Hepatitis B

Prepared by:
Dr Chee Huey Li
MO, KK Sandakan
2014
EPIDEMIOLOGY

HBV: A Global Problem
2 billion people worldwide have been infected with HBV

> 350 million chronic carriers
90% of those infected as infants and
1-10% infected as adults

Leading cause of cirrhosis and HCC worldwide

30% to 50% of HCC associated with HBV in the absence of cirrhosis

Second only to tobacco in causing the most cancer deaths

50-100 times more infectious than HIV

Geographic distribution of chronic HBV infection
HEPATITIS B VIRUS

Hepatitis b virus a major cause of hepatitis

Structure of hepatitis b virus
Dr.T.V.Rao MD 7
HBV Genotypes
HBV classified into 8 well-documented genotypes (A-H)
A: North America, Western Europe, and Africa
B and C: Asia
D: Southern Europe, Africa, and India
E: West Africa
F: Central and South America and Alaska
G: United States, France, and Germany
H: Central America
Genotype B associated with less active disease, slower progression,
and lower incidence of HCC than genotype C
Genotypes A and B respond better to IFN than genotypes C and D
Kramvis A, et al. J Viral Hepat. 2005;12:456-464.
Geographic Distribution of HBV Genotypes
Liaw YF, et al. Liver Int. 2005;25:472-489. Chu CJ, et al. Gastroenterology. 2003;125:444-451.
A, B, C,
D, G
F
A, D, E
D
B, C
A, B,
C, D
A
Hepatitis B Virus Variants
1. Wild type
Usually HBeAg+ hepatitis
2. Precore mutation (27% US patients)
[1]
Abolishes HBeAg production
3. Core promoter mutation (44% US patients)
[1]
Down-regulates HBeAg production
4. Treatment-induced mutations
YMDD: induced by lamivudine ( 20%/yr)
[2,3]
N236T and A181V: induced by adefovir (0% at Yr 1, 3% at Yr 2, 11% at Yr
3, 18% at Yr 4, and 29% at Yr 5)
[4]
1. Chu CJ, et al. Hepatology. 2003;38:619-628. 2. Chang TT, et al. J Gastroenterol Hepatol.
2004;19:1276-1282. 3. Lok AS, et al. Gastroenterology. 2003;125:1714-1722. 4. Hadziyannis SJ, et al.
Gastroenterology. 2006;131:1743-1751.
Child-to-child
Contaminated needles
Sexual contacts
Healthcare worker
Blood transfusion
6% of
people
infected over
the age of 5
become
chronically
infected
Perinatal
90% of
infected
infants
become
chronically
infected
Vertical transmission Horizontal transmission
Transmission of HBV
CDC. Available at: http://www.cdc.gov/hepatitis. Accessed December 2006.
Lee WM. N Engl J Med. 1997;337:1733-1745.
Lavanchy D. J Viral Hepat. 2004;11:97-107.
Host
Mother
Infant
Recipient
Surveillance and control

Candidates for HBV Screening
Persons born in high and
intermediate endemic areas
( 2% prevalence)
Household and sexual contacts
of HBV carriers
All pregnant women
Infants born to HBV carrier
mothers
Persons who have injected drugs
Persons with multiple sexual
partners or history of STDs

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

Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.
Lok AS, et al. Hepatology. 2009;50:661-662.
Assess HBsAg
Positive
CHB*
Evaluate for
treatment
Negative
Assess anti-HBs
Negative
(no antibodies)
Positive
(antibodies present)
Vaccinate Immune to HBV
*Time from positive HBsAg test to diagnosis of CHB is 6 mths.
HBV Screening Algorithm
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
Hepatitis B Vaccine
Composition Recombinant HBsAg
Efficacy 95% (Range, 80%-100%)
Duration of
Immunity 10 - 15 years
Schedule 3 Doses
Booster doses not routinely recommended unless
anti-Hbs below seroprotective level (10 mIU/ml)
Hepatitis B Vaccination schedule
Two main immunization dose schedules
1. 3 injections at 0, 1, and 6 months
Routine preexposure prophylaxis

2. 4 injections at 0, 1, 2, and 12 months
immunocompromised patients
postexposure prophylaxis situations

*seroprotective levels: anti-Hbs 10 mIU/ml
Postvaccination Serologic Testing
Not routinely recommended following vaccination
of infants, children, adolescents, or most adults
Recommended for:
Infants born to HBsAg+ women
Sex partners of persons with chronic HBV infection
Hemodialysis patients
Immunodeficient persons
Certain healthcare personnel
Management of Nonresponse to Hepatitis B Vaccine
Complete a second series of three doses
Should be given on the usual schedule of 0, 1 and 6
months
Retest 1-2 months after completing the second series


Prevention of Perinatal Hepatitis B Virus Infection
Hepatitis B vaccine (first dose) and HBIG at different
sites
Begin treatment within 12 - 48 hours of birth
Complete vaccination series at 6 months of age
Test for response after completion of at least 3 doses of
the HepB series at 9 - 18 months of age (generally at the
next well-child visit)
Which of the Following Patient(s) Should Be
Screened for HBV?
A. 20-yr-old student who was vaccinated against HBV at birth
B. 64-yr-old male with lymphoma currently undergoing evaluation for
chemotherapy
C. 42-yr-old businessman from South Africa
D. 28-yr-old female who just registered for ANC booking.
E. 58 yr old male, ESRF planned for initiation of HD
The HBsAg is positive.
What next?
NATURAL HISTORY AND DIAGNOSIS

Clinical outcomes of Hepatitis B infections
Natural History of HBV Infection
Childhood
Adulthood
Immune tolerance
HBeAg+ CHB
Inactive carrier HBeAg- CHB
Cirrhosis
< 5%
> 95%
Chen DS, et al. J Gastroenterol Hepatol. 1993;8:470-475. Seeff L, et al. N Engl J Med. 1987;316:965-970.
Fattovich G, et al. J Hepatol. 2008;48:335-352.
5-Yr Incidence Rates
Cirrhosis: 8% to 38% of
chronically infected patients
HCC: 10% to 17% of
patients with cirrhosis
Phase Immune Tolerant Immune Clearance Inactive Carrier
State
Reactivation
Liver
Minimal
inflammation and
fibrosis
Chronic active
inflammation
Mild hepatitis
and minimal
fibrosis
Active
inflammation
Optimal treatment times
Anti-HBe
HBV DNA
ALT activity
Current Understanding of HBV Infection
4 Phases of Chronic HBV Infection
HBeAg
Yim HJ, et al. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in
2005. Hepatology. 2006;43:S173-S181. Copyright 19992012 John Wiley & Sons, Inc. All Rights Reserved.
Differentiating HBeAg-Negative Chronic Hepatitis B
From Inactive Carrier State
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
Status HBeAg-Negative Disease Inactive Carrier
HBsAg positive
Anti-HBe positive
Anti-HBc positive
HBV DNA Moderate, often fluctuating
levels; serum HBV DNA
> 2000 IU/mL
Low or undetectable; serum
HBV DNA negative or
< 2000 IU/mL
ALT Elevated,
often fluctuating levels
Normal
Serologic Markers in HBV Infection
HBsAg
Marker of acute hepatitis B (<6 mths)
Marker of chronic hepatitis B (found in serum > 6 mths)
Anti-HBs
Marker of immunity
HBeAg
An index of active viral replication and high infectivity
Anti-HBe
Appears in recovery phase or reactivation phase
Anti-HBc
Marker of past and possibly current infection
Interpretation of
Serologic Test Results for HBV Infection
Acute Hepatitis B Virus Infection with Recovery
Typical Serologic Course
Weeks after Exposure
Titer
Symptoms
HBeAg anti-HBe
Total anti-HBc
IgM anti-HBc
anti-HBs
HBsAg
0 4 8 12 16 20 24 28 32 36 52 100
Progression to Chronic Hepatitis B Virus
Typical Serologic Course
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
MANAGEMENT AND TREATMENT

When to Start HBV Treatment?
Benefits Risks
Patients age and
preference
Costs
Likelihood of
Adverse outcome
without treatment
Long-lasting response

Adverse effects
Drug resistance

Likelihood of adverse outcome without treatment
Activity and stage of liver disease at presentation
Risk of cirrhosis/HCC in the next 10-20 yrs
Likelihood of long-term benefit with treatment
Pre-therapeutic assessment of liver disease
1. Biochemical markers - LFT, FBC, PT/PTT/INR
AST/ALT ratio - >1 - indication of cirrhosis

2. HBeAg
3. HBV DNA levels
4. Liver histology
5. Co - infections - HIV, HCV, HDV
6. Family history?
Goals and Benefits of Hepatitis B Treatment
Prevention of progression to negative clinical outcomes (eg,
cirrhosis, liver transplantation, HCC, death) by durable
suppression of HBV DNA
Primary endpoint
Sustained decrease in serum HBV DNA level to undetectable
Secondary endpoints
Decrease or normalize serum ALT
Improve liver histology
Induce HBeAg loss or seroconversion in HBeAg-positive disease
Induce HBsAg loss or seroconversion

Types of Response to treatment
1. Biochemical
Normalization of ALT levels
2. Serological
HBeAg - HBeAg loss and seroconversion to anti- Hbe
HBsAg - HBsAg loss and development to anti - Hbs
3. Virological
HBV DNA < 2000 IU/ml
4. Histological
necroinflammatory activity without worsening in fibrosis
5. Complete
sustained off-treatment virological response + loss of HbsAg
Guidelines HBeAg Positive HBeAg Negative
HBV DNA, IU/mL ALT HBV DNA, IU/mL ALT
AASLD 2009
[1]
> 20,000
> 2 x ULN or
positive biopsy*
20,000

2 x ULN or
positive biopsy*
EASL 2009
[2]
> 2000 > ULN

> 2000 > ULN
APASL 2008
[3]
20,000

> 2 x ULN

2000

> 2 x ULN
NIH Consensus
Conference 2009
[4]

> 20,000
> 2 x ULN or
positive biopsy*
20,000

2 x ULN or
positive biopsy*
Determining Treatment Candidacy for Chronic
Hepatitis B: Guidelines
*Moderate/severe inflammation or significant fibrosis.
Expert guidelines also published with recommendations specific for
HBV management in US and more recently for Asian Americans

Some key differences between these guidelines
What Is an Elevated ALT Level?
Reference ranges for ALT vary between 2 most widely used
commercial laboratories
Men: 4-60 IU/L; women: 6-40 IU/L
Men: 0-55 IU/L; women: 0-40 IU/L
Both AASLD and US treatment algorithms recommend lower
ULN levels for ALT when making treatment-initiation
decisions
30 IU/L for men
19 IU/L for women
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
Prati D, et al. Ann Intern Med. 2002;137:1-10. Lok AS, et al. Hepatology. 2009;50:661-662.
q3-6 mths ALT
q6-12 mths HBeAg
q3 mths ALT
q6 mths HBeAg
Consider biopsy if persistent
or pt > 40
Treat as needed
q1-3 mos ALT, HBeAg
Treat if persistent
Liver biopsy optional
Immediate treatment if
jaundice or decompensated

HBeAg +ve
HBsAg +ve
Lok AS, et al. Hepatology. 2009;50:661-662.
2009 AASLD Guidelines: Treatment Candidacy for
HBeAg +ve Patients
ALT < 1 x ULN
HBV DNA < 20,000 IU/mL
ALT 1-2 x ULN
HBV DNA > 20,000 IU/mL
ALT > 2 x ULN
HBV DNA > 20,000 IU/mL
q1-3 mos ALT, HBeAg
Treat if persistent
Liver biopsy optional
q3 mths ALT and HBV DNA
Consider biopsy if persistent
Treat as needed
q3 mths ALT x 3,
then q6-12 mths if
ALT still < 1 x ULN
HBeAg -ve
ALT 2 x ULN
HBV DNA 20,000 IU/mL
HBsAg +ve
ALT 1-2 x ULN
HBV DNA 2000-20,000 IU/mL
ALT < 1 x ULN
HBV DNA < 2000 IU/mL
2009 AASLD Guidelines: Treatment Candidacy for
HBeAg -ve Patients
Lok AS, et al. Hepatology. 2009;50:661-662.
Current Guideline Recommendations for
First-line Therapy
Peginterferon alfa-2a
Exceptions: pregnancy, chemotherapy prophylaxis, decompensated
cirrhosis, acute infection
Entecavir
Tenofovir
Treatment strategies: how-to-treat
There are two different treatment strategies for
both HBeAg +ve and HBeAg -ve patients:
1. Treatment of nite duration with (PEG-)IFN or a NA
2. Long-term treatment with NA(s).




*IFN = interferon, NA = nucleoside analogues
Comparison between IFN and NA
in chronic HBV infection
Clinical Scenarios of Concern during treatment
Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661-662. Copyright
19992012 John Wiley & Sons, Inc. All Rights Reserved.
H
B
V

D
N
A

(
l
o
g
1
0

I
U
/
m
L
)

A
L
T

(
U
/
L
)

Yrs
Biochemical
breakthrough

ULN
Virologic
rebound
Virologic
breakthrough
Hepatitis
flare
8
6
4
2
0
-1 0 1 2 3
When to Consider PegIFN
Favorable predictors of
response
[1,2]

Low HBV DNA*
High ALT*
Genotype A or B > C or D
[3-5]
Not advanced disease
Specific patient demographics
[1,2]
Generally young people
Young women wanting
pregnancy in near future
Absence of comorbidities
Patient preference[1,2]
Concomitant HCV infection


*Also predictive of response to nucleos(t)ide analogues.
How to Use PegIFN alfa-2a
Dosage/administration
180 g/wk by SC injection
Duration of therapy
48 wks
Treatment endpoints: how to determine success or failure
Finite duration therapy; not based on specific endpoints
Virologic response to therapy defined as decrease in serum
HBV DNA to undetectable levels by PCR at end of treatment
and loss of HBeAg in patients who were initially HBeAg
positive
Lok AS, et al. Hepatology. 2009;50:661-662.
Monitoring of Patients Receiving PegIFN alfa-2a
Time Point Monitoring
q 1 mths
FBC
ALT
q3 mths TSH
q6 - 12 mths
HBV DNA levels
HBeAg/anti-HBe (if initially HBeAg +ve)
q12 mths
HBsAg in HBeAg -ve patients with persistently
undetectable HBV DNA
Lok AS, et al. Hepatology. 2009;50:661-662.
5-Yr Rates of Resistance With Oral Agents in
Nucleos(t)ide-Naive Patients
70
29
17
1.2
0
0
20
40
60
80
100
Lamivudine
[1]
Adefovir
[1]
Telbivudine*
[1]
Entecavir
[1]
Tenofovir
[2]

C
u
m
u
l
a
t
i
v
e

R
e
s
i
s
t
a
n
c
e

R
a
t
e

(
%
)

1. EASL. J Hepatol. 2009;50:227-242. 2. Marcellin P, et al. AASLD 2011. Abstract 1375.
*Telbivudine rate determined at Yr 2.
Selection of Entecavir vs Tenofovir: Either Is an
Excellent Choice for Most Patients
Lok AS. Hepatology. 2010;52:743-747.
21
2
< 1
21
3
0
0
5
10
15
20
25
HBeAg
seroconversion
HBsAg
loss
Entecavir
Tenofovir
HBeAg Negative
HBsAg
loss
HBeAg Positive
R
e
s
p
o
n
s
e

a
t

W
k

4
8
-
5
2

(
%
)

Parameter Entecavir Tenofovir
Log HBV DNA at Wk
48-52
HBeAg positive 6.9 6.2
HBeAg negative 5.0 4.6
Genotypic resistance, %
NA naive 1.2 (Yr 5) 0 (Yr 3)
Lamivudine
experienced
51 (Yr 5) NR
Pregnancy rating Class C Class B
AEs None
Renal toxicity;
BMD
How to Use Entecavir or Tenofovir
Dosage and administration
1. Entecavir: oral
Patients naive to lamivudine therapy: 0.5 mg OD
Patients who are refractory/resistant to lamivudine: 1.0 mg OD
Dose adjustment needed if eGFR < 50 mL/min
2. Tenofovir: oral
300 mg OD
Dose adjustment needed if eGFR < 50 mL/min
Lok AS, et al. Hepatology. 2009;50:661-662.
How to Use Entecavir or Tenofovir
Duration, based on clinical endpoints
HBeAg positive
continue treatment until HBV DNA undetectable and HBeAg
seroconversion achieved;
continue for 6 mos after anti-HBe appearance
Close monitoring for relapse required after treatment
discontinuation
HBeAg negative:
continue treatment until HBsAg clearance
Lok AS, et al. Hepatology. 2009;50:661-662.
Monitoring of Patients Receiving Nucleos(t)ide
Analogue Therapy
Time Point Monitoring
q 3 mths
Liver panel
Serum creatinine (if receiving TDF or ADV)
q3 - 6 mths HBV DNA levels
q6 mths HBeAg/anti-HBe (if initially HBeAg +ve)
q6-12 mths
HBsAg in HBeAg -ve patients with persistently
undetectable HBV DNA
Lok AS, et al. Hepatology. 2009;50:661-662.
Discussion

One of Your HBV Patients Tests Positive for HBeAg
What does this tell you about the patients HBV status?
Immune tolerant phase : ALT = Normal
immune-clearance phase : ALT = High
What additional tests should you perform?
HBV DNA - likely high
ALT - likely high
What would you do if this patients ALT is 220 IU/L?
Treat

Case 1
47-yr-old woman recently found to be HBsAg positive during life
insurance checkup
No previous history of jaundice or acute hepatitis
No symptoms
Only medical problem: mild hypertension
Family history
No known history of hepatitis B or liver cancer
Husband and 2 sons aged 20 and 25 yrs not yet tested for HBV

Case 1
Exam: normal, no jaundice or hepatosplenomegaly
Labs
Hb 14 g/dL, WBC 5200 cells/mm
3
, platelets 142,000 cells/mm
3

AST 11 IU/L, ALT 12 IU/L
Alb 4.4 g/dL, alk phos 105 IU/L, T bil 0.8 mg/dL
AFP 4.3 ng/mL
HBsAg positive, HBeAg negative, anti-HBe positive
HBV DNA 110 IU/mL
Ultrasound
Liver normal size and texture with no mass, borderline
splenomegaly

For Discussion: What Would You Recommend for
This Patient?
A. Start treatment now
B. Order liver biopsy; start treatment if cirrhosis confirmed
C. Observe, repeat labs q3 mos, start treatment if ALT/HBV DNA
increase
D. Reassure and discharge patient
Case 1: Follow-up
Repeat labs
Time Point Platelet Count,
cells/mm
3
AST, IU/L ALT, IU/L HBV DNA, IU/mL
Mo 3 154,000 25 29 45
Mo 6 148,000 35 41 1180
Mo 9 137,000 42 59 7375
Case 1: Management Decisions
Liver biopsy performed
Mild inflammation, bridging fibrosis
Oral antiviral therapy started
Case 2
49-Yr-Old, filipino male
Test results
HBsAg +ve
HBeAg -ve
anti-Hbe +ve
ALT 17 IU/L
1. Which phase of chronic hepatitis B is the patient in?
2. How would you manage this patient?
HBV DNA 100 IU/mL
AFP 5.1 ng/mL
Liver U/S: no mass lesion detected