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  1. 1. Stages of Liver Disease <ul><li>Inflammation </li></ul><ul><li>Fibrosis Thickening and accumulation of scar tissue in the liver </li></ul><ul><li>Cirrhosis Extensive destruction of liver cells with associated scarring </li></ul><ul><li>Liver Cancer </li></ul>
  2. 2. Progression of Hepatitis B Infection Short-term Infection Long-term Hepatitis Cirrhosis 30 - 50 Years Liver Cancer Death Long-term Carrier Resolution Cirrhosis Resolution Death Silent Cirrhosis
  3. 3. Hepatic Fibrosis Cirrhosis Liver Cancer Healthy Liver
  4. 4. Hepatic Fibrosis Cirrhosis Liver Cancer Healthy Liver
  5. 5. Types of Hepatitis <ul><li>Hepatitis How is it acquired? </li></ul><ul><li>A Oral via contaminated food or water </li></ul><ul><li>B Blood/body fluids and mother-to-child </li></ul><ul><li>C Blood/body fluids and mother-to-child </li></ul><ul><li>D Blood/body fluids (only found with hepatitis B virus) </li></ul><ul><li>E Oral via contaminated water </li></ul><ul><li>G Blood </li></ul>Hoofnagle 1994; Linnen et al. 1996
  6. 6. What is Hepatitis B? <ul><li>Hepatitis B is a potentially fatal liver disease caused by the hepatitis B virus (HBV) and is one of the most common infectious diseases in the world </li></ul>
  7. 7. Hepatitis B is a Devastating Global Healthcare Issue <ul><li>350 million long-term carriers worldwide 1 </li></ul><ul><li>Up to 25% will die due to hepatitis B or related complications 2 </li></ul><ul><li>Around 1 million die each year from HBV infection 3 , making it the 9th leading cause of death worldwide 4 </li></ul>RoW Asia Pacific 75% <ul><ul><li>75% of long-term carriers live in Asia Pacific 5 </li></ul></ul>1 WHO 1998; 2 Mast 1993; 3 Lee 1997; 4 Boag 1991; 5 Gust 1996
  8. 8. Hepatitis – Disease Terminology <ul><li>Acute hepatitis </li></ul><ul><li>Short-term hepatitis, during which the body’s immune system clears the virus from the body within 6 months </li></ul><ul><li>Chronic hepatitis </li></ul><ul><li>Long-term hepatitis, in which the infection persists beyond 6 months because the body’s immune system cannot clear the virus from the body </li></ul>
  9. 9. How Hepatitis B is Acquired? <ul><li>In the Asia Pacific region, most people acquire the virus at or near the time of birth 1 - 9 out of 10 of those infected with hepatitis B will still be infected when they reach adulthood 2 </li></ul><ul><li>In the rest of the world, hepatitis B virus is more likely acquired in adolescence or adult life through sexual contact or exposure to contaminated blood 1 </li></ul>1 Margolis et al. 1991; 2 Thomas 1996
  10. 10. How the Infection is Acquired in the West? Transfusion and transplant recipients Individuals with multiple sexual partners Healthcare workers Newborns of long-term carriers Intravenous drug users Prisoners and other institutionalised people
  11. 11. Where Are the Long-term HBV Carriers? Percentage long-term HBV carriers (350 million long-term carriers): < 2% - Low 2-7% - Intermediate > 8% - High Margolis et al. 1991
  12. 12. Hepatitis B – Diagnosis Terminology <ul><li>HBeAg Viral protein produced when virus replicates </li></ul><ul><li>HBV DNA Genetic material of the hepatitis B virus </li></ul><ul><li>ALT/AST Liver enzymes (proteins)-detected at high levels in blood when liver cells are damaged </li></ul><ul><li>Histology Liver tissue sample seen under the microscope to assess liver damage </li></ul>
  13. 13. Diagnosis of Chronic Hepatitis B <ul><li>Medical history and physical examination </li></ul><ul><li>Tests needed because majority of patients have no symptoms </li></ul><ul><li>Blood Tests </li></ul><ul><ul><li>Viral replication (HBV DNA and HBeAg levels) </li></ul></ul><ul><ul><li>Liver damage (liver enzymes - ALT/AST) </li></ul></ul><ul><li>Liver tissue sample (histology) - allows determination of the extent of liver damage </li></ul>
  14. 14. Signs and Symptoms of HBV Infection The majority of patients with chronic hepatitis B have no symptoms <ul><li>Short-Term Infection </li></ul><ul><li>Tiredness or “flu-like” symptoms </li></ul><ul><li>Nausea or stomach ache </li></ul><ul><li>Diarrhoea </li></ul><ul><li>Skin rash </li></ul><ul><li>Yellow eyes/skin (jaundice) </li></ul><ul><li>Light-coloured stools </li></ul><ul><li>Dark yellow urine </li></ul><ul><li>Long-Term Infection </li></ul><ul><li>Same symptoms as acute </li></ul><ul><li>Muscles and joints ache </li></ul><ul><li>Weakness </li></ul><ul><li>Signs and symptoms of cirrhosis </li></ul><ul><li>Signs and symptoms of liver cancer </li></ul>
  15. 15. Prevention of Hepatitis B <ul><li>HBV infection can be prevented in non-infected individuals by vaccination with HBV vaccine. However the millions of infected people will not benefit </li></ul><ul><li>Series of 3 injections at 0, 1 and 6 months </li></ul><ul><li>Vaccination is effective in over 90% of recipients </li></ul><ul><li>By 1998, 80 countries had introduced vaccination programmes </li></ul>Return to Main Index
  16. 16. Universal Hepatitis B Vaccination <ul><li>The Strategy </li></ul><ul><li>All infants to be immunised before the age of 18 months – regardless of country </li></ul><ul><li>In 1998, 80 countries have achieved this goal </li></ul><ul><li>The Experience </li></ul><ul><li>Other childhood vaccines do not interfere with response </li></ul><ul><li>Protection lasts >10 years and booster doses not required </li></ul><ul><li>Screening of pregnant women for HBV markers, ensuring immediate vaccination of infants borne to HBsAg+ve mothers </li></ul>
  17. 17. Hepatitis B Vaccines: Where Further Attention is Needed <ul><li>Immune responses </li></ul><ul><ul><li>seroconversion levels poor in neonates, dialysis patients </li></ul></ul><ul><ul><li>antigenic repertoire restricted to S epitopes </li></ul></ul><ul><ul><li>responses predominantly class II </li></ul></ul><ul><ul><li>assessing importance of HBV “escape” mutants </li></ul></ul><ul><li>Logistics and delivery </li></ul><ul><ul><li>number of doses required annually exceeds 300m </li></ul></ul><ul><ul><li>reaching 60% of infants borne at home </li></ul></ul><ul><ul><li>improving ease of administration </li></ul></ul>
  18. 18. Recommendations for Pre-exposure Vaccination <ul><li>Health care workers at risk of exposure to infected tissues </li></ul><ul><li>Staff at institutions for the developmentally disabled </li></ul><ul><li>Haemophiliacs </li></ul><ul><li>Haemodialysis patients </li></ul><ul><li>Inmates of long-term custodial facilities </li></ul><ul><li>Close family contacts of HBV infected individuals </li></ul>
  19. 19. Recommendations for Post-exposure Vaccination <ul><li>Infants born to HBsAg+ve mothers or to mothers who had acute hepatitis B during pregnancy </li></ul><ul><li>Healthcare workers after needlestick injury involving blood from a HBV infected patient </li></ul><ul><li>Sexual partners of individuals with HBV infection </li></ul>
  20. 20. Conclusions <ul><li>Hepatitis B-related chronic liver disease and hepatocellular carcinoma are best prevented by universal childhood immunisation </li></ul><ul><li>Current vaccines are adequate and safe </li></ul><ul><li>Surveillance is required to monitor for disease and HBV variants </li></ul><ul><li>Improved vaccines are being developed for ease of adminstration, better immunogenicity and postexposure immunotherapy </li></ul>
  21. 21. Global Control of Hepatitis B <ul><li>The two most important interventions in the global control of hepatitis B are………. </li></ul>– the integration of hepatitis B vaccine into national immunisation schedules and – effective treatment of the many millions of chronic carriers of hepatitis B
  22. 25. liver biopsy <ul><li>Percutaneous liver biopsy with or without ultrasonic guidance is a standard diagnostic approach for establishing the presence of chronic hepatitis. Laparoscopic liver biopsy, which is used in large referral centers, has the advantage of minimizing the sample error by facilitating gross inspection of the liver and thus ensuring an adequate biopsy sample size. This figure depicts a laparoscopic view of a patient with chronic active hepatitis and early cirrhosis [20] [21]. (Courtesy of David Bernstein and Eugene R. Schiff.) </li></ul>
  23. 29. Detection of serologic markers of hepatitis B virus (HBV) infection, as a function of time, in acute cases.
  24. 30. The Efficacy and Safety of Lamivudine in HBeAg-positive Chronic Hepatitis B Return to Main Index Enter
  25. 31. Lamivudine is a Potent Inhibitor of HBV Replication <ul><li>A nucleoside analogue: (-)-2’,3’-dideoxy-3’-thiacytidine </li></ul><ul><li>Antiviral activity against HBV and HIV </li></ul><ul><li>Inhibits viral RNA-dependent DNA polymerase </li></ul>
  26. 32. Lamivudine has an Excellent Pharmacokinetic Profile <ul><li>Optimal dose is 100 mg once daily </li></ul><ul><li>Rapidly absorbed </li></ul><ul><li>Minimal liver metabolism </li></ul><ul><li>Excreted unchanged in the urine </li></ul><ul><li>Moderate to severe renal impairment requires dose reduction </li></ul><ul><li>No significant drug interactions </li></ul>
  27. 33. What Patient Populations Have Been Studied in Controlled Clinical Trials? <ul><li>Primary </li></ul><ul><li>Compensated chronic hepatitis B (CHB) with evidence of viral replication in treatment naïve patients </li></ul><ul><li>Others </li></ul><ul><li>Pre-core mutant CHB </li></ul><ul><li>Interferon failures </li></ul>
  28. 34. Key Lamivudine Clinical Studies (1) <ul><li>Lai - Asia Pacific, placebo controlled NUCB3009 study (n=358) - LAM100, LAM25 and PLB </li></ul><ul><li>Leung - Asia Pacific, placebo controlled NUCB3018 follow-on study to NUCB3009 (n=334) - 3 and 4 years LAM100 vs 1 and 2 years LAM100 </li></ul><ul><li>Dienstag - US placebo controlled study NUCA3010 (n=143) - LAM100 and PLB </li></ul>
  29. 35. Key Lamivudine Clinical Studies (2) <ul><li>Tassopoulos - EU placebo controlled study NUCB3014 in pre-core mutants (n=125) - LAM100 and PLB </li></ul><ul><li>Schalm - EU active controlled study in NUCB3010 IFN naïve patients (n=230) - LAM100, IFN and LAM+IFN </li></ul><ul><li>Schiff - EU/US placebo controlled study NUCAB3011 in IFN failures (n=238) - LAM100, PLB and LAM+IFN </li></ul>
  30. 36. Patient Entry Criteria <ul><li>Patients had to have evidence of:- </li></ul><ul><li>CHB - HBsAg +ve for at least 6m </li></ul><ul><li>HBV replication - HBeAg +ve and HBV DNA +ve at screen and for  1m prior to screen </li></ul><ul><li>Liver disease - elevated ALT  1.3xULN but < 10xULN in western studies; normal or elevated ALT in the Asian study </li></ul>
  31. 37. Lamivudine Rapidly Suppresses Serum HBV DNA Study Week Median % Change 0 10 20 30 40 50 Schiff Dienstag Lai Dienstag Schiff Lai Schalm Lamivudine -100 -80 -60 -40 -20 0 10 Placebo
  32. 38. Lamivudine Leads to HBeAg Seroconversion (HBeAg-, Anti-HBe+) Lamivudine + IFN 6 7 21 0 5 10 15 20 25 30 Placebo Lamivudine IFN Lai Dienstag Schalm *p<0.04 compared to placebo Patients (%) 13 14 Schiff 29 * 17 * 20 21 20
  33. 39. One Year of Lamivudine - Conclusions <ul><li>Virology </li></ul><ul><li>Suppresses serum HBV DNA </li></ul><ul><li>Leads to HBeAg seroconversion </li></ul><ul><li>Liver disease </li></ul><ul><li>Improves hepatic necro-inflammation </li></ul><ul><li>Reduces progression of fibrosis </li></ul><ul><li>Reduces progression to cirrhosis </li></ul><ul><li>Normalises serum ALT </li></ul><ul><li>Improves liver histology irrespective of baseline ALT </li></ul>
  34. 40. Resistance to Anti-Viral Drugs <ul><li>Genotypic resistance – changes in the virus that disrupt interactions between the drug and its molecular target </li></ul><ul><li>Clinical resistance – loss of efficacy due to above changes </li></ul>
  35. 42. Concurrent immunologic diseases in type 1 autoimmune hepatitis.
  36. 43. Probabilities of clinical, biochemical, and histologic remission during corticosteroid therapy.
  37. 44. Clinical features of type 2 autoimmune hepatitis. <ul><li>The diagnosis requires the presence of antibodies to liver–kidney microsome type 1 (Anti-LKM1) B ut antibodies to hepatitis C virus and hepatitis C virus RNA may be present </li></ul><ul><li>The disease has been described mainly in pediatric patients in Western Europe, but adults may also be afflicted]. In the United States, seropositivity for Anti-LKM1 has been found in only 4% of adults and hepatitis C virus infection has not been a feature of the disease. </li></ul><ul><li>Patients with type 2 autoimmune hepatitis typically have concurrent immunologic diseases, including autoimmune thyroiditis, insulin-dependent diabetes, vitiligo, and ulcerative colitis </li></ul><ul><li>They have a high frequency of organ-specific autoantibodies, such as parietal cell antibodies, antibodies to the islets of Langerhans, and thyroid antibodies . </li></ul><ul><li>An acute, even fulminant, presentation may occur, and patients uncommonly have a pronounced hypergammaglobulinemia </li></ul>
  38. 45. Liver transplantation for autoimmune hepatitis. <ul><li>Decompensated patients should be considered for liver transplantation. </li></ul><ul><li>The 5-year survival rate after transplantation is 92%. </li></ul><ul><li>Recurrence of disease is rare but possible in inadequately immunosuppressed recipients and in HLA-DR3–positive recipients of HLA-DR3–negative grafts </li></ul>
  39. 46. Survival expectations and probability of developing cirrhosis during and after corticosteroid treatment . <ul><li>Patients without cirrhosis at presentation have better 5- and 10-year survival rates than patients with cirrhosis at presentation </li></ul><ul><li>Cirrhosis develops in 47% of patients within 10 years after presentation despite corticosteroid treatment </li></ul><ul><li>The highest probability of cirrhosis is during initial therapy when the disease is most active. The mean annual incidence of cirrhosis after initial remission is 2.6% </li></ul><ul><li>Survival after the development of cirrhosis during or after treatment is similar to that of patients without cirrhosis </li></ul>