PREVENTION & TREATMENT OF HEPATITIS B

WAQUAR UDDIN AHMED

PMRC RESEARCH COUNCIL JINNAH POSTGRADUATE MEDICAL CENTRE KARACHI

Hepatitis B Virus
HBsAg HBcAg Double-Stranded RNA DNA Polymerase

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 > 8% High
Margolis et al, 1991

National Prevalence of Hepatitis B

HBsAg Anti HBc

1156/47043 (2.5%) 338/1044 (32%)

Anti HBs
HBeAg Anti HBe

135/541

(25%)

787/1156 (14.5%) 395/654

(Meta analysis of published data)

(60%)

Prevalence of HBV according to Gender Gender Overall Males Females No. of Prevalence of HBV Subjects No. % 95% C.I. 47043 1156 2.5 2.3 2.6 24444 22599 709 447 2.9 2.0 2.7 3.1 1.8 2.2

Prevalence of HBV according to Provinces

SINDH

PUNJAB

NWFP

BALOCH

HBsAg +ve HCV coinfection

2.5% 0.2%

2.4% 0.2%

1.3% 0.1%

4.3% 0.1%

HBV in Pakistan
Acute Hepatitis Children 6% Adults 28%
Chronic Liver Disease 26% Hepatocellular cancer 35%

HBV in Pakistan
HBsAg in: Blood donors Pregnant Women Children

3% 2.7% 3%

HBV in Pakistan
High risk groups:
Spouses 24% Doctors 6.8% Nurses 7.3% Paramedics 14.7% Medical students 5.9% Thalassaemia 6.5% Haemodialysis 13% Transvestites 37% CSWs 44%

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 A B&C D E F G H Countries North Western Europe, North America, Africa Asia Mediterranean countries East Africa Americas Yet to be described 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. SouthEast Asia, perinatal transmission is the most common mode of transmission
7090% of children born to infected mothers become chronic carriers In industrialised nations, sexual transmission & I/V DU is more common

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:

Chronic infection:

0.5%1%
<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 Anti HBc IgM HBe Ag HBV-DNA + ve + ve + ve + 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

12 16 20 24 28 32 36

52

100

Weeks after exposure

Spectrum of Disease
Acute HBV infection
2%

9095% neonatal infection

50% childhood infection 510% adult infection

Chronic HBV infection

1540%

Fatal progressive liver failure

Cirrhosis

HCC

Fulminant hepatic failure

Decompensated cirrhosis

Death

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 (6 months) Chronic (years)

HBeAg
HBsAg

anti-HBe

Titer

Total anti-HBc

IgM anti-HBc

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 control phase

HBV DNA

ALT

Immune tolerance phase

Immune HBsAg carrier phase Reactivation clearance phase (resolved hepatitis B HBsAg/anti-HBs)

HBV CARRIER

Asymptomatic Normal ALT / 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)
"Elevated

No (men) 589 3887 4068 11975 36589 37425

RR (95% CI) 59.0 (43.4-80.1) 30.0 (25.0-36.1) 19.2 9.5 2.9 1.0 (15.3-24.2) (7.9-11.5) (2.4-3.5) (0.7-1.4)

100 50-99 40-49 30-39 20-29 < 20

"Normal

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 Signposts
Start Rx Normal ALT HBV DNA Negative HBeAg loss Ant-HBe Seroconversion HBsAg loss

Goals of treatment

HBeAg negative
Start Rx Normal ALT HBsAg loss

HBV DNA Negative

Prevent cirrhosis Prevent liver failure Prevent HCC Improve survival

Liver inflammation and fibrosis

Treatment Options for CHB

Levamisole, Thymosin

+
TH

Immunostimulants

+ +
Interferon
NK

+
TC

TS
Prednisone

Immunosuppressives

Nucleoside/ nucleotide analogues

Lamivudine Adefovir 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

120 100

Integrated Phase III Data

Serum ALT concentration 60 (U/L)

40 20

80

Placebo

Lamivudine
ULN

0 0 4 8 12 20 28 36 44 52

n=199 n=410
Schiff et al., J Med Virol 2000

Weeks of therapy

n=173 n=359

HBeAg Seroconversion During 4 Years of Lamivudine in Patients With Elevated ALT

Seroconversion = HBeAg-ve and anti-HBe+ve
80 ALT >1xULN 70 60 Patients 50 (%) 40 30 20 10 27 (n=41) ALT >2xULN 49 42 37 65 59 73

(n=26)
38

0
1 2 3 Duration of therapy (years) 4

Based on Chang et al., J Gastro Hepatol 2000 (Abstr)

Lamivudine suppresses serum HBV DNA

0

-20
Serum HBV DNA -40 (Median % Change) -60 -80

Placebo

Lamivudine
-100

0
n=192 n=404

12 16 20 24 28 32 36 40 44 48 52
Weeks of Therapy n=171 n=359

Integrated Phase III Data

HBV DNA and ALT Response with Lamivudine Treatment

100 Serum HBV DNA 80 (% positive)
* p<0.05 compared with baseline

160 140 HBV DNA ALT 120 ALT (U/L) 100 80 60

60

*
40

* * *
Last visit

40
20 0

6 9 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

Rarely severe 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)
75
Placebo ADV 10 mg od

Percent of patients

60
45 30 15 0

53%

25% 11%

27% 12% 6% e seroconversion

Marcellin et al. AASLD 2002.

Improved histology

HBeAg loss

Response to Adefovir in HBeAg ve Hepatitis B

EOT response (48 weeks)
75
Placebo ADV 10 mg od

72% 64% 51%

Percent of patients

60
45

33%
30 15

29%

0%
0

Improved histology

ALT normal

Undetectable HBV DNA

Hadziyannis et al. EASL 2002.

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 / seroconversion Undetectable HBV DNA Combined response* 07% 1.925.6% 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
50%
% of patients with HBeAg seroconversion
100% 80%
% of patients PCR negative

HBeAg Seroconversion
49%

96%

95%

40% 30% 30% 20% 10% 0%

60% 40% 20% 0% Entecavir, N=159 Telbivudine, N=203

Entecavir, N=159

Telbivudine, N=203

Entecavir, PCR positive 400 copies/mL Telbivudine, PCR positive 300 copies/mL
1

HBV DNA (-) at week 24

HBV DNA (-) at week 24

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 DERIVED VACCINES 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 Post vaccination testing should be done every 6-12 months Booster is required in patients of: Ch.renal failure, HIV +ve

POST EXPOSURE PROPHYLAXIS

Sexual contact
Accidental needle-stick injury Perinatal exposure 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