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Hepatitis B State of the Art

Hepatitis B State of the Art. Joanna Ready, M.D. SGNA September, 2013. Magnitude of HBV Infection(s). World wide: 2 billion persons infected 350 million cases of chronic HBV 15-40% progress to cirrhosis/HCC US: 1.25 million persons with chronic HBV In Asian Americans: 7-16% carrier rate.

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Hepatitis B State of the Art

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  1. Hepatitis B State of the Art Joanna Ready, M.D. SGNA September, 2013

  2. Magnitude of HBV Infection(s) World wide: 2 billion persons infected 350 million cases of chronic HBV 15-40% progress to cirrhosis/HCC US: 1.25 million persons with chronic HBV In Asian Americans: 7-16% carrier rate

  3. HBV is a life long, dynamic disease • Changes over time • Risk of end stage liver disease and cancer increases with ongoing inflammation and viremia in adults • Fibrosis can be reversible • Drugs can decrease fibrosis progression • HBV can be controlled but not cured • Reactivation can occur even in those who have lost HBsAg

  4. Who should be tested for HBV? • Blood and organs donors • Hemodialysis patients • Pregnant women • Infants of HBsAg + mothers • Behavioural contacts: • Household and sexual contacts • HIV+, MSM, IDU • Individuals from countries where prevalence is ≥2% • Patients receiving immunosuppressive therapy • Abnormal ALT of unknown cause CDC 2008

  5. 8: High Geographic Distribution of Chronic HBV Infection HBsAg Prevalence (%)1 2–8: Intermediate <2: Low 1. WHO. Hepatitis B. 2002. 2. Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158. 3. WHO/WPRO data.

  6. Geographic Distribution of HBV Genotypes Greenland: A, B, D Ae, Bj, C, D, F B, A/Bj Ae D B,C,A,D C G A D Bj G D Ba B F1, H F & H E B3 H F2 B C D Aa

  7. Why is Genotype Important? • Risk of cirrhosis • B/C: highest risk of cirrhosis (B<C) • D: also high risk • Risk of Heptocellular carcinoma • B/C: highest risk of HCC • B: HCC at younger age; absence of cirrhosis • Response to treatment • A: most responsive to IFN

  8. How to test for HBV? • HBsAg • Anti-HBs • Anti-HBc

  9. What to do with results? HBsAg HBsAb HBcAb • + - + refer to care • - + + past infection • - - - vaccinate • - + - vaccinated

  10. Hepatitis B Vaccine • Vaccine licensed in 1982 • Plasma-derived  recombinant vaccine • 3-dose series, high efficacy, no boosters, safe • Since licensing, adolescents and adults at high risk recommended to receive vaccine • Comprehensive strategy to eliminate HBV transmission implemented in 1991 • 1991: universal infant vaccination recommended • 1995: expansion to include vaccination of all adolescents ages 11-12 yrs • 1998: vaccination of all persons age 0-18 yrs not previously vaccinated

  11. Achievements With HBV Vaccination • Decline in acute HBV in past decade by 67% • Reflects effects of routine infant and childhood vaccination • Vaccination rates high in this population but decline to ~ 60% in adolescents • Slowest rate of decline in adults • Some adult subgroups showing increase in incidence (men ≥ 19 yrs, women ≥ 40 yrs) • Decline in risk of serious complications of chronic HBV • Reduced rates of childhood HCC in countries of high endemnicity Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2004;52:1252-1254.

  12. The phases of chronic hepatitis B Immune Immune Immune Immune tolerance clearance control escape HBeAg+ve HBeAg–ve > < < > HBV-DNA ALT HBeAg +ve chronic hepatitis HBeAg –ve active chronic hepatitis Inactive (carrier) state* *Previously considered to be ‘healthy carriers’

  13. HBV Controlthe goal • Inflammatory: normalize serum ALT, biopsy • Virologic: decrease HBV DNA • Immune: seroconversion • HBeAg to HBeAb • HBsAg to HBsAb • HBV never “cured” but controlled

  14. Immune Immune Immune Immune tolerance clearance control escape HBeAg+ve HBeAg–ve > < < > HBV-DNA ALT treat treat HBeAg +ve chronic hepatitis Inactive (carrier) state HBeAg –ve/+ve active chronic hepatitis Who should be considered for treatment?

  15. Overview of Algorithm Used to Determine Need for Treatment of HBV HBeAg Positive HBeAg Negative HBV DNA >20,000 IU/mL HBV DNA >2,000 IU/mL ALT Level Normal ALT Elevated ALT Monitor ALT Q3mos for 1y Consider Liver Biopsy If >40yrs Significant fibrosis or inflammation Treat Lok AS et al Hepatology, 2009

  16. Approved HBV treatments 2013 Interferon alfa-2b – 1991 Lamivudine – 1998 Adefovir – 2002 Entecavir – 2005 Peginterferon alfa-2a – 2005 Telbivudine – 2006 Tenofovir - 2008 For HIV: Emtricitabine Tenofovir + emtricitabine (single pill co-formulation)

  17. Therapeutic endpoints over time Improvedsurvival Improvedhistology Anti-HBs+ Loss of HBsAg Anti-HBe+ Loss of HBeAg Loss of HBV DNA TIME

  18. Treatment Goals in CHB: Remission Differences between the two strategies

  19. HBV Nucs: Nonresponse, Suboptimal Response, and Virologic Breakthrough 1.0 Antiviral Drug 0 Primary nonresponse Virologic breakthrough -1.0 Change in HBV DNA (log10 IU/mL) Suboptimal response -2.0 -3.0 1 log Nadir -4.0 0 6 12 18 Months Lok AS, et al. Hepatology. 2007;45:507-539.

  20. HBeAg Seroconversion Rates Over Time in HBeAg-Positive Patients Not head-to-head trials; different patient populations and trial designs Extended Treatment With Nucleos(t)ide Analogues* vs Limited Duration (1 Yr) Peginterferon Treatment 100 EntecavirTenofovirPeginterferon 80 60 HBeAg Seroconversion (%) 39 35 40 31 29-32 26 26 22-27 21 22 20 0 1.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs *With sustained undetectable HBV DNA. Chang TT, et al. J Viral Hepat. 2009;16:784-789. Chang TT, et al. AASLD 2006. Abstract 109. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al. Gastroenterology. 2008;135;459-467. Heathcote J, et al. AASLD 2008. Abstract 158. Heathcote J, et al. AASLD 2009. Abstract 483. Janssen HL, et al. Lancet. 2005;365;123-129.

  21. HBsAg Loss Over Time in HBeAg-Positive Patients Not head-to-head trials; different patient populations and trial designs Extended Treatment With Nucleos(t)ide Analogues* vs 1 Yr Peginterferon Treatment 100 EntecavirTenofovirPeginterferon 80 60 HBsAg Loss (%) 40 20 8 8 6 6 5 5 3 2 NA 0 1.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs *With sustained undetectable HBV DNA. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al. Gastroenterology. 2008;135;459-467. Gish R, et al. Gastroenterology. 2007;133:1437-1444. Heathcote J. AASLD 2008. Abstract 158. Heathcote J, et al. AASLD 2009. Abstract 483. Janssen HL, et al. Lancet. 2005;365:123-129.

  22. Undetectable HBV DNA Over Time in HBeAg-Negative Patients Not head-to-head trials; different patient populations and trial designs Extended Treatment With Nucleos(t)ide Analogues vs 1 Yr Peginterferon Treatment 100* 96 100 93 90 91 87 EntecavirTenofovirPeginterferon 80 63 60 Undetectable HBV DNA (%) 40 20 15 16 NA 0 1 Yr 2 Yrs 3 Yrs *Single center study. Lok AS, et al. Hepatology. 2009;50:661-662. Marcellin P, et al. AASLD 2008. Abstract 146. Marcellin P, et al. AASLD 2009. Abstract 481. Marcellin P, et al. Gastroenterology. 2009;136:2169-2179. Baqai S, et al. AASLD 2009. Abstract 476. Lai CL, et al. Hong Kong International Liver Congress 2006.

  23. HBsAg Loss Over Time in HBeAg-Negative Patients Not head-to-head trials; different patient populations and trial designs Extended Treatment With Nucleos(t)ide Analogues* Vs 1 Yr Peginterferon Treatment 100 80 EntecavirTenofovirPeginterferon 60 Patients (%) 40 20 9 7 4 < 1 0 < 1 0 0 NA 0 1.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs *With sustained undetectable HBV DNA. Lai CL, et al. N Engl J Med. 2006;354:1011-1020. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Marcellin P, et al. AASLD 2008. Abstract 146. Shouval D, et al. J Hepatol. 2009;50:289-295. Marcellin P, et al. AASLD 2009. Abstract 481. Brunetto M, et al. EASL 2008. Abstract 683.

  24. Duration of nucleoside analogue treatment in Chronic HBV • HBeAg-positive: until HBeAg seroconversion to anti-HBe and consolidation 6-12 mos (80% durable) • HBeAg-negative: until HBsAg clearance • Normal ALT and HBV DNA low in 65-70% at 5 years • ADV d/c Rx 5y: 18/33 inactive and 13/18 cleared HBsAg • IFN f/u 5y 230 pts: 12% lost HBsAg • Compensated cirrhosis: long-term treatment unless confirmed HBsAg clearance • Close monitoring for viral relapse and hepatitis flare is mandatory if treatment is stopped • Decompensated cirrhosis and post-liver transplantation: life-long treatment Lok AASLD 2009; Hadziyannis Gastro 2012

  25. Selection of Entecavir vs Tenofovir 25 21 21 20 Entecavir Tenofovir 15 Response at Wk 48-52 (%) 10 5 3 2 < 1 0 0 HBeAg seroconversion HBsAg loss HBsAg loss HBeAg Neg HBeAg Positive Lok AS. Hepatology. 2010;52:743-747.

  26. HBV Therapy and Chronic renal disease • All nucleos(t)ide analogues must be dosed according to GFR in patients with chronic kidney disease (CKD) • TDF can cause renal disease • TDF filtered by glomerulus • Toxicities reported: • Acute tubular necrosis • Fanconi’s • Proteinuria/glucosuria/phophoturia/hypokalemicRTA/bone loss • Diabetes insipidus (rare)

  27. Tenofovir Nephrotoxicity • Exposure in 10,841 HIV+ VA pts on ART from 1997–2007 • Events: 3400 proteinuria, 3078 GFR (>3ml/min/y) and 533 CKD (<60 ml/min) • De novo appearance of 3 of 5 of proteinuria, glucosuria, hypophosphatemia, hypouricemia, Cr. • 51 HBV patients followed for mean 6.4y • 7/51 had renal tubular dysfunction • Associated with older patients, lower baseline GFR • Improved with switch to ETV Scherzer and Shlipak AIDS 2012; Gara and Hoofnagle AASLD 2011

  28. Efficacy of Entecavir vs Tenofovir in the Setting of Resistance Similar antiviral activity against nonresistant HBV; efficacy against drug-resistant strains differs Lok AS. Hepatology. 2010;52:743-747.

  29. NAs: Potency versus resistance Nucleoside analogue Nucleotide analogue TDF ETV LdT LAM Potency of HBV DNA suppression ADV Likelihood of resistance development

  30. Antiviral resistance increases over time 70% 65% 53% 42% 40% 29% 25% 24% 20% 18% 15% 12% 11% 5% 2% 0.4% 0.8% 0.1% 0% 0.3% 80 Lamivudine1 Adefovir2 Entecavir (LAM-resistant)3 60 Entecavir (naive)3 *** Telbivudine4 Incidence of resistance (%) 40 20 0 Year 1 Year 2 Year 3 Year 4 Year 5 Resistance to NAs…is it just a matter of time?? 1 Lai, Clin Infect Dis 2003; 2 Westland, Hepatology 2003; 3Colonno R, EASL 2007; 4 Gane, EASL 2006

  31. Special Populations with HBV • Cirrhosis • Decompensated cirrhosis • Organ transplantation • Acute hepatitis B • Pregnancy • Co infection with HCV or HDV • Chronic renal failure • Children

  32. Cirrhosis • 5 y Survival 84% for compensated • 5 y Survival 14-35% for decompensated6 • Interferons are safe and effective in compensated HBV cirrhosis only1 • Nucleoside analogues have been shown prospectively to be safe, decrease rates of liver decompensation and to decrease the development of HCC2 • All cirrhotic patients with HBV DNA>2000 IU/mL should be treated regardless of ALT3-5 • Many experts recommend treating compensated cirrhotics with any detectable viral load3 1Buster, 2007; 2Liaw, 2004; 3Keeffe, 2008; 4Liaw 2008 (APASL); 5Lok 2007; 6Kim 2004

  33. Treatment decreases HBV disease progression even with YMDD mutant status 25 Placebo (n=215) 21% YMDD mutants (n=209) (49%) 20 Wild-type (n=221) 15 13% Patients with diseaseprogression (%) 10 5% 5 0 0 6 12 18 24 30 36 Time after randomisation (months) Liaw et al. N Engl J Med 2004

  34. Lamivudine in Decompensated Cirrhosis 23 consecutive UCSF patients compared with 23 historical controls 100 80 60 40 20 0 Lamivudine treated Survival (%) P < .001 Controls 0 6 12 18 24 30 36 42 48 Time (mo) Cumulative probability of survival without liver transplantation Yao FY, et al. Hepatology. 2001;34:411.

  35. 5-year survival rates ~50% Many centers consider HBV to be contraindication for LT 5-year survival rates as good or better than for other indications for LT HBIG LAM Liver Transplantation and HBVProgress in Past Decade Era 1 (1987-1991) Era 3 (1997-2002) 1 0.9 0.8 0.7 0.6 0.5 1 0.9 0.8 0.7 0.6 0.5 P < 0.01 P = .14 HBV Survival % Other Survival % Other HBV 0 1 2 3 4 5 0 1 2 3 4 5 Time (years) Time (years) Kim WR, et al. Liver Transpl. 2004;10:968.

  36. Pregnancy and Hepatitis B • Vertical transmission remains the most frequent route of infection worldwide • Endemic areas: • 20% women of childbearing age infected with HBV • Perinatal acquisition: 90% rate of chronicity • In contrast to: • Acquisition age 1-5: 20-30% chance of chronic infection • Acquisition as adult: < 5% chance of chronic infection • Risk of infection to the infant: • HBeAg + status of the mother • Viral load of the mother • >106 copies/mL; 200,000IU/ml

  37. Pregnancy (cont) • HBIg and HBV vaccination • HBIg within 12 hrs of birth & HBV vaccination series by month six: • Beasley et (1981): reduction of HBV transmission from 90% to 26% with HBIg • Follow up studies using active and passive immunization: 3-7% rate of transmission to the infant • Failures: eAg positive mothers with high viral loads • Data on the Rx of HBV during pregnancy remains limited: Category BCategory C telbivudine lamivudinetenofovir entecavir emtricitabine adefovir

  38. Pregnancy (cont) • All current drugs have the potential for mitochondrial toxicity  lactic acidosis syndrome; deleterious effects on organogenesis; no study has reported long-term effects (i.e. after one year) • Safety data: • Antiretroviral Pregnancy Registry (APR) & the Development of Antiretroviral Therapy Study (DART): • 112 mono-infected patients Rx with antiretrovirals: • 2.7% birth defects (APR); 3% (DART) • 2.4% in all births reported by CDC

  39. Pregnancy (cont) • Lamivudine most extensively studied agent • Suu et al (2003): • 38 women who became pregnant on lamivudine • None of the infants positive at 1 year • 26% of historical controls • von Zonneveld et al (2003): • 8 women eAg + with DNA >1.2 X 109 during the last 4 weeks of pregnancy • 1 of 8 infants sAg positive at 1 year (12.5%) vs 28% of historical controls • Xu et al (2009): • Double-blind, placebo-controlled trial of lamivudine and immunoprophylaxis during the last 8 weeks of pregnancy vs HBIg and HBV vaccination alone • 151 women • 18% of babies in arm A were sAg positive at 1 year • 39% of babies in arm B were sAg positive at 1 year • In large part due to a significant number of mothers/infants lost to follow-up • For those with complete data: • At 1 year: 13% positive in arm A 31% in arm B no significant difference • No study has reported increased adverse fetal events with lamivudine

  40. Pregnancy (cont) • Tenofovir • Class B drug • High genetic barrier to resistance • No increased adverse fetal events • Telbivudine • Similar results • Low genetic barrier to resistance • No published studies using entecavir, adefovir, emtricitabine to prevent vertical transmission • Current CDC/AASLD guidelines have not made specific recommendations regarding the treatment of pregnant women with HBV

  41. Pregnancy (cont) • Effect on successful delivery • Theoretical but not proven: • Increased bleeding/abruption • Gestational diabetes • LBW • Pregnancy’s effect on HBV • Rare, usually eAg + mothers • Effect of Rx on mother’s disease: • No change in disease progression • Stopping Rx after delivery: • ALT flare 12-25%; rarely clinically significant; responds to reinstitution of Rx • 12-17% of women will have a mild flare after deliver without withdrawal of drugs

  42. Pregnancy (cont) • When to begin treatment? • No data available • First/second trimester if mother has evidence of significant liver impairment/ongoing damage • High ALT and VL • Evidence of fibrosis  low platelet count; radiographic evidence • Check VL at the end of the second trimester consider Rx for VL>106 (200,000IU/ml) OR history of prior children with chronic hepatitis B, regardless of the VL • When to end treatment? • Again, no data available • Consider if in immunotolerant phase • Risk  hepatic decompensation

  43. Reactivation of HBV • High rate of reactivation in immunosuppressed patients • Chemotherapy • HIV after immune reconstitution • Post organ transplant • Biologic response modifiers: rituximab (anti-CD20), TNF- inhibitors: GI, hematologists, rheumatologists, dermatologists • Reactivation can occur in immunocompetent treated with steroids, BRMs

  44. Reactivation of HBV • Highest in HBV active disease • HBsAg and HBeAg pos, high HBV DNA • HBsAg and HBeAb pos, low HBV DNA • HBsAg neg, anti-HBs neg, anti-HBc pos • “occult HBV” • Deaths occur in all groups • ALL patients undergoing chemotherapymust have tested HBsAg, HBsAb and HBcAb prior to treatment

  45. Screening for Liver Cancer:Lack of Consensus Optimal age for initiation of screening unknown1 Patients ≥ 35 yrs are at much higher risk for HCC than those < 35 years2 Asian males aged 40; females aged 50 Sub-Saharan Africans > 20 Cirrhosis, any age Co-infection with HCV/HIV ? ETOH Among HBV-infected individuals, HCC can occur at any age, including childhood (genotype B?) Up to 1/3 of patients with HCC have normal AFP AFP may be elevated in 1/3 of patients with cirrhosis without HCC Current AASLD guidelines 1. Lok AS, and McMahon BJ. Hepatology. 2001; 34:1225-1241. 2. Liaw YF, et al. Gastroenterology. 1986;90:263-267.

  46. HBV is a dynamic disease • Diagnose • Initial evaluation includes education • Family and sexual contacts should be tested • counsel drugs to avoid- steroids, chemo, BRM • Monitor as status changes over time • ALT /HBV DNA may not remain normal over time especially in anti-HBe • Selection who to treat • Individualize treatment decisions • Change if no/ poor response • Long term monitoring HCC, reactivation

  47. HBV: The importance of monitoring HBV is a dynamic disease!!! Require treatment 40% 60% Require monitoring… • Inactive disease may not remain inactive • Liver damage may occur if HBV reactivates HBV can be controlled but not cured

  48. Serology of HBV (addendum)

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