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Chronic Hepatitis B Evaluation and Management

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

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  1. 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

  2. Screening Tests • HBsAg – surface antigen • HBsAb (anti-HBs) – surface antibody • HBcAb (anti-HBc) – core antibody

  3. Definitions • Chronic Hepatitis B • Inactive HBsAg carrier state • Resolved HBV infection • Reactivation of hepatitis B • HBeAg clearance, seroconversion, reversion

  4. 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.

  5. 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

  6. 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.

  7. Screening for HCC • AFP every 6 – 12 months • Ultrasound every 6-12 months • Frequency depends on assessment of risk

  8. 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

  9. 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

  10. 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

  11. 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

  12. HBV Genotype Association with Outcome

  13. 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.

  14. 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.

  15. Treatment of Chronic HBV • Goals • Prevent cirrhosis • Prevent hepatic failure • Prevent hepatocellular carcinoma (HCC)

  16. Treatment of Chronic HBV • Assessment of treatment response • Normal ALT • Decrease in HBV DNA • Loss of HBeAg • Improvement in liver histology

  17. 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

  18. 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

  19. Nucleoside and Nucleotide Analogues • L-Nucleoside analogues • Lamivudine • Telbivudine • Emtricitabine • Clevudine • Acyclic phosphate nucleotide analogues • Adefovir • Tenofovir • Carbocyclic analogues • Entecavir

  20. 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

  21. 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.

  22. 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.

  23. 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

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