Hepatitis B Virus

Sadia AnjumVirology Lec 6

Hepatitis B Virus

Hepatitis B is a liver disease caused by the hepatitis B virus (HBV).

It ranges in severity from a mild illness, lasting a few weeks (acute), to a serious long-term (chronic) illness that can lead to liver disease or liver cancer.

2 billion people have been infected (1 out of 3 people). 400 million people are chronically infected. 10-30 million will become infected each year. An estimated 1 million people die each year from hepatitis B and its complications. Approximately 2 people die each minute from hepatitis B.

HBV Overview

Hepatitis B Virus - Virology

HBV Genome

Circular DNA genome (partially ssDNA, partially dsDNA The infectious virion has an incomplete (partially single stranded), open circular DNA genome of 3200 base pairs 3.2 kbAlthough the genome is small, it can produce these four large proteins because the genes overlap. For example, the S gene overlaps the P gene completely, whereas the C and P genes partially overlap•

HBV Virology Under Electron Microscope

Enveloped proteins on surface of virions and surplus 22 nm diameter spherical and filamentous particles constitute the B surface antigens

HBs Ag consists two major polypeptides and is glycolated

HBV open reading frames There are 4 open reading frames derived from the same strand (the incomplete + strand)

• S - the 3 polypeptides of the surface antigen (preS1, preS2 and S - produced from alternative translation start sites. glycoprotein emanating from lipid envelop

• C •Core protein packages genome

• P - the polymerase; Viral Reverse-transcriptase (copies RNA Pregenome into DNA)

• X - a trans activator of viral transcription (and cellular genes?). HBx is conserved in all mammalian (but not avian) hepadnaviruses. Though not essential in transfected cells, it is required for infection in vivo

appears to be more frequently expressed in patients with severe liver disease and HCC in clinical practice, this viral protein is of limited relevance or application

HBV Polymerase

Pk: protein kinase

Pr: priming domain

RT: reverse transcriptase

HBV Replication

Prevalence of Divergent Strains

ayw – common in Europe,Australia,and America. adr - Prevalent in south, East India and Far east, ayr - very rareCore antigen HB c agBe HBe is a soluble non particle nucelocapsid protien Both Hbc and Hbe are coded by same genes

Immunopathogenesis

HBV is not cytotoxic but destroys liver cells indirectly by provoking an immunologic response (Fig. 4).

Kupffer cells endocytose viral antigens and present them bound to MHC class II molecules to T-helper cells.

These CD4+ cells recognize the antigens and release cytokines that direct B-cell and cytolytic T-cell (CTL) activity.

Stimulated B cells produce specific antibodies, including neutralizing antibodies. CTLs recognize viral peptides bound to MHC class I molecules on hepatocyte surfaces, leading to destruction of infected hepatocytes.

In persons who fail to mount a sufficiently vigorous immune response to HBV during acute infection, chronic infection develops, and the persistent, ineffective immune response results in progressive liver damage and fibrosis.6

Model forHBx functions.

HBx could activate transcription directly through binding to CREB or indirectly through the induction of Ca2+ release, resulting in the enhancement of viral RNA synthesis and DNA replication

HBX HBx is a154 aminoacids protein ,found both in the nucleus and cytoplasm and does not bind to ds-DNAweak oncogenic potential.Several Tranactivating functions.Enhancer 1 and enhancer2 of HBV and E1, E2, and E4 promoters of adeno virusmay activate tyrosinekinases and/or mitochondrial signaling calcium channels.Interacts with Transcriptional factors eg ATF2, CREB, TBP, TFIIB, RBP5, Oct-1, VADC3,C-FLIP, RNA polymerase subunit Bcl2 ,and Fas ligand ,to alter key cellular functions.Also bind with p53 andssDNA, ERCC2/ERCC3 of TFIIH and XAP1 which are relevant toDNArepair

Hepatitis B Pathogenesis; Modes of Transmission

Risk Factors

IDU16%

Other5%

Unknown16%

Hetero-sexual, multiple partners

39%

MSM24%

Hepatitis B Perinatal Transmission

If mother positive for HBsAg and HBeAg70%-90% of infants infected90% of infected infants become chronically infectedIf positive for HBsAg only5%-20% of infants infected90% of infected infants become chronically infected

Hepatitis B is Serious – Global Impact It’s a common disease!Over 350 million people in the world have chronic hepatitis B1

1 Centers for Disease Control and Prevention. Hepatitis B FAQs for Health Professionals. Available at: http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm#b12. Accessed January 28, 2010.

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Pathogenesis of HBV infection

Disease is Immune mediatedHepatocytes carry viral antigenImmune response subject to antibody dependent.N K cell and cytotoxic T cell attackIn the absence of adequate immune response HBV infection may not cause hepatitis.But lead to carrier state.Infection – Immunodeficient person are likely to because asymptomatic carrier followed infection

Incubation period: Average 60-90 daysRange 45-180

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%

Hepatitis B - Clinical Features

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Spectrum of Chronic Hepatitis B Diseases

Chronic Persistent Hepatitis - asymptomatic

Chronic Active Hepatitis - symptomatic exacerbations of hepatitis

Cirrhosis of Liver

Hepatocellular Carcinoma

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0

10

20

30

40

50

60

70

80

90

100

Birth 1-6 mo 7-12 mo 1-4 yrs 5+ yrs

Age of infection

Ca

rrie

r ri

sk

(%

)Risk of Chronic HBV Carriage by

Age of Infection

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Diagnosis

A battery of serological tests are used for the diagnosis of acute and chronic hepatitis B infection.HBsAg - used as a general marker of infection.HBsAb - used to document recovery and/or immunity to HBV infection. anti-HBc IgM - marker of acute infection.anti-HBcIgG - past or chronic infection.HBeAg - indicates active replication of virus and therefore infectiveness.Anti-Hbe - virus no longer replicating. However, the patient can still be positive for HBsAg which is made by integrated HBV.HBV-DNA - indicates active replication of virus, more accurate than HBeAg especially in cases of escape mutants. Used mainly for monitoring response to therapy.

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Treatment

Interferon - for HBeAg +ve carriers with chronic active hepatitis. Response rate is 30 to 40%.

alpha-interferon 2b (original)

alpha-interferon 2a (newer, claims to be more efficacious and efficient)

Lamivudine - a nucleoside analogue reverse transcriptase inhibitor. Well tolerated, most patients will respond favorably. However, tendency to relapse on cessation of treatment. Another problem is the rapid emergence of drug resistance.

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Treatment

Adefovir – less likely to develop resistance than Lamivudine and may be used to treat Lamivudine resistance HBV. However more expensive and toxicEntecavir – most powerful antiviral known, similar to AdefovirSuccessful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg.

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Statistics on HBVMost healthy adults (90%) who are infected will recover and develop protective antibodies against future hepatitis B infections

90% of infants and up to 50% of young children infected with hepatitis

B will develop chronic infections.

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Protect Yourself And Your Family!

Hepatitis B can infect EVERYONE, regardless of ageBy getting tested and vaccinated, you can protect your familyIf you test positive go for treatment/management options Prevention is the best approach to hepatitis B.

Dr.T.V.Rao MD 28

Prevention

Vaccination - highly effective recombinant vaccines are now available.

Vaccine can be given to those who are at increased risk of HBV infection such as health care workers.

It is also given routinely to neonates as universal vaccination in many countries.

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Hepatitis B Vaccine

Composition Recombinant HBsAgEfficacy 95% (Range, 80%-100%)Duration ofImmunity 20 years or moreSchedule 3 DosesBooster doses not routinely recommended

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