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Hepatitis B

Hepatitis B. Jay H. Hoofnagle, M.D. Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health. FDA Advisory Panel Meeting: August 7, 2002. Hepatitis B. HBV, small double stranded DNA virus Hepadnaviridae

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Hepatitis B

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  1. Hepatitis B Jay H. Hoofnagle, M.D. Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health FDA Advisory Panel Meeting: August 7, 2002

  2. Hepatitis B • HBV, small double stranded DNA virus • Hepadnaviridae • Infection restricted to humans and higher apes • High levels in blood (102 to 1010 copies/ml) • Causes both acute and chronic hepatitis • Parenteral, sexual and maternal-infant spread • Marked geographic variation in incidence • Common in Asia & Africa, uncommon in the United States and Western Europe

  3. Hepatitis B Virus HBeAg HBsAg HBsAg HBcAg Sphere HBsAg Dane Particle Tubule

  4. A A A A A A A A A A A A Hepatitis B Virus RNAs 2.1kb RNA 2.4kb RNA Pre-S1 Pre-S2 -strand ORF-S +strand 3.5kb RNA 5’ DR1 ORF-C ORF-P 5’ DR2 Pre-C ORF-X 0.7kb RNA

  5. Hepatitis B Viral Genome • Circular, partially doubled-stranded DNA • Four open reading frames • HBsAg (pre-S1, pre-S2 and S) • HBcAg (pre-core & core) • Polymerase (multifunctional) • HBxAg (transactivating factor) • Replicates largely in liver • Through RNA intermediate and reverse transcription

  6. Infectious cycle of hepatitis B virus Y Y Y degradation - antigen-specific - non-specific Y Y Y Y Y Virus-half-life: 1-2 days -production:1011-1013/day mutation rate:1-3 x 10-5/site/yr cell death Zeuzem et al: 2000

  7. Hepatitis B Virus Mutants • Variations in nucleotide sequence in one of the HBV genes can result in change in the virological and, in some cases, clinical features of the infection. • S gene: vaccine or HBIG escape mutants • C gene: can affect disease severity or serological and clinical manifestations • P gene: can effect replicative efficiency and resistance to antiviral therapy

  8. Hepatitis B Core Antigen Mutants Nucleocapsid region: Pre-core and Core • Pre-core:May result in inability to produce HBeAg. HBeAg-negative mutants.Most frequently, GA at nt 1896. • Core: Substitutions in core region are frequent among pts with severe disease or resistance to interferon, in areas of major B cell and T cell epitopes, thus important in T cell cytotoxicity and viral clearance

  9. HBeAg-negative Variants • GA at nt 1896 creates a stop codon in the pre-core region that therefore blocks the synthesis of HBeAg. • nt 1896 is in the highly structured stem-loop  encapsidation signal region of HBV RNA and base-pairs with nt 1858 • If nt 1858 is a T (ayw, adr, some adw), stem loop ofis maintained by either G or A; if it is a C (adw), stem loop is disrupted by A and replication is stopped. • Thus HBeAg-negative variants are more common with genotypes B, C and D than genotype A

  10. Outcome of Hepatitis B Virus Infection 35% Acute Hepatitis B 65% <1% Asymptomatic subclinical infection Fulminant Hepatitis 5% Chronic Hepatitis B 30% 50% Inactive Carrier State Cirrhosis ? Liver Cancer

  11. Typical Acute Hepatitis B HBsAg HBeAg ALT ALT and HBV DNA IU/L and million copies/ml Symptoms HBV DNA Normal Months After Exposure

  12. Typical Chronic Hepatitis B HBsAg HBeAg ALT and HBV DNA IU/L or million copies/ml HBV DNA ALT Normal Months After Exposure

  13. Chronic Hepatitis B: Transition to Inactive Carrier State `` HBsAg HBeAg ALT and HBV DNA IU/L and million copies/ml HBV DNA Anti-HBe ALT Normal Months After Exposure

  14. Evolution of HBeAg Negative Mutant HBsAg HBeAg Anti-HBe ALT ALT and HBV DNA IU/L and million copies/ml HBV DNA Normal ALT levels Months

  15. Chronic Hepatitis B: Three Clinical Forms: • HBeAg Positive Chronic Hepatitis B • HBeAg, raised ALT, HBV DNA in serum and chronic hepatitis on biopsy • HBeAg Negative Chronic Hepatitis B • Anti-HBe, raised ALT and HBV DNA in serum, chronic hepatitis on biopsy • Inactive HBsAg Carrier State • Anti-HBe, normal ALT & no HBV DNA, minimal nonspecific changes on biopsy

  16. Chronic Hepatitis B: Clinical Forms: HBV DNA levels • HBeAg Positive Chronic Hepatitis B 107 to 1011 copies per ml • HBeAg Negative Chronic Hepatitis B 104 to 108 copies per ml • Inactive HBsAg Carrier State < 101 to 104 copies per ml

  17. HBV DNA Detection 10 35,000 8 350 6 3.5 pg/mL Log10 copies/mL 4 .035 2 .0035 Dynamic Range of Detection of HBV DNA: 5 Assays

  18. Genotypes of Hepatitis B Virus Type Subtype Geographical Distribution A adw, adw2, ayw1 US, Northern Europe, Africa B adw2, ayw1 China, Indonesia, Vietnam C adr, ayr China, Korea, Japan, Vietnam D ayw2, ayw3 Mediterranian, Middle East, India E ayw4 West Africa F adw4 Polynesia, US (rare) G Europe, US (rare)

  19. Acute Hepatitis BSentinel County Study: 1982-98 • Currently, HBV causes 34% of viral hepatitis • Decline in incidence by 76% between 1987-98 • 20% hospitalized, 1% fatal • Gradual rise in median age (27 to 32 yrs) • More common in men than women • African-Americans > Hispanic whites > whites • Current proportions with risk factors • Injection drug use: 14% • Men who has sex with men: 15% • Heterosexual activity: 40% • Occupational exposure: 2% Goldstein et al: 2002

  20. Acute Hepatitis B Incidence in the U.S.: 1978-1998 HBsAg screening of pregnant women Vaccine licensed Routine infant immunization OSHA Rule Routine adolescent immunization Infections per 100,000 Decline in high-risk heterosexuals Decline in MSM & HCW Decline in injecting drug users Year Alter et al: CDC

  21. Chronic Liver Disease: United States 1999 Other Hepatitis B NASH 10% Hepatitis C 57% Alcohol 25% Hepatitis B accounted for only 4.4% of newly-diagnosed chronic liver disease Bell et al 2001

  22. Chronic Hepatitis BLong-Term Complications • Cirrhosis • Hepatocellular carcinoma • Glomerulonephritis • Polyarteritis Nodosa

  23. Chronic Hepatitis BHistology • Necroinflammatory Changes (Grade) • Periportal inflammation and necrosis (piecemeal necrosis, interface hepatitis) • Lobular inflammation and single cell necrosis • Portal inflammation • Fibrosis (Stage) • Portal • Septa formation • Bridging fibrosis • Cirrhosis

  24. Chronic Hepatitis BHistology Scoring Systems • Histology Activity Index (Knodell) : • Periportal necrosis & inflammation (0-10) • Lobular necrosis & inflammation (0-4) • Portal inflammation (0-4) • Fibrosis • None = 0 • Portal fibrosis = 1 • Bridging fibrosis = 3 • Cirrhosis = 4

  25. Chronic Hepatitis BHistology Scoring Systems • Histology Activity Index (Ishak) : • Periportal necrosis & inflammation (0-4) • Bridging necrosis (0-6) • Lobular necrosis & inflammation (0-4) • Portal inflammation (0-4) • Fibrosis • None = 0 • Portal fibrosis = 1 or 2 • Bridging fibrosis = 3 or 4 • Cirrhosis = 5 or 6

  26. Therapy of Hepatitis B

  27. Chronic Hepatitis BGoals of Therapy • Improve symptoms and quality of life • Decrease infectivity • Prevent progression of disease • Hepatic Decompensation • Death from liver disease What surrogate end-points correlate with these outcomes ?

  28. Therapy of Chronic Hepatitis B: Major Issues • What are appropriate end-points? • Are they the same for different forms of HBV? • Loss of HBeAg • Loss of HBsAg • Loss of HBV DNA (fall below 105 copies/ml) • Normalization of ALT • Improvement in histology • What amount of follow up is appropriate in assessing benefit of therapy?

  29. Definition of Responses to Therapy in Chronic Hepatitis B • Type: • Virological: Loss of HBeAg and/or HBV DNA • Biochemical: Normal ALT • Histological: Improvement in histology scores • Complete: All of above & loss of HBsAg • Timing: • Initial: within first 6 mo of therapy • End-of-therapy: when therapy is stopped • Sustained: 6 or 12 mo after stopping • Maintained: present while continuing therapy

  30. Virological Response in Chronic Hepatitis B Loss of HBeAg and fall of HBV DNA levels to below 105 copies/mL • Occurs in 25-48% of patients given a 4-5 month course of alpha interferon • Occurs in 20-32% of patients given a 12 month course of lamivudine • Occurs in 8-12% of patients on no therapy • Is this response durable and does it result in long-term improvement in disease and lack of progression to cirrhosis and HCC?

  31. Virological Response in Chronic Hepatitis B Loss of HBeAg cannot be used as an endpoint in patients with HBeAg-negative disease • Generally rely upon decrease in HBV DNA to below 105 copies/ml • HBV DNA levels, however, can fluctuate widely, and with nucleoside therapy will rapidly return to baseline when treatment is stopped. • How durable is decrease in HBV DNA without other changes in viral status?

  32. Virological Response in Chronic Hepatitis B Loss of HBsAg and development of anti-HBs • Occurs in 8% of patients given a 4-5 month course of alpha interferon • Occurs in 1-2% of patients given a 12 month course of lamivudine • Occurs in <1% of patients on no therapy • Extremely rare in treatment trials of HBeAg-negative chronic hepatitis B • This response is durable and associated with resolution of liver disease

  33. Biochemical Response in Chronic Hepatitis B Fall of ALT levels into the Normal Range • Often accompanies loss of HBeAg or decrease in HBV DNA to below 105 copies/mL • Not durable unless the decrease in HBV DNA is durable. • Surrogate, indirect marker for decrease in necroinflammatory disease

  34. Histological Response in Chronic Hepatitis B Improvements in Histology • Used in virtually all studies of antiviral therapy • Typically, improvement is called a > 2 point improvement in HAI score (0-22) compared to baseline • However, necroinflammatory scores can change rapidly and improve and worsen • Fibrosis scores represent best evidence for progression of disease and are unlikely to improve with treatment

  35. Alpha Interferon • Human cytokine made by lymphocytes in response to viral infection • Acts through cell-surface receptors • Activates Jak/Stat system • Induces transcription of proteins with antiviral activity (2-5 OAS, PKR, eIF2) • Recombinant human alpha interferon • Pegylated forms now available

  36. Chronic Hepatitis BLong-term Response to Interferon Alpha Interferon ALT HBV DNA (dot blot) Anti-HBe HBeAg Anti-HBs HBsAg Months After Start of Therapy Patient A

  37. Chronic Hepatitis BResponse to Interferon & Relapse Alpha Interferon ALT HBeAg Anti-HBe HBeAg HBsAg Months After Start of Therapy Patient B

  38. HBeAg-Negative Chronic Hepatitis BResponse to Interferon and Relapse Alpha Interferon - - - + + + + HBV DNA HBsAg ALT Anti-HBe Months After Start of Therapy Patient C

  39. Interferon for Chronic Hepatitis B: Problems • Effective in only 1/3rd of cases • Expensive • Side effects are common and can be severe • Not appropriate for many categories of pts: • Immune suppressed • Renal failure or dialysis • Solid organ transplant • Decompensated liver disease

  40. Lamivudine • Negative enantiomer of 3-thiacytidine • Both an unnatural nucleoside and chain terminator • Highly active against HBV in vitro • Dose: 100 mg, once daily by mouth • Approved for use in chronic hepatitis B as one year course of therapy • Continuous, long-term use is common but must be considered experimental

  41. Lamivudine TherapyMaintained Response Therapy with Lamivudine (100 mg/d) ALT 108 HAI Scores: Pre: 14 Yr 1: 4 Yr 4: 1 HBV DNA 106 HBV DNA Levels HBeAg 104 HBsAg 102 Patient B

  42. HBeAg-Negative Chronic Hepatitis B Lamivudine Liver Biopsy HBV DNA HAI = 13 53.1 million copies/ml HAI = 4 200 copies/ml HAI = 1 <100 copies/ml ALT HBsAg and Anti-HBe Months After Start of Therapy Patient C

  43. Lamivudine Therapy:Viral Resistance Therapy with Lamivudine (100 mg) wt 1010 108 HBV DNA YVDD HBV DNA Levels 106 ALT 104 Normal 102 HAI Scores: Pre: 14 Yr 1: 10 Yr 4: 17 (Cirrhosis) Patient D

  44. Lamivudine for Chronic Hepatitis BHistology Activity Index Scores 9.8 9.9 8.4 7.1 Total HAI Scores (0 to 18) 2.5 1.3 9 9 9 13 13 4

  45. Lamivudine for Chronic Hepatitis B: Fibrosis Scores 4.3 4.2 3.9 3.3 2.9 Fibrosis Score (0 to 6) 1.3 9 9 9 13 13 4

  46. Lamivudine TherapyLate Relapse Therapy with Lamivudine (100 mg/d) ALT 108 HAI Scores: Pre: 14 Yr 1: 4 Yr 4: 1 HBV DNA 106 HBV DNA Levels HBeAg 104 HBsAg 102 Patient B

  47. 85% 50%

  48. Lamivudine • The major shortcoming of long-term lamivudine therapy for hepatitis B is emergence of lamivudine resistance • Occurs in 20%-30% of patients per yr, approaching 90% by 5 yrs • Loss of HBsAg, but not loss of HBeAg, appears to reliably predict long-term benefit & ability to stop lamivudine • Future studies should focus on combinations that might prevent resistance

  49. Optimal Therapy of Hepatitis B? • Monotherapy or combination therapy? • For a defined period (48 wks) or continuous? • For all pts or only those with mod-severe disease? • If monotherapy, which agent? • If combination, which combination? • Standard interferon and lamivudine • Pegylated interferon and lamivudine • Lamivudine and adefovir • Lamivudine and entecavir

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