Recent advances in the management of viral hepatitis handout

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

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

Hepatitis B Viral infection (HBV)

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

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

Natural History of HBV

• Spontaneous clearance:

- Horizontal transmission

- Post pubertal

- Androgens

- ?? Nutritional status/ Environmental

Natural History of HBV

• Risk of HCC:

-2-5%

-Males

-Cirrhosis

-Viral load

-genotype

Family History

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

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

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

HBV treatment options

Interferon Nucleos(t)ides

analogues

Lamivudine Adefovir Entecavir

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%

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

Response to Entecavir in Adults

P=0.009 P<0.001 P=0.33

Pe

rce

nta

ge

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

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.

Hepatitis C Viral infection (HCV)

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

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

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

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

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

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

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

New &Future therapies for HCV

• Viral Target

Anti protease:

- Boceprovir

- Telaprevir

Anti Polymerase

- Sofosbuvir

• Host protein Target

Anti Cyclophilin A

- Alisporvir

Anti miR122

-Miravirsen