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Hepatitis B

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Anti-HBe, raised ALT and HBV DNA in serum, chronic hepatitis on biopsy ... Normal ALT. Histological: Improvement ... Fall of ALT levels into the Normal Range ... – PowerPoint PPT presentation

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Title: Hepatitis B


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
(No Transcript)
5
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
6
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

7
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
8
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

9
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

10
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

11
Outcome of Hepatitis B Virus Infection
35
Acute Hepatitis B
65

Asymptomatic subclinical infection
Fulminant Hepatitis
5
Chronic Hepatitis B
30
50
Inactive Carrier State
Cirrhosis
?
Liver Cancer
12
Typical Acute Hepatitis B
HBsAg
HBeAg
ALT
ALT and HBV DNA IU/L and million copies/ml
Symptoms
HBV DNA
Normal
Months After Exposure
13
Typical Chronic Hepatitis B
HBsAg
HBeAg
ALT and HBV DNA IU/L or million copies/ml
HBV DNA
ALT
Normal
Months After Exposure
14
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
15
Evolution of HBeAg Negative Mutant
HBsAg
Anti-HBe
HBeAg
ALT
ALT and HBV DNA IU/L and million copies/ml
HBV DNA
Normal ALT levels
Months
16
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

17
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

18
HBV DNA Detection
10
35,000
8
350
6
3.5
pg/mL
Log10 copies/mL
.035
4
2
.0035

Dynamic Range of Detection of HBV DNA 5 Assays
19
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)

20
Acute Hepatitis B Sentinel 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
21
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
22
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
23
Chronic Hepatitis B Long-Term Complications
  • Cirrhosis
  • Hepatocellular carcinoma
  • Glomerulonephritis
  • Polyarteritis Nodosa

24
Chronic Hepatitis B Histology
  • 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

25
Chronic Hepatitis B Histology 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

26
Chronic Hepatitis B Histology 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

27
Therapy of Hepatitis B
28
Chronic Hepatitis B Goals 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 ?

29
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?

30
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

31
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?

32
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?

33
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
  • Extremely rare in treatment trials of
    HBeAg-negative chronic hepatitis B
  • This response is durable and associated with
    resolution of liver disease

34
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

35
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

36
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

37
Chronic Hepatitis B Long-term Response to
Interferon
Alpha Interferon
ALT
Anti-HBe
HBV DNA (dot blot)
HBeAg
Anti-HBs
HBsAg
Months After Start of Therapy
Patient A
38
Chronic Hepatitis B Response to Interferon
Relapse
Alpha Interferon
ALT
HBeAg
HBeAg
Anti-HBe
HBsAg
Months After Start of Therapy
Patient B
39
HBeAg-Negative Chronic Hepatitis B Response to
Interferon and Relapse
Alpha Interferon
-
-
-




HBV DNA
HBsAg
ALT
Anti-HBe
Months After Start of Therapy
Patient C
40
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

41
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

42
Lamivudine Therapy Maintained 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
43
HBeAg-Negative Chronic Hepatitis B
Lamivudine
HAI 4 200 copies/ml
HAI 13 53.1 million copies/ml
HAI 1 Liver Biopsy HBV DNA
ALT
HBsAg and Anti-HBe
Months After Start of Therapy
Patient C
44
Lamivudine Therapy Viral Resistance
Therapy with Lamivudine (100 mg)
wt
1010
108
HBV DNA
YVDD
HBV DNA Levels
106
ALT
104
102
Normal
HAI Scores Pre 14 Yr 1 10 Yr 4 17 (Cirrhosis)
Patient D
45
Lamivudine for Chronic Hepatitis B Histology
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
46
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
47
Lamivudine Therapy Late 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
48
85
50
49
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

50
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

51
Management of Hepatitis B
  • Initial evaluation Routine liver tests, HBsAg,
    HBeAg anti-HBe, HBV DNA, anti-HDV, abdominal US
  • If ALT elevated HBV DNA present liver biopsy
    and assess for therapy
  • Reserve therapy for patients with significant
    underlying liver disease
  • Therapy?

Lok, Heathcote Hoofnagle 2001
52
Therapy of Chronic Hepatitis B Future Directions
  • Focus must be on combination therapy
  • Long term outcomes with histological verification
    of long-term benefit
  • Loss of HBsAg might be a gold standard
  • Appropriate directions
  • Combinations of alpha interferon lamivudine
  • Nucleoside combinations without cross-reactive
    resistance (lamivudine adefovir or entecavir)
  • Novel approaches immunological or molecular
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