Recent advances in the management of viral hepatitis handout
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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
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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
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Hepatitis B Viral infection (HBV)
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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
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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
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Natural History of HBV
• Spontaneous clearance:
- Horizontal transmission
- Post pubertal
- Androgens
- ?? Nutritional status/ Environmental
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Natural History of HBV
• Risk of HCC:
-2-5%
-Males
-Cirrhosis
-Viral load
-genotype
Family History
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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
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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
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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
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HBV treatment options
Interferon Nucleos(t)ides
analogues
Lamivudine Adefovir Entecavir
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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=0.037 286 patients, ALT > 1. 3 x ULN
NEJM 2002;346:1706 ; Expert Opin Pharmacother 2002;3:329; AASLD 2003
28%
30%
35%
21%
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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
Me
dia
n L
og
10 H
BV
DN
A (
co
pie
s/m
L)
ADV 2-6 years
ADV 7-11 years
ADV 12-17 years
Placebo all ages
P=0.007
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Response to Entecavir in Adults
P=0.009 P<0.001 P=0.33
Pe
rce
nta
ge
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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
Tota
l of
5 y
rs o
n s
tud
y
ENTECAVIR
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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.
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Hepatitis C Viral infection (HCV)
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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
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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
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0
5
10
15
20
25
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
Nu
mb
er
of
pa
tie
nts
Years of referral
Other
VT
TAC
Mode of transmission BCH experience
Abdel-Hady et al, JVH,2011
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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
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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
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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
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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
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New &Future therapies for HCV
• Viral Target
Anti protease:
- Boceprovir
- Telaprevir
Anti Polymerase
- Sofosbuvir
• Host protein Target
Anti Cyclophilin A
- Alisporvir
Anti miR122
-Miravirsen