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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,Replication Cycle of HBV,EPIDEMIOLOGY,Prevalence of Chronic Hepatitis B,HBsAg Prevalence, 8% - High,2-8% - Intermediate, 2% - Low,Immigration numbers summed by c
2、ontinent from 1996-2002, 2 million Asians, 400,000 South 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.
3、 Hepatitis B statistics. Available at: http:/www.hepb.org/hepb/statistics.org. Accessed January 31, 2006.,NATURAL HISTORY OF HEPATITIS VIRUS INFECTION,Natural History of Hepatitis B,FACTORS AFFECTING THE CLINICAL COUSE OF HEPATITIS VIRUS INFECTION,Host Age of Infection Virus : Genotype Mutants / Var
4、iants Route of Infection Other Factors,- Perinatal Transmission - Childhood Infection - Adolescent/Adult Onset Disease,Age of Infection and Outcome,HBV GENOTYPE AND HBeAg SEROCONVERSION,Kao JH, Chen DS. Current Hepatitis Report 2006 (in press).,Kao JH, Chen DS. Current Hepatitis Report 2006,Worldwid
5、e Distribution of HBV Genotypes. The Size of the Capitals indicates the Relative Prevalence of the Genotypes,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.,Age in Years,HBeAg Seropositivity,Gen
6、otype C,Genotype B,Ni YH, Chang MH, et al. Gastroenterology 2004 ;127:1733-8.,Genotype C,Genotype B,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 Infec
7、tion and HCC in Taiwan,Ni YH, Chang MH, et al. Gastroenterology 2004 ;127:1733-8.,HBV VARIANTS / MUTANTS,A Point Mutation at Codon 28 ( Nucleotide 1896) of HBV Precore Gene,TGG,TAG,(Tryptophan),(Stop Codon),Leading to HBeAg Negative Strains,CHANGES OF HBV PRECORE GENE 1896 IN 80 HBsAg CARIER CHILDRE
8、N,Chang MH, et al. J Hepatol. 1998 ;28:915-22.,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 wh
9、ole 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.,Comparisons of HBV Core Gene Between 31 Chronic Carriers and 12 HCC Children,Ni YH, et al. Gut 2003;52:122-5,Comparisons of
10、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 chron
11、ic infection group.,Ni YH, et al. Gut 2003;52:122-5,DISCUSSION,These mutations may help HBV to escape host immune pressure, to expand viral proteins, and finally bring in the cancer development.,TREATMENT OF HEPATITIS B CURRENT THERAPY FOR HEPATITIS B IS NOT SATISFACTORY,CURRENT GOAL OF ANTIVIRAL TH
12、ERAPY FOR HEAPTITIS B,Reduction of Viral Replication Amelioration of Hepatic Dysfunction,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 Th
13、erapy.,CURRENT APPROVED THERAPY FOR HEPATITIS B,Interferon Interferon * Pegylated Interferon- Nucleoside Analog Lamivudine* Adefovir Entecavir,* Approved for use in children,Effects of interferon in childhood hepatitis B,Place & ALT HBeAg Clearance (%) Authors at Rx Control IFN Rx Barbera no limit 1
14、4% (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),Efficacy according to baseline ALT,% complete virologic response (HBeAg(-), HBV DNA(-),Jonas et
15、 al, N Engl J Med 2002; 346: 1706.,Lamivudine paediatric phase 3 study (NUC30903),Placebo (n=97),Wk 52,Baseline,No treatment (n=63),One year placebo controlled study,Two year follow-on study,Lamivudine 3 mg/kg (n=191),Lamivudine 3mg/kg,HBeAg-ve,HBeAg+ve,Treatment (n=213),89% Durability of response a
16、t month 36,Sokal E et al. Hepatology. 2006; 43: 225-32.,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 mutatio
17、ns 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.,PREVENTION OF VIRAL HEPATITIS,IMPORTANT TRANSMISSION ROUTE IN HYPERENDEMIC AREAS : MOTHER TO CHILD,EFFECTIVE PREVENTION OF HEPATITIS B : VACCINATION IN IN
18、FANCY,HEPATITIS B VACCINATION AND CONTROL OF HEPATITIS B RELATED LIVER DISEASES,Acute /Fulminant Hepatitis Chronic Hepatitis Liver Cirrhosis ? Hepatocellular Carcinoma,Universal HBV Vaccination and Decreased Mortality from Fulminant Hepatitis in Infants in Taiwan,Universal HBV Vaccination July 1984,
19、Kao JH, Hsu HM, Shau WY, Chang MH, Chen DS. J Pediatr. 2001;139:349-52.,*The average mortality rate per 105 infants Mortality Ratio: 3.2 (p 0.001),1974-1984: 5.36*,1985-1998: 1.71*,Incidence Rate Ratios (IRR) of HBV-Positive v.s. -Negative FHF in 15 Years of the Universal Vaccination Program (Chen e
20、t al. Hepatology 2004 ;39:58-63),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,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 Positiv
21、e Chang MH et al. Hepatology 1991;13:316-20 Chang MH et al. Cancer 1989; 64: 2377-80,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.,Incidence of
22、 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 o
23、f the next year. R.R.: risk ratio; CI: confidence interval.,Chang MH, et al. Clin Cancer Res 2005;11: 7953-7.,Chang MH et al. JAMA2000;284:3040-42,Problems that remain to be solved for the control of Hepatitis & related Diseases,Chang MH. Liver International 2003; 23: 309-14.,Inadequate Resources 2.
24、 Poor Compliance 3. Vaccine Failure Intrauterine Infection Genetic Hyporesponsiveness Vaccine Escape Mutants / Variants,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,Thank You Very Much,