NEW INSIGHT IN NEW INSIGHT IN HEPATITIS B IN CHILDRENHEPATITIS B IN CHILDREN

Mei-Hwei Chang , M.D.Mei-Hwei Chang , M.D.Department of Pediatrics,Department of Pediatrics,National Taiwan University National Taiwan University

Hospital,Hospital,Taipei, TAIWANTaipei, TAIWAN

Chang MHReplication Cycle of HBV

Chang MH

EPIDEMIOLOGYEPIDEMIOLOGY

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Prevalence of Chronic Prevalence of Chronic Hepatitis B Hepatitis B

HBsAg Prevalence

> 8% - High 2-8% - Intermediate< 2% - Low

Immigration numbers summed by continent from 1996-2002

~ 2 million Asians

~ 400,000South Americans

~ 350,000 Africans

~ 930, 000 Europeans

Centers for Disease Control. Hepatitis B fact sheet. Available at: http://www.cdc.gov/hepatitis. Accessed January 31, 2006. Mahoney FJ. Clin Microbiol Rev. 1999;12:351-366. Hepatitis B Foundation. Hepatitis B statistics. Available at: http://www.hepb.org/hepb/statistics.org. Accessed January 31, 2006.

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NATURAL HISTORY NATURAL HISTORY OF OF HEPATITIS VIRUS HEPATITIS VIRUS

INFECTIONINFECTION

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Natural History of Hepatitis B

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FACTORS AFFECTING THE FACTORS AFFECTING THE CLINICAL COUSE OF CLINICAL COUSE OF HEPATITIS VIRUS INFECTIONHEPATITIS VIRUS INFECTION

• Host Host Age of Infection Age of Infection

• VirusVirus : : Genotype Genotype Mutants / VariantsMutants / Variants

• Route of InfectionRoute of Infection • Other FactorsOther Factors

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- Perinatal Transmission- Perinatal Transmission

- Childhood Infection- Childhood Infection

- Adolescent/Adult Onset - Adolescent/Adult Onset

DiseaseDisease

Age of Infection and OutcomeAge of Infection and Outcome

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HBV GENOTYPE AND HBV GENOTYPE AND HBeAg HBeAg

SEROCONVERSIONSEROCONVERSION

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Kao JH, Chen DS. Current Hepatitis Report 2006 (in press).Kao JH, Chen DS. Current Hepatitis Report 2006

Worldwide Distribution of HBV Genotypes. The Size of the Capitals indicates the Relative Prevalence of the Genotypes

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0%

20%

40%

60%

80%

100%

HBeAg(+/+) HBeAg(+/-) Anti-HBe(+) HCC

A

B+C

B→ C

C→ B

Genotype C

Genotype B

No. of Children with Chronic HBV Infection 160 238 62 26

HBV GenotypeFollow-up

B B B B

C C C

C

Ni YH, Chang MH, et al. Gastroenterology 2004 ;127:1733-8.

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Age in Years

HB

eAg

Ser

opos

itiv

ity

Genotype C

Genotype B

Ni YH, Chang MH, et al. Gastroenterology 2004 ;127:1733-8.

Genotype C

Genotype B

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HBV Genotype and Clinical HBV Genotype and Clinical Course in ChildrenCourse in Children

• Genotype C Delays HBeAg Genotype C Delays HBeAg Seroconversion in Chronic HBV Seroconversion in Chronic HBV Infection in ChildrenInfection in Children

• Genotype Changes : RareGenotype Changes : Rare

• Genotype B Dominates in Genotype B Dominates in Children with Chronic HBV Children with Chronic HBV Infection and HCC in TaiwanInfection and HCC in Taiwan

Ni YH, Chang MH, et al. Gastroenterology 2004 ;127:1733-8.

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HBV VARIANTS / HBV VARIANTS / MUTANTS MUTANTS

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A Point Mutation at Codon 28 ( Nucleotide 1896) of HBV Precore Gene

TGG TAG(Tryptophan) (Stop Codon)

Leading to HBeAg Negative Strains

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CHANGES OF HBV PRECORE GENE CHANGES OF HBV PRECORE GENE 1896 IN 80 HBsAg CARIER 1896 IN 80 HBsAg CARIER CHILDRENCHILDREN

0%10%20%30%40%50%60%70%80%90%

100%

1st HBeAgPositive

Last HBeAgPositive

1st HBeAgNegative

Last HBeAgNegative

PCR Neg.

Mutant Only

Mixed

Wild Only

Chang MH, et al. J Hepatol. 1998 ;28:915-

22.

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Peak ALT levels during follow-up in 3 Peak ALT levels during follow-up in 3 groups with different patterns of HBV groups with different patterns of HBV precore 1896precore 1896

Peak ALT Peak ALT Group 1Group 1 Group 2 Group 2 Group 3Group 3 Total Total(IU/l) (IU/l) ((n=n=37)37) ( (n=n=22) 22) ((n=n=21)21) ( (n=n=80)80)

Mean Mean 136 136 179 179 209 209 167 167+- SD +- SD +- 149+- 149 +- 141 +- 141 +- 195+- 195 +-161 +-161

Group 1: Wild type throughout the whole Group 1: Wild type throughout the whole course.course.

Group 2: Mutant after HBe seroconversionGroup 2: Mutant after HBe seroconversionGroup 3: Mutant before HBe seroconversion.Group 3: Mutant before HBe seroconversion.• ALT levels between groups, ALT levels between groups, p=p=0.07.0.07.

Chang MH, et al. J Hepatol 1998; 28: 915-22.

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Comparisons of HBV Core Gene Between Comparisons of HBV Core Gene Between 31 Chronic Carriers and 12 HCC Children31 Chronic Carriers and 12 HCC Children

Codon Mutated Cases (No.) in HCC

Mutated Cases (No.) in Chronic carrier

Mutations P value

Precore 28 58% (7) 52.2% (12) WX 0.73

Core 21 8% (1) 21.7% (5) SP or A 0.32

Core 65 33% (4) 17.3% (4) LW or V 0.29

Core 74 33% (4) 0 SG 0.0032

Core 87 33% (4) 0 SG 0.0032

Core 131 8% (1) 0 AD 0.16

Core 143 33% (4) 4.3% (1) LP 0.015

Core 147 8% (1) 21.6% (5) TC or S 0.32

Core 159 42% (5) 0 RS 0.0006

Core 182 42% (5) 4.3% (1) QX 0.0035

Ni YH, et al. Gut 2003;52:122-5

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Comparisons of HBV Core Gene Comparisons of HBV Core Gene Between Between 31 Chronic Carriers and 12 HCC 31 Chronic Carriers and 12 HCC ChildrenChildren - SUMMARY - SUMMARY

• Core gene codon 21, 65, and 147 were Core gene codon 21, 65, and 147 were the commonest mutation sites in the commonest mutation sites in children with chronic HBV infection. All children with chronic HBV infection. All were located in HBcAg epitopes of CTL. were located in HBcAg epitopes of CTL.

• Codon 74, 87, and 159 mutations are Codon 74, 87, and 159 mutations are found in HCC children, but not in the found in HCC children, but not in the chronic infection group.chronic infection group.

Ni YH, et al. Gut 2003;52:122-5

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DISCUSSIONDISCUSSION

•These mutations may help These mutations may help HBV to escape host HBV to escape host immune pressure, to immune pressure, to expand viral proteins, and expand viral proteins, and finally bring in the cancer finally bring in the cancer development. development.

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TREATMENT TREATMENT OF OF

HEPATITIS BHEPATITIS B

CURRENT THERAPY FOR CURRENT THERAPY FOR HEPATITIS B IS NOT HEPATITIS B IS NOT SATISFACTORY SATISFACTORY

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CURRENT GOAL OF CURRENT GOAL OF ANTIVIRAL ANTIVIRAL THERAPY FOR HEAPTITIS B THERAPY FOR HEAPTITIS B

•Reduction of Viral Reduction of Viral ReplicationReplication

•Amelioration of Amelioration of Hepatic DysfunctionHepatic Dysfunction

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HBV Antiviral Therapy Is HBV Antiviral Therapy Is Not Recommended inNot Recommended in

• HBeAg Negative & Normal ALT HBeAg Negative & Normal ALT Subjects : Relatively Stable Subjects : Relatively Stable Course with Low Rate of Course with Low Rate of Progression.Progression.

• HBeAg Positive & Normal ALT HBeAg Positive & Normal ALT Subjects : May Progress , But Subjects : May Progress , But No Effective Therapy.No Effective Therapy.

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CURRENT APPROVED THERAPY CURRENT APPROVED THERAPY FOR HEPATITIS B FOR HEPATITIS B

• InterferonInterferon Interferon –Interferon –αα** Pegylated Interferon-Pegylated Interferon-αα

• Nucleoside AnalogNucleoside Analog Lamivudine*Lamivudine* Adefovir Adefovir Entecavir Entecavir

* Approved for use in children

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Effects of interferon in Effects of interferon in childhood hepatitis Bchildhood hepatitis B

Place &Place & ALT HBeAg Clearance (%) ALT HBeAg Clearance (%)

Authors at RxAuthors at Rx Control IFN Control IFN RxRx

Barbera no limit 14% (5/37) 26% (10/39)Barbera no limit 14% (5/37) 26% (10/39)

Gregorio > 1.5xN 13% (4/31) 38% (24/64)Gregorio > 1.5xN 13% (4/31) 38% (24/64)

Lai no limit 0% (0/30) 8% (5/60)Lai no limit 0% (0/30) 8% (5/60)

Tsai, Hsu > 2xN 38% (5/13) 44% (8/18)Tsai, Hsu > 2xN 38% (5/13) 44% (8/18)

Sokal > 2xN 11% (8/74) 26% (18/70)Sokal > 2xN 11% (8/74) 26% (18/70)

Meta-Ana no limit 11% (12/113) 23%(29/126)Meta-Ana no limit 11% (12/113) 23%(29/126)

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Efficacy according to baseline Efficacy according to baseline ALTALT

0

10

20

30

40

50

60

> 1xULN > 2xULN > 5xULN

Baseline ALT

Placebo (n=95) Lamivudine (n=191)

11/88

43/1839/58

33/97

4/17

8/16

50%

24%

34%

16%

23%

13%

% complete virologic response

(HBeAg(-), HBV DNA(-)

Jonas et al, N Engl J Med 2002; 346: 1706.

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LamivudineLamivudine p paediatric phase 3 aediatric phase 3 study study (NUC30903)(NUC30903)

Placebo (n=97)Placebo (n=97)

Wk 52Wk 52Baseline

No treatment (n=63)No treatment (n=63)

One year placebo One year placebo controlled studycontrolled study

Two yearTwo yearfollow-on studyfollow-on study

Lamivudine 3 mg/kg (n=191)Lamivudine 3 mg/kg (n=191)

Lamivudine 3mg/kgLamivudine 3mg/kg

HBeAg-ve

HBeAg+veTreatment (n=213)

89% Durability of response at month 36

Sokal E et al. Hepatology. 2006; 43: 225-32.

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Long term lamivudine therapy Long term lamivudine therapy for children with HBeAg+ve CHB for children with HBeAg+ve CHB (2)(2)

• Virologic response in the treatment armVirologic response in the treatment arm 21%21% after 12 + 24 months of Rx (n=133) after 12 + 24 months of Rx (n=133) 30%30% after 0 + 24 months Rx (n=77) after 0 + 24 months Rx (n=77) * VR = loss of HBeAg loss and HBV DNA * VR = loss of HBeAg loss and HBV DNA

• The incidence of YMDD mutationsThe incidence of YMDD mutations was was 64%64% (66/103) after 12 + 24 months of (66/103) after 12 + 24 months of

lamivudinelamivudine 49%49% (34/70) after 0 + 24 months of (34/70) after 0 + 24 months of lamivudine lamivudine

Sokal E et al. Hepatology. 2006; 43: 225-32.

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PREVENTION OF PREVENTION OF VIRAL VIRAL

HEPATITISHEPATITIS

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IMPORTANT IMPORTANT TRANSMISSION ROUTE IN TRANSMISSION ROUTE IN HYPERENDEMIC AREAS : HYPERENDEMIC AREAS : MOTHER TO CHILD MOTHER TO CHILD

EFFECTIVE PREVENTION EFFECTIVE PREVENTION

OF HEPATITIS B :OF HEPATITIS B :

VACCINATION IN VACCINATION IN INFANCY INFANCY

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HEPATITIS B VACCINATION HEPATITIS B VACCINATION AND AND CONTROL OF HEPATITIS B CONTROL OF HEPATITIS B RELATED LIVER DISEASES RELATED LIVER DISEASES

•Acute /Fulminant Acute /Fulminant HepatitisHepatitis

•Chronic Hepatitis Chronic Hepatitis

•Liver Cirrhosis ?Liver Cirrhosis ?

•Hepatocellular CarcinomaHepatocellular Carcinoma

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Annual mortality rate of fulminant hepatitis per100,000 infants in Taiwan

0

2

4

6

8

1970 1975 1980 1985 1990 1995 2000

year

Universal HBV Vaccination and Universal HBV Vaccination and Decreased Decreased Mortality from Fulminant Hepatitis Mortality from Fulminant Hepatitis in in Infants in Taiwan Infants in Taiwan

Universal HBV Vaccination July 1984Universal HBV Vaccination July 1984

Kao JH, Hsu HM, Shau WY, Chang MH, Chen DS. J Pediatr. 2001;139:349-52.

*The average mortality rate per 105 infantsMortality Ratio: 3.2 (p <0.001)

1974-1984: 5.36*

1985-1998: 1.71*

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Incidence Rate Ratios (IRR) of HBV-Positive v.s. -Negative FHF in 15 Years of the Universal Vaccination Program (Chen et al. Hepatology 2004 ;39:58-63)   Year 1985~99,Case

No. (Incidence per 10 5)

P-ValueHBV(+) FHF 43    

<1 Yr 33 (0.74) 54.2[26.1, 123.2]

<0.01

1-15 Yr 10 (0.014)    

       

   

1-15 Yr <0.01

   

IRR(1 v.s. 1-15Y)[95% C.I.]

HBV (-) FHF

< 1 Yr 52 25 (0.56)

72 (0.039)

15.2 [8.5, 27.2]

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Childhood HCC

1. Male Predominance :

M/F = 3-4 : 1

2. HBV, But Not HCV, Related . HBV, But Not HCV, Related >90% HBsAg Positive, 86% HBeAg >90% HBsAg Positive, 86% HBeAg

Negative, HBV Genome Integration Negative, HBV Genome Integration into Host Genome, 94% Maternal into Host Genome, 94% Maternal HBsAg PositiveHBsAg Positive

Chang MH et al. Hepatology 1991;13:316-Chang MH et al. Hepatology 1991;13:316-2020

Chang MH et al. Cancer 1989; 64: 2377-80Chang MH et al. Cancer 1989; 64: 2377-80

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EFFECT OF UNIVERSAL HEPATITIS B EFFECT OF UNIVERSAL HEPATITIS B VACCINATION ON HCC IN VACCINATION ON HCC IN

TAIWANESE CHILDREN, 6-9 YEARSTAIWANESE CHILDREN, 6-9 YEARS Birth HCC Incidence Birth HCC Incidence

Year in ChildrenYear in Children

1974-84 0.52/10 1974-84 0.52/10 55

1984-86 0.13/10 1984-86 0.13/10 55

Chang MH, et al. N Engl Med Chang MH, et al. N Engl Med 1997; 336:1855-9.1997; 336:1855-9.

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Incidence of HCC in Children Diagnosed at Aged 6 to 14 Years from July 1981 to June 2000 According to Birth Year

Birth Population No. of Incidence R.R. 95%

Year* Cases (per 10 5) CI

1966-84 48,764,799 263 0.54 1  1984-94 17,817,510 35 0.20 0.36 0.26-0.52 __________________________________________________ * Birth Year was counted from July of one year to June of the next year. R.R.: risk ratio; CI: confidence interval.

Chang MH, et al. Clin Cancer Res 2005;11: 7953-7.

Chang MH Chang MH et al. JAMA2000;284:3040-42

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Problems that remain to be solved Problems that remain to be solved for the control of Hepatitis & for the control of Hepatitis & related Diseasesrelated Diseases

Chang MH. Liver International 2003; 23: 309-14.

1. Inadequate Resources

2. Poor Compliance

3. Vaccine Failure

Intrauterine Infection

Genetic Hyporesponsiveness

Vaccine Escape Mutants / Variants

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ACKNOWLEDGEMENT ACKNOWLEDGEMENT

1. Hepatitis B Study : Hong-Yuan Hsu, Yen-Hsuan Ni, Huey-Ling Chen,

Chien-Jen Chen, Ding-Shinn Chen

2. Hepatoma Study : Tony Chen, Hsu-Mei Hsu, Tzee-Chung Wu, Man-

Shan Kong, Der-Cherng Liang, Tai-Tsung Chang, Jiann-Shiuh Chen, Chieh-Chung Lin, Fu-Chen Huang, Ming-Tzong Cheng, Chia-Hsian Chu, Su-Fen Wu, Pei-Shin Chang

Chang MH

Thank You Thank You

Very MuchVery Much