Recent advances in the management of viral hepatitis handout

885 views

Published on

Dr Mona Abdel-Hady
Consultant Paediatric Hepatologist
Liver Unit
Birmingham Children’s Hospital
Birmingham,UK

Published in: Health & Medicine
0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
885
On SlideShare
0
From Embeds
0
Number of Embeds
2
Actions
Shares
0
Downloads
56
Comments
0
Likes
2
Embeds 0
No embeds

No notes for slide

Recent advances in the management of viral hepatitis handout

  1. 1. Recent advances in the Management of Viral hepatitis B&C in children & adolescents Dr Mona Abdel-Hady Consultant Paediatric Hepatologist Liver Unit Birmingham Children’s Hospital Birmingham,UK
  2. 2. 1960s 2000s 1990s 1980s 1970s Au antigen linked to leukaemia and VH HBV Blood product screening HAV, NANB HBV vaccine Delta Ag. HCV Blood product screening HBV / HCV Treatment Viral Hepatitis time line
  3. 3. Hepatitis B Viral infection (HBV)
  4. 4. HBV Variants and disease implications Genotypes: (A-H) • Geographical distribution • Delayed spontaneous seroconversion in G (C) Livingstone et al, 2007 • Increased risk of HCC in G (C&F) Yu M et al, 2005 • Higher rate of response to treatment in G (A&B) Flink HJ et al, 2006 Pre-core and core promoter mutations • Role in initiating immune clearance phase • Vaccine escape mutant
  5. 5. Natural History of HBV Phase HBeAg Anti-HBe Serum ALT HBV DNA Liver inflammation/ Fibrosis Immune Tolerance +ve -ve Normal Very high Minimal Immune clearance -ve +/- Elevated Low Significant Inactive carrier -ve +ve Normal Low/ undetectable None Reactivation -ve +ve Elevated Detectable
  6. 6. Natural History of HBV • Spontaneous clearance: - Horizontal transmission - Post pubertal - Androgens - ?? Nutritional status/ Environmental
  7. 7. Natural History of HBV • Risk of HCC: -2-5% -Males -Cirrhosis -Viral load -genotype Family History
  8. 8. Efficacy of HBV vaccination • Vaccine success: • Taiwan: 68% decline in mortality from fulminant hepatitis in infants • In USA: 98% decline in HBV in children < 15 years (1990-2006) • Alaska: Decrease in annual incidence of acute HBV from 202/100,000 in 1981 to zero in 2008 Chang, 2006, Harber et al, 2009, McMahon 2010
  9. 9. Limitations of current interventions • Even with HBIG and vaccine to the babies at high risk of infection - there are still ‘vaccine failures’ • Some are ‘failures to deliver’ vaccine according to schedule • Immunisation or host factors may influence response • The need for a booster dose later in life. Chang, 2006 ; Boxall, 2005; Mc Mahon, 2009
  10. 10. Antiviral Therapy of childhood HBV • Short-term goals of treatment – HBeAg +ve: Seroconversion – HBeAg –ve: HBV DNA suppression/ALT normalisation • Long-term goals – Prevent/stop/reduce liver cirrhosis and/or HCC • Ultimate goal – HBsAg: seroconversion – Prolong survival *Treatment response maintained beyond end-of-treatment during a follow-up period of 6 months or more
  11. 11. HBV treatment options Interferon Nucleos(t)ides analogues Lamivudine Adefovir Entecavir
  12. 12. Lamivudine Paediatric Trial Virologic Response up to 36 m 0 5 10 15 20 25 30 35 40 12 m 18 m 24 m 36m up to 36 m Placebo Lamivudine (%) 23% Virologic Response = HBeAg -ve, HBV DNA -ve p=0.037286 patients, ALT > 1. 3 x ULN NEJM 2002;346:1706 ; Expert Opin Pharmacother 2002;3:329; AASLD 2003 28% 30% 35% 21%
  13. 13. Adefovir dipivoxil(ADV) Study 158 HBV DNA Change From Baseline -4 -3.5 -3 -2.5 -2 -1.5 -1 -0.5 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Weeks MedianLog10HBVDNA(copies/mL) ADV 2-6 years ADV 7-11 years ADV 12-17 years Placebo all ages P=0.007
  14. 14. Response to Entecavir in Adults P=0.009 P<0.001 P=0.33 Percentage
  15. 15. Consolidation therapy 24 weeks Complete Post-Dosing, On-Study Follow-up period Subjects can receive commercially available anti-HBV therapy No Response Protocol Defined Response Additional ETV 48 weeks D/C ETV D/C ETV ETV 48 weeks Virologic Response Totalof5yrsonstudy ENTECAVIR
  16. 16. New drugs • Telbuvidine Phase 1 clinical trial Novartis • Tenofovir • Phase 1 study completed Hazara R etal, 2004/ Bouzza N et al, 2011 • Phase III ongoing Gilead Sciences.
  17. 17. Hepatitis C Viral infection (HCV)
  18. 18. HCV Variants • Six Genotypes (1-6): response to treatment • >100 subtypes • Quasispecies: closely related but distinct viruses within single host • Difficulty developing vaccine due to genetic diversity
  19. 19. 1a, 1b 2a, 2b, 3a 1a, 1b 2a, 2b, 2c, 3a 4 5a 1b 1b, 6 1b, 3a 1b, 3a 3b 4 Fang et al. Clin Liver Dis. 1997. HCV Infection: Worldwide Genotype Distribution 1a, 1b, 2b, 3a 2a
  20. 20. 0 5 10 15 20 25 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Numberofpatients Yearsof referral Other VT TAC Mode of transmission BCH experience Abdel-Hady et al, JVH,2011
  21. 21. Natural History & Clinical Picture HCV • Acute hepatitis C is uncommon in children • Most children are asymptomatic • Fibrosis absent or minimal Mohan P et al, 2007, Abdel-Hady et al 2011 • Fibrosis is a slow progressive and severity relates to the duration of infection • Spontaneous clearance 10-40% with lower rates in vertically transmitted Locasciulli A et al, 1997,Yeung LTF et al, 2007, Abdel-hady el al, 2011
  22. 22. Current Therapy • Pegylated Interferon alpha and Ribavirin: 24 weeks for G 2&3 48 weeks for G 1&4 • Response rates: 47-68% in G1 89-94-% in G2&3 • Side effects well tolerated Wirth et al, 2005 ; Sokal et al, 2009;Abdel-Hady et al, 2010
  23. 23. Treatment of chronic hepatitis C in children and adolescents: Experience of 3 UK national centres. Abdel-Hady M, Bansal S, Davison SM , Brown M, Tizzard SA, Mulla,S, Davies P, Mieli-Vergani G, Kelly DA
  24. 24. Predictors of response to HCV treatment-IL-28 • Recent discovery of two single-nucleotide polymorphisms (SNPs) on chromosome 19 in the region of interleukin (IL)-28B gene • Significant increase SVR in association with C/C genotype of rs12979860 and T/T of rs8099917 • May explain race dependant response • Tailoring treatment choice and duration Gonzalez 2011 PearlmanB. 2011. ,Cheveliez et al, 2010
  25. 25. New &Future therapies for HCV • Viral Target Anti protease: - Boceprovir - Telaprevir Anti Polymerase - Sofosbuvir • Host protein Target Anti Cyclophilin A - Alisporvir Anti miR122 -Miravirsen

×