1 / 52

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

liam
Download Presentation

Hepatitis B

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related