1. Hepatitis B Virus Huamin Wang 王华民 Department of Microbiology & Immunology Hainan Medical College 2007

2. 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.

3. Hepatitis B In the World 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.

4. Hepatitis B In the United States 12 million Americans have been infected (1 out of 20 people). More than one million people are chronically infected. Up to 100,000 new people will become infected each year. 5,000 people will die each year from hepatitis B and its complications. Approximately 1 health care worker dies each day from hepatitis B.

5. Hepatitis B in China 1.3 billion people the world's largest population of hepatitis B patients, with nearly half a million people dieing of the liver disease every year 120 million Chinese have tested positive for hepatitis B, which has become a severe public health problem in the country

6. General Concepts Hepatitis = 'inflammation of the liver'. six medically important viruses are commonly described as “hepatitis viruses”: HAV,HBV,HCV,HDV,HEV,HGV.

7. Definitions for Hepatitises Acute （急性） : Short term and/or severe. Chronic （慢性） : Lingering or lasting - may or may not be severe Fulminant （爆发性） : Developing quickly and lasting a short time, high mortality rate. Cirrhosis （硬化） : Hardening: may be the result of infection or toxins (e.g. alcohol) Jaundice （黄疸） : Yellowing of the skin, eyes, etc due to raised levels of bilirubin in the blood due to liver damage. Hepatocellular carcinoma （肝细胞癌）： is closely associated with hepatitis B, and at least in some regions of the world with hepatitis C virus.

8. A “Infectious” “Serum” Viral hepatitis Enterically transmitted Parenterally transmitted F, G, TTV ? other E NANB BD C Viral Hepatitis - Historical Perspectives

9. Table 24.12

10. Hepatitis B Virus

11. 1 、 Properties of HBV a member of the hepadnavirus group Circular partially double-stranded DNA viruses Replication involves a reverse transcriptase. endemic in the human population and hyperendemic in many parts of the world. a number of variants It has not yet been possible to propogate the virus in cell culture

12. HBV: Structure HBV : Structure

13. Virion also referred to as Dane particle (ds-tranded DNA) 42nm enveloped virus Core antigens located in the center (nucleocapsid) * Core antigen (HBcAg) * e antigen (HBeAg)- an indicator of transmissibility (minor component of the core- antigenically distinct from HBcAg) 22nm spheres and filaments other forms- no DNA in these forms so they are not infectious (composed of surface antigen)- these forms outnumber the actual virions

14. HBV Structure & Antigens Dane particle Dane particle HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr) HBcAg = inner core protein ( a single serotype) HBeAg = secreted protein; function unknown

15. decoy particles HBsAg-containing particles are released into the serum of infected people and outnumber the actual virions. Spherical or filamentous They are immunogenic and were processed into the first commercial vaccine against HBV.

16. GENOME

17. 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. C - the core protein P - the polymerase X - a transactivator 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. Open Reading Frames

18. 2 、 HBV: Replication Reverse transcription: one of the mRNAs is replicated with a reverse transcriptase making the DNA that will eventually be the core of the progeny virion RNA intermediate: HBV replicates through an RNA intermediate and produces and release antigenic decoy particles. Integration: Some DNA integrates into host genome causing carrier state

19. Replication of HBV

20.  Parenteral - IV drug abusers, health workers are at increased risk.  Sexual - sex workers and homosexuals are particular at risk.  Perinatal( Vertical) - mother(HBeAg+) → infant. 3 、 HBV: Modes of Transmission

22. High (>8%): 45% of global population –lifetime risk of infection >60% –early childhood infections common Intermediate (2%-7%): 43% of global population –lifetime risk of infection 20%-60% –infections occur in all age groups Low (<2%): 12% of global population –lifetime risk of infection <20% –most infections occur in adult risk groups Global Patterns of Chronic HBV Infection

23. 4 、 Epidemiology 350,000,000 carriers worldwide 120,000,000 carriers in China - the carrier rate can exceed 10% -15 to 25% of chronically infected patients will die from chronic liver disease 500,000 deaths/year in China 982,297 liver disease in China 2005 50% of children born to mothers with chronic HBV in the US are Asian American

24. HighModerate Low/Not Detectable bloodsemenurine serumvaginal fluidfeces wound exudatessalivasweat tears breastmilk Concentration of Hepatitis B Virus in Various Body Fluids 伤口渗出液 唾液 精液 阴道分泌液

26. High-risk groups for HBV infection People from endemic regions Babies of mothers with chronic HBV Intravenous drug abusers People with multiple sex partners Hemophiliacs and other patients requiting blood and blood product treatments Health care personnel who have contact with blood Residents and staff members of institutions for the mentally retarded

27. Symptomatic Infection Chronic Infection Age at Infection Chronic Infection (%) Symptomatic Infection (%) Birth 1-6 months7-12 months 1-4 years Older Children and Adults 0 20 40 60 80 100 80 60 40 20 0 Outcome of Hepatitis B Virus Infection by Age at Infection Chronic Infection (%)

28. 5 、 Pathogenesis & Immunity Virus enters hepatocytes via blood Immune response (cytotoxic T cell) to viral antigens expressed on hepatocyte cell surface responsible for clinical syndrome 5 % become chronic carriers (HBsAg> 6 months) Higher rate of hepatocellular ca in chronic carriers, especially those who are “e” antigen positive Hepatitis B surface antibody likely confers lifelong immunity (IgG anti-HBs) Hepatitis B e Ab indicates low transmissibility

29. 6 、 Clinical Features Incubation period:Average 60-90 days Range 45-180 days Insidious onset of symptoms. Tends to cause a more severe disease than Hepatitis A. Clinical illness (jaundice): <5 yrs, <10% ≥ 5 yrs, 30%-50% 1/3 adults-no symptoms Clinical Illness at presentation 10 - 15% Acute case-fatality rate: 0.5%-1% Chronic infection: < 5 yrs, 30%-90% ≥ 5 yrs, 2%-10% More likely in ansymptomatic infections Premature mortality from chronic liver disease: 15%-25%

30. Possible Outcomes of HBV Infection Acute hepatitis B infection Chronic HBV infection 3-5% of adult- acquired infections 95% of infant- acquired infections Cirrhosis Chronic hepatitis 12-25% in 5 years Liver failure Hepatocellular carcinoma Liver transplant 6-15% in 5 years 20-23% in 5 years Death

31. Symptoms HBeAg anti-HBe Total anti-HBc IgM anti-HBc anti-HBs HBsAg 0481216 20 242832 36 52100 Acute Hepatitis B Virus Infection with Recovery Typical Serologic Course Weeks after Exposure Titre

32. Acute HBV Infection with Progression to Chronic Infection: Typical Serologic Course

33. 7 、 Laboratory Diagnosis

34. 8-1 、 Current Treatment Options Interferon alfa (Intron A) （干扰素） Response rate is 30 to 40%. Lamivudine (Epivir HBV) （拉米呋啶） (relapse,drug resistance) Adefovir dipivoxil (Hepsera) （阿德福韦酯）

35. 8-2 、 Prevention Vaccination - highly effective recombinant vaccines Hepatitis B Immunoglobulin (HBIG) -exposed within 48 hours of the incident/ neonates whose mothers are HBsAg and HBeAg positive. Other measures -screening of blood donors, blood and body fluid precautions.

36. Hepatitis B Vaccine Infants: several options that depend on status of the mother –If mother HBsAg negative: birth, 1-2m,6-18m –If mother HBsAg positive: vaccine and Hep B immune globulin within 12 hours of birth, 1-2m, <6m Adults * 0,1, 6 months Vaccine recommended in –All those aged 0-18 –Those at high risk

37. summary General concepts for hepatitis Types of hepatitis Properties of HBV : Structure\ ORF\Replication Transmission \Epidemiology Pathogenesis & Immunity Clinical Features Laboratory Diagnosis Treatment \Prevention

38. Questions What is hepatitis B? What are the properties of HBV? How many ORFs of HBV? How is HBV spread? How does the HBV curse the liver diseases? How do you interpret serological lab results for HBV? How to treat and prevent hepatitis B?

39. Review Quiz Following transmission of HBV from mother to infant, which of the following is the most common medical problem for the infant? A. Liver failure. B. Chronic HBV carrier state C. Development of lymphoma. D. Opportunistic infections. E. Development of CNS disease.

40. Why are the Chinese at greater risk than Westerners? Because there are more Asian people already infected with hepatitis B than Westerners. Although hepatitis B is not an "Asian disease", it affects hundreds of millions of Asians. Since the Asian community starts with such a large number of infected people, there are more people who can pass the hepatitis B virus on to others. This increases the risk that you could get infected. Since there is a smaller number of Westerners who are infected, this group has a lower risk of infection

41. How is hepatitis B spread differently among the Chinese? Asians and Westerners can both get hepatitis B through contact with blood, unprotected sex, shared needles, and from an infected mother to newborn baby during delivery. Jobs and lifestyle choices can create an equal risk for both groups. However, hepatitis B is often spread differently among Asians. Asians are most commonly infected as newborns - from a mother who unknowingly passes the virus on during delivery. Young children are also at risk if they live in close daily contact with an infected family member. Babies and children are more likely to develop a chronic hepatitis B infection because their young immune systems have trouble getting rid of the virus. Westerners are most commonly infected as young adults through unprotected sex. As adults, their immune systems can usually get rid of the virus and they "recover" from an infection.

42. What does it mean to be a "chronic carrier" of hepatitis B? People who are unable to get rid of the hepatitis B virus are diagnosed as being a "chronic carrier". The virus can stay in their blood and liver for a long time. They can unknowingly pass the virus on to other people. Chronic hepatitis B can also lead to serious liver diseases, such as cirrhosis or liver cancer. Not every chronic carrier will develop serious liver disease. However, they have a greater chance than someone who is not infected.

43. Why should Chinese people be worried about chronic hepatitis B infections? Because chronic hepatitis B can lead to cirrhosis or liver cancer. It's important to get tested because early diagnosis can lead to early treatment which can save your life. Also, chronic carriers can spread the virus to others. Since most chronic carriers don't know they are infected, they are unknowingly spreading it to many other people. If people are not tested, hepatitis B can pass through several generations in one family and throughout the community.

44. How can I stop the spread of hepatitis B? The good news is that you can break the cycle of infection in your family and in the Chinese community. Get tested for hepatitis B. Make sure everyone in your family is vaccinated against hepatitis B. Get the vaccine yourself. Look for good medical care. Discuss treatment options with your family doctor or a liver specialist if you already have chronic hepatitis B.

45. Are there any treatments if I have chronic hepatitis B? Currently, there are five approved drugs in the United States for people who have chronic hepatitis B infections. These drugs are also available in China: 1 、 Epivir-HBV or Zeffix (lamivudine) is a pill that is taken orally 2 、 Hepsera (adefovir dipivoxil) is a pill that is taken orally 3 、 Baraclude (entecavir) is a pill that is taken orally 4 、 Intron A (interferon alpha) is a drug given by injection 5 、 Pegasys (pegylated interferon) is a drug that is give by injection

46. Are there any treatments if I have chronic hepatitis B? It is important to know, not every chronic hepatitis B patient needs to be on medication. Some patients only need to be monitored by their doctor on a regular basis (at least once a year, or more). Other patients with active signs of liver disease may benefit the most from treatment. Be sure to talk to your doctor about whether you could benefit from treatment and discuss the treatment options. In addition, there are promising new drugs in clinical trials and in the research pipeline. However, it is vital that all people with chronic hepatitis B visit their doctor on a regular basis, whether they receive treatment or not!