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Chronic HBV: Current Management

Chronic HBV: Current Management. Natalie Bzowej, MD, PhD, FRCPC Director Transplant Research Ochsner Medical Center New Orleans, LA. Chronic HBV: Current Management. Agenda Screening Guidelines Prevalence (global and in the US) Phases of Hepatitis B Natural History Overview of Treatment.

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Chronic HBV: Current Management

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  1. Chronic HBV:Current Management Natalie Bzowej, MD, PhD, FRCPC Director Transplant Research Ochsner Medical Center New Orleans, LA

  2. Chronic HBV: Current Management Agenda • Screening Guidelines • Prevalence (global and in the US) • Phases of Hepatitis B • Natural History • Overview of Treatment

  3. Case 1 • 30 year-old white male in for routine check up • Patient reports no problems with health • No significant personal or family history • Wife was recently found to be HBsAg+ • O/E • No stigmata of CLD • Exam normal • Would you screen the patient for hepatitis B?

  4. Case 2 • 47-year-old woman born in the US comes in for a routine physical • PMHx and Family Hx unremarkable • Social hx - parents immigrated from Korea • Would you screen this patient for hepatitis B?

  5. Case 3 • 22-year-old Chinese woman born in China comes in for physical • c/o fatigue and nausea • PMHx and Family Hx unremarkable • Social Hx: immigrated at the age of 2 • Would you screen this patient for hepatitis B?

  6. Candidates for Screening for HBVWeinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. • Household and sexual contacts of HBsAg-positive persons • US born children of immigrants from high-risk areas • Persons born in high endemic areas (>2% prevalence) • Persons who have ever injected drugs • Persons with multiple sexual partners, or history of STDs • Men who have sex with men • Inmates of correctional facilities • Individuals infected with HIV or HCV • Patients undergoing dialysis • All pregnant women • Individuals with chronically elevated ALT/AST

  7. Prevalence of HBV:Global Estimates HBsAg Prevalence High (>8%) Intermediate (2%-7%) Low (<2%) Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

  8. HBV Infection in the United States Revised HBV prevalence in the United States taking into account recent estimates of foreign-born persons 847,145 to 2,243,757 persons with chronic HBV Average chronic HBV prevalence rate among foreign-born persons living in the United States is 2.0% to 5.4% Kowdley KV, et al. Hepatology. 2012;56:422-433.

  9. Estimated HBV PrevalenceAmong Foreign-Born Americans (2009) Foreign-Born Americans: 13.6% of General Population 11.8% 7.9% Chronic HBV Prevalence (%) 3.7% 2.3% 2.2% 1.6% 1.3% 0.3% All Foreign Born (n=41,329,349) Asia (n=10,970,572) Central America (n=16,068,537) Caribbean (n=3,588,352) South America (n=2,856,583) Africa (n=1,669,101) Europe (n=5,113,072) North America (n=888,318) Kowdley KV, et al. Hepatology. 2012;56:422-433.

  10. Upper Limit of Normal ALT Levels • Updated upper limits • Males: 30 U/L (-25% from prior ULN) • Females: 19 U/L (-37% from prior ULN) • Based on retrospective cohort study • 6835 first time blood donors 1995-1999 • Anti-HCV negative and no contraindication to donation • ALT activity independently related to • BMI • Abnormal lipid or carbohydrate metabolism Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. Prati D, et al. Ann Intern Med. 2002;137:1-9.

  11. CASE 1: 30 yr old male Labs • HBsAg+, HBeAg+, Anti-HBe–, Anti-HBc (IgM)– • HBV DNA: 1,263,500 IU/mL, ALT: 128 U/L • In what phase is this patient? • Is this patient a candidate for treatment? • If treatment is indicated, what treatment would you choose? • What clinical and laboratory markers will you assess to determine effectiveness and duration?

  12. CASE 2 (47 yr old Asian female) Labs • HBsAg+, HBeAg-, Anti-Hbe+ • HBV DNA: 1,300 IU/mL, ALT: 17 U/L • In what phase is this patient? • Is this patient a candidate for treatment?

  13. CASE 3 (22 yr old Asian female) Labs • HBsAg+, HBeAg+, Anti-Hbe- • HBV DNA: 33,000,000 IU/mL, ALT: 12 U/L • In what phase is this patient? • Is this patient a candidate for treatment?

  14. 4 Phases of Chronic HBV Infection Immune tolerance phase HBeAg positive; high HBV DNA (105-10 copies/mL); normal ALT HBeAg-positive chronic hepatitis (immune clearance) High HBV DNA (105-10 copies/mL); high or fluctuating ALT; active inflammation on liver biopsy Inactive HBsAg carrier (low or non-replication) HBeAg negative; low HBV DNA (<104 copies/mL); normal ALT HBsAg may become undetectable HBeAg-negative chronic hepatitis (precore/bcp mutant) Intermediate to high HBV DNA (104-8 copies/mL); high or fluctuating ALT; active inflammation on liver biopsy Pungpapong S, et al. Mayo Clin Proc. 2007;82:967-975.

  15. CASE 1: 30 yr old male Labs • HBsAg+, HBeAg+, Anti-HBe–, Anti-HBc (IgM)– • HBV DNA: 1,263,500 IU/mL, ALT: 128 U/L • In what phase is this patient? • HBeAg-positive chronic hepatitis • (immune clearance)

  16. CASE 2 (47 yr old Asian female) Labs • HBsAg+, HBeAg-, Anti-Hbe+ • HBV DNA: 1,300 IU/mL, ALT: 17 U/L • In what phase is this patient? Inactive HBsAg carrier (low or no replication)

  17. CASE 3 (22 yr old Asian female) Labs • HBsAg+, HBeAg+, Anti-Hbe- • HBV DNA: 33,000,000 IU/mL, ALT: 12 U/L • In what phase is this patient? • Immune tolerance phase

  18. Chronic HBV Infection:Disease Progression Disease Progression Occurs in 15% to 40% With Chronic HBV Infection Liver Cancer (HCC) 5%-10% 10%-15% in 5 years Chronic HBV Infection Liver Transplantation* 30% Cirrhosis Death 23% in 5 years Acute Flare Liver Failure *Chronic HBV infection is the 6th leading cause for liver transplantation the United States. Fattovich G, et al. Gastroenterology. 2004;127:S35-S50. Seef LB, et al. Hepatology. 2001;33:455-463.Torresi J, et al. Gastroenterology. 2000;118:S83-S103. Fattovich G, et al. Hepatology. 1995;21:77-82.

  19. Chronic HBV: Goals of Therapy Control disease (not cure) by limiting viral replication Sustained suppression of HBV replication Prevent cirrhosis, hepatic failure, and HCC Markers of treatment response Decreased serum HBV DNA to low/undetectable levels Improved liver histology Decreased or normalized serum ALT Endpoints of treatment HBeAg loss or seroconversion (in HBeAg+ patients) HBsAg loss or seroconversion Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

  20. NIH Guidelines:Candidates for HBV Therapy • HBV therapy indicated • Acute liver failure • Cirrhosis and clinical complications • Cirrhosis or advanced fibrosis and HBV DNA in serum • Receiving cancer chemotherapy or immunosuppressive therapy • HBV therapy may be indicated • Chronic HBV (HBeAg positive or negative) without advanced fibrosis or cirrhosis Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.

  21. NIH Guidelines: Immediate HBV Therapy Is Not Routinely Indicated • Immune-tolerant phase • HBeAg positive, high HBV DNA levels, normal ALT or little activity on liver biopsy • Inactive carrier phase • HBsAg positive, low or undetectable HBV DNA levels, persistently normal ALT • Latent HBV infection • Detectable HBV DNA levels without HBsAg Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.

  22. Approved Treatments for HBV

  23. Candidates for HBV Treatment Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org/Pages/Default.aspx. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. EASL. J Hepatol. 2009:50:227-242. Liaw Y-F, et al. Hepatol Int. 2008;2:263-283.

  24. AASLD Guidelines:HBeAg-Positive Patients (non-cirrhotic) Case 1: ALT (128), HBV DNA (1,263,500 IU/mL) IU/mL to copies/mL conversion: Versant HBV DNA 3.0 (bDNA): 1 IU/mL=5.2 copies/mL. Cobas Amplicor HBV monitor: 1 IU/mL=5.6 copies/mL. Cobas TaqMan 48 HBV: 1 IU/mL=5.8 copies/mL. Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org.

  25. AASLD Guidelines:HBeAg-Negative Patients (non-cirrhotic) IU/mL to copies/mL conversion: Versant HBV DNA 3.0 (bDNA): 1 IU/mL=5.2 copies/mL. Cobas Amplicor HBV monitor: 1 IU/mL=5.6 copies/mL. Cobas TaqMan 48 HBV: 1 IU/mL=5.8 copies/mL. Case 2: HBV DNA: 1,300 IU/mL, ALT: 17 U/L Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org.

  26. AASLD Guidelines: HBeAg-Positiveor Negative Patients With Cirrhosis IU/mL to copies/mL conversion: Versant HBV DNA 3.0 (bDNA): 1 IU/mL=5.2 copies/mL. Cobas Amplicor HBV monitor: 1 IU/mL=5.6 copies/mL. Cobas TaqMan 48 HBV: 1 IU/mL=5.8 copies/mL. Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org.

  27. Duration of HBV Treatment HBeAg-positive An additional 12 months after HBeAg seroconversion to reduce relapse rate (non-cirrhotics) HBeAg-negative Relapse common after cessation of therapy Long-term treatment currently recommended Cirrhosis Long-term therapy required or until HBsAg loss Combination therapy may be considered Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

  28. Case 1 • 30 year-old male, eAg+, high ALT, high HBV DNA • liver biopsy: stage 2 fibrosis • genotype A • Treated with pegasys x 48 weeks • finite treatement duration • Check ALT, HBV DNA at 1, 3, 6 and 12 months • Virus negative at 24, 48 and 72 weeks • eAg- loss, eAb + at 2 years • sAg loss at 5 years

  29. HBV Genotyping and Response to Therapy Peginterferon alfa 2a • At least 8 genotypes have been identified • Prevalence varies by geographic region • Type A: North America, northern Europe, India, and Africa • Types B and C: Asia • Type G: United States and Europe • Type H: Central America and California • HBeAg-negative precore mutant seen more frequently in genotypes B, C, and D 52% HBeAg Seroconversion (%) 31% 30% 22% A (n=23) B (n=76) C (n=162) D (n=9) Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. Lau GK, et al. N Engl J Med. 2005;352:2682-2695.

  30. Case 1 (Alternate Scenario) • 30 year-old male, eAg+, high ALT, high HBV DNA • liver biopsy: stage 2 fibrosis • Treated with tenofovir or entecavir • Check ALT, HBV DNA at 1, 3, 6 and 12 months • Monitor creatinine periodically • Virus becomes negative at 24 wks • HBeAg-, HBeAb+ at 4 yrs (treat for one more year) • 6 mos off treatment HBV DNA 1500 IU/mL, ALT 33 • HBeAg remains negative, HBeAb positive • Monitor HBV DNA q 3mos x 1 yr, then q 6 mos • Treat only if rising DNA and ALT

  31. Cumulative Incidence ofDrug Resistance During HBV Therapy HBV Treatment-Naïve Patients (baseline wild-type virus) HBeAg status Positive Negative Mixture of both 73% Patients (%) 29% 25% 20% 11% 1.2% 0% 0% Tenofovir DF 4 Years Adefovir 5 Years Entecavir 6 Years Telbivudine 2 Years Lamivudine 5 Years Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org.

  32. Summary • Chronic HBV infection is a common problem that leads to morbidity and mortality • Understand the prevalence of your patient population • A wide range of treatment options exist • Treatment should be initiated and tailored to the individual based on • HBV DNA levels • Elevated ALT or abnormal liver biopsy • HBeAg status • HBV genotype • Tenofovir DF, entecavir, and peginterferon are preferred first-line agents

  33. A 25-year-old Asian female who is HBsAg (+) and HBeAg (+) with serum HBV DNA of >170, 000, 000 int. unit/mL has a serum ALT of 17 int. unit/L. Initialevaluation of this patient with chronic hepatitis B should not include: • History and physical examination • Laboratory tests to assess liver disease - complete blood counts with platelets, hepatic panel, and prothrombin time • Tests to rule out viral coinfections - anti-HCV, anti-HIV • Liver biopsy to grade and stage liver disease 10

  34. A patient with HBV and decompensated cirrhosis can be treated with all of the following agents except: • a) tenofovir • b) lamivudine • c) interferon • d) entecavir 10

  35. Groups at high risk who should be screened for HBV include: • ) Household and sexual contacts of HBsAg-positive persons • b) Persons needing immunosuppressive therapy • c) Men who have sex with men  • d) Patients undergoing renal dialysis • e) a, b, c and d 10

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