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  • hepatitis(hbv)07

    1. 1. Hepatitis B Virus Huamin Wang 王华民 Department of Microbiology & Immunology Hainan Medical College 2007
    2. 2. Statistics on HBV <ul><li>Most healthy adults (90%) who are infected will recover and develop protective antibodies against future hepatitis B infections </li></ul><ul><li>90% of infants and up to 50% of young children infected with hepatitis B will develop chronic infections . </li></ul>
    3. 3. Hepatitis B In the World <ul><li>2 billion people have been infected (1 out of 3 people). </li></ul><ul><li>400 million people are chronically infected. </li></ul><ul><li>10-30 million will become infected each year. </li></ul><ul><li>An estimated 1 million people die each year from hepatitis B and its complications. </li></ul><ul><li>Approximately 2 people die each minute from hepatitis B. </li></ul>
    4. 4. Hepatitis B In the United States <ul><li>12 million Americans have been infected (1 out of 20 people). </li></ul><ul><li>More than one million people are chronically infected . </li></ul><ul><li>Up to 100,000 new people will become infected each year. </li></ul><ul><li>5,000 people will die each year from hepatitis B and its complications. </li></ul><ul><li>Approximately 1 health care worker dies each day from hepatitis B. </li></ul>
    5. 5. Hepatitis B in China <ul><li>1.3 billion people </li></ul><ul><li>the world's largest population of hepatitis B patients, with nearly half a million people dieing of the liver disease every year </li></ul><ul><li>120 million Chinese have tested positive for hepatitis B, which has become a severe public health problem in the country </li></ul>
    6. 6. General Concepts <ul><li>Hepatitis = 'inflammation of the liver'. </li></ul><ul><li>six medically important viruses are commonly described as “hepatitis viruses”: </li></ul><ul><li>HAV,HBV,HCV,HDV,HEV,HGV . </li></ul>
    7. 7. Definitions for Hepatitises <ul><li>Acute (急性) : Short term and/or severe. </li></ul><ul><li>Chronic (慢性) : Lingering or lasting - may or may not be severe </li></ul><ul><li>Fulminant (爆发性) : Developing quickly and lasting a short time, high mortality rate. </li></ul><ul><li>Cirrhosis (硬化) : Hardening: may be the result of infection or toxins (e.g. alcohol) </li></ul><ul><li>Jaundice (黄疸) : Yellowing of the skin, eyes, etc due to raised levels of bilirubin in the blood due to liver damage. </li></ul><ul><li>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. </li></ul>
    8. 8. A “ Infectious” “ Serum” Viral hepatitis Enterically transmitted Parenterally transmitted F, G, TTV ? other E NANB B D C Viral Hepatitis - Historical Perspectives
    9. 9. Table 24.12
    10. 10. Hepatitis B Virus
    11. 11. 1 、 Properties of HBV <ul><li>a member of the hepadnavirus group </li></ul><ul><li>Circular partially double-stranded DNA viruses </li></ul><ul><li>Replication involves a reverse transcriptase . </li></ul><ul><li>endemic in the human population and hyperendemic in many parts of the world. </li></ul><ul><li>a number of variants </li></ul><ul><li>It has not yet been possible to propogate the virus in cell culture </li></ul>
    12. 12. HBV : Structure
    13. 13. HBV : Structure <ul><li>Virion also referred to as Dane particle (ds-tranded DNA) </li></ul><ul><li>42nm enveloped virus </li></ul><ul><li>Core antigens located in the center (nucleocapsid) </li></ul><ul><ul><li>* Core antigen (HBcAg) </li></ul></ul><ul><li>* e antigen (HBeAg)- an indicator of transmissibility (minor component of the core- antigenically distinct from HBcAg) </li></ul><ul><li>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 </li></ul>
    14. 14. HBV Structure & Antigens 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. 15. decoy particles <ul><li>HBsAg-containing particles are released into the serum of infected people and outnumber the actual virions. </li></ul><ul><li>Spherical or filamentous </li></ul><ul><li>They are immunogenic and were processed into the first commercial vaccine against HBV. </li></ul>
    16. 16. GENOME
    17. 17. <ul><li>There are 4 open reading frames derived from the same strand (the incomplete + strand) </li></ul><ul><li>S - the 3 polypeptides of the surface antigen ( preS1, preS2 and S - produced from alternative translation start sites. </li></ul><ul><li>C - the core protein </li></ul><ul><li>P - the polymerase </li></ul><ul><li>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. </li></ul>Open Reading Frames
    18. 18. 2 、 HBV: Replication <ul><li>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 </li></ul><ul><li>RNA intermediate: HBV replicates through an RNA intermediate and produces and release antigenic decoy particles. </li></ul><ul><li>Integration: Some DNA integrates into host genome causing carrier state </li></ul>
    19. 19. Replication of HBV
    20. 20. <ul><li>Parenteral - IV drug abusers , h ealth w orkers are at increased risk. </li></ul><ul><li>Sexual - sex workers and homosexuals are particular at risk. </li></ul><ul><li>Perinatal ( Vertical) - mother( HBeAg +) -> infant . </li></ul>3 、 HBV: Modes of Transmission
    21. 22. <ul><li>High (>8%): 45% of global population </li></ul><ul><ul><li>lifetime risk of infection >60% </li></ul></ul><ul><ul><li>early childhood infections common </li></ul></ul><ul><li>Intermediate (2%-7%): 43% of global population </li></ul><ul><ul><li>lifetime risk of infection 20%-60% </li></ul></ul><ul><ul><li>infections occur in all age groups </li></ul></ul><ul><li>Low (<2%): 12% of global population </li></ul><ul><ul><li>lifetime risk of infection <20% </li></ul></ul><ul><ul><li>most infections occur in adult risk groups </li></ul></ul>Global Patterns of Chronic HBV Infection
    22. 23. 4 、 Epidemiology <ul><li>350,000,000 carriers worldwide </li></ul><ul><li>120,000,000 carriers in China </li></ul><ul><li>- the carrier rate can exceed 10% </li></ul><ul><li>-15 to 25% of chronically infected patients will die from chronic liver disease </li></ul><ul><li>500,000 deaths/year in China </li></ul><ul><li>982,297 liver disease in China 2005 </li></ul><ul><li>50% of children born to mothers with chronic HBV in the US are Asian American </li></ul>
    23. 24. High Moderate Low/Not Detectable blood semen urine serum vaginal fluid feces wound exudates saliva sweat 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
    24. 26. High-risk groups for HBV infection <ul><li>People from endemic regions </li></ul><ul><li>Babies of mothers with chronic HBV </li></ul><ul><li>Intravenous drug abusers </li></ul><ul><li>People with multiple sex partners </li></ul><ul><li>Hemophiliacs and other patients requiting blood and blood product treatments </li></ul><ul><li>Health care personnel who have contact with blood </li></ul><ul><li>Residents and staff members of institutions for the mentally retarded </li></ul>
    25. 27. Symptomatic Infection Chronic Infection Age at Infection Chronic Infection (%) Symptomatic Infection (%) Birth 1-6 months 7-12 months 1-4 years Older Children and Adults 0 20 40 60 80 100 100 80 60 40 20 0 Outcome of Hepatitis B Virus Infection by Age at Infection Chronic Infection (%)
    26. 28. 5 、 Pathogenesis & Immunity <ul><li>Virus enters hepatocytes via blood </li></ul><ul><li>Immune response (cytotoxic T cell) to viral antigens expressed on hepatocyte cell surface responsible for clinical syndrome </li></ul><ul><li>5 % become chronic carriers (HBsAg> 6 months) </li></ul><ul><li>Higher rate of hepatocellular ca in chronic carriers, especially those who are “e” antigen positive </li></ul><ul><li>Hepatitis B surface antibody likely confers lifelong immunity (IgG anti-HBs) </li></ul><ul><li>Hepatitis B e Ab indicates low transmissibility </li></ul>
    27. 29. 6 、 Clinical Features <ul><li>Incubation period: Average 60-90 days </li></ul><ul><li> Range 45-180 days </li></ul><ul><li>Insidious onset of symptoms. </li></ul><ul><li>Tends to cause a more severe disease than Hepatitis A. </li></ul><ul><li>Clinical illness (jaundice): <5 yrs, <10% ≥ 5 yrs, 30%-50% </li></ul><ul><li>1/3 adults-no symptoms </li></ul><ul><li>Clinical Illness at presentation 10 - 15% </li></ul><ul><li>Acute case-fatality rate: 0.5%-1% </li></ul><ul><li>Chronic infection: < 5 yrs, 30%-90% ≥ 5 yrs, 2%-10% </li></ul><ul><li>More likely in ansymptomatic infections </li></ul><ul><li>Premature mortality from chronic liver disease: 15%-25% </li></ul>
    28. 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 Death
    29. 31. Symptoms HBeAg anti-HBe Total anti-HBc IgM anti-HBc anti-HBs HBsAg 0 4 8 12 16 20 24 28 32 36 52 100 Acute Hepatitis B Virus Infection with Recovery Typical Serologic Course Weeks after Exposure Titre
    30. 32. Acute HBV Infection with Progression to Chronic Infection: Typical Serologic Course IgM anti-HBc Total anti-HBc HBsAg Acute (6 months) HBeAg Chronic (Years) Anti-HBe 0 4 8 12 16 20 24 28 32 36 52 Years Weeks after Exposure Titer
    31. 33. 7 、 Laboratory Diagnosis
    32. 34. 8-1 、 Current Treatment Options <ul><li>Interferon alfa (Intron A) (干扰素) Response rate is 30 to 40%. </li></ul><ul><li>Lamivudine (Epivir HBV) (拉米呋啶) </li></ul><ul><li>( relapse , drug resistance ) </li></ul><ul><li>Adefovir dipivoxil (Hepsera) ( 阿德福韦酯) </li></ul>
    33. 35. 8-2 、 Prevention <ul><li>Vaccination </li></ul><ul><li>- highly effective recombinant vaccines </li></ul><ul><li>Hepatitis B Immunoglobulin ( HBIG ) </li></ul><ul><li>-exposed within 48 hours of the incident / neonates whose mothers are HBsAg and HBeAg positive. </li></ul><ul><li>Other measures </li></ul><ul><li>-screening of blood donors, blood and body fluid precautions. </li></ul>
    34. 36. Hepatitis B Vaccine <ul><li>Infants: several options that depend on status of the mother </li></ul><ul><ul><li>If mother HBsAg negative: birth, 1-2m,6-18m </li></ul></ul><ul><ul><li>If mother HBsAg positive: vaccine and Hep B immune globulin within 12 hours of birth, 1-2m, <6m </li></ul></ul><ul><li>Adults </li></ul><ul><li>* 0,1, 6 months </li></ul><ul><li>Vaccine recommended in </li></ul><ul><ul><li>All those aged 0-18 </li></ul></ul><ul><ul><li>Those at high risk </li></ul></ul>
    35. 37. summary <ul><li>General concepts for hepatitis </li></ul><ul><li>Types of hepatitis </li></ul><ul><li>Properties of HBV : Structure ORFReplication </li></ul><ul><li>Transmission Epidemiology </li></ul><ul><li>Pathogenesis & Immunity </li></ul><ul><li>Clinical Features </li></ul><ul><li>Laboratory Diagnosis </li></ul><ul><li>Treatment Prevention </li></ul>
    36. 38. Questions <ul><li>What is hepatitis B? </li></ul><ul><li>What are the properties of HBV? </li></ul><ul><li>How many ORFs of HBV? </li></ul><ul><li>How is HBV spread? </li></ul><ul><li>How does the HBV curse the liver diseases? </li></ul><ul><li>How do you interpret serological lab results for HBV? </li></ul><ul><li>How to treat and prevent hepatitis B? </li></ul>
    37. 39. Review Quiz <ul><li>Following transmission of HBV from mother to infant, which of the following is the most common medical problem for the infant?  </li></ul><ul><li>A. Liver failure. </li></ul><ul><li>B. Chronic HBV carrier state </li></ul><ul><li>C. Development of lymphoma. </li></ul><ul><li>D. Opportunistic infections. </li></ul><ul><li>E. Development of CNS disease. </li></ul>
    38. 40. Why are the Chinese at greater risk than Westerners? <ul><li>Because there are more Asian people already infected with hepatitis B than Westerners. Although hepatitis B is not an &quot;Asian disease&quot;, 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 </li></ul>
    39. 41. How is hepatitis B spread differently among the Chinese? <ul><li>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. </li></ul><ul><li>Jobs and lifestyle choices can create an equal risk for both groups. However, hepatitis B is often spread differently among Asians. </li></ul><ul><li>Asians are most commonly infected as newborns - from a mother who unknowingly passes the virus on during delivery. </li></ul><ul><li>Young children are also at risk if they live in close daily contact with an infected family member. </li></ul><ul><li>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. </li></ul><ul><li>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 &quot;recover&quot; from an infection. </li></ul>
    40. 42. What does it mean to be a &quot;chronic carrier&quot; of hepatitis B? <ul><li>People who are unable to get rid of the hepatitis B virus are diagnosed as being a &quot;chronic carrier&quot;. </li></ul><ul><li>The virus can stay in their blood and liver for a long time. </li></ul><ul><li>They can unknowingly pass the virus on to other people. </li></ul><ul><li>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. </li></ul><ul><li>However, they have a greater chance than someone who is not infected. </li></ul>
    41. 43. Why should Chinese people be worried about chronic hepatitis B infections? <ul><li>Because chronic hepatitis B can lead to cirrhosis or liver cancer. </li></ul><ul><li>It's important to get tested because early diagnosis can lead to early treatment which can save your life. </li></ul><ul><li>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. </li></ul><ul><li>If people are not tested, hepatitis B can pass through several generations in one family and throughout the community. </li></ul>
    42. 44. How can I stop the spread of hepatitis B? <ul><li>The good news is that you can break the cycle of infection in your family and in the Chinese community. </li></ul><ul><li>Get tested for hepatitis B. </li></ul><ul><li>Make sure everyone in your family is vaccinated against hepatitis B. </li></ul><ul><li>Get the vaccine yourself. </li></ul><ul><li>Look for good medical care. </li></ul><ul><li>Discuss treatment options with your family doctor or a liver specialist if you already have chronic hepatitis B. </li></ul>
    43. 45. Are there any treatments if I have chronic hepatitis B? <ul><li>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: </li></ul><ul><li>1 、 Epivir-HBV or Zeffix (lamivudine) is a pill that is taken orally </li></ul><ul><li>2 、 Hepsera (adefovir dipivoxil) is a pill that is taken orally </li></ul><ul><li>3 、 Baraclude (entecavir) is a pill that is taken orally </li></ul><ul><li>4 、 Intron A (interferon alpha) is a drug given by injection </li></ul><ul><li>5 、 Pegasys (pegylated interferon) is a drug that is give by injection  </li></ul>
    44. 46. Are there any treatments if I have chronic hepatitis B? <ul><li>It is important to know, not every chronic hepatitis B patient needs to be on medication. </li></ul><ul><li>Some patients only need to be monitored by their doctor on a regular basis (at least once a year, or more). </li></ul><ul><li>Other patients with active signs of liver disease may benefit the most from treatment. </li></ul><ul><li>Be sure to talk to your doctor about whether you could benefit from treatment and discuss the treatment options. </li></ul><ul><li>In addition, there are promising new drugs in clinical trials and in the research pipeline. </li></ul><ul><li>However, it is vital that all people with chronic hepatitis B visit their doctor on a regular basis, whether they receive treatment or not! </li></ul>
    45. 47. Thanks!