Hepatitis B Virus

1. Hepatitis B Virus SadiaAnjum Virology Lec 6

2. 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.

3. HBV Overview

4. Hepatitis B Virus - Virology

5. HBV Genome Circular DNA genome (partially ssDNA, partially dsDNAThe infectious virion has an incomplete (partially single stranded), open circular DNA genome of 3200 base pairs 3.2 kb Although 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 •

6. 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

7. 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

8. HBV Polymerase • Pk: protein kinase • Pr: priming domain • RT: reverse transcriptase

9. HBV Replication

10. Prevalence of Divergent Strains • ayw – common in Europe,Australia,and America. • adr - Prevalent in south, East India and Far east, • ayr - very rare • Core antigen HB c ag • Be HBe is a soluble non particle nucelocapsidprotien • Both Hbc and Hbe are coded by same genes

12. 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

13. 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

14. HBX • HBx is a154 aminoacids protein ,found both in the nucleus and cytoplasm and does not bind to ds-DNA • weak oncogenic potential. • Several Tranactivating functions. • Enhancer 1 and enhancer2 of HBV and E1, E2, and E4 promoters of adeno virus • may 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 Fasligand ,to alter key cellular functions. • Also bind with p53 andssDNA, ERCC2/ERCC3 of TFIIH and XAP1 which are relevant toDNArepair

15. Hepatitis B Pathogenesis; Modes of Transmission

16. Risk Factors

17. Hepatitis B Perinatal Transmission • If mother positive for HBsAg and HBeAg • 70%-90% of infants infected • 90% of infected infants become chronically infected • If positive for HBsAg only • 5%-20% of infants infected • 90% of infected infants become chronically infected

18. 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.

20. Pathogenesis of HBV infection • Disease is Immune mediated • Hepatocytes carry viral antigen • Immune response subject to antibody dependent. • N K cell and cytotoxic T cell attack • In 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

21. Hepatitis B - Clinical Features • Incubation period: Average 60-90 days Range 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 fromchronic liver disease: 15%-25%

22. Spectrum of Chronic Hepatitis B Diseases • Chronic Persistent Hepatitis - asymptomatic • Chronic Active Hepatitis - symptomatic exacerbations of hepatitis • Cirrhosis of Liver • Hepatocellular Carcinoma

23. Risk of Chronic HBV Carriage by Age of Infection

24. 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-HBcIgM - 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.

25. 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.

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

27. Statistics on HBV • Most 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.

28. Protect Yourself And Your Family! • Hepatitis B can infect EVERYONE, regardless of age • By getting tested and vaccinated, you can protect your family • If you test positive go for treatment/management options • Prevention is the best approach to hepatitis B. Dr.T.V.Rao MD

29. 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.

30. Hepatitis B Vaccine • Composition Recombinant HBsAg • Efficacy 95% (Range, 80%-100%) • Duration ofImmunity 20 years or more • Schedule 3 Doses • Booster doses not routinely recommended