
• Recommendation
– Cleared for employment with no work restrictions
– Cleared for employment with work restrictions (specify
the restriction)
– Not cleared (state reason)
• Plan for treatment and monitoring
This is to certify that MR. APOLLO PLANETA, 30 y/o, from Tondo, Manila
was diagnosed to have Chronic hepatitis B. HBeAg positive, immune
TOLERANCE.

Laboratory results:
HBsAg positive ALT 35
HBeAg positive HBV DNA 200,000 IU/ml
Anti-Hbe negative

Type of occupation: Radiology technician

Risk of transmission: Category 2, low risk**

Recommendations:
He is cleared for employment with work restriction**
Restriction: cannot assist/do exposure-prone procedures (EPP)**
Plan: Monitor ALT every 3 months
 FAMILY DYNAMICS
• The ability of the family to maintain
semblance of a normal life under the
abnormal presence of chronic illness and
heightened uncertainty is a key task of this
period.

The Family Medicine

specialist plays a major
role in making this a
reality
 KEY POINTS
 Disease burden of CHB affects quality of life
 At risk population should be screened based on
guidelines recommendation
 Vaccination should be given to those not yet
immune
 Follow established guidelines for monitoring &
treating patients
 Educate patients & their family members on
preventive measures
 Use the biopsychosocial approach