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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 l.jpg
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 l.jpg
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 l.jpg
Hepatitis B Virus

HBeAg

HBsAg

HBsAg

HBcAg

Sphere

HBsAg

Dane Particle

Tubule


Slide5 l.jpg

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


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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


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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


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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 l.jpg
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


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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


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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


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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 l.jpg
Typical Chronic Hepatitis B

HBsAg

HBeAg

ALT and HBV DNA

IU/L or million copies/ml

HBV DNA

ALT

Normal

Months After Exposure


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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


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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


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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


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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


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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


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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)


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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


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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


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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


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Chronic Hepatitis BLong-Term Complications

  • Cirrhosis

  • Hepatocellular carcinoma

  • Glomerulonephritis

  • Polyarteritis Nodosa


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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


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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


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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


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Therapy of Hepatitis B


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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 ?


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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?


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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 l.jpg
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?


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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?


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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


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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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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


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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 l.jpg
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


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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


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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


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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


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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 l.jpg

85%

50%


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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


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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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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


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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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