Update on Chronic Hepatitis B

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Update on Chronic Hepatitis B

  1. 1. Dr Nasir Khokhar MD FACP FACG Professor of Medicine and Director, Division of Gastroenterology Shifa International Hospital Islamabad Pakistan Strategies for Optimal HBV Screening, Diagnosis, and Treatment
  2. 2. Diagnosing HBV Infection and Identifying Clinical Status
  3. 3. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Burden of Chronic HBV Disease  ~ 400 million people worldwide living with chronic HBV infection[1] – Yearly, ~ 500,000 people die of HBV-related cirrhosis and HCC – Up to two thirds are unaware of their infection[2]  To reduce disease complications, need to – Identify infected individuals – Assess disease status and need for treatment and other monitoring – Optimize treatment outcomes: issues of who, when, and how to treat 1. Sorrell MF, et al. Ann Intern Med. 2009;150:104-110. 2. Lin SY, et al. Hepatology. 2007;46:1034-1040. 3. CDC. MMWR. 2007;56:446-448.
  4. 4. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Global Distribution of HBV Centers for Disease Control and Prevention. CDC Health Information for International Travel 2010. Prevalence of HBsAg High ≥ 8% Intermediate 2% to 7% Low < 2%
  5. 5. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Impact of Immigration HBsAg Prevalence[2] ≥ 8% (high) 2% to 7% (intermediate) < 2% (low) Immigration Numbers by Continent: 2000-2009[1] ~ 3.6 million Asians ~ 875,000 South Americans ~ 804,000 Africans ~ 1.3 million Europeans 1. US Department of Homeland Security. Yearbook of Immigration Statistics: 2009. 2. Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.
  6. 6. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management  4 overlapping open reading frames  Reverse transcriptase/ DNA polymerase domain overlaps with surface gene  100 times more infective than HIV  Found in blood and body fluids MMWR. 2003;52:1-33. Ott MJ and Aruda M. J Pediatr Health Care. 1999;13:211- 216. Ribeiro RM, et al. Microbes and Infection. 2002;4:829-835. 1622 EcoRI 3221, 1 (+) (-) polymerase Hepatitis B Virus (HBV)
  7. 7. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Transmission Routes and Endemicity  Most primary HBV infections in highly endemic countries occur during infancy or early childhood[1] – Vertical transmission (from infected mother via perinatal exposure) or horizontal transmission  Most primary HBV infections in low prevalence countries occur during adolescence/young adulthood[1] – Transmission routes: unsafe sex practices or injection drug use  ~ 21 million HBV infections worldwide in 2000 attributable to unsafe injection administration in healthcare settings[2] 1. Shepard CW, et al. Epidemiol Rev. 2006;28:112-125. 2. Hauri AM, et al. Int J STD AIDS. 2004;15:7-16.
  8. 8. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management HBeAg and the Risk of HCC Yang et al. N Engl J Med. 2002;347:168-174.  11,893 Taiwanese men; 92,359 person-years (PYs) follow-up  111 cases of HCC diagnosed during follow-up – Incidence highest among individual HBeAg- and HBs Ag+ 39.1 324.3 1169.4 0 200 400 600 800 1000 1200 1400 HBsAg(-) HBeAg(-) HBsAg(+) HBeAg(-) HBsAg(+) HBeAg(+) IncidenceofHCC, Cases/100,000PYs P < .001 P < .001
  9. 9. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Risk of HCC and Cirrhosis According to Baseline HBV DNA HBV DNA (copies/mL) HCC(%perYr)[1] 1. Chen CJ, et al. JAMA. 2006;295:65-73. 2. Iloeje UH, et al. Gastroenterology. 2006;130:678-686. < 300 300-9999 10,000-99,999 100,000-999,999 ≥ 1 million 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 Cirrhosis(%perYr)[2] HBV DNA (copies/mL) < 300 300-9999 10,000-99,999 100,000-999,999 ≥ 1 million 3.0 2.5 2.0 1.5 1.0 0.5 0
  10. 10. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Yim HJ, et al. Hepatology. 2006;43:S173-S181. . Chronic active inflammation Mild hepatitis and minimal fibrosis Minimal inflammation and fibrosis Active inflammation HBeAg Anti-HBeAg HBV DNA ALT activity Classic Concept of HBV Infection in the1980s Phases of Chronic HBV Infection
  11. 11. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Phase Immune Tolerant Immune Clearance Inactive Carrier State Reactivation Liver Minimal inflammation and fibrosis Chronic active inflammation Mild hepatitis and minimal fibrosis Active inflammation Yim HJ, et al. Hepatology. 2006;43:S173-S181. Optimal treatment times Anti-HBeAg HBV DNA ALT activity Current Understanding of HBV Infection 4 Phases of Chronic HBV Infection HBeAg
  12. 12. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management HBV Disease Progression 1. Torresi J, et al. Gastroenterology. 2000;118:S83. 2. Fattovich G, et al. Hepatology. 1995;21:77. 3. Perrillo RP, et al. Hepatology. 2001;33:424. Chronic Infection Cirrhosis Death 5%–10%1 Liver Failure 30%[1] 23% in 5 yr2 Liver Cancer (HCC) Chronic HBV is the 6th leading indication for liver transplantation in the United States:[3] ~5% Liver Transplantation Acute flare 6% in 5 yr[2]
  13. 13. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management HBV ACUTE /CHRONIC HEPATITIS B CIRRHOSIS ESLD HEPATOCELLULAR CARCINOMA 20−30 years Cirrhosis HCCNormal Cirrhosis Chronic hepatitis B – consequences Liver disease progression over time Liver damage = the result of attempts, usually unsuccessful, to clear infected hepatocytes as part of the immunoclearance stage of disease
  14. 14. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Clinical Significance of Viral Replication Worsening histology, including cirrhosis HCC Elevated ALT Viral replication
  15. 15. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962. Lok AS, et al. Hepatology. 2007;45:507-539. Marker Acute HBV Acute HBV Recovery Chronic HBV Disease Inactive HBeAg Carrier StateHBeAg Positive HBeAg Negative HBsAg  (may clear)    Anti-HBs  Anti-HBc IgM  Anti-HBc      HBeAg   Anti-HBe  (in some cases)   Serologic Markers of HBV Infection
  16. 16. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Surrogate Clinical Markers for Hepatitis B Outcomes Prevention of Death, Cirrhosis, and HCC Liver histology Serum HBV DNA ALTSeroconversion
  17. 17. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106. Chu CJ, et al. Gastroenterology. 2003;125:444-451. Chronic Hepatitis B Disease Types  HBeAg positive – Also known as “wild type” – Antibody to HBeAg negative – HBV DNA > 20,000 IU/mL (> 105 copies/mL)  HBeAg negative – Also known as “precore mutant” – Antibody to HBeAg positive – HBV DNA > 2000 IU/mL (> 104 copies/mL)
  18. 18. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Differentiating HBeAg-Negative Chronic HBV from Inactive Carrier State HBeAg-Negative Disease Inactive Carrier HBsAg positive   Anti-HBe positive   Anti-HBc positive   HBV DNA > 104-5 copies/mL* < 103 copies/mL ALT Elevated† Normal Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962. Lok AS, et al. Hepatology. 2007;45:507-539.
  19. 19. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Role of ALT in Assessment of HBV Patients  ALT > 20 IU/L associated with increased risk for liver disease-related death[1]  Patients with mildly elevated ALT (> 1 to 2 x ULN) may be at increased risk of developing complications or fibrosis progression[2,3]  Up to 24% of patients with normal ALT have stage 2-4 fibrosis by biopsy[4,5] 1. Kim HC, et al. BMJ. 2004;328:983-986. 2. Yuen MF, et al. Gut. 2005;54:1610-1614. 3. Lai M, et al. J Hepatol. 2007;47:760-767. 4. Lai M, et al. Hepatology. 2005;42(suppl 1):720A. 5. Alberti A, et al. Ann Intern Med. 2002;137:961-964. 6. Kim WR, et al. Hepatology. 2008;47:1363-1370.
  20. 20. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Histology  Liver biopsy – Establishes disease baseline before initiation of therapy – Helps to exclude other causes of liver disease – More sensitive and accurate than ALT – Limitations – Invasive procedure – Sampling error – Interobserver variability
  21. 21. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Initial Evaluation
  22. 22. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Initial Evaluation of Patients With Chronic HBV Infection  Medical history and physical examination – Family history of HBV infection and liver cancer  Consider liver biopsy to grade and stage possible liver disease  Laboratory tests to assess liver disease – CBC with platelets, hepatic panel, prothrombin time  Serology – HBeAg/anti-HBe – HBsAg/anti-HBs  Virology – HBV DNA (PCR based)  Test for viral coinfection (HIV, HCV, ± HDV) Lok AS, et al. Hepatology. 2007;45:507-539.
  23. 23. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management What Is a “Normal” ALT Level?  9221 first-time potential blood donors  74% suitable donors after exclusion of anemia, seizure, sexual, and other risk – 57% determined to be at “low risk” for liver disease – Negative viral serology – BMI < 25  Updated healthy ALT ranges determined from the group of low-risk individuals – Males: 30 IU/L – Females: 19 IU/L Prati D, et al. Ann Intern Med. 2002;137:1-10.
  24. 24. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Brunetto MR, et al. J Hepatol. 2002;36:263-270. Significance of ALT Fluctuation  A single normal ALT level does not always indicate a patient is immune tolerant  64.1% of 164 HBsAg-positive/HBeAg-negative patients followed for 1 yr had recurrent flares  ALT should be monitored over time
  25. 25. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management  1387 asymptomatic HBsAg-positive patients with ≥ 1-yr follow-up  21% of HBeAg-negative patients with PNALT and HBV DNA < 5 log copies/mL had HAI ≥ 3 and/or fibrosis stage ≥ 2 Kumar M, et al. Gastroenterology. 2008;134:1376-1384. *≥ 3 ALT values in the previous 1 yr prior to baseline liver biopsy that were all ≤ 40 IU/L and remained so until the start of treatment or the last follow-up. 60.3 39.735.3 13.8 0 20 40 60 80 100 HBV DNA ≥ 5 log copies/mL Histologic Fibrosis Stage ≥ 2 HBeAg positive HBeAg negative Patients(%) Patients With Normal ALT May Have Significant Fibrosis
  26. 26. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Advanced Fibrosis in Patients With Normal/Near-Normal ALT  Mean stage of fibrosis similar between patients with normal and elevated ALT – Elevated ALT: 2.0 – Normal ALT: 1.7 Goebel T, et al. AASLD 2008. Abstract 973. Patients With Normal ALT 24 42 26 0 20 40 60 80 100 Cirrhosis Fibrosis Inflammation Patients(%)
  27. 27. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Favorable Outcomes in Patients With High HBV DNA, Normal ALT  240 HBeAg-positive individuals (male 130, female 110); mean age: 27.6 yrs  Mean follow-up: 10.5 yrs (range: 3-20)  Spontaneous HBeAg seroconversion in 85% between the ages of 20 and 39 yrs  Reactivation of hepatitis after HBeAg seroconversion in 2.2% per yr  Progression to cirrhosis in 5.4% after 10 yrs  HCC: none Chu CM, et al. Am J Med. 2004;116:829-834.
  28. 28. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management HBV DNA Testing  Indicates chronic hepatitis when still positive 6 months after diagnosis of acute HBV infection – Can differentiate chronic, inactive carrier (< 2000 IU/mL) vs resolved HBV infection (undetectable)  Change in HBV DNA level used to monitor response to therapy  Increasing HBV DNA level during antiviral therapy indicates emergence of resistant variants  HBV DNA level correlates with disease progression Adapted from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.
  29. 29. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Impact of HBV Genotype on Disease Progression  Genotype C (Asia) – More frequently associated with severe liver disease and HCC than genotype B  Genotype B – Associated with seroconversion from HBeAg to anti-HBe at younger age than genotype C  Genotypes A and B – Higher rates of antiviral response and HBeAg loss following pegIFN alfa than genotypes D and C, respectively Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962. HBV Genotyping Line Probe Assay Marker line Conj. control Amp. control Genotype A Genotype B Genotype C Genotype D Genotype E Genotype F Genotype G 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
  30. 30. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Can HBV Infection Be Cured?  HBV is not curable with current therapy (none targets cccDNA intra-hepatocyte) but it is controllable  HBsAg seroconversion is the ultimate form of viral control
  31. 31. Goals of HBV Therapy
  32. 32. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Primary Goal of Hepatitis B Therapy: Preventing Cirrhosis, HCC, and Death  Prolonged viral suppression is associated with – Reduction in necroinflammation, fibrosis, and cirrhosis – Reduction in decompensation/reactivation – Reduction in rates of HCC – Reduction in mortality Durable Suppression of HBV Replication Impact of viral suppression on liver disease outcomes
  33. 33. Who to Treat
  34. 34. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Benefits Risks Patient’s age and preference, costs Likelihood of  Adverse outcome  Long-lasting response Adverse effects Drug resistance Likelihood of adverse clinical outcome without treatment Activity and stage of liver disease at presentation Risk of cirrhosis/HCC in the next 10-20 yrs Likelihood of long-term benefit with treatment HBV: Who Should Be Treated?
  35. 35. What to Treat With
  36. 36. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Interferon alfa-2b Lamivudine Adefovir Peginterferon alfa-2a Telbivudine Tenofovir 1990 1998 2002 2005 2006 2008 Entecavir HBV Treatment Landscape
  37. 37. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Decision to treat IFN (PegIFN alfa-2a) Nucleos(t)ide analogues The First Branch Point in Choosing What to Treat With
  38. 38. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Advantages and Disadvantages of Interferon Pro Con Finite course of therapy Subcutaneous administration No resistance Adverse effects Higher rate of HBeAg loss in 1 year vs oral drugs HBeAg loss “catches up” with > 1 year oral drugs; prolonged IFN use not feasible Potential for HBsAg clearance with short duration therapy HBsAg clearance also occurs with oral agents
  39. 39. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management  Favorable predictors of response – Genotype A or B > C or D – Low HBV DNA – High ALT  Specific patient demographics – Generally young people – Young woman wanting future pregnancy – Absence of comorbidities  Patient preference  Concomitant HCV infection When to Consider PegIFN
  40. 40. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Interferon -alfa Antiviral action Immunomodulatory action T helper cell Natural killer cell Cytotoxic T cell Reduction in viral load Destruction of infected cells Induction of antiviral state through gene activation prevents infection of new cells Tipping the balance of immune control in CHB through IFN therapy Effects translate into a response that is sustained post-treatment
  41. 41. Treatment of HBeAg-Positive Patients
  42. 42. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Keeffe EB, et al. DDW 2008. SP198. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962. HBeAg positive HBV DNA < 20,000 IU/mL HBV DNA ≥ 20,000 IU/mL ALT normal ALT elevated  No treatment  Monitor every 6-12 months  Monitor ALT every 3-12 months (immune tolerant)  Consider biopsy, if age is > 35-40 years and treat if significant disease  Treat to HBeAg seroconversion  ETV, TDF, and pegIFN are first-line options HBV Patients With Compensated Disease: HBeAg Positive
  43. 43. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Adapted from Lok AS, et al. Hepatology. 2007;45:507-539. Heathcote EJ, et al. AASLD 2007. Abstract LB6. *By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies. 40-44 21 67 25 69 PatientsWithUndetectable HBVDNA(%) 60 0-16 Not head-to-head trials; different patient populations and trial designs 76 Virologic Response in HBeAg+ Patients (Undetectable* HBV DNA at Wk 48-52) 100 80 60 40 20 0 LAM ADV ETV LdT TDF Peg- IFN Peg- IFN + LAM PLB
  44. 44. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management 27* *Response 6 months after stopping treatment. Adapted from Lok AS, et al. Hepatology. 2007;45:507-539. Heathcote EJ, et al. AASLD 2007. Abstract LB6. Virologic Response in HBeAg+ Patients (HBeAg Seroconversion at Wk 48-52) PatientsAchieving HBeAgSeroconversion(%) 100 80 60 40 20 0 LAM ADV ETV LdT TDF Peg- IFN Peg- IFN + LAM PLB 16-21 12 21 32* 4-6 27 24 22 21 Not head-to-head trials; different patient populations and trial designs
  45. 45. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Chang TT, et al. J Gastro Hepatol. 2004;19:1276-1282. Lok AS et al. Gastroenterol. 2003;125:1714-1722. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Chang TT, et al. Hepatology. 2006;44(suppl 1):229A. Marcellin P, et al. N Engl J Med. 2003;348:808-816. Marcellin P, et al. Hepatology. 2006;44(suppl 1):548A. Lai CL, et al, Hepatology. 2005;42(suppl 1):748A. Lai CL, et al. Hepatology. 2006;44(suppl 1):222A. Han S, et al. AASLD 2007. A938. *(ETV-022 + ETV-901) 16% additional to 31% HBeAg seroconversion in ETV-022 (Year 2). HBeAg Seroconversion During Continued Treatment 5047 40 29 22 0 20 40 60 LAM ADV ETV LdT 1 2 3 4 5 Years of Therapy Patients(%) 80 100 47* 37 31 21 0 20 40 60 80 100 48 12 0 20 40 60 80 100 23 29 1 2 3 4 5 Years of Therapy 0 20 40 60 80 100 Not head-to-head trials; different patient populations and trial designs
  46. 46. Treatment of HBeAg-Negative Patients
  47. 47. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management HBeAg negative HBV DNA < 2000 IU/mL HBV DNA ≥ 2000 IU/mL ALT normal ALT elevated  No treatment  Monitor every 6-12 months  Monitor ALT and HBV DNA, or  Consider biopsy, since ALT often fluctuates and treat if significant disease  Treat long term  ETV, TDF, or PegIFN are first-line options Keeffe EB, et al. DDW 2008. Abstract 198. HBV Patients With Compensated Disease: HBeAg Negative
  48. 48. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management LAM ADV ETV LdT TDF Peg- IFN Peg- IFN + LAM*By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies. ~ 70 51 90 63 8788 Adapted from Lok AS, et al. Hepatology 2007;45:507-539. Marcellin P, et al. AASLD 2007. Abstract LB2. 93 Virologic Response in HBeAg- Patients (Undetectable* HBV DNA at Wk 48-52) PatientsWithUndetectable HBVDNA(%) Not head-to-head trials; different patient populations and trial designs 100 80 60 40 20 0
  49. 49. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Tolerability and Safety: Nucleos(t)ide Analogues vs Peginterferon Nucleos(t)ide Analogues  Safe at all stages of disease, including decompensated cirrhosis  Safe in immunocompromised populations – Selected drugs probably safe in pregnancy  Reported toxicities are rare Peginterferon  Contraindications – Decompensated cirrhosis – Pregnancy – Significant cardiopulmonary disease – Uncontrolled seizures, psychiatric disease – Autoimmune diseases  Not recommended – Cirrhosis  Adverse effects common Lok AS, et al. Hepatology. 2007;45:507-539. Lok AS, et al. Hepatology. 2009;50:661-662.
  50. 50. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Treatment End Point
  51. 51. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Treatment Endpoints in Chronic Hepatitis B Potential Treatment Endpoints in Chronic Hepatitis B Treatment Endpoints Normal ALT Histological Improvement Undetectable Serum HBV DNA HBeAg Seroconversion HBeAg Loss cccDNA Clearance HBsAg Clearance
  52. 52. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management End Points of Therapy Two Distinct Patient Populations  HBeAg+ (wild-type) – HBeAg response/seroconversion a potential endpoint-?  HBeAg-/anti-HBe+/HBV DNA+ (precore mutant) – HBeAg seroconversion not an endpoint – High relapse rate and long-term therapy the rule
  53. 53. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management HBsAg clearance – closest outcome to cure  HBsAg seroconversion – Natural course of resolved infection – Closest we can get to a „clinical cure‟ of HBV – cccDNA = reservoir for reactivation – Reactivation: in patients with immunosuppression – eg BMT, chemotherapy – Organ transplant
  54. 54. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management What is so special about HBsAg?
  55. 55. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management HBsAg is found free in serum in various forms  Present in lipid envelope of virus  Various forms in serum  Defective particles exceed virions by a factor of 103–105
  56. 56. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Replication of HBV – the stealth virus cccDNA acts as a viral reservoir allowing re-activation LHBs SHBs mRNA X mRNA SHBs/MHBs mRNA LHBs mRNA Core/Pol cccDNA AAA pgRNA 3.5kb Core protein Polymerase negative strand positive strand AAA AAA
  57. 57. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Measuring cccDNA  cccDNA can be measured in liver biopsy samples  Can we measure it without a biopsy?
  58. 58. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Is serum HBsAg an indicator of cccDNA?  cccDNA acts as transcription template  Serum HBsAg levels reflect cccDNA (A) and intrahepatic HBV DNA (B)  Non-invasive marker of infected cells A B Chan et al. Clin Gastro Hepatol 2007 HBsAgatbaseline HBsAgatbaseline Log (cccDNA) at baseline Log (intrahepatic HBV DNA) at baseline A
  59. 59. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Steps along the way to cure are used to monitor response  Markers of response to therapy used in clinical trials HBsAg clearance – the closest outcome to cure Marcellin et al. EASL 2008; Perrillo et al. Hepatology 2006 Fattovich et al. Am J Gastroenterol 1998 HBV DNA suppression HBeAg seroconversion HBsAg clearance Time
  60. 60. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management HBsAg – Anti-HBs seroconversion: The hallmark of recovery from CHB HBsAg clearance: the gold standard of immune control of HBV infection Go for gold – not only at the Olympic games!
  61. 61. Nucleos(t)ide Resistance
  62. 62. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management *Defined as < 2 log reduction in serum HBV DNA after 6 months of therapy. Adapted from Lok AS, et al. Hepatology. 2007;45:507-539. LogHBVDNA 0.0 -1.0 -2.0 -3.0 -4.0 +1.0 1 log Antiviral Drug Mutant Primary nonresponse* Secondary treatment failure Time 2 log Antiviral Treatment Failure in HBV
  63. 63. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management HBV Resistance Mutations 845 a.a. Terminal protein Spacer Pol/RT RNaseH A B C ED YMDDGVGLSPFLLA I(G) II(F) Allen MI, et al. Hepatology. 1998;27:1670-1677. Qi X, et al. J Hepatol. 2004;40(suppl 1):20-21. Tenney D, et al. Antimicrob Agents Chemother. 2004;48:3498-3507. Tyzeka [package insert]. Lai CL, et al. Gastroenterology. 2005;129:528-536. Schildgen O, et al. N Engl J Med. 2006;354:1807-1812. Locarnini S. 2006 IDRW. Abstract P2. rtL80V/I rtM204V/I/SLAM resistance rtV173L rtL180M rtA181T/V rtN236T rtl233V ? ADV resistance rtM204V/I rtS202G/C rtM250I/VrtT184S/A/I/L ETV resistance rtL180M rtM204ILdT resistance rtL80V/I rtL180M TDF resistance rtA194T rtM204V rtL180M
  64. 64. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Emergence of Resistance During Antiviral Therapy Fung SK, et al. Antivir Ther. 2004;9:1013-1026. Locarnini S, et al. Antivir Ther. 2004;9:679-693. Time Wild-type virus Naturally occurring viral variants Drug-resistant mutant virus Factors contributing to resistance include those related to the drug, the patient, and the virus Treatment begins HBVReplication
  65. 65. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Liaw YF, et al. N Engl J Med. 2004;351:1521-1531. PatientsWithDisease Progression(%) Wild type (n = 221) YMDDm (n = 209) Time After Randomization (Months) 0 5 10 15 20 25 0 6 12 18 24 30 36 Placebo (n = 215) 5 13 21 LAM Resistance Associated With Faster Progression of Liver Disease
  66. 66. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management n = HBV DNA at Month 6 of LAM Predicts Later Risk of Resistance N = 159 HBeAg-positive patients Median follow-up: 29.6 months Yuen ME, et al. Hepatology. 2001;34:785-791. PatientsWithResistance(%) 8 13 32 64 0 20 40 60 80 100 ≤ 2 ≤ 3 ≤ 4 > 4 PatientsWith YMDDVariants(%) HBV DNA at 6 Months (log10 copies/mL) 12 23 41 118
  67. 67. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management ADV (N236T/A181V)[1] IncidenceofResistanceCumulative Incidence HBV Antiviral Resistance 1. Qi, et al. EASL 2004, Abstract 57. 2. Lai, et al. Clin Infect Dis. 2003;36:687. 3. Tenney DJ, et al. AASLD 2004 Abstract 184. LAM (M204V/I)[2] ETV (WT / LAM refractory)[3] 70% 0 10 20 30 40 50 60 70 80 Year 1 Year 2 Year 3 Year 4 3.9%0% / 6% LAM ETV ADV
  68. 68. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Elevated HBVDNA = Increased resistance
  69. 69. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Current Recommendations on Antiviral Resistance Testing Lok ASF, et al. Hepatology. 2007;46:254-265.  2007 HBV Drug Resistance Working Group – If a rise in serum HBV DNA (≥ 1.0 log10 IU/mL) above nadir (virologic breakthrough) occurs, assess drug compliance – Consider evaluation for genotypic resistance – Tests for antiviral-resistance mutations should be performed to – Confirm genotypic resistance (≥ 1.0 log10 IU/mL increase in HBV DNA from nadir) – Determine the pattern of mutations (ie, cross-resistance)
  70. 70. Potential Role of Combination Therapy
  71. 71. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Any Present Role for Combination Therapy as Initial Treatment?  No combination therapy has convincingly shown increased short-term efficacy as initial treatment – L-dT + LAM vs L-dT vs LAM[1] – LAM + ADV vs LAM[2] – FTC + ADV vs ADV[3] – TDF + FTC vs TDF[4]  Currently available drugs have excellent resistance profile  Studies to establish any advantage of combination therapy require – Large number of patients – Long duration – Shorter-term endpoints than resistance 1. Lai CL, et al. Gastroenterology. 2005;129:528-36. 2. Sung JJ, et al. J Hepatol. 2008;48:728-735. 3. Hui CK, et al. J Hepatol. 2008;48:714-720. 4. Berg T, et al. 2008 EASL. Abstract 76.
  72. 72. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Potential Populations in Which to Consider Combination Therapy  Cirrhotics – Risk of hepatitis flare with emergence of resistance is high  HIV/HBV coinfection – ETV monotherapy no longer optimal with recent data on HIV susceptibility and genotypic resistance – Risk of resistance with any monotherapy in HIV/HBV coinfection  Suboptimal response to an initial drug – Especially if high-level viremia on potent drug  Established resistance to antiviral medication(s) – Lessons learned from ADV switch vs add-on in patients with LAM resistance Jacobson IM. J Hepatol. 2008;48:687-691.
  73. 73. Predictors of Long-term Virologic Success
  74. 74. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Early, Profound Suppression Leads to Greater Sustained Response HBV DNA at Week 24HBV DNA at Week 12 1. Farci P, et al. EASL 2005 Abstract 484. 2. Zeuzem S. EASL 2006. Abstract 51. PatientsPCRNegative atFollow-up(%) 0 20 40 60 80 100 PegIFN alfa-2a at Week 72[1] HBeAg Negative < 400 c/mL ≥ 400 c/mL n = 61 31 70 106 LdT at Week 52[2] HBeAg Positive < QL ≥ QL 95 33 255203 LAM at Week 52[2] HBeAg Positive < QL ≥ QL 84 20 146 317
  75. 75. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management 68 LdT PCRUndetectable atWeek104(%) 61 40 20 88 78 63 20 73 60 28 7 60 25 5 82 0 10 20 30 40 50 60 70 80 90 100 < QL QL-3 3-4 > 4 < QL QL-3 3-4 > 4 LAM HBeAg Positive HBeAg Negative HBV DNA at Week 24 (log10 copies/mL) DiBisceglie A, et al. AASLD 2006. Abstract 112. GLOBE: Week 24 HBV DNA Predicts Week 104 Undetectable HBV DNA
  76. 76. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management HBeAgSeroconversion atWeek104(%) HBV DNA at Week 24 (log10 copies/mL) 39 46 19 6 0 20 40 100 < QL QL-3 3-4 > 4 HBeAg Positive: Combined Treatment Groups (LAM + LdT) DiBisceglie A, et al. AASLD 2006. Abstract 112. 80 60 GLOBE: Week 24 HBV DNA Predicts Week 104 HBeAg Seroconversion
  77. 77. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Early Suppression of HBVDNA = Increased sustained response Increased seroconversion
  78. 78. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management  2007 AASLD guidelines[1] – IFN (preferably pegIFN alfa-2a) – Monitor HBV DNA levels every 12-24 weeks during treatment – Monitor HBV DNA levels every 12 weeks during the first 24 weeks of posttreatment – Nucleos(t)ide analogues – Monitor HBV DNA levels every 12-24 weeks 1. Lok AS, et al. Hepatology. 2007;45:507-539. 2. Lok, AS, et al. Hepatology. 2007;46:254-265. On-Treatment HBV Monitoring Recommendations
  79. 79. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Prevention and Monitoring of Resistance Prevention Avoid unnecessary treatment Initiate potent antiviral that has low rate of drug resistance or use combination therapy Switch to alternative therapy in patients with primary nonresponse Monitoring Test for serum HBV DNA (PCR) every 3-6 mos during tx Check for medication compliance in patients with virologic breakthrough Confirm antiviral resistance with genotypic testing Lok AS, et al. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, www.aasld.org. Copyright@2009. American Association for the Study of Liver Diseases. Reproduced with permission of the American Association for the Study of Liver Diseases.
  80. 80. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management The Road Map Concept
  81. 81. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Management Roadmap According to Week 12 Virologic Response Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897. Week 12 Assess for primary nonresponse Primary response HBV DNA 1 log10 IU/mL drop Primary treatment failure HBV DNA < 1 log10 IU/mL drop Continue Start treatment If nonadherent, counsel If adherent, add a more potent drug
  82. 82. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Management Roadmap According to Week 24 Virologic Response Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897. Patients with primary response Week 24 Assess early predictors of efficacy Complete response HBV DNA negative by PCR Partial response HBV DNA 60 to < 2000 IU/mL Continue therapy; monitor every 6 months Inadequate response HBV DNA ≥ 2000 IU/mL Add a more potent drug; monitor every 3 months
  83. 83. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Outcome of hepatitis viral infection and liver disease • Immune system Virus Antiviral treatment is aimed at changing the “pathogenic equilibrium” into a “non pathogenic one”
  84. 84. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Treatment of Special Populations
  85. 85. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Reactivation of chronic hepatitis B  Seen as early as 1991  Occurs most frequently with immunosuppression and chemotherapy  Can range to subclinical enzyme elevation to fatal hepatitis  General physicians and other subspecialists are not aware of risk with prescribing agents  Patients should be tested for HBsAg status and placed on antiviral therapy if positive Khokhar et al.. Chemotherapy 2009; 55: 69-75
  86. 86. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Reactivation of Hepatitis B: Chemotherapy or Immunoprophylaxis  Alkylators – Cyclophosphamide – Ifosfamide – Chlorambucil – Carboplatin, cisplatin  Antimetabolites – Cytarabine – Fluorouracil – Gemcitabine – Mercaptopurine – Methotrexate – Thioguanine  Corticosteroids – Prednisone/dexamethasone, etc  Antitumor antibiotics – Anthracyclines – Bleomycin – Mitomycin – Actinomycin  Immunotherapy – Rituximab (anti-CD20) – Alemtuzumab (anti-CD52) – Infliximab (anti-TNF)  Plant alkaloids – Vincristine – Vinblastine  Others Lalazar G, et al. Br J Haematol. 2007;136:699-712.
  87. 87. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Reactivation of HBV With Rituximab Administration  Retrospective analysis of patients who received 1 course of rituximab at single center: 2005-2007  180 of 258 patients (70%) treated with rituximab tested for HBV – Vaccinated: 46% – Negative: 39% – Anti-HBc/anti-HBs positive: 11% – HBV DNA positive: < 1% Metzler F, et al. AASLD 2008. Abstract 848.
  88. 88. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Reactivation of Hepatitis B: EASL Management Guidelines  Screen for HBsAg and anti-HBc prior to chemotherapy or immunosuppressive therapy  HBV vaccination in seronegative patients  HBsAg-positive individuals – Prophylactic oral therapy continuing 12 mos after cessation of therapy – ETV or TDF in most patients, particularly with high HBV DNA – LAM may be possible for patients with low HBV DNA, low risk of resistance  HBsAg-negative, anti-HBc positive, undetectable HBV DNA patients – Monitor ALT and HBV DNA – Treat with oral therapy upon HBV reactivation before ALT elevation EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol. In press.
  89. 89. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Hepatitis B Management Guidelines: Cirrhotics HBV DNA (copies/mL) Management < 104 Treat or follow ≥ 104 Treat Keeffe et al. Clin Gastroenterol Hepatol. 2004;2:87-106. HBV DNA Management Undetectable Follow; waitlist for transplant Detectable Treat carefully with oral antiviral; waitlist for transplant Compensated Decompensated
  90. 90. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Management of Patients With Compensated Cirrhosis Preferred therapies ETV or TDF – NAs should be used; IFN can be associated with hepatitis flare Treatment duration Long-term treatment – Can discontinue in HBeAg-positive patients with confirmed HBeAg seroconversion and ≥ 6 mos consolidation therapy – Can discontinue in HBeAg-negative patients with confirmed HBsAg clearance Treatment discontinuation requires close monitoring for flare or relapse Lok AS, et al. Hepatology. 2009;50:661-662.
  91. 91. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Management of Patients With Decompensated Cirrhosis Lok AS, et al. Hepatology. 2009;50:661-662. Preferred therapies  (LAM or LdT) + (ADV or TDF); TDF or ETV monotherapy* – Treatment should be coordinated with transplantation center – IFNs should not be used in decompensated cirrhosis Treatment duration  Lifelong treatment recommended *Clinical data documenting safety and efficacy of TDF or ETV monotherapy in decompensated cirrhosis are lacking.
  92. 92. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Hepatitis B and Pregnancy Mother  Worsening of hepatitis before or during pregnancy?  Worsening of hepatitis after delivery?  Hepatitis B and other disorders during pregnancy Infant  Transmission of HBV?  Teratogenicity of drugs?  Risk of fulminant hepatic failure?  Breast-feeding?
  93. 93. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management HBV Transmission: When Does It Happen?  In utero transmission – Very rare (< 10%); associated with high HBV DNA levels[1]  During amniocentesis – Very rare; no transmission reported in 2 case series[2,3]  At birth! – HBeAg-positive mothers: 85% – HBeAg-negative mothers: 31%[4] 1. Wang Z, et al. J Med Virol. 2003;71:360-366. 2. Alexander JM, et al. Infect Dis Obstet Gynecol. 1999;7:283-286. 3. Towers CV, et al. Am J Obstet Gynecol. 2001;184:1514-1518. 4. Beasley RP, et al. Am J Epidemiol. 1977;105:94-98.
  94. 94. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management  No effect of cesarean section on incidence of immunoprophylaxis failure[1]  If immunoprophylaxis cannot be provided, elective cesarean section might reduce mother-to-child- transmission of HBV[2] 1. Wang J, et al. Chin Med J. 2002;115:1510-1512. 2. Yang J, et al. Virol J. 2008;5:100. Mode of Delivery Has No Effect on HBV Transmission
  95. 95. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management 1. Linnemann CC, et al. Lancet. 1974;2:155. 2. Hill JB, et al. Obstet Gynecol. 2002;99:1049-1052. 3. Cornberg M, et al. J Viral Hepat. 2008;15:1-21. 4. Johnson MA, et al. Clin Pharmacokinet. 1999;36:41-66. Breast-feeding and Risk of HBV Transmission  HBV can be detected in breast milk[1]  Neonates that are correctly immunized may be breast- fed[2,3]  Caveat: nucleos(t)ide analogues can be detected in breast milk[4]
  96. 96. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Prevention of HBV Transmission by Postnatal Vaccination  Active plus passive immunization most effective[1]  Role of maternal HBV DNA on transmision[2] – HBV DNA < 150 pg/mL (1.1 x 107 IU/mL) = 0% transmission – HBV DNA > 150 pg/mL = 32% transmission No Vaccine Passive Immunization Passive + Active Immunization Infants without HBV, % 5 72 95 1. Ranger-Rogez S, et al. Expert Rev Ant Infect Ther. 2004;2:133-145. 2. del Canho R, et al. Vaccine. 1997;15:1624-1630.
  97. 97. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Can Antiviral Treatment Reduce Vertical HBV Transmission?  No complete prevention of transmission, even in case of successful LAM treatment[1]  LAM given 1 month before delivery decreased HBV transmission from 28.0% in untreated historical controls to 12.5% (OR: 2.9; 95% CI: 0.29-28.0)[2] – All received standard prophylaxis – High maternal viremia associated with vaccination failure – No adverse events noted with LAM 1. Kazim SN, et al. Lancet. 2002;359;1488-1489. 2. van Zonneveld M, et al. J Viral Hepat. 2003;10:294-297.
  98. 98. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Recommendations for HBV-Infected Women Who Desire Pregnancy  Women with mild liver disease, low viremia – Pregnancy before treatment  Women with moderate liver disease, no cirrhosis – Treatment before pregnancy; if response, stop treatment before pregnancy  Women with advanced liver disease – Treatment before and during pregnancy; continue treatment after delivery  Women with mild liver disease, very high viremia – Treatment in last trimester Wedemeyer H, et al. Dtsch Med Wochenschr. 2007;132:1775-1782. EASL Clinical Practice Guidelines. J Hepatol. In press.
  99. 99. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management HBV Recurrence After Liver Transplantation  Prospective NIH-HBV-OLT study (N = 191) – US patients who received OLT for HBV at 15 centers between March 2001 and September 2007 prospectively followed  Status at time of transplantation – HBeAg positive: 29% – HBV DNA > 5 log10 copies/mL: 38% – On antiviral therapy: 74% (LAM monotherapy: 68%) – Viral breakthrough prior to OLT: 19% – Confirmed genetic resistance: 67% Lok A, et al. AASLD 2008. Abstract 594.
  100. 100. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Management of Patients With HIV Coinfection 1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. DHHS Adults and Adolescents Guidelines. 2009.  HBV/HIV-coinfected patients who require HBV therapy should be treated[1] Not on or Anticipating Antiretroviral Therapy* Planning Antiretroviral Therapy Already Receiving Antiretroviral Therapy  Treat with antiviral therapy that is not active vs HIV, such as pegIFN or ADV 10 mg  Although LdT does not target HIV, it should not be used in this circumstance  Treat with therapies that are effective against both viruses: TDF + (FTC or LAM) preferred (plus ≥ 1 other anti-HIV agent)  If regimen does not include drug active against HBV, may add pegIFN or ADV  If LAM resistance, add TDF *DHHS guidelines recommend that any HBV/HIV-coinfected patient in whom HBV treatment is indicated should initiate a fully suppressive antiretroviral regimen containing 2 drugs with anti-HBV activity.[2]
  101. 101. HBV Screening and Counseling
  102. 102. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Risk Factors Associated With HBV Risk Factor Cases,* % Multiple sex partners 38.3 Injection drug use 15.0 Surgery 11.7 Men who have sex with men 10.5 Sexual contact with hepatitis B patient 6.2 Percutaneous injury 4.3 Household contact of hepatitis B patient 2.3 Medical employee with blood contact 0.6 Blood transfusion 0.5 Hemodialysis 0.2 Unknown 58.0 Daniels D, et al. MMWR Surveill Summ. 2009;58(3):1-27. *Percentage of cases calculated based on total number of cases for which any data for that exposure type were reported. Percentages do not total 100% because multiple risk factors could be reported by a single case.
  103. 103. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management HCC Screening  AASLD guideline – AFP and ultrasound q 6 months  Other recommendations – AFP L3% – PIVKA-II – MRI Bruix et al. Hepatology. 2005;42:1208-1236 Sangiovanni et al. Hepatology. 2007;46:406A. [#375]
  104. 104. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management AASLD Guideline Recommendations for HBV Screening “1. The following groups should be tested for HBV infection (Grade I)” Lok AS, et al. Hepatology. 2009;50:661-662.  US-born persons not vaccinated as infants whose parents were born in regions with high HBV endemicity  Persons with chronically elevated aminotransferases  Persons needing immunosuppressive therapy  Men who have sex with men  Persons with multiple sexual partners or history of sexually transmitted disease  Inmates of correctional facilities  Persons who have ever used injection drugs  Dialysis patients  HIV- or HCV-infected individuals  Pregnant women  Family members, household members, and sexual contacts of HBV-infected persons
  105. 105. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management AASLD Guideline Recommendations for Screening “1. . . . Testing for HBsAg and anti-HBs should be performed, and seronegative persons should be vaccinated (Grade I)” Lok AS, et al. Hepatology. 2009;50:661-662. CDC. Hepatitis B FAQs for Health Professionals. HBsAg Anti-HBs Total Anti-HBc IgM Anti-HBc  Indicates that the person is infected  Indicates recovery and immunity from HBV infection  Develops in a person who has been successfully vaccinated against hepatitis B  Indicates previous or ongoing infection with HBV in an undefined time frame  Appears at the onset of symptoms in acute hepatitis B and persists for life  Indicates recent infection with HBV (≤ 6 mos)  This test is used to distinguish acute from chronic HBV infection
  106. 106. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management HCC Surveillance: AASLD Practice Guideline Recommendations  Hepatitis B – Cirrhosis regardless of age – Asian males 40 yrs of age or older – Asian females 50 yrs of age or older – HCC in first-degree relative (start before 40 yrs of age) – African older than 20 yrs of age  Cirrhosis from other causes Bruix J, et al. Hepatology. 2005;42:1208-1236.
  107. 107. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management AASLD Guideline Recommendations for Counseling Lok AS, McMahon BJ. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, www.aasld.org. Copyright@2009. American Association for the Study of Liver Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases. Recommendations Regarding Prevention of Transmission of HBV to Others Persons who are HBsAg positive should:  Have sexual contacts vaccinated  Use barrier protection during sexual intercourse if partner not vaccinated or naturally immune  Not share toothbrushes or razors  Cover open cuts and scratches  Clean blood spills with detergent or bleach  Not donate blood, organs, or sperm Children and adults who are HBsAg positive:  Can participate in all activities including contact sports  Should not be excluded from daycare or school participation and should not be isolated from other children  Can share food, utensils, or kiss others
  108. 108. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Who Should Be Vaccinated for HBV? CDC. Hepatitis B FAQs for Health Professionals. Infants  At birth Children  Who were not vaccinated as infants At-Risk Adults  Regions of intermediate/high endemicity  Susceptible sex partners and household contacts of HBsAg-positive persons  Persons seeking evaluation or treatment for an STD  Persons with behavioral or occupational exposures  Persons with end-stage renal disease, chronic liver disease, or HIV infection  Residents/staff in certain settings with clients with known HBV risk factors
  109. 109. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Summary and Conclusions
  110. 110. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Take home messages  Hepatitis B is common in our country.  A normal ALT does not mean that everything is OK.  Appropriate work up must be ensured before starting therapy.  HBsAg clearance, HBeAg disappearance, development of Anti HBe and disappearance of HBV DNA should be the goal.  Potent and durable HBV DNA suppression may take years.  Resistance to antivirals is common and should be monitored.  Patients after seroconversion should be monitored periodically.  Screening for HCC in all patients is recommended.
  111. 111. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management Take home messages (cont’d)  Chemotherapy administration is associated with reactivation of hepatitis B and should be monitored and managed.  Perinatal transmission should be prevented by appropriate vaccination and immune globulins to newborn.  Low rate of HBV recurrence when antiviral therapy and HBIG given together as prophylaxis after liver transplantation  Liver fibrosis and cirrhosis developes in many patients with chronic HBV infection and normal or moderately elevated ALT levels.  The goal in all patients should be undetectable HBV DNA
  112. 112. clinicaloptions.com/hep HBV Core Curriculum 2008: Treatment and Management THANK YOU

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