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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
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 b2
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
hepatitis b virus
Hepatitis B Virus

HBeAg

HBsAg

HBsAg

HBcAg

Sphere

HBsAg

Dane Particle

Tubule

slide5

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

hepatitis b viral genome
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
infectious cycle of hepatitis b virus
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

hepatitis b virus mutants
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
hepatitis b core antigen mutants
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
hbeag negative variants
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
slide11

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

typical acute hepatitis b
Typical Acute Hepatitis B

HBsAg

HBeAg

ALT

ALT and HBV DNA

IU/L and million copies/ml

Symptoms

HBV DNA

Normal

Months After Exposure

typical chronic hepatitis b
Typical Chronic Hepatitis B

HBsAg

HBeAg

ALT and HBV DNA

IU/L or million copies/ml

HBV DNA

ALT

Normal

Months After Exposure

chronic hepatitis b transition to inactive carrier state
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

evolution of hbeag negative mutant
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

chronic hepatitis b three clinical forms
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
chronic hepatitis b clinical forms hbv dna levels
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

slide18

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

genotypes of hepatitis b virus
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)

acute hepatitis b sentinel county study 1982 98
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

slide21

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

chronic liver disease united states 1999
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

chronic hepatitis b long term complications
Chronic Hepatitis BLong-Term Complications
  • Cirrhosis
  • Hepatocellular carcinoma
  • Glomerulonephritis
  • Polyarteritis Nodosa
chronic hepatitis b histology
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
chronic hepatitis b histology scoring systems
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
chronic hepatitis b histology scoring systems26
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
chronic hepatitis b goals of therapy
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 ?

therapy of chronic hepatitis b major issues
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?
definition of responses to therapy in chronic hepatitis b
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
virological response in chronic hepatitis b
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?
virological response in chronic hepatitis b32
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?
virological response in chronic hepatitis b33
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
biochemical response in chronic hepatitis b
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
histological response in chronic hepatitis b
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
alpha interferon
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
chronic hepatitis b long term response to interferon
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

chronic hepatitis b response to interferon relapse
Chronic Hepatitis BResponse to Interferon & Relapse

Alpha Interferon

ALT

HBeAg

Anti-HBe

HBeAg

HBsAg

Months After Start of Therapy

Patient B

hbeag negative chronic hepatitis b response to interferon and relapse
HBeAg-Negative Chronic Hepatitis BResponse to Interferon and Relapse

Alpha Interferon

-

-

-

+

+

+

+

HBV DNA

HBsAg

ALT

Anti-HBe

Months After Start of Therapy

Patient C

interferon for chronic hepatitis b problems
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
lamivudine
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
lamivudine therapy maintained response
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

hbeag negative chronic hepatitis b
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

lamivudine therapy viral resistance
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

lamivudine for chronic hepatitis b histology activity index scores
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

slide46

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

lamivudine therapy late relapse
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

slide48

85%

50%

lamivudine49
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
optimal therapy of hepatitis b
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
management of hepatitis b
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

therapy of chronic hepatitis b future directions
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
ad