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

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. 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. Hepatitis B Viral infection (HBV)

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. 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. Natural History of HBV
• Spontaneous clearance:
- Horizontal transmission
- Post pubertal
- Androgens
- ?? Nutritional status/ Environmental

7. Natural History of HBV
• Risk of HCC:
-2-5%
-Males
-Cirrhosis
-Viral load
-genotype
Family History

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. 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. 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. HBV treatment
options
Interferon
Nucleos(t)ides
analogues
Lamivudine
Adefovir
Entecavir

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. 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. Response to Entecavir in Adults
P=0.009 P<0.001 P=0.33
Percentage

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. 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. Hepatitis C Viral infection (HCV)

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. 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. 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. 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. 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. 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. 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. New &Future therapies for HCV
• Viral Target
Anti protease:
- Boceprovir
- Telaprevir
Anti Polymerase
- Sofosbuvir
• Host protein Target
Anti Cyclophilin A
- Alisporvir
Anti miR122
-Miravirsen