PREVENTION &

TREATMENT OF HEPATITIS
B

WAQUAR UDDIN AHMED

PMRC RESEARCH COUNCIL

JINNAH POSTGRADUATE MEDICAL
CENTRE
Hepatitis B Virus

HBsAg

DNA
HBcAg Polymerase

Double-Stranded
RNA HBeAg

Dane Particle

Partially double-stranded circular DNA virus

A member of the Hepadnaviridae family
Central core nucleocapsid containing viral DNA;
surrounding envelope with surface protein or antigen
MAGNITUDE OF THE PROBLEM
More than 2 billion people exposed to HBV

Currently 350 million HBV carriers

Over 1 million die each year from HBV infection

Three quarters of the worlds population i.e

5.2 billion people live in endemic regions

Asian HBV Carriers > 250 million

HBV infection in Pakistan 1.6 million

GLOBAL PATTERN OF HBV INFECTION

Low(<2%): 12% of world population

Life time risk of infection <20%
Most infections occur in adult risk groups

Intermediate(2-7%): 43% of world Population

Life time risk of infection 20-60%
Infection occurs in all age groups

High(>8%): 45% of world population

Life time risk of infection >60%
Early childhood infections are common
Prevalence of Chronic HBV Carriers

Percentage chronic HBsAg carriers:

< 2% Low
27% Intermediate
Margolis et al, 1991
> 8% High
 National Prevalence of Hepatitis B
HBsAg 1156/47043 (2.5%)

Anti HBc 338/1044 (32%)

Anti HBs 135/541 (25%)

HBeAg 787/1156 (14.5%)

Anti HBe 395/654 (60%)

(Meta analysis of published data)
Prevalence of HBV according to Provinces

SINDH PUNJAB NWFP BALOCH

HBsAg 2.5% 2.4% 1.3% 4.3%

+ve
HCV co- 0.2% 0.2% 0.1% 0.1%
infection
 HBV in Pakistan
Acute Hepatitis
Children 6%
Adults 28%

Chronic Liver Disease 26%

Hepatocellular cancer 35%

HBV in Pakistan

HBsAg in:
Blood donors 3%
Pregnant Women 2.7%
Children 3%
HBV in Pakistan
High risk groups:

Spouses 24% Thalassaemia 6.5%

Doctors 6.8% Haemodialysis 13%
Nurses 7.3% Transvestites 37%
Paramedics 14.7% CSWs 44%
Medical students 5.9%
Hepatitis B Viral Genotypes
Genotypic classification of HBV has
been extended to include eight
genotypes (A-H).

HBV genotypes have distinct

geographical distribution.
 Geographical distribution of HBV genotypes
Genotypes Countries

A North Western Europe,

North America, Africa
B&C Asia
D Mediterranean countries
E East Africa
F Americas
G Yet to be described
H Nicaragua, Mexico, California

A & D are the most prevalent genotypes in Pakistan

Routes of Transmission
Percutaneous
Contaminated needle stick
Haemodialysis
Human bite
Transplant/transfusion of unscreened
blood/blood products
Acupuncture, tattooing, body-piercing

Permucosal
Sexual Intercourse
Perinatal
Contact with infected household objects
Prevalence of Transmission

In highly endemic areas e.g.

South-
East Asia, perinatal transmission is
the
most common mode of
transmission
7090% of children born to
infected
 Hepatitis B Clinical Features

Incubation period: Average 6090 days

Range 45180 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%
ACUTE HEPATITIS B
LFTs:Bilirubin Raised
SGPT - Raised
Alk Phos - Normal / Raised

Markers: HBsAg + ve
Anti HBc IgM + ve
HBe Ag + ve
HBV-DNA + ve
Acute Hepatitis B Virus Infection with
Recovery Typical Serologic Course
Symptoms

HBeAg anti-HBe

Total anti-HBc
Titer

HBsAg IgM anti-HBc anti-HBs

0 4 8 12 16 20 24 28 32 36 52 100
Weeks after exposure
 Spectrum of Disease

9095% neonatal infection Chronic 1540% Fatal

Acute
HBV progressive
HBV 50% childhood infection
infection liver failure
infection
510% adult infection
2%
Cirrhosis HCC

Fulminant
hepatic
Decompensated
failure Death
cirrhosis
 Chronic Hepatitis B: Definition
HBsAg + for > 6 months
Variable clinical course

HBV Carrier Chronic Liver Dis

 Progression to Chronic Hepatitis B
Virus Infection Typical Serologic
Course
Acute Chronic
(6 months) (years)
HBeAg anti-HBe
HBsAg
Total anti-HBc
Titer

IgM anti-HBc

0 4 8 12 16 20 24 28 32 36 52

Weeks after exposure Years

Complex Phases of Chronic HBV Infection
Fattovich G. J Hepatol 2003;39(suppl 1):S50-S58.

Patients with CHB can progress through four well-defined phases

Increasing age
HBeAg+

HBeAg+ HBeAg - / anti-HBe +

Immune
HBV DNA control
phase

ALT

Immune tolerance Immune HBsAg carrier phase Reactivation

phase clearance phase (resolved hepatitis B
HBsAg/anti-HBs)
HBV CARRIER
Asymptomatic
NormalALT / SGPT
HBsAg + ve
HBeAg + ve / - ve
HBV-DNA - ve

No Treatment is required
Advise Followup Yearly with HBV-DNA,
LFT, HBsAg, Alphafetoprotien & ultrasound
 Normal Aminotransferase Levels and Risk of
Mortality from Liver Diseases
Kim HC et al. BMJ 2004; 328:983

ALT (IU/L) No (men) RR (95% CI)

100 589 59.0 (43.4-80.1)
"Elevated

50-99 3887 30.0 (25.0-36.1)

40-49 4068 19.2 (15.3-24.2)
30-39 11975 9.5 (7.9-11.5)
"Normal

20-29 36589 2.9 (2.4-3.5)

< 20 37425 1.0 (0.7-1.4)
Korea Medical Insurance Corporation
94,533 men; 47,522 women ( 35 59 years old)
Relative risk for liver mortality compared with AST and ALT <20 IU/l
 CHRONIC HEPATITIS B
LFTs : Bilirubin Normal / Raised
SGPT - Normal / Raised
Alk Phos - Normal
GGT - Normal
Serum Protine & Albumin Normal / Low
Prothrombin time Normal / Raised
Markers : HBsA +ve
Anti HBc IgM ve
Anti HBc IgG + ve
HBeAg - ve / + ve
Anti HBe - ve / + ve
Types of Chronic Hepatitis B
Wild type
HBsAg +
HBeAg +
HBV DNA +
Precore Mutant type
HBsAg +
HBeAg -
HBV DNA +
Indications of therapy in
Chronic Hepatitis B

HBsAg positive for >6 months

ALT > 2 times ULN

ALT may be normal in

decompensated liver disease
 EXCLUSION CRITERIA

Co-infection with HCV

Co-infection with Delta Virus

Children less than 5 years of age

 Treatment Objectives for
Chronic Hepatitis B
Improve hepatitis: Normalise ALT
HBeAg seroconversion
Sustained suppression of HBV replication
Arrest / reverse hepatic fibrosis
Improve long-term prognosis
Stop progressive liver damage cirrhosis
Reduce the rate of decompensation in cirrhosis
Prolong life
 Therapeutic Signposts for CHB
HBeAg positive Goals of
treatment
Signposts
Prevent
Normal Ant-HBe cirrhosis
Start HBV DNA HBeAg HBsAg
ALT Serocon-
Rx Negative loss
version
loss Prevent
liver failure
HBeAg negative
Prevent
HCC
Normal
Improve
Start
Rx
ALT HBV DNA
Negative
HBsAg
loss
survival

Liver
inflammation and fibrosis
Treatment Options for CHB
Levamisole, Thymosin
Immunostimulants
+
TH
+ + TS
- Prednisone
+ TC

+ NK - Immunosuppressives
+
Interferon -
- Nucleoside/ Lamivudine
nucleotide Adefovir
analogues Entecavir
Telbivudine
Current Therapies for CHB
Nucleoside/Nucleotide analogues:
Lamivudine
Adefovir
Entecavir
Telbivudine
Tenofovir

INTERFERON

PEGASYS
 LAMIVUDINE IN HBV
DOSE AND DURATION
100 mg daily before breakfast

RESPONSE
HBe Ag seroconversion 16-18%
HBe Ag loss 30-33%
Sustained normalization of ALT 41- 49%
Histologic improvement 52%
HBeAg seroconversion increases with prolonged therapy. 27% at
year 2, 40% at year 3, 47% at year 4.
Those with normal ALT, suppressed HBV DNA but
+ ve HBeAg post treatment, have variable prognosis.
HBsAg seroconversion are observed in those with sustained
HBeAg seroconversion.
 Lamivudine Normalises Serum ALT
Integrated Phase III Data
120

100
Placebo
80
Serum ALT
concentration
60
(U/L) Lamivudine
40 ULN

20

0
0 4 8 12 20 28 36 44 52
n=199 n=173
n=410 Weeks of therapy n=359
Schiff et al., J Med Virol 2000
HBeAg Seroconversion During 4 Years of
Lamivudine in Patients With Elevated ALT
Seroconversion = HBeAg-ve and anti-HBe+ve
80 73
ALT >1xULN
70 65
(n=41)
59
60 ALT >2xULN
Patients 49
(n=26)
(%) 50 42
38 37
40
27
30

20

10

0
1 2 3 4
Duration of therapy (years)
Based on Chang et al., J Gastro Hepatol 2000 (Abstr)
Lamivudine suppresses serum
HBV DNA
0

-20
Placebo
Serum
HBV DNA -40
(Median
% Change) -60

-80
Lamivudine
-100
0 4 8 12 16 20 24 28 32 36 40 44 48 52
n=192 Weeks of Therapy n=171
n=404 n=359

Integrated Phase III Data

 HBV DNA and ALT Response with
Lamivudine Treatment
* p<0.05 compared with baseline
100 160
140
Serum
HBV DNA 80 HBV DNA 120 ALT
(% positive) ALT (U/L)
100
80
60
60
* * 40
40 * 20
*
0
0 3 6 9 Last visit
Time (months)
Mutation in YMDD molif of HBV DNA polymerase identified in three patients.
Villeneuve et al., Hepatology 2000
 Monitoring HBe Ag+ve patients
(Wild) on Lamivudine Therapy
ALT at least once every 3 months
HBV-DNA at six months
HBeAg at nine months
If
HBe Ag has become -ve,
Anti-HBe at one year
Treatment has to be continued for at
least six months after seroconversion
 Monitoring HBe Ag-ve patients
(Mutant) on Lamivudine Therapy

ALT at least once every 3 months

HBV-DNA at six months
If HBV-DNA has become -ve,

Treatment has to be continued for at

least 12 months or three consecutive
PCR -ve done at six months intervals
DISADVANTAGES OF LAMIVUDINE

Development of YMDD mutants

Rarelysevere clinical exacerbations

are seen after YMDD mutation.

Longer duration
 Incidence of YMDD Variant HBV
Rarely detectable by PCR (limit of detection = 500
copies/mL) during the first 36 weeks of therapy
Incidence of detectable serum YMDD variant HBV in
HBeAg+ve patients after lamivudine therapy for:
1 year = 24% (Lai et al., 2001)
2 years = 38% (Liaw et al., 2000)
3 years = 49% (Leung et al., 1999)
4 years = 66% (Chang et al., 2000)

Emergence of YMDD variants does not necessarily equate

to clinical resistance
 Response to Adefovir in
HBeAg +ve Hepatitis B
EOT response (48 weeks)
Placebo
ADV 10 mg od
75
Percent of patients

60 53%

45

30 25% 27%

11% 12%
15
6%
0
Improved histology HBeAg loss e seroconversion

Marcellin et al. AASLD 2002.

 Response to Adefovir in
HBeAg ve Hepatitis B
EOT response (48 weeks) Placebo
ADV 10 mg od
75 72%
64%
Percent of patients

60 51%

45
33% 29%
30

15
0%
0
Improved histology ALT normal Undetectable HBV DNA

Hadziyannis et al. EASL

 Adefovir in the Treatment of CHB
Advantages
Modest end-treatment response
Effective in LAM-Resistant HBV
Oral administration
Few side effects

Disadvantages
Sustained treatment response is no better
Dose adjustment with renal insufficiency
Post-treatment ALT flares in 27 %
Entecavir in the Treatment of Patients
With HBeAg +ve and ve CHB
24 weeks (EOT)
0.010.5 mg qd (n=129)
HBeAg Loss / 07%
seroconversion
Undetectable HBV DNA 1.925.6%
Combined response* 624%

*Undetectable HBV DNA, HBeAg loss (for HBeAg +ve) normal ALT

Lai et al. Gastroenterology. 2002.

Entecavir in the Treatment of Patients
With HBeAg +ve and ve CHB
Advantages
Good end-treatment response
Oral administration
Few side effects

Disadvantages
Post-treatment ALT flares
 Comparative Efficacy of Entecavir vs
Telbivudine at 1 year
PCR Negativity HBeAg Seroconversion
49%
50%
96% 95%
100%

% of patients with HBeAg

40%
80%

seroconversion
30%
30%
PCR negative
% of patients

60%
20%
40%

10%
20%

0%
0% Entecavir, Telbivudine,
Entecavir, Telbivudine, N=159 N=203
N=159 N=203
HBV DNA (-) at week 24
HBV DNA (-) at week 24
Entecavir, PCR positive 400 copies/mL
Telbivudine, PCR positive 300 copies/mL

1
BMS Entecavir AVDAC Briefing Document 2005. Accessed 5/08.
2
Zeuzem S, et al. Journal of Hepatology 2006;44 (Suppl S2):S24.
PREVENTION OF
HEPATITIS B
PREVENTION OF HEPATITIS B
ROUTS OF TRANSMISSION:
1. Blood & Blood products
2. Excretions & Secretions
3. Tissues of infected patients

HBV can survive on environmental

surface for 7 days
Prevention/Prophylaxis
World Health Organization (WHO) recommends:
Worldwide screening of blood and
blood products
Destruction of disposable needles,
and adequate sterilization of reusable
materials
Effective use of universal precautions
and barrier techniques
Education about the risks of
using inadequately sterilized
or unsterilized equipment
Prenatal Screening
Hepatitis B Immunoglobulin (H-BIG)
Hepatitis B vaccine
 GUIDELINES FOR PREVENTION
Universal precautions
Use of protective barriers
Safe handling & disposal of sharps
Proper use of disinfection and sterilization
techniques
Sterilization: Boiling for 20 min
Dry heat sterilization
Chemical Disinfection: Bleaching powder
1 % Bleach (sodium hypochloride)
Methylated spirit or Alcohol 70 %
Gluteraldehyde 2 % or Savlon 1 %
 HBV VACCINATION
WHO SHOULD BE VACCINATED ?
Vaccination of total population
Vaccination of high-risk population
1. Health care workers
2. Recipients of blood & blood products
3. Hemodialysis
4. Staff of mentally handicapped institutions
5. Homosexual men, sexual partners of HBV
6. Individuals with multiple sexual partners
7. Parenteral drug abusers
8. Spouses and children of HBV patients
Vaccination of newborns or infants
 HEPATITIS B VACCINE
PLASMA DERIVEDVACCINES
RECOMBINANT DNA VACCINES

RECOMMENDED SHEDULE:
0, 1 and 6 month

DOSAGE:
Adults: One ml (20 ug)
Pediatric: 0.5 ml (10 ug)
 HBV VACCINE - BOOSTER
No booster is required for healthy persons

REQUIRED WHEN anti- HBs titer falls

below 10 mlU / ml
Titers fall <10mlU in 7- 50 % in 5 years
30 60 % in 9-11 years
Usually single booster dose at 5 yrs
required
 VACCINATION IN IMMUNE
COMPROMISED PATIENTS
Recommended dose is 40 ug at 0,1,2,6
months

Postvaccination testing should be done

every 6-12 months

Boosteris required in patients of:

Ch.renal failure, HIV +ve
POST EXPOSURE PROPHYLAXIS
Sexual contact

Accidental needle-stick injury

Perinatalexposure from HBV

positive mother
 RISK OF TRANSMISSION
If mother is infected in 1st or 2nd trimester
risk of transmission is very low
But Ac.Hepatitis in 3rd trimester- risk of
transmission is very high
If mother is HBeAg +ve risk of transmission
is 85 %
If mother is Anti-HBe +ve & HBeAg ve risk
of transmission is 6 %
Breast feeding is allowed in HBV +ve cases
NEONATAL PROPHYLAXIS
Prophylaxis should be given if the
mother is HBeAg +ve
Hepatitis B Immunoglobulin given
at birth and at 3 & 6 months of age
HBV vaccine soon after birth & at
1 and 6 months
Infants of BHeAg ve mothers reqire
HBV vaccine only
POST EXPOSURE PROPHYLAXIS

Immediate HBIg 0.06 ml/kg i/m

HBV vaccination within 7 days
Check for anti-HBs if the titer is

>10mlU/ml, No further vaccine

If <10mlU/ml repeat vaccine at 1

and 6 months
 Future Hope: Hepatitis free
world soon

THANK YOU ALL FOR PATIENT LISTENING

Thank you