Management Of Chronic Hepatitis B
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Management Of Chronic Hepatitis B by Dr S Khan Courtesy Of Javed iqbal Farooqi http://www.drkhanblogs.com/2015/05/management-of-chronic-hepatitis-b.html
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Management Of Chronic Hepatitis B
- 1. Management of CHBManagement of CHB (Translating Guidelines into Everyday Practice)(Translating Guidelines into Everyday Practice) Dr. Javed Iqbal FarooqiDr. Javed Iqbal Farooqi FCPS (Med), FCPS (Gastro) Associate Prof of MedicineAssociate Prof of Medicine, LRH, KMU, Peshawar Senior Vice PresidentSenior Vice President, Pakistan Society of Hepatology
- 2. Management of CHBManagement of CHB (Translating Guidelines into Everyday Practice)(Translating Guidelines into Everyday Practice) Concept Building ActivityConcept Building Activity
- 3. Management of CHBManagement of CHB (Translating Guidelines into Everyday Practice)(Translating Guidelines into Everyday Practice) Dedicated toDedicated to World Hepatitis Day 2012World Hepatitis Day 2012
- 7. Learning ObjectivesLearning Objectives • What are the goals and end points of treatment? • How should liver disease be assessed before therapy? • What are the definitions of response? • What is the optimal approach to first-line treatment? • What are the predictors of response? • What definitions of resistance should be applied and how should resistance be managed? • How should treatment be monitored? • When can treatment be stopped? • How should special groups be treated? • What are the current unresolved issues?
- 8. Management of CHBManagement of CHB (Translating Guidelines into Everyday Practice)(Translating Guidelines into Everyday Practice) Burden of CHB?Burden of CHB?
- 9. Geographic Distribution of Chronic HBV Infection HBsAg Prevalence ≥ 8% (high) 2% to 7% (intermediate) < 2% (low) Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.
- 10. Geographic Distribution of Chronic HBV Infection • Approximately one third of the world’s population has serological evidence of past or present infection with HBV • 350–400 million people are chronic HBsAg carriers • The spectrum of disease and natural history of CHB infection are diverse and variable • HBV-related end stage liver disease or HCC are responsible for over 0.5–1 million deaths per year and currently represent 5–10% of cases of liver transplantation • CHB may present either as HBeAg +ive or HBeAg –ive disease
- 11. Management of CHBManagement of CHB (Translating Guidelines into Everyday Practice)(Translating Guidelines into Everyday Practice) Virological profile of HBV?Virological profile of HBV?
- 13. Structure of Hepatitis B Virus
- 14. Structure of Hepatitis B Virus
- 15. Structure of Hepatitis B Virus HBeAg
- 16. Structure of Hepatitis B Virus HBeAg HBcAg
- 20. HBV DNA Wild Type HBV Variant HBV • Eradication is Ideal • Suppression is Possible • Quantification is Mandatory
- 21. Management of CHBManagement of CHB (Translating Guidelines into Everyday Practice)(Translating Guidelines into Everyday Practice) Pathogenesis of CHB?Pathogenesis of CHB?
- 22. Infectious HBV virion cccDNA Replication cycle for HBV Pathogenesis of HBV InfectionPathogenesis of HBV Infection
- 23. A(n) Infectious HBV virion mRNAcccDNA Replication cycle for HBV Pathogenesis of HBV InfectionPathogenesis of HBV Infection
- 24. Partially double- stranded DNA A(n) Infectious HBV virion (-)-DNA mRNAcccDNA DNA pol RT Encapsidated pregenomic mRNA Replication cycle for HBV Pathogenesis of HBV InfectionPathogenesis of HBV Infection
- 25. HBsAg envelopes Partially double- stranded DNA A(n) Infectious HBV virion (-)-DNA mRNAcccDNA DNA pol RT Encapsidated pregenomic mRNA Replication cycle for HBV Pathogenesis of HBV InfectionPathogenesis of HBV Infection
- 26. HBsAg envelopes Partially double- stranded DNA A(n) Infectious HBV virion (-)-DNA mRNAcccDNA DNA pol RT Encapsidated pregenomic mRNA Replication cycle for HBV Pathogenesis of HBV InfectionPathogenesis of HBV Infection
- 27. HBsAg envelopes Partially double- stranded DNA A(n) Infectious HBV virion (-)-DNA Infectious HBV virion mRNAcccDNA DNA pol RT Encapsidated pregenomic mRNA Replication cycle for HBV Pathogenesis of HBV InfectionPathogenesis of HBV Infection
- 28. Management of CHBManagement of CHB (Translating Guidelines into Everyday Practice)(Translating Guidelines into Everyday Practice) Natural Hx of CHB?Natural Hx of CHB?
- 29. Natural History of HBV Infection
- 30. HBeAg +ve HBeAg –ve / anti-HBe +ve Phases of HBV infection Replicative & immune tolerance phase Replicative & Immune clearance Phase Low/Non-Replicative Immune Control Phase Wild-type HBV Variant HBV Brunetto J Hepatol 1991 Replicative Immune Escape Phase Natural History of HBV Infection
- 31. <> HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants) ALT HBV DNA Normal / Mild CH Moderate / Severe CH Moderate / Severe CHNormal / Mild CH Cirrhosis Immune Tolerance Immune Clearance Immune Control Immune Escape Cirrhosis < 2000 IU/mL > 2000 IU/mL Inactive Cirrhosis 2 x 108 - 2 x 1011 IU/mL 200,000 - 2 x 109 IU/mL < > Wild Type HBV Natural History of HBV Infection
- 32. <> HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants) ALT HBV DNA Normal / Mild CH Moderate / Severe CH Moderate / Severe CHNormal / Mild CH Cirrhosis Immune Tolerance Immune Clearance Immune Control Immune Escape Cirrhosis < 2000 IU/mL > 2000 IU/mL Inactive Cirrhosis 2 x 108 - 2 x 1011 IU/mL 200,000 - 2 x 109 IU/mL < > Wild Type HBV Variant HBV Natural History of HBV Infection
- 33. <> HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants) ALT HBV DNA Normal / Mild CH Moderate / Severe CH Moderate / Severe CHNormal / Mild CH Cirrhosis Immune Tolerance Immune Clearance Immune Control Immune Escape Cirrhosis < 2000 IU/mL > 2000 IU/mL Inactive Cirrhosis 2 x 108 - 2 x 1011 IU/mL 200,000 - 2 x 109 IU/mL < > HBs-Seroconversion may occur spontaneously in 1–3% of cases per year, usually after several years with persistently undetectable HBV DNA Natural History of HBV Infection
- 34. Phases of Chronic HBV Infection IndicesIndices Immune Tolerance Phase Immune Clearance Phase (HBeAg+ive CHB) Immune Control Phase Immune Escape Phase (HBeAg-ive CHB) HBV DNA,HBV DNA, IU/mLIU/mL 105 - 1010 104 - 1010 < 104 103 - 108 HBeAgHBeAg HBeAg+ HBeAg+ HBeAg- HBeAg- ALTALT Normal High or fluctuating Normal High or fluctuating OtherOther -- Active inflammation on liver biopsy HBsAg may become undetectable Active inflammation on liver biopsy CandidatesCandidates forfor therapy?therapy? No Yes No Yes Yim HJ, et al. Hepatology. 2006;43:S173-S181. Natural History of HBV Infection
- 35. Cirrhosis Inactive Carrier < 5% Immune Tolerance Early Childhood > 95% HBeAg- Chronic Hepatitis B Natural History of HBV Infection HBeAg+ Chronic Hepatitis B Adulthood (8-20% in 5 years) 20% decompensate in 5 years 65-84% die in 5 years
- 36. Cirrhosis Inactive Carrier < 5% Immune Tolerance Early Childhood > 95% HBeAg- Chronic Hepatitis B Natural History of HBV Infection HBeAg+ Chronic Hepatitis B Adulthood (8-20% in 5 years) 20% decompensate in 5 years 65-84% die in 5 years HCC 2-5% /yr
- 37. Cirrhosis Inactive Carrier < 5% Immune Tolerance Early Childhood > 95% HBeAg- Chronic Hepatitis B Natural History of HBV Infection HBeAg+ Chronic Hepatitis B Adulthood (8-20% in 5 years) 20% decompensate in 5 years 65-84% die in 5 years HCC 2-5% /yr
- 39. Management of CHBManagement of CHB (Translating Guidelines into Everyday Practice)(Translating Guidelines into Everyday Practice) How many Guidelines?How many Guidelines?
- 40. HBV Landscape till 2012 2000 2001 2002 2003 2005 2007 2008 2009 2009 2012 APASL AASLD EASL APASL APASL AASLD APASL EASL AASLD EASL Guidelines
- 42. Management of CHBManagement of CHB (Translating Guidelines into Everyday Practice)(Translating Guidelines into Everyday Practice) How many AV Agents?How many AV Agents?
- 43. HBV Landscape till 2012 1990 1998 2002 2004 2005 2006 2008 IFN Lamivudine Adefovir Peg-IFNL Entacavir Telbivudine Tenofovir Treatment
- 45. Management of CHBManagement of CHB (Translating Guidelines into Everyday Practice)(Translating Guidelines into Everyday Practice) How to go about?How to go about?
- 46. HBV Landscape till 2012 2000 2001 2002 2003 2005 2007 2008 2009 2009 2012 APASL AASLD EASL APASL APASL AASLD APASL EASL AASLD EASL 1990 1998 2002 2004 2005 2006 2008 IFN Lamivudine Adefovir Peg-IFNL Entacavir Telbivudine Tenofovir Guidelines Treatment
- 47. <> HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants) ALT HBV DNA Normal / Mild CH Moderate / Severe CH Moderate / Severe CHNormal / Mild CH Cirrhosis Immune Tolerance Immune Clearance Immune Control Immune Escape Cirrhosis < 2000 IU/mL > 2000 IU/mL Inactive Cirrhosis 2 x 108 - 2 x 1011 IU/mL Phases of Chronic HBV Infection 200,000 - 2 x 109 IU/mL < > Wild Type HBV Variant HBV
- 48. <> HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants) ALT HBV DNA Normal / Mild CH Moderate / Severe CH Moderate / Severe CHNormal / Mild CH Cirrhosis Immune Tolerance Immune Clearance Immune Control Immune Escape Cirrhosis < 2000 IU/mL > 2000 IU/mL Inactive Cirrhosis 2 x 108 - 2 x 1011 IU/mL Phases of Chronic HBV Infection 200,000 - 2 x 109 IU/mL < > Wild Type HBV Variant HBV AVTAVT AVTAVT
- 49. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB: No HDV, HCV, HIVNo HDV, HCV, HIV No Fulminant or Severe HepatitisNo Fulminant or Severe Hepatitis
- 50. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB: No HDV, HCV, HIVNo HDV, HCV, HIV No Fulminant or Severe HepatitisNo Fulminant or Severe Hepatitis
- 51. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB: No HDV, HCV, HIVNo HDV, HCV, HIV No Fulminant or Severe HepatitisNo Fulminant or Severe Hepatitis
- 52. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB: No HDV, HCV, HIVNo HDV, HCV, HIV No Fulminant or Severe HepatitisNo Fulminant or Severe Hepatitis Initiate AVTInitiate AVT Follow-upFollow-up ++ --
- 53. Management of CHBManagement of CHB (Translating Guidelines into Everyday Practice)(Translating Guidelines into Everyday Practice) What are the possibleWhat are the possible Scenarios?Scenarios?
- 54. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB:
- 55. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB: What about Liver Biopsy?What about Liver Biopsy? Consider liver biopsy ± therapy in:Consider liver biopsy ± therapy in: - HBeAg +ive CHB (ITP) patients over 30 years of age and/or with a family history of HCC or cirrhosis - HBeAg -ive CHB (IEP) patients with persistently normal ALT Levels and HBV DNA levels above 2000 but below 20,000 IU/ml EASL Guidelines 2012EASL Guidelines 2012
- 56. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB: What about Liver Biopsy?What about Liver Biopsy? Liver Biopsy not needed in:Liver Biopsy not needed in: - Liver Cirrhosis - HBeAg-positive and HBeAg-negative patients with ALT above 2 times ULN and serum HBV DNA above 20,000 IU/ml - Start treatment even without a liver biopsy EASL Guidelines 2012EASL Guidelines 2012
- 57. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB:
- 58. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB:
- 59. Management of CHBManagement of CHB (Translating Guidelines into Everyday Practice)(Translating Guidelines into Everyday Practice) When to start AVT?When to start AVT? What about the dosage?What about the dosage? What are the types of AVT?What are the types of AVT?
- 60. Liver Society Guidelines* HBeAg Positive HBeAg Negative HBV DNA, IU/mL ALT HBV DNA, IU/mL† ALT APASL 2008 ≥ 20,000 > 2 x ULN ≥ 2000 > 2 x ULN AASLD 2009 > 20,000 > 2 x ULN or positive biopsy ≥ 20,000 ≥ 2 x ULN or positive biopsy EASL 2012 > 2000 > ULN > 2000 > ULN 1. APASL: Liaw YF, et al. Hepatol Int. 2008;3:263-283. 2. AASLD: Lok AS, et al. Hepatology. 2009;50:661-662. 3. EASL.: CPG on Management of CHB. J Hepatol (2012), http://dx.doi.org/10.1016/j.jhep.2012.02.010 When to start Treatment? CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice
- 61. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB: Agent Route Recommended Dosing Adult Children Interferon alfa S/C 5 MU daily or 10 MU 3 x per wk 6 MU/m2 3 x per wk (max: 10 MU) Peginterferon alfa-2a S/C 180 µg/wk Not approved Lamivudine PO 100 mg QD*† 3 mg/kg/day (max: 100 mg/day) Adefovir PO 10 mg QD* Not approved‡ Entecavir PO 0.5 mg QD (no previous LAM) 1.0 mg QD (if refr/resist to LAM)* Not approved Telbivudine PO 600 mg QD* Not approved Tenofovir PO 300 mg QD* Not approved *Dose adjustment needed if eGFR < 50 mL/min.
- 62. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB: Agent Route Recommended Dosing Adult Children Interferon alfa S/C 5 MU daily or 10 MU 3 x per wk 6 MU/m2 3 x per wk (max: 10 MU) Peginterferon alfa-2a S/C 180 µg/wk Not approved Lamivudine PO 100 mg QD*† 3 mg/kg/day (max: 100 mg/day) Adefovir PO 10 mg QD* Not approved‡ Entecavir PO 0.5 mg QD (no previous LAM) 1.0 mg QD (if refr/resist to LAM)* Not approved Telbivudine PO 600 mg QD* Not approved Tenofovir PO 300 mg QD* Not approved *Dose adjustment needed if eGFR < 50 mL/min.
- 63. Approximate Relative Antiviral Potency 20081998 2002 2005 2006 + ++ ++++ +++ ++++ ADV LdTETV TDFLAM Genetic Barrier* 1 1 3 1 ? *Number of mutations needed for primary antiviral drug resistance. CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice
- 64. Entecavir Tenofovir Log HBV DNA ↓ at Wk 48-52 HBeAg positive 6.9 6.2 HBeAg negative 5.0 4.6 Genotypic resistance, % NA naive 1.2 (Yr 5) 0 (Yr 3) Lamivudine experienced 51 (Yr 5) NR Pregnancy rating Class C Class B AEs None Renal toxicity; ↓ BMD Lok AS. Hepatology. 2010;52:743-747. 21 2 < 1 21 3 0 0 5 10 15 20 25 HBeAg seroconversion HBsAg loss Entecavir Tenofovir HBeAg Negative HBsAg loss HBeAg Positive ResponseatWk48-52(%) CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice
- 66. Management of CHBManagement of CHB (Translating Guidelines into Everyday Practice)(Translating Guidelines into Everyday Practice) When to stop AVT?When to stop AVT?
- 67. <> HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants) ALT HBV DNA Normal / Mild CH Moderate / Severe CH Moderate / Severe CHNormal / Mild CH Cirrhosis Immune Tolerance Immune Clearance Immune Control Immune Escape Cirrhosis < 2000 IU/mL > 2000 IU/mL Inactive Cirrhosis 2 x 108 - 2 x 1011 IU/mL Phases of Chronic HBV Infection 200,000 - 2 x 109 IU/mL < > AVTAVT AVTAVT Wild Type HBV Variant HBV
- 68. <> HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants) ALT HBV DNA Normal / Mild CH Moderate / Severe CH Moderate / Severe CHNormal / Mild CH Cirrhosis Immune Tolerance Immune Clearance Immune Control Immune Escape Cirrhosis < 2000 IU/mL > 2000 IU/mL Inactive Cirrhosis 2 x 108 - 2 x 1011 IU/mL Phases of Chronic HBV Infection 200,000 - 2 x 109 IU/mL < > AVTAVT AVTAVT HBeAg - Serological ResponseHBeAg - Serological Response Wild Type HBV Variant HBV
- 69. <> HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants) ALT HBV DNA Normal / Mild CH Moderate / Severe CH Moderate / Severe CHNormal / Mild CH Cirrhosis Immune Tolerance Immune Clearance Immune Control Immune Escape Cirrhosis < 2000 IU/mL > 2000 IU/mL Inactive Cirrhosis 2 x 108 - 2 x 1011 IU/mL Phases of Chronic HBV Infection 200,000 - 2 x 109 IU/mL < > AVTAVT AVTAVT HBeAg - Serological ResponseHBeAg - Serological Response Virological ResponseVirological Response
- 70. <> HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants) ALT HBV DNA Normal / Mild CH Moderate / Severe CH Moderate / Severe CHNormal / Mild CH Cirrhosis Immune Tolerance Immune Clearance Immune Control Immune Escape Cirrhosis < 2000 IU/mL > 2000 IU/mL Inactive Cirrhosis 2 x 108 - 2 x 1011 IU/mL Phases of Chronic HBV Infection 200,000 - 2 x 109 IU/mL < > AVTAVT AVTAVT HBeAg - Serological ResponseHBeAg - Serological Response Virological ResponseVirological Response Biochemical ResponseBiochemical Response
- 71. <> HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants) ALT HBV DNA Normal / Mild CH Moderate / Severe CH Moderate / Severe CHNormal / Mild CH Cirrhosis Immune Tolerance Immune Clearance Immune Control Immune Escape Cirrhosis < 2000 IU/mL > 2000 IU/mL Inactive Cirrhosis 2 x 108 - 2 x 1011 IU/mL Phases of Chronic HBV Infection 200,000 - 2 x 109 IU/mL < > AVTAVT AVTAVT HBeAg - Serological ResponseHBeAg - Serological Response Virological ResponseVirological Response Biochemical ResponseBiochemical Response Histological ResponseHistological Response
- 72. <> HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants) ALT HBV DNA Normal / Mild CH Moderate / Severe CH Moderate / Severe CHNormal / Mild CH Cirrhosis Immune Tolerance Immune Clearance Immune Control Immune Escape Cirrhosis < 2000 IU/mL > 2000 IU/mL Inactive Cirrhosis 2 x 108 - 2 x 1011 IU/mL Phases of Chronic HBV Infection 200,000 - 2 x 109 IU/mL < > AVTAVT AVTAVT HBeAg - Serological ResponseHBeAg - Serological Response Virological ResponseVirological Response Biochemical ResponseBiochemical Response Histological ResponseHistological Response HBsAg - Serological ResponseHBsAg - Serological Response
- 73. <> HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants) ALT HBV DNA Normal / Mild CH Moderate / Severe CH Moderate / Severe CHNormal / Mild CH Cirrhosis Immune Tolerance Immune Clearance Immune Control Immune Escape Cirrhosis < 2000 IU/mL > 2000 IU/mL Inactive Cirrhosis 2 x 108 - 2 x 1011 IU/mL Phases of Chronic HBV Infection 200,000 - 2 x 109 IU/mL < > AVTAVT AVTAVT HBeAg - Serological ResponseHBeAg - Serological Response Virological ResponseVirological Response Biochemical ResponseBiochemical Response Histological ResponseHistological Response HBsAg - Serological ResponseHBsAg - Serological Response CompleteComplete Response:Response: Defined as sustained off- treatment Virological Response together with loss of HBsAg
- 74. Management of CHBManagement of CHB (Translating Guidelines into Everyday Practice)(Translating Guidelines into Everyday Practice) How should I treat?How should I treat?
- 75. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB:
- 76. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB: • Compensated Liver Cirrhosis:Compensated Liver Cirrhosis: – Peg-IFN / Tenofovir / Entecavir [0.5 mg], (No Lamivudine) – Close monitoring of HBV DNA levels every 3 Months – NA therapy should usually be continued indefinitely in cirrhotic patients – After at least 12 months of consolidation therapy, treatment might be stopped: • In HBeAg-positive patients after confirmed HBe-Seroconversion or ideally HBs-Seroconversion • In HBeAg-negative patients after confirmed HBs-Seroconversion
- 77. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB: • Decompensated Liver Cirrhosis:Decompensated Liver Cirrhosis: – Tenofovir / Entecavir [1mg], (No Peg-IFN & Lamivudine) – Close monitoring of HBV DNA levels every 3 Months – Life-long therapy needed – Liver Transplantation is needed in most of the cases
- 78. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB:
- 80. Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday PracticeCHB: PatientsPatients Finite TherapyFinite Therapy Long-term TherapyLong-term Therapy HBeAg +ive CHBHBeAg +ive CHB Peg-IFN or IFN Entecavir or Tenofovir Entecavir or Tenofovir HBeAg –ive CHBHBeAg –ive CHB Peg-IFN or IFN
- 81. Response (%), 6M Peg-IFN Nucleoside analogues Nucleotide analogues Peg-IFN-2a Peg-IFN-2b Lamivudine Telbivudine Entecavir Adefovir Tenofovir Dose (12M) 180 µg 100 µg 100 mg 600 mg 0.5 mg 10 mg 245 mg HBeAg +ive CHB Biochemical 41 32 41-72 77 68 48-54 68 Virological 14 7 36-44 60 67 13-21 76 HBeAg Serological 32 29 16-18 22 21 12-18 21 HBsAg Serological 3 7 0-1 0.5 2 0 3 HBeAg -ive CHB Biochemical 59 71-79 74 78 72-77 76 Virological 19 72-73 88 90 51-63 93 HBsAg Serological 4 0 0 0 0 0 CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice
- 82. CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice
- 83. CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice HBeAg +ive CHBHBeAg +ive CHB HBeAg –ive CHBHBeAg –ive CHB
- 84. CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice 3 M HBeAg +ive CHBHBeAg +ive CHB HBeAg –ive CHBHBeAg –ive CHB Primary non-responsePrimary non-response has not been well established
- 85. 6 M CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice 3 M HBeAg +ive CHBHBeAg +ive CHB HBeAg –ive CHBHBeAg –ive CHB Primary non-responsePrimary non-response has not been well established Virological responseVirological response is defined as an HBV DNA concentration of less than 2000 IU/ml. It is usually evaluated at 6 months and at the end of therapy as well as at 6 and 12 months after the end of therapy. + 12 M
- 86. + + 12 M 12 M6 M CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice 3 M HBeAg +ive CHBHBeAg +ive CHB HBeAg –ive CHBHBeAg –ive CHB Primary non-responsePrimary non-response has not been well established Virological responseVirological response is defined as an HBV DNA concentration of less than 2000 IU/ml. It is usually evaluated at 6 months and at the end of therapy as well as at 6 and 12 months after the end of therapy. Sustained off-treatment ResponseSustained off-treatment Response is defined as HBV DNA levels below 2000 IU/ml for at least 12 months after the end of therapy.
- 87. CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice
- 88. CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice HBeAg +ive CHBHBeAg +ive CHB
- 89. CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice 3 M HBeAg +ive CHBHBeAg +ive CHB Primary ResponsePrimary Response is defined as more than 1 log10 IU/ml decrease in HBV DNA level from baseline at 3 months of therapy.
- 90. 6 M CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice 3 M HBeAg +ive CHBHBeAg +ive CHB Virological ResponseVirological Response is defined as undetectable HBV DNA by a sensitive PCR assay. It is usually evaluated every 3–6 months during therapy depending on the severity of liver disease and the type of NA. + ? M Primary ResponsePrimary Response is defined as more than 1 log10 IU/ml decrease in HBV DNA level from baseline at 3 months of therapy.
- 91. + + ? M 12 M6 M CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice 3 M HBeAg +ive CHBHBeAg +ive CHB Maintained RMaintained Response is defined as Virological Response along-with HBeAg Seroconversion maintained for at least 12 months after the end of therapy. Primary ResponsePrimary Response is defined as more than 1 log10 IU/ml decrease in HBV DNA level from baseline at 3 months of therapy. Virological ResponseVirological Response is defined as undetectable HBV DNA by a sensitive PCR assay. It is usually evaluated every 3–6 months during therapy depending on the severity of liver disease and the type of NA.
- 92. + + ? M 12 M6 M CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice 3 M HBeAg +ive CHBHBeAg +ive CHB Maintained RMaintained Response is defined as Virological Response along-with HBeAg Seroconversion maintained for at least 12 months after the end of therapy. Primary ResponsePrimary Response is defined as more than 1 log10 IU/ml decrease in HBV DNA level from baseline at 3 months of therapy. Virological ResponseVirological Response is defined as undetectable HBV DNA by a sensitive PCR assay. It is usually evaluated every 3–6 months during therapy depending on the severity of liver disease and the type of NA. Finite therapy with NAs Finite therapy with NAs
- 93. CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice HBeAg +ive CHB:HBeAg +ive CHB: Who do not achieve HBeAg Seroconversion during initial treatment HBeAg -ive CHBHBeAg -ive CHB Long-term therapy Long-term therapy X X
- 94. CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice Few Issues Few Issues
- 95. CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice 3 M Primary non-responsePrimary non-response seems to be more frequent with Adefovir (approximately 10– 20%) than with other NAs because of suboptimal antiviral efficacy. In NA(s) naive patients with primary non-response to Adefovir, a rapid switch to Tenofovir or Entecavir is recommended
- 96. CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice Partial Virological ResponsePartial Virological Response is defined as a decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA after at least 6 months of therapy in compliant patients. What to do in case of PVR?What to do in case of PVR? - Check for compliance - Change to Entecavir or Tenofovir: -Lamivudine or Telbivudine with PVR at week 24 - Adefovir with PVR at week 48 -In case of Entecavir or Tenofovir: - In case of declining levels of viremia, Continue the same or Change over - Otherwise, Add-on approach
- 97. CHB: Translating GuidelinesTranslating Guidelines into Everyday Practiceinto Everyday Practice Virological breakthroughVirological breakthrough is defined as a confirmed increase in HBV DNA level of more than 1 log10 IU/ml compared to the nadir (lowest value) HBV DNA level on therapy; it may precede a biochemical breakthrough, characterized by an increase in ALT levels. The main causes of virological breakthrough on NA therapy are poor adherence to therapy and/or selection of drug-resistant HBV variants (resistance) The rates of resistance at 5 years in NA naive patients are <1.5% and 0% for Entecavir and Tenofovir, respectively; thus, virological breakthroughs in NA naive patients receiving Entecavir or Tenofovir are usually due to poor drug compliance
- 98. 0%0% 0% 24%24% 49%49% 67%67%38%38% 0%0% 3%3% 11%11% 18%18% 70%70% 4%4% 17%17% 29%29% 0.2% 1.2% 1.2%0.5% 1.2% 1.2% Yr 3 Yr 4Yr 2Yr 1 Yr 5 Yr 6 LAM ETV LdT ADV TDF EASL. J Hepatol. 2009;50:227-242. Tenny DJ, et al. EASL 2009. Abstract 20. Marcellin P, et al. AASLD 2009. Abstract 481. Heathcote E, et al. AASLD 2009. Abstract 483. Not head-to-head trials; different patient populations and trial designs Cumulative Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients Drug Generation 1st 2nd 3rd
- 99. HBVDNA(log10IU/mL) ALT(U/L) Biochemical breakthrough ULN Viral breakthrough 0 1 2 3 Years 0 2 4 6 8 Hepatitis flare Genotypic resistance -1 Antiviral Treatment HBV Resistance to Antiviral Drugs
- 100. HBV Resistance to Antiviral Drugs • Genotypic resistance: detection of mutations in the HBV genome, known to confer resistance, that develop during antiviral therapy • Virologic breakthrough: rebound in serum HBV DNA levels following the development of genotypic resistance; consistent (at least twice, 1 month apart) increase in serum HBV DNA by > 1 log above nadir while on treatment, after achieving initial response • Viral rebound: Increase in serum HBV DNA to > 20,000 IU/mlor above pretreatment level after achieving virologic response, during continued treatment • Biochemical breakthrough: virologic breakthrough with increased ALT levels or worsening histology, after achieving initial response NIH Meeting; Bethesda, Md; April 2006.
- 101. PegIFN HBeAg+ive CHB Virologic Response 0 1 2 3 4 5 6 7 8 Primary Response 2000 IU/mL (10000 cop/mL) Limit of detection (< 10 – 15 IU/ml) Weeks 0 4 12 18 2424 30 36 42 4848 60 72 84 96968 108 HBVDNA(log10IU/mL) SVR Breakthrough Relapse 1 log10 decline Primary Non-response
- 102. Oral (A,E,T) HBeAg+ive CHB Virologic Response 0 1 2 3 4 5 6 7 8 Primary Response Limit of detection (< 10 – 15 IU/ml) Weeks 0 4 12 18 24 30 36 42 4848 60 72 84 96968 108 HBVDNA(log10IU/mL) Breakthrough Relapse 1 log10 decline Primary Non-response SVR Partial Response
- 103. Oral (L,Tlb) HBeAg+ive CHB Virologic Response 0 1 2 3 4 5 6 7 8 Primary Response Limit of detection (< 10 – 15 IU/ml) Weeks 0 4 12 18 2424 30 36 42 4848 60 72 84 96968 108 HBVDNA(log10IU/mL) Breakthrough Relapse 1 log10 decline Primary Non-response SVR Partial Response
- 104. PegIFN HBeAg-ive CHB Virologic Response 0 1 2 3 4 5 6 7 8 Primary Response 2000 IU/mL (10000 cop/mL) Limit of detection (< 10 – 15 IU/ml) Weeks 0 4 12 18 2424 30 36 42 4848 60 72 84 96968 108 HBVDNA(log10IU/mL) SVR Breakthrough Relapse 1 log10 decline Primary Non-response
- 105. Oral (A,E,T) HBeAg-ive CHB Virologic Response 0 1 2 3 4 5 6 7 8 Limit of detection (< 10 – 15 IU/ml) Weeks 0 4 12 18 24 30 36 42 48 54 60 66 728 78 HBVDNA(log10IU/mL) Breakthrough Relapse 1 log10 decline Primary Non-response 102 MVR Primary Response Partial Response
- 106. Oral (L,Tlb) HBeAg-ive CHB Virologic Response 0 1 2 3 4 5 6 7 8 Limit of detection (< 10 – 15 IU/ml) Weeks 0 4 12 18 24 30 36 42 48 54 60 66 728 78 HBVDNA(log10IU/mL) Breakthrough Relapse 1 log10 decline Primary Non-response 102 MVR Partial Response Primary Response
- 107. Management of CHB – “Rule of 2”Management of CHB – “Rule of 2” 2 Prerequisites2 Prerequisites HBsAg+ive for > 6 M HBV-DNA PCR +ive (> 2000 IU/ml) 2 Determinants2 Determinants Ultrasound abdomen Normal CLPD Serum ALT Normal > 2 x ULN 2 Types of Patients2 Types of Patients HBeAg+ive CHB HBeAg-ive CHB 2 Types of AVT2 Types of AVT Peg-IFN Oral Entecavir Tenofovir 2 Types of Response2 Types of Response PCR ± HBeAg Seroconversion ALT Normalization 2 Types of DNA Suppression2 Types of DNA Suppression Sustained Maintained 2 Types of Therapies2 Types of Therapies Finite Therapy Long-term / Life-long Therapy
- 108. Learning ObjectivesLearning Objectives • What are the goals and end points of treatment? • How should liver disease be assessed before therapy? • What are the definitions of response? • What is the optimal approach to first-line treatment? • What are the predictors of response? • What definitions of resistance should be applied and how should resistance be managed? • How should treatment be monitored? • When can treatment be stopped? • How should special groups be treated? • What are the current unresolved issues?
Notas del editor
- HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. Worldwide, the endemicity of chronic hepatitis B varies by geographic region as shown on this slide. High endemic regions are defined by a hepatitis B surface antigen (HBsAg) prevalence of 8% or higher; regions of intermediate endemicity demonstrate 2% to 7% HBsAg seropositivity; and low endemic regions are defined as populations with &lt; 2% HBsAg seropositivity.
- Message: Reverse transcription of RNA into DNA is a critical step in the viral replication pathway and is the site of action for oral antiviral therapies. Information: The replication cycle of HBV begins with the attachment of the infectious HBV virus particle (the virion) to the hepatocyte. After virus entry, HBV DNA is transported to the cell nucleus, where the partially double-stranded DNA viral genome is converted by host enzymes into covalently closed circular DNA (cccDNA). This highly stable form of HBV DNA acts as a template for transcription of mRNA encoding viral proteins and for transcription of the pregenomic RNA. Once the core protein, the pregenomic RNA, and the HBV polymerase have been transcribed, they are transported into the cell cytoplasm and the viral capsid is assembled. Replication of the viral genome occurs within the capsid. In the viral capsid, HBV polymerase reverse transcribes the pregenomic RNA template to produce a negative-sense strand of HBV DNA. Once the negative-sense strand is complete, it is used as a template to produce a positive-sense strand and restore the original, double-stranded DNA configuration. However, as HBV DNA synthesis proceeds, the nascent viral particles acquire viral envelopes within the endoplasmic reticulum. This terminates synthesis of the positive-sense strand and results in an incomplete double-stranded genome. The newly-formed viral particles are exported from the host cell by budding through the cell membrane. Alternatively, the nucleocapsid particles may be recycled back to the nucleus to maintain a stable pool of viral cccDNA. Reference: 1. Jilbert AR et al. Hepatitis virus guides 2. Lai CL, Locarnini S, ed. Int Med Press 2002:43-53.
- Message: Reverse transcription of RNA into DNA is a critical step in the viral replication pathway and is the site of action for oral antiviral therapies. Information: The replication cycle of HBV begins with the attachment of the infectious HBV virus particle (the virion) to the hepatocyte. After virus entry, HBV DNA is transported to the cell nucleus, where the partially double-stranded DNA viral genome is converted by host enzymes into covalently closed circular DNA (cccDNA). This highly stable form of HBV DNA acts as a template for transcription of mRNA encoding viral proteins and for transcription of the pregenomic RNA. Once the core protein, the pregenomic RNA, and the HBV polymerase have been transcribed, they are transported into the cell cytoplasm and the viral capsid is assembled. Replication of the viral genome occurs within the capsid. In the viral capsid, HBV polymerase reverse transcribes the pregenomic RNA template to produce a negative-sense strand of HBV DNA. Once the negative-sense strand is complete, it is used as a template to produce a positive-sense strand and restore the original, double-stranded DNA configuration. However, as HBV DNA synthesis proceeds, the nascent viral particles acquire viral envelopes within the endoplasmic reticulum. This terminates synthesis of the positive-sense strand and results in an incomplete double-stranded genome. The newly-formed viral particles are exported from the host cell by budding through the cell membrane. Alternatively, the nucleocapsid particles may be recycled back to the nucleus to maintain a stable pool of viral cccDNA. Reference: 1. Jilbert AR et al. Hepatitis virus guides 2. Lai CL, Locarnini S, ed. Int Med Press 2002:43-53.
- Message: Reverse transcription of RNA into DNA is a critical step in the viral replication pathway and is the site of action for oral antiviral therapies. Information: The replication cycle of HBV begins with the attachment of the infectious HBV virus particle (the virion) to the hepatocyte. After virus entry, HBV DNA is transported to the cell nucleus, where the partially double-stranded DNA viral genome is converted by host enzymes into covalently closed circular DNA (cccDNA). This highly stable form of HBV DNA acts as a template for transcription of mRNA encoding viral proteins and for transcription of the pregenomic RNA. Once the core protein, the pregenomic RNA, and the HBV polymerase have been transcribed, they are transported into the cell cytoplasm and the viral capsid is assembled. Replication of the viral genome occurs within the capsid. In the viral capsid, HBV polymerase reverse transcribes the pregenomic RNA template to produce a negative-sense strand of HBV DNA. Once the negative-sense strand is complete, it is used as a template to produce a positive-sense strand and restore the original, double-stranded DNA configuration. However, as HBV DNA synthesis proceeds, the nascent viral particles acquire viral envelopes within the endoplasmic reticulum. This terminates synthesis of the positive-sense strand and results in an incomplete double-stranded genome. The newly-formed viral particles are exported from the host cell by budding through the cell membrane. Alternatively, the nucleocapsid particles may be recycled back to the nucleus to maintain a stable pool of viral cccDNA. Reference: 1. Jilbert AR et al. Hepatitis virus guides 2. Lai CL, Locarnini S, ed. Int Med Press 2002:43-53.
- Message: Reverse transcription of RNA into DNA is a critical step in the viral replication pathway and is the site of action for oral antiviral therapies. Information: The replication cycle of HBV begins with the attachment of the infectious HBV virus particle (the virion) to the hepatocyte. After virus entry, HBV DNA is transported to the cell nucleus, where the partially double-stranded DNA viral genome is converted by host enzymes into covalently closed circular DNA (cccDNA). This highly stable form of HBV DNA acts as a template for transcription of mRNA encoding viral proteins and for transcription of the pregenomic RNA. Once the core protein, the pregenomic RNA, and the HBV polymerase have been transcribed, they are transported into the cell cytoplasm and the viral capsid is assembled. Replication of the viral genome occurs within the capsid. In the viral capsid, HBV polymerase reverse transcribes the pregenomic RNA template to produce a negative-sense strand of HBV DNA. Once the negative-sense strand is complete, it is used as a template to produce a positive-sense strand and restore the original, double-stranded DNA configuration. However, as HBV DNA synthesis proceeds, the nascent viral particles acquire viral envelopes within the endoplasmic reticulum. This terminates synthesis of the positive-sense strand and results in an incomplete double-stranded genome. The newly-formed viral particles are exported from the host cell by budding through the cell membrane. Alternatively, the nucleocapsid particles may be recycled back to the nucleus to maintain a stable pool of viral cccDNA. Reference: 1. Jilbert AR et al. Hepatitis virus guides 2. Lai CL, Locarnini S, ed. Int Med Press 2002:43-53.
- Message: Reverse transcription of RNA into DNA is a critical step in the viral replication pathway and is the site of action for oral antiviral therapies. Information: The replication cycle of HBV begins with the attachment of the infectious HBV virus particle (the virion) to the hepatocyte. After virus entry, HBV DNA is transported to the cell nucleus, where the partially double-stranded DNA viral genome is converted by host enzymes into covalently closed circular DNA (cccDNA). This highly stable form of HBV DNA acts as a template for transcription of mRNA encoding viral proteins and for transcription of the pregenomic RNA. Once the core protein, the pregenomic RNA, and the HBV polymerase have been transcribed, they are transported into the cell cytoplasm and the viral capsid is assembled. Replication of the viral genome occurs within the capsid. In the viral capsid, HBV polymerase reverse transcribes the pregenomic RNA template to produce a negative-sense strand of HBV DNA. Once the negative-sense strand is complete, it is used as a template to produce a positive-sense strand and restore the original, double-stranded DNA configuration. However, as HBV DNA synthesis proceeds, the nascent viral particles acquire viral envelopes within the endoplasmic reticulum. This terminates synthesis of the positive-sense strand and results in an incomplete double-stranded genome. The newly-formed viral particles are exported from the host cell by budding through the cell membrane. Alternatively, the nucleocapsid particles may be recycled back to the nucleus to maintain a stable pool of viral cccDNA. Reference: 1. Jilbert AR et al. Hepatitis virus guides 2. Lai CL, Locarnini S, ed. Int Med Press 2002:43-53.
- Message: Reverse transcription of RNA into DNA is a critical step in the viral replication pathway and is the site of action for oral antiviral therapies. Information: The replication cycle of HBV begins with the attachment of the infectious HBV virus particle (the virion) to the hepatocyte. After virus entry, HBV DNA is transported to the cell nucleus, where the partially double-stranded DNA viral genome is converted by host enzymes into covalently closed circular DNA (cccDNA). This highly stable form of HBV DNA acts as a template for transcription of mRNA encoding viral proteins and for transcription of the pregenomic RNA. Once the core protein, the pregenomic RNA, and the HBV polymerase have been transcribed, they are transported into the cell cytoplasm and the viral capsid is assembled. Replication of the viral genome occurs within the capsid. In the viral capsid, HBV polymerase reverse transcribes the pregenomic RNA template to produce a negative-sense strand of HBV DNA. Once the negative-sense strand is complete, it is used as a template to produce a positive-sense strand and restore the original, double-stranded DNA configuration. However, as HBV DNA synthesis proceeds, the nascent viral particles acquire viral envelopes within the endoplasmic reticulum. This terminates synthesis of the positive-sense strand and results in an incomplete double-stranded genome. The newly-formed viral particles are exported from the host cell by budding through the cell membrane. Alternatively, the nucleocapsid particles may be recycled back to the nucleus to maintain a stable pool of viral cccDNA. Reference: 1. Jilbert AR et al. Hepatitis virus guides 2. Lai CL, Locarnini S, ed. Int Med Press 2002:43-53.
- ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CH, chronic hepatitis; HBeAg, hepatitis B e antigen. This section of the slide illustrates the histology. A patient can develop cirrhosis during any of these different phases but most commonly this occurs when the ALT is oscillating or elevated and HBV DNA is actively replicating.
- ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CH, chronic hepatitis; HBeAg, hepatitis B e antigen. This section of the slide illustrates the histology. A patient can develop cirrhosis during any of these different phases but most commonly this occurs when the ALT is oscillating or elevated and HBV DNA is actively replicating.
- ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CH, chronic hepatitis; HBeAg, hepatitis B e antigen. This section of the slide illustrates the histology. A patient can develop cirrhosis during any of these different phases but most commonly this occurs when the ALT is oscillating or elevated and HBV DNA is actively replicating.
- To answer these questions, we can review the phases of chronic HBV infection, as recently summarized in Hepatology. Across the top of this slide are the 4 recognized phases of chronic HBV infection: the immune-tolerance phase, the immune-clearance phase (and these are patients with HBeAg-positive chronic hepatitis B), the inactive, nonreplicative carrier stage, and finally, the reactivation phase, which is characterized clinically as HBeAg-negative chronic hepatitis B. The characteristics of each stage are shown on the table in this slide. For the immune tolerance phase, the DNA level is high, HBeAg is positive, and ALT is persistently normal in repetitive tests. If a liver biopsy were performed—which is not typically done in a clinical practice—it would be normal. Given these characteristics, these individuals are not considered candidates for therapy because there is no immune reaction against the virus. After a period of many years or decades in the immune-tolerance phase, patients infected vertically early in life proceed to the immune-clearance phase. The key difference in this phase is that the ALT level is high or fluctuating. If performed, a liver biopsy would show active inflammation and may show variable amounts of scar tissue. These individuals are candidates for therapy. The next state is the inactive, nonreplicative carrier state that an individual will eventually enter, even if they do not undergo treatment. In this situation, the HBV DNA level is low (usually &lt; 104 IU/mL), HBeAg becomes negative, anti‑HBe becomes positive, and ALT levels normalize. These individuals, at a low frequency of approximately 1% per year, may lose HBsAg later in life. Because of their inactive status, these individuals are not candidates for therapy. Some patients, after entering the nonreplicative phase, experience reactivation because of the development of a precore or core promoter mutation. In this case, HBV DNA becomes high once again (although HBeAg remains negative), the ALT level again becomes high or fluctuates, and a liver biopsy would show active inflammation. This category is the second one in which patients are considered candidates for therapy.
- HBeAg, hepatitis B e antigen; HBV, hepatitis B virus. The diagram on this slide shows the natural history of HBV infection. A patient who acquires HBV infection early in childhood typically goes through a period of immune tolerance during which the HBV DNA level is very high, liver enzymes are normal, and there is minimal histologic injury. At some point, the disease may evolve into active, HBeAg-positive chronic HBV infection during which liver injury occurs. Patients who are infected with HBV later in life and develop chronic infection may enter directly into the active, HBeAg-positive phase. From this phase, patients may enter into inactive carrier or nonreplicative status from which they may either have subsequent reactivation of wild-type HBeAg-positive disease or develop HBeAg-negative, precore or basal core promoter mutant chronic HBV infection. Ongoing liver injury from either HBeAg-positive or HBeAg-negative infection can lead to cirrhosis and progressive liver disease.
- HBeAg, hepatitis B e antigen; HBV, hepatitis B virus. The diagram on this slide shows the natural history of HBV infection. A patient who acquires HBV infection early in childhood typically goes through a period of immune tolerance during which the HBV DNA level is very high, liver enzymes are normal, and there is minimal histologic injury. At some point, the disease may evolve into active, HBeAg-positive chronic HBV infection during which liver injury occurs. Patients who are infected with HBV later in life and develop chronic infection may enter directly into the active, HBeAg-positive phase. From this phase, patients may enter into inactive carrier or nonreplicative status from which they may either have subsequent reactivation of wild-type HBeAg-positive disease or develop HBeAg-negative, precore or basal core promoter mutant chronic HBV infection. Ongoing liver injury from either HBeAg-positive or HBeAg-negative infection can lead to cirrhosis and progressive liver disease.
- HBeAg, hepatitis B e antigen; HBV, hepatitis B virus. The diagram on this slide shows the natural history of HBV infection. A patient who acquires HBV infection early in childhood typically goes through a period of immune tolerance during which the HBV DNA level is very high, liver enzymes are normal, and there is minimal histologic injury. At some point, the disease may evolve into active, HBeAg-positive chronic HBV infection during which liver injury occurs. Patients who are infected with HBV later in life and develop chronic infection may enter directly into the active, HBeAg-positive phase. From this phase, patients may enter into inactive carrier or nonreplicative status from which they may either have subsequent reactivation of wild-type HBeAg-positive disease or develop HBeAg-negative, precore or basal core promoter mutant chronic HBV infection. Ongoing liver injury from either HBeAg-positive or HBeAg-negative infection can lead to cirrhosis and progressive liver disease.
- ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CH, chronic hepatitis; HBeAg, hepatitis B e antigen. This section of the slide illustrates the histology. A patient can develop cirrhosis during any of these different phases but most commonly this occurs when the ALT is oscillating or elevated and HBV DNA is actively replicating.
- ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CH, chronic hepatitis; HBeAg, hepatitis B e antigen. This section of the slide illustrates the histology. A patient can develop cirrhosis during any of these different phases but most commonly this occurs when the ALT is oscillating or elevated and HBV DNA is actively replicating.
- AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; APASL, Asian Pacific Association for the Study of the Liver; EASL, European Association for the Study of the Liver; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; ULN, upper limit of normal. How do the AASLD treatment guidelines compare to the guidelines from the other societies? An important difference is in the recommended HBV DNA threshold levels. The EASL guidelines recommend that therapy should be considered in HBeAg-positive and HBeAg-negative patients with HBV DNA levels &gt; 2000 IU/mL, whereas the AASLD guidelines recommend an HBV DNA threshold of 20,000 IU/mL for both groups. The HBV DNA threshold recommended in the APASL guidelines is 2000 IU/mL for HBeAg-negative patients and 20,000 IU/mL for HBeAg-positive patients. Furthermore, the EASL guidelines suggest that any elevation of liver enzymes be considered an indication for treatment, whereas the APASL and the AASLD guidelines recommend initiation of therapy at ALT levels &gt; 2 times the upper limit of normal.
- AE, adverse event; BMD, bone mineral density; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; NA nucleos(t)ide analogue. Available data suggest that first-line use of entecavir or tenofovir results in similar virologic response rates in HBeAg-positive and HBeAg-negative patients. Rates of e-antigen seroconversion in HBeAg-positive patients are also similar between the 2 agents, as is the rate of surface-antigen loss. In HBeAg-negative patients, rates of surface-antigen loss are also comparable between treatments. The resistance profiles of entecavir and tenofovir are broadly similar, particularly in patients who are treatment naive. However, in patients who have previously received lamivudine, entecavir resistance rates can be as high as 51% after 5 years of entecavir treatment. Both drugs have favorable pregnancy ratings: tenofovir is rated class B and entecavir is class C. Use of entecavir has not been associated with a risk of major adverse events, whereas a risk of renal toxicity and possibly a decline in bone mineral density is associated with tenofovir treatment in some patients. should this be nucleos(t)ide throughout?
- ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CH, chronic hepatitis; HBeAg, hepatitis B e antigen. This section of the slide illustrates the histology. A patient can develop cirrhosis during any of these different phases but most commonly this occurs when the ALT is oscillating or elevated and HBV DNA is actively replicating.
- ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CH, chronic hepatitis; HBeAg, hepatitis B e antigen. This section of the slide illustrates the histology. A patient can develop cirrhosis during any of these different phases but most commonly this occurs when the ALT is oscillating or elevated and HBV DNA is actively replicating.
- ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CH, chronic hepatitis; HBeAg, hepatitis B e antigen. This section of the slide illustrates the histology. A patient can develop cirrhosis during any of these different phases but most commonly this occurs when the ALT is oscillating or elevated and HBV DNA is actively replicating.
- ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CH, chronic hepatitis; HBeAg, hepatitis B e antigen. This section of the slide illustrates the histology. A patient can develop cirrhosis during any of these different phases but most commonly this occurs when the ALT is oscillating or elevated and HBV DNA is actively replicating.
- ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CH, chronic hepatitis; HBeAg, hepatitis B e antigen. This section of the slide illustrates the histology. A patient can develop cirrhosis during any of these different phases but most commonly this occurs when the ALT is oscillating or elevated and HBV DNA is actively replicating.
- ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CH, chronic hepatitis; HBeAg, hepatitis B e antigen. This section of the slide illustrates the histology. A patient can develop cirrhosis during any of these different phases but most commonly this occurs when the ALT is oscillating or elevated and HBV DNA is actively replicating.
- ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CH, chronic hepatitis; HBeAg, hepatitis B e antigen. This section of the slide illustrates the histology. A patient can develop cirrhosis during any of these different phases but most commonly this occurs when the ALT is oscillating or elevated and HBV DNA is actively replicating.
- ADV, adefovir; ETV, entecavir; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir. Exposure to oral anti-HBV agents presents a risk of evolving drug resistance. Cumulative rates of resistance differ between agents, with higher rates reported with the use of older agents. In nucleos(t)ide-naive patients, treatment with lamivudine was associated with relatively high rates of resistance: 24% at Year 1, rising to 70% by Year 5. Reported rates of resistance were lower with use of the second-generation drugs adefovir and telbivudine. Data on telbivudine are limited to 2 years of follow-up, at which point resistance was reported in 17% of patients on first-line therapy. The cumulative rate for adefovir was 29% at Year 5. The resistance profile of the third-generation agents entecavir and tenofovir is different. For tenofovir, 3-year follow-up of naive patients found no evidence of emergent resistance. For entecavir, the rate of resistance in comparable populations remained low: 1.2% at Year 6 of therapy. For more information, go online to http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Copenhagen%202009/Tracks/HBV%20Treatment/Capsules/20.aspx
- cEVR, complete early virologic response; EVR, early virologic response; PegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response. After the initiation of hepatitis C treatment, it is important to assess viral clearance at various time points. The first key time point for assessing viral clearance is at Week 4. This should be conducted using a sensitive quantitative or qualitative assay. Rapid virologic response (RVR) is defined as the clearance of the virus by Week 4. Many HCV-infected patients who do not clear the virus by Week 4 will achieve viral clearance by Week 12. These patients are said to have achieved a complete early virologic response. Patients who experience a decline in HCV RNA of at least 2 log10 IU/mL by Week 12 and then later clear the virus between Weeks 12-24 are known as partial early virologic responders or slow virologic responders. Given these differences in response rates in individuals, a fixed duration of therapy of 48 weeks in genotype 1 HCV–infected patients results in varied treatment efficacy. For example, 48 weeks of therapy among the rapid virologic responders would result in 44 weeks of therapy after virologic negativity was achieved whereas a fixed duration of 48 weeks among the slow virologic responders would result in only 24 weeks of therapy after virologic negativity was achieved. This variation in the duration of therapy following the achievement of virologic negatively has an impact on the eventual SVR rates such that the slow virologic responders tend to have a lower SVR rate when compared with the rapid virologic responders who would be predicted to have the highest SVR rate. This trend has been well documented in clinical trials and retrospective analyses of data.
- cEVR, complete early virologic response; EVR, early virologic response; PegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response. After the initiation of hepatitis C treatment, it is important to assess viral clearance at various time points. The first key time point for assessing viral clearance is at Week 4. This should be conducted using a sensitive quantitative or qualitative assay. Rapid virologic response (RVR) is defined as the clearance of the virus by Week 4. Many HCV-infected patients who do not clear the virus by Week 4 will achieve viral clearance by Week 12. These patients are said to have achieved a complete early virologic response. Patients who experience a decline in HCV RNA of at least 2 log10 IU/mL by Week 12 and then later clear the virus between Weeks 12-24 are known as partial early virologic responders or slow virologic responders. Given these differences in response rates in individuals, a fixed duration of therapy of 48 weeks in genotype 1 HCV–infected patients results in varied treatment efficacy. For example, 48 weeks of therapy among the rapid virologic responders would result in 44 weeks of therapy after virologic negativity was achieved whereas a fixed duration of 48 weeks among the slow virologic responders would result in only 24 weeks of therapy after virologic negativity was achieved. This variation in the duration of therapy following the achievement of virologic negatively has an impact on the eventual SVR rates such that the slow virologic responders tend to have a lower SVR rate when compared with the rapid virologic responders who would be predicted to have the highest SVR rate. This trend has been well documented in clinical trials and retrospective analyses of data.
- cEVR, complete early virologic response; EVR, early virologic response; PegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response. After the initiation of hepatitis C treatment, it is important to assess viral clearance at various time points. The first key time point for assessing viral clearance is at Week 4. This should be conducted using a sensitive quantitative or qualitative assay. Rapid virologic response (RVR) is defined as the clearance of the virus by Week 4. Many HCV-infected patients who do not clear the virus by Week 4 will achieve viral clearance by Week 12. These patients are said to have achieved a complete early virologic response. Patients who experience a decline in HCV RNA of at least 2 log10 IU/mL by Week 12 and then later clear the virus between Weeks 12-24 are known as partial early virologic responders or slow virologic responders. Given these differences in response rates in individuals, a fixed duration of therapy of 48 weeks in genotype 1 HCV–infected patients results in varied treatment efficacy. For example, 48 weeks of therapy among the rapid virologic responders would result in 44 weeks of therapy after virologic negativity was achieved whereas a fixed duration of 48 weeks among the slow virologic responders would result in only 24 weeks of therapy after virologic negativity was achieved. This variation in the duration of therapy following the achievement of virologic negatively has an impact on the eventual SVR rates such that the slow virologic responders tend to have a lower SVR rate when compared with the rapid virologic responders who would be predicted to have the highest SVR rate. This trend has been well documented in clinical trials and retrospective analyses of data.
- cEVR, complete early virologic response; EVR, early virologic response; PegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response. After the initiation of hepatitis C treatment, it is important to assess viral clearance at various time points. The first key time point for assessing viral clearance is at Week 4. This should be conducted using a sensitive quantitative or qualitative assay. Rapid virologic response (RVR) is defined as the clearance of the virus by Week 4. Many HCV-infected patients who do not clear the virus by Week 4 will achieve viral clearance by Week 12. These patients are said to have achieved a complete early virologic response. Patients who experience a decline in HCV RNA of at least 2 log10 IU/mL by Week 12 and then later clear the virus between Weeks 12-24 are known as partial early virologic responders or slow virologic responders. Given these differences in response rates in individuals, a fixed duration of therapy of 48 weeks in genotype 1 HCV–infected patients results in varied treatment efficacy. For example, 48 weeks of therapy among the rapid virologic responders would result in 44 weeks of therapy after virologic negativity was achieved whereas a fixed duration of 48 weeks among the slow virologic responders would result in only 24 weeks of therapy after virologic negativity was achieved. This variation in the duration of therapy following the achievement of virologic negatively has an impact on the eventual SVR rates such that the slow virologic responders tend to have a lower SVR rate when compared with the rapid virologic responders who would be predicted to have the highest SVR rate. This trend has been well documented in clinical trials and retrospective analyses of data.
- cEVR, complete early virologic response; EVR, early virologic response; PegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response. After the initiation of hepatitis C treatment, it is important to assess viral clearance at various time points. The first key time point for assessing viral clearance is at Week 4. This should be conducted using a sensitive quantitative or qualitative assay. Rapid virologic response (RVR) is defined as the clearance of the virus by Week 4. Many HCV-infected patients who do not clear the virus by Week 4 will achieve viral clearance by Week 12. These patients are said to have achieved a complete early virologic response. Patients who experience a decline in HCV RNA of at least 2 log10 IU/mL by Week 12 and then later clear the virus between Weeks 12-24 are known as partial early virologic responders or slow virologic responders. Given these differences in response rates in individuals, a fixed duration of therapy of 48 weeks in genotype 1 HCV–infected patients results in varied treatment efficacy. For example, 48 weeks of therapy among the rapid virologic responders would result in 44 weeks of therapy after virologic negativity was achieved whereas a fixed duration of 48 weeks among the slow virologic responders would result in only 24 weeks of therapy after virologic negativity was achieved. This variation in the duration of therapy following the achievement of virologic negatively has an impact on the eventual SVR rates such that the slow virologic responders tend to have a lower SVR rate when compared with the rapid virologic responders who would be predicted to have the highest SVR rate. This trend has been well documented in clinical trials and retrospective analyses of data.
- cEVR, complete early virologic response; EVR, early virologic response; PegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response. After the initiation of hepatitis C treatment, it is important to assess viral clearance at various time points. The first key time point for assessing viral clearance is at Week 4. This should be conducted using a sensitive quantitative or qualitative assay. Rapid virologic response (RVR) is defined as the clearance of the virus by Week 4. Many HCV-infected patients who do not clear the virus by Week 4 will achieve viral clearance by Week 12. These patients are said to have achieved a complete early virologic response. Patients who experience a decline in HCV RNA of at least 2 log10 IU/mL by Week 12 and then later clear the virus between Weeks 12-24 are known as partial early virologic responders or slow virologic responders. Given these differences in response rates in individuals, a fixed duration of therapy of 48 weeks in genotype 1 HCV–infected patients results in varied treatment efficacy. For example, 48 weeks of therapy among the rapid virologic responders would result in 44 weeks of therapy after virologic negativity was achieved whereas a fixed duration of 48 weeks among the slow virologic responders would result in only 24 weeks of therapy after virologic negativity was achieved. This variation in the duration of therapy following the achievement of virologic negatively has an impact on the eventual SVR rates such that the slow virologic responders tend to have a lower SVR rate when compared with the rapid virologic responders who would be predicted to have the highest SVR rate. This trend has been well documented in clinical trials and retrospective analyses of data.