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Chronic Hepatitis B Evaluation and Management. Healthcare in the Global Village: Serving Refugees in Indiana J. Carey Jackson MD, MPH, MA Frank Stackhouse MD, MS 24-25 September 2009 . Screening Tests. HBsAg – surface antigen HBsAb (anti-HBs) – surface antibody

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chronic hepatitis b evaluation and management

Chronic Hepatitis BEvaluation and Management

Healthcare in the Global Village: Serving Refugees in Indiana

J. Carey Jackson MD, MPH, MA

Frank Stackhouse MD, MS

24-25 September 2009

screening tests
Screening Tests
  • HBsAg – surface antigen
  • HBsAb (anti-HBs) – surface antibody
  • HBcAb (anti-HBc) – core antibody
definitions
Definitions
  • Chronic Hepatitis B
  • Inactive HBsAg carrier state
  • Resolved HBV infection
  • Reactivation of hepatitis B
  • HBeAg clearance, seroconversion, reversion
hbeag chronic hepatitis b
HBeAg (–) Chronic Hepatitis B
  • Moderate or high levels of HBV replication after HBeAg seroconversion.
    • HBV DNA > 2000 IU/ml (10,000 copies/ml) and continued inflammation
  • Most patients have HBV variants, with mutations in precore or core promotor region.
  • Often fluctuating course.
initial evaluation of chronic hepatitis b
Initial Evaluation of Chronic Hepatitis B
  • History, Family History, Physical
  • CBC, platelets, hepatic panel, prothrombin time
  • HBeAg , HBV DNA
  • Co-infections
  • Alpha fetoprotein (AFP) , ultrasound
  • Consider liver biopsy
natural history
Natural History
  • Categories are not fixed and shifts from one phase to another are common.
  • Clearance of HBeAg, in transition to carrier state or resolution.
  • Active disease can reappear with reactivation from carrier state or even resolved state.
screening for hcc
Screening for HCC
  • AFP every 6 – 12 months
  • Ultrasound every 6-12 months
  • Frequency depends on assessment of risk
progression to hcc
Progression to HCC
  • Longer duration of infection
  • Male gender; family history of HCC
  • HBV genotype C
  • Cirrhosis
  • High levels of HBV DNA
  • HBeAg positive ; history of reversion to HBeAg
  • Habitual Alcohol
  • Concurrent infection with HCV
  • Carcinogens – aflatoxin, smoking
progression to cirrhosis
Progression to Cirrhosis
  • Longer duration of infection
  • HBV genotype C
  • High levels of HBV DNA
  • HBeAg positive
  • Habitual Alcohol
  • Concurrent infections with HIV,HCV, HDV
  • Carcinogens – aflatoxin, smoking
hbv genotypes
HBV Genotypes
  • 8 Genotypes identified: A-H
  • Based on > 8% divergence of HBV complete sequence
  • Sub-genotypes: Differ in complete genomic sequence by between 4% and 8%
  • Disease outcome appears to be strongly associated with HBV genotype
geographic distribution of hbv genotypes
Geographic distribution of HBV genotypes

Greenland:

B6,D, A

A2, B6, C2,

D, F1

B6, A/B

A2

D

B,C,A2,D

C

C

G

A

D

B1

G

D

B2-5

F, H

A3

F & H

E

A,B1,C

H

F1

B

C

D

A1

A,B,C,D

slide13

Chronic HBV Treatment: Simplified Flow Chart for HBEAg

HBeAg Positive

HBeAg Negative

HBV DNA >20,000 IU/mL

HBV DNA >2,000 IU/mL

ALT Evaluation

Elevated ALT

Normal ALT

Liver Biopsy

Monitor

Abnormal Histology

Treat

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

chronic hbv treatment simplified flow chart for patients with cirrhosis
Chronic HBV Treatment: Simplified Flow Chart for Patients With Cirrhosis

Compensated

Decompensated

DetectableHBV DNA

UndetectableHBV DNA

HBV DNA >2,000 IU/mL

HBVDNA <2,000IU/mL

Treat

Observe or Treat

Treat

Observe

Wait List for Transplant

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

treatment of chronic hbv
Treatment of Chronic HBV
  • Goals
    • Prevent cirrhosis
    • Prevent hepatic failure
    • Prevent hepatocellular carcinoma (HCC)
treatment of chronic hbv16
Treatment of Chronic HBV
  • Assessment of treatment response
    • Normal ALT
    • Decrease in HBV DNA
    • Loss of HBeAg
    • Improvement in liver histology
treatment of chronic hbv17
Treatment of Chronic HBV
  • Interferons
    • Limited efficacy
  • Nucleoside analogues
    • Most commonly used treatment
    • Impair replication
    • Resistance can develop
    • Prolonged or indefinite treatment necessary
    • Combination therapy may be required
hbv replication
HBV replication
  • Double stranded DNA virus
  • Replication steps:

1. Transcription from DNA to RNA

2. Reverse transcription from RNA to negative strand of DNA

3. Synthesis of positive DNA from negative DNA

  • Requires both DNA polymerase and reverse transcriptase
nucleoside and nucleotide analogues
Nucleoside and Nucleotide Analogues
  • L-Nucleoside analogues
    • Lamivudine
    • Telbivudine
    • Emtricitabine
    • Clevudine
  • Acyclic phosphate nucleotide analogues
    • Adefovir
    • Tenofovir
  • Carbocyclic analogues
    • Entecavir
primary nucleoside analogues
Primary Nucleoside Analogues
  • Tenofovir
    • acyclic nucleoside analogue of AMP
    • Inhibits reverse transcriptase
  • Approved for HBV in August 2008
  • Very potent, low resistance
  • Now first line treatment drug
tenofovir df versus adefovir in hbeag positive patients primary and secondary endpoints at 48 weeks
Tenofovir DF Versus Adefovir in HBeAg-PositivePatients: Primary and Secondary Endpoints at 48 Weeks

Tenofovir DF (n=176)

Adefovir (n=90)

74%

76%*

68%

67%*

Patients (%)

13%

12%

Complete Response

Histologic

Improvement

HBV DNA

<400 copies/mL

*P<0.001 versus adefovir.

ITT: missing=failure.

Heathcote J, et al. 58th AASLD. Boston, 2007. Abstract LB6.

tenofovir df versus adefovir in hbeag negative patients primary and secondary endpoints at 48 weeks
Tenofovir DF Versus Adefovir in HBeAg-NegativePatients: Primary and Secondary Endpoints at 48 Weeks

93%*

Tenofovir DF (n=250)

Adefovir (n=125)

72%

69%

71%*

63%

49%

Patients(%)

HBV DNA

<400 copies/mL

Complete Response

Histologic

Improvement

*P<0.001 versus adefovir.

ITT: missing=failure.

Marcellin P, et al. 58th AASLD. Boston, 2007. Abstract LB2.

primary treatment candidates
Primary Treatment Candidates
  • HBeAg positive chronic HBV
    • ALT > 2 times normal and HBV DNA > 20,000 IU/ml
    • Treat until 6 months after HBeAgseroconversion.
  • HBeAg negative chronic HBV
    • ALT > 2 times normal and HBV DNA > 2,000 IU/ml
    • Treat until HBsAg clearance