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Chronic Hepatitis B East meets West

B Informed , Doylestown PA. 2002. Chronic Hepatitis B East meets West. Dr Sharat C Misra MD,DM,FACG Gastroenterologist & Hepatologist New Delhi, India. New Delhi. The Ballad of East and West Rudyard Kipling. Oh, East is East and West is West, and never the twain shall meet,

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Chronic Hepatitis B East meets West

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  1. B Informed , Doylestown PA. 2002 Chronic Hepatitis B East meets West Dr Sharat C Misra MD,DM,FACG Gastroenterologist & Hepatologist New Delhi, India

  2. NewDelhi

  3. The Ballad of East and WestRudyard Kipling Oh, East is East and West is West, and never the twain shall meet, Till Earth and Sky stand presently at God's great Judgement Seat; But there is neither East nor West, Border, nor Breed, nor Birth, When two strong men stand face to face, tho' they come from the ends of the earth!

  4. Population GDP/capita Population/Hosp bed Population/Doctor Life Expectancy(birth) Cost of Hosp stay/day Average PCP Fee Average Specialist Fee Direct Insurance cover 1040 mill 285 mill $2200 $36000 1700 0.5 2500 400 65 77 $30 $1200 $1 $30-50 $10 $75 Nil Yes East(India) West(USA) How do we compare?

  5. Hepatitis B Virus

  6. How is Hepatitis B detected? • Incidental blood test Asymptomatic, Blood Donor, Hospitalised for another illness Dialysis • Jaundice • Prodrome, nausea,vomiting: Acute • Ascites, Bleeding, Coma : Chronic

  7. HBV in India What happens next? • Direct access to Labs and Doctors • More blood tests • Family Physician • Medical Specialist • GI/Liver specialist • Go to a hospital/clinic • Do nothing

  8. General Practitioners Dispense medicines/ Inj Charge a low fee Symptomatic Treatment 100 pts/ day Specialists Superspecialists Consultations Procedures Fee 5- 10 high Govt / Private 10-30 pts/day Doctors in India

  9. How I do itHbsAg +ve HBV in India Doc DAY 1 $ 50

  10. HBV in India Hbs Ag +ve Doc DAY 2 • Family screening • Hep B Vaccination for contacts • Hep A Vaccination • Viral Load • Endoscopy $ 250-350

  11. HBV in India Hbs Ag+ve Doc DAY 7-21 • To treat or not to treat? • Interferon : $ 50/wk • Lamivudine: $ 5/wk • Thymosin: $ 300/wk • Peg IFN :$ 300/wk • Indigenous: Phylanthus,”Liver Tonics”

  12. Magnitude of HBV Prevalence Of HBV

  13. 45/400 Million 4 % Carriers Young Age Perinatal Spread Precore mutant HBV Early Complications More Liver Cancer 25% - E antigen +ve 1.25/400 Million 0.5 % Carriers Adults or older Horizontal Spread Wild Type HBV Late Complications Less Liver Cancer 68%- E antigen +ve How HBV effects us?India USA

  14. HBV in India Facts and Figures • 45 million have HBV (2nd after China) • 25% are E antigen +ve • 30% present as Acute Hepatitis • 75% of Cirrhosis/Cancer is due to HBV • 1% of all deaths due to HBV • 5th most important cause of death(15-45y)

  15. HBV in India Why HBV prevalence is high? • Lack of public awareness • No measures for HBV control at National Level • No proper control over blood transfusion practices, sterilization of needles, instruments, use of disposables • Lethargy in HBV vaccination

  16. HBV Vaccination programme New Delhi, India • Free HBV vaccination • At Birth : HepB , Polio • 1 ½ month : DPT, Polio, Hep B • 2 ½ month : DPT, Polio, Hep B • 3 ½ month : DPT, Polio, Hep B

  17. HBV in India Mode of transmission • Parenteral exposure 45% • Sexual 5% • Not Known 50% (Horizontal/At Birth)

  18. HBV in India Horizontal Transmission • Intrafamilial clustering • Sharing of personal articles • Sexual Saliva, body fluids, open wounds

  19. HBV in India Parenteral Transmission • Negligible with screened BT • No commercial blood donation • Acute Hep B in only 1.3% patients in patients undergoing CABG (Misra et al ; Liver 1992)

  20. HBV in India Clinical Spectrum • 30% of all Acute Hepatitis • 50-75% of all Chronic Liver Disease(CLD) • 25% of all CLD is due to Mutant HBV • 30 % of all Fulminant Hepatitis • 80% of all Liver Cancer

  21. Terminology of Chronic HBV Infection Chronic Hepatitis B NIH 2001 • HBsAg positive > 6 months • HBV-DNA>100,000 copies/ml • ALT elevated • HAI on liver biopsy > 3 INASL 1998 Routine DNA testing is expensive

  22. Terminology of Chronic HBV Infection NIH 2001 InactiveHBsAg Carrier State • HBsAg positive > 6 months • HBeAg negative, Anti-HBe positive • ALT normal • HBV-DNA < 100.000 copies/ml • HAI on liver biopsy < 3

  23. Terminology of Chronic HBV Infection INASL 1998 • Chronic HBV Infection without chronic liver disease • Incidentally detected asymptomatic HBsAg positive subjects Not “carriers” as they may reactivate, unlike Caucasions

  24. Terminology of Chronic HBV Infection Resolved hepatitis B • History of acute or chronic Hep B • HBsAg negative • HBV-DNA undetectable • ALT normal

  25. Natural History of CHB ASIA Infection at early age Four Stages • Prolonged Immune Tolerance • Immune Clearance • Non-replicative phase (HBeAg negative) • Reactivation/Replicative phase Carrier Precore mutant Cirrhosis , HCC

  26. Natural History of CHB West Infection is acquired in adulthood • Short Immune tolerance phase • Chronic HBeAg positive hepatitis • Non-replicative phase (Anti-HBe positive) Carrier Mild-Moderate CH Fibrosis Cirrhosis, HCC

  27. Dynamics of HBV infection Recovery Transplant FHF Death symptoms Recovery Acute DNA++ ALT - E+ HBV ChrHep DNA+ ALT++ E+ Chronic ? DNA- ALT - E- Fibrosis asymptomatic mild symptoms DNA +, ALT+E- Cirrhosis complications HCC

  28. Birth HBsAg, E + 5-21yr CLD, E + 30yr Chr Hep ,E – 45yr Cirrhosis 55yr HCC Precore mutant Healthy HbsAg, E + CH No symptom, E - HbsAg,E+ Cirrhosis HCC Asia-Pacific Caucasian

  29. HBV MutantsAsia/MediterraneanGenotype B to E • Precore:Stop codon mutation G 1896 A • Core: Basic core promoter region • Surface – vaccine escape, non-vaccine • X gene, Pre S gene

  30. Life Cycle of Wild HBV

  31. From where does the mutant virus come? Emergence of Precore Mutant HBV • During course of Chronic HepB with Wild/Mutant HBV • De Novo Infection: Unlikely (Reported in a Baby born of HBeAg –ve Mother with Precore mutant HBV)

  32. Emergence of Precore Mutant HBV HBeAg -ve HBeAg +ve G 1896 A mutation Precore Core 1896 DNA

  33. How it happens?Immunopathogenesis of HBeAg Negative CH Tolerance Non Replicative Replicative/ Reactivation Clearance DNA HBeAg + HBeAg - ALT

  34. How it happens? HLA 1 T T T T T T T E ab T C E T T C Immune Clearance PCM WT Immune Tolerance

  35. How it happens? E ab Host Immunity PCM C Inactive phase cccDNA Reactivation phase Liver Progressive Liver Disease Integration

  36. Diagnosis of HbeAg negative CH-B • E antigen -ve, maybe Anti-HBe + • HBV-DNA positive> 106 copies/ml • Intermittent high/normal ALT • Progressive liver disease ( Biopsy) • Core antigen staining in liver tissue • HBV-DNA ( Hybridisation)

  37. Management of Chronic Hep B • Clear the virus • Reduce liver injury • Prevent fibrosis Goal of treatment • Eliminate • Suppress HBV

  38. Short term goals: 6months Normal • ALT • Prevent decompensation of liver • Seroconversion (E Ag to E antibody) • Undetectable HBV-DNA

  39. Long term goals • Prevent flares / reactivation • Prevent fibrosis and cirrhosis • Prolong survival

  40. Who to treat? • ALT X 2-7 times high • HBV-DNA +ve (100,000 copies/ml) • Liver Biopsy is recommended Who not to treat • Normal ALT

  41. When to treat? Lam 700 Drug IFN ALT ALT DNA DNA ALT D 0

  42. Treatment StrategiesViral Kinetics Drug DNA 2 log 0 2wk

  43. Treatment Strategies Liver biopsy Lam I F N HAI>3 35-45% ETR

  44. How to defeat HBV? Universal Vaccination IFN Eliminate from host HBV Newer Strategies Suppress activity in the host LAM

  45. InterferonHbeAg positive CH-B • 30-40% lose E antigen, 80% is sustained 10% lose HBV-DNA, HBsAG • Loss of E antigen - Increased survival - Decreased mortality & complications - Decreased liver cancer

  46. InterferonHbeAg negative CH-B • Meta-analysis of 4 RCTs (1989-1997) ETR: 38-90 % SR : 10-47 % • Longer duration of therapy: 1 year • 2.5 fold in disease progression • 20% lose HBsAg

  47. Lamivudine(HBeAg +/- CHB) • E antigen loss in 35% • ALT normalisation: 50% • Improvement in liver histology: 50% • HBsAg loss < 1% • YMDD mutant emergence • 15-30% - 1yr ; 50% - 3yrs • Relapse after stopping therapy

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