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NEW INSIGHT IN HEPATITIS B IN CHILDREN

NEW INSIGHT IN HEPATITIS B IN CHILDREN. Mei-Hwei Chang , M.D. Department of Pediatrics, National Taiwan University Hospital, Taipei, TAIWAN. Replication Cycle of HBV. EPIDEMIOLOGY. Prevalence of Chronic Hepatitis B. ~ 2 million Asians. ~ 930, 000 Europeans. ~ 400,000

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NEW INSIGHT IN HEPATITIS B IN CHILDREN

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  1. NEW INSIGHT IN HEPATITIS B IN CHILDREN Mei-Hwei Chang , M.D. Department of Pediatrics, National Taiwan University Hospital, Taipei, TAIWAN

  2. Replication Cycle of HBV

  3. EPIDEMIOLOGY

  4. Prevalence of Chronic Hepatitis B ~ 2 million Asians ~ 930, 000 Europeans ~ 400,000 South Americans HBsAg Prevalence ~ 350,000 Africans > 8% - High 2-8% - Intermediate < 2% - Low Immigration numbers summed by continent from 1996-2002 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.

  5. NATURAL HISTORY OF HEPATITIS VIRUS INFECTION

  6. Natural History of Hepatitis B

  7. FACTORS AFFECTING THE CLINICAL COUSE OF HEPATITIS VIRUS INFECTION • Host Age of Infection • Virus : Genotype Mutants / Variants • Route of Infection • Other Factors

  8. Age of Infection and Outcome - Perinatal Transmission - Childhood Infection - Adolescent/Adult Onset Disease

  9. HBV GENOTYPE AND HBeAg SEROCONVERSION

  10. Worldwide Distribution of HBV Genotypes. The Size of the Capitals indicates the Relative Prevalence of the Genotypes Kao JH, Chen DS. Current Hepatitis Report 2006 (in press). Kao JH, Chen DS. Current Hepatitis Report 2006

  11. No. of Children with Chronic HBV Infection 160 238 62 26 HBV GenotypeFollow-up C C C C B B B B Ni YH, Chang MH, et al. Gastroenterology 2004 ;127:1733-8.

  12. Genotype C Genotype C HBeAg Seropositivity Genotype B Genotype B Age in Years Ni YH, Chang MH, et al. Gastroenterology 2004 ;127:1733-8.

  13. HBV Genotype and Clinical Course in Children • Genotype C Delays HBeAg Seroconversion in Chronic HBV Infection in Children • Genotype Changes : Rare • Genotype B Dominates in Children with Chronic HBV Infection and HCC in Taiwan Ni YH, Chang MH, et al. Gastroenterology 2004 ;127:1733-8.

  14. HBV VARIANTS / MUTANTS

  15. A Point Mutation at Codon 28 ( Nucleotide 1896) of HBV Precore Gene TGG TAG (Stop Codon) (Tryptophan) Leading to HBeAg Negative Strains

  16. CHANGES OF HBV PRECORE GENE 1896 IN 80 HBsAg CARIER CHILDREN Chang MH, et al. J Hepatol. 1998 ;28:915-22.

  17. Peak ALT levels during follow-up in 3 groups with different patterns of HBV precore 1896 Peak ALT Group 1 Group 2 Group 3 Total (IU/l) (n=37) (n=22) (n=21) (n=80) Mean 136 179 209 167 +- SD +- 149 +- 141 +- 195 +-161 Group 1: Wild type throughout the whole course. Group 2: Mutant after HBe seroconversion Group 3: Mutant before HBe seroconversion. • ALT levels between groups, p=0.07. Chang MH, et al. J Hepatol 1998; 28: 915-22.

  18. Codon Mutated Cases (No.) in HCC Mutated Cases (No.) in Chronic carrier Mutations P value Precore 28 58% (7) 52.2% (12) WX 0.73 Core 21 8% (1) 21.7% (5) SP or A 0.32 Core 65 33% (4) 17.3% (4) LW or V 0.29 Core 74 33% (4) 0 SG 0.0032 Core 87 33% (4) 0 SG 0.0032 Core 131 8% (1) 0 AD 0.16 Core 143 33% (4) 4.3% (1) LP 0.015 Core 147 8% (1) 21.6% (5) TC or S 0.32 Core 159 42% (5) 0 RS 0.0006 Core 182 42% (5) 4.3% (1) QX 0.0035 Comparisons of HBV Core Gene Between 31 Chronic Carriers and 12 HCC Children Ni YH, et al. Gut 2003;52:122-5

  19. Comparisons of HBV Core Gene Between 31 Chronic Carriers and 12 HCC Children - SUMMARY • Core gene codon 21, 65, and 147 were the commonest mutation sites in children with chronic HBV infection. All were located in HBcAg epitopes of CTL. • Codon 74, 87, and 159 mutations are found in HCC children, but not in the chronic infection group. Ni YH, et al. Gut 2003;52:122-5

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

  21. TREATMENT OF HEPATITIS B CURRENT THERAPY FOR HEPATITIS B IS NOT SATISFACTORY

  22. CURRENT GOAL OF ANTIVIRAL THERAPY FOR HEAPTITIS B • Reduction of Viral Replication • Amelioration of Hepatic Dysfunction

  23. HBV Antiviral Therapy Is Not Recommended in • HBeAg Negative & Normal ALT Subjects : Relatively Stable Course with Low Rate of Progression. • HBeAg Positive & Normal ALT Subjects : May Progress , But No Effective Therapy.

  24. CURRENT APPROVED THERAPY FOR HEPATITIS B • Interferon Interferon –α* Pegylated Interferon-α • Nucleoside Analog Lamivudine* Adefovir Entecavir * Approved for use in children

  25. Effects of interferon in childhood hepatitis B Place & ALT HBeAg Clearance (%) Authors at Rx Control IFN Rx Barbera no limit 14% (5/37) 26% (10/39) Gregorio > 1.5xN 13% (4/31) 38% (24/64) Lai no limit 0% (0/30) 8% (5/60) Tsai, Hsu > 2xN 38% (5/13) 44% (8/18) Sokal > 2xN 11% (8/74) 26% (18/70) Meta-Ana no limit 11% (12/113) 23%(29/126)

  26. 50% 34% 8/16 24% 23% 33/97 16% 4/17 13% 43/183 9/58 11/88 Efficacy according to baseline ALT % complete virologic response (HBeAg(-), HBV DNA(-) Jonas et al, N Engl J Med 2002; 346: 1706.

  27. Lamivudine paediatric phase 3 study (NUC30903) One year placebo controlled study Two year follow-on study Lamivudine 3 mg/kg (n=191) No treatment (n=63) HBeAg-ve 89% Durability of response at month 36 Treatment (n=213) HBeAg+ve Lamivudine 3mg/kg Placebo (n=97) Baseline Wk 52 Sokal E et al. Hepatology. 2006; 43: 225-32.

  28. Long term lamivudine therapy for children with HBeAg+ve CHB (2) • Virologic response in the treatment arm 21% after 12 + 24 months of Rx (n=133) 30% after 0 + 24 months Rx (n=77) * VR = loss of HBeAg loss and HBV DNA • The incidence of YMDD mutations was 64% (66/103) after 12 + 24 months of lamivudine 49% (34/70) after 0 + 24 months of lamivudine Sokal E et al. Hepatology. 2006; 43: 225-32.

  29. PREVENTION OF VIRAL HEPATITIS

  30. IMPORTANT TRANSMISSION ROUTE IN HYPERENDEMIC AREAS : MOTHER TO CHILD EFFECTIVE PREVENTION OF HEPATITIS B : VACCINATION IN INFANCY

  31. HEPATITIS B VACCINATION AND CONTROL OF HEPATITIS B RELATED LIVER DISEASES • Acute /Fulminant Hepatitis • Chronic Hepatitis • Liver Cirrhosis ? • Hepatocellular Carcinoma

  32. Universal HBV Vaccination and Decreased Mortality from Fulminant Hepatitis in Infants in Taiwan Universal HBV Vaccination July 1984 1974-1984: 5.36* 1985-1998: 1.71* *The average mortality rate per 105 infants Mortality Ratio: 3.2 (p <0.001) Kao JH, Hsu HM, Shau WY, Chang MH, Chen DS. J Pediatr. 2001;139:349-52.

  33. 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-Value HBV(+) 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.] 52 HBV (-) FHF 15.2 [8.5, 27.2] < 1 Yr 25 (0.56) 72 (0.039)

  34. Childhood HCC • Male Predominance : • M/F = 3-4 : 1 • 2. HBV, But Not HCV, Related • >90% HBsAg Positive, 86% HBeAg Negative, HBV Genome Integration into Host Genome, 94% Maternal HBsAg Positive • Chang MH et al. Hepatology 1991;13:316-20 • Chang MH et al. Cancer 1989; 64: 2377-80

  35. EFFECT OF UNIVERSAL HEPATITIS B VACCINATION ON HCC IN TAIWANESE CHILDREN, 6-9 YEARS Birth HCC Incidence Year in Children 1974-84 0.52/10 5 1984-86 0.13/10 5 Chang MH, et al. N Engl Med 1997; 336:1855-9.

  36. 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 0.360.26-0.52__________________________________________________ * 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.

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

  38. Problems that remain to be solved for the control of Hepatitis & related Diseases • Inadequate Resources • 2. Poor Compliance • 3. Vaccine Failure • Intrauterine Infection • Genetic Hyporesponsiveness • Vaccine Escape Mutants / Variants Chang MH. Liver International 2003; 23: 309-14.

  39. ACKNOWLEDGEMENT • Hepatitis B Study : • Hong-Yuan Hsu, Yen-Hsuan Ni,Huey-Ling Chen, Chien-Jen Chen, Ding-Shinn Chen • 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

  40. Thank You Very Much

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