儿童乙肝的新认识(英文版)-文档

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)
• Codon 74, 87, and 159 mutations are
found in HCC children, but not in the chronic infection group.
Chang MH
Ni YH, et al. Gut 2003;52:122-5
DISCUSSION
• These mutations may help HBV
HBsAg Prevalence
> 8% - High 2-8% - Intermediate < 2% - Low
~ 350,000 Africans
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.
Replication Cycle of HBV
Chang MH
EPIDEMIOLOGY
Chang MH
Prevalence of Chronic Hepatitis B
~ 2 million Asians
~ 400,000 South Americans
~ 930, 000 Europeans
Chang MH
CURRENT APPROVED THERAPY FOR HEPATITIS B
• Interferon
Interferon –α* Pegylated Interferon-α
• Nucleoside Analog
Lamivudine* Adefovir Entecavir
Chang MH
Disease
Chang MH
HBV GENOTYPE AND HBeAg
SEROCONVERSION
Chang MH
Worldwide Distribution of HBV Genotypes. The Size of the Capitals indicates the Relative PrKeavoaJlHe,nCcheenoDfSt.hCeurGrenetnHoeptyatpities sReport 2006 (in press).
TGG (Tryptophan)
TAG (Stop Codon)
Leading to HBeAg Negative Strains
Chang MH
CHANGES OF HBV PRECORE GENE 1896 IN 80 HBsAg CARIER CHILDREN
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
• 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
Chang MH
Chang MH, et al. J Hepatol 1998; 28: 915-22.
Comparisons of HBV Core Gene Between 31 Chronic Carriers and 12 HCC Children
Codon
Mutated Cases Mutated Cases (No.) (No.) in HCC in Chronic carrier
Mutations
P value
Precore 28 Core 21 Core 65 Core 74 Core 87 Core 131 Core 143 Core 147 Core 159 Core 182 Chang MH
58% (7) 8% (1) 33% (4) 33% (4) 33% (4) 8% (1) 33% (4) 8% (1) 42% (5) 42% (5)
CURRENT GOAL OF ANTIVIRAL THERAPY FOR HEAPTITIS B
•Reduction of Viral
Replication
•Amelioration of Hepatic
Dysfunction
Chang MH
HBV Antiviral Therapy Is Not Recommended in
Genotype C
Genotype B
Genotype C
Genotype B
Age in Years
Ni YH, Chang MH, et al. Gastroenterology 2004 ;127:1733-8.
HBV Genotype and Clinical Course in Children
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.
Chang MH
Ni YH, Chang MH, et al. Gastroenterology 2004 ;127:1733-8.
HBV VARIANTS / MUTANTS
Chang MH
A Point Mutation at Codon 28 ( Nucleotide 1896) of HBV Precore Gene
11% (12/113) 23%(29/126)
Chang MH
Efficacy according to baseline ALT
60 % complete 50
virologic response 40 (HBeAg(-), HBV DNA(-) 30
20 10 0
Chang MH
Placebo (n=95)
Mean
+- SD
136
179
209
167
+- 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.
Sokal
> 2xN
Meta-Ana no limit
HBeAg Clearance (%)
Control
IFN Rx
14% (5/37) 26% (10/39)
13% (4/31) 38% (24/64)
0% (0/30)
8% (5/60)
38% (5/13) 44% (8/18)
11% (8/74) 26% (18/70)
Lamivudine (n=191) 50%
23% 13% 43/183
11/88
34%
33/97
16%
9/58
8/16
24%
4/17
> 1xULN
> 2xULN
Baseline ALT
> 5xULN
Jonas et al, N Engl J Med 2002; 346: 1706.
Lamivudine paediatric phase 3 study (NUC30903)
• Host
Age of Infection
• Virus :
Genotype Mutants / Variants
• Route of Infection • Other Factors
Chang MH
Age of Infection and Outcome
- Perinatal Transmission - Childhood Infection - Adolescent/Adult Onset
to escape host immune pressure, to expand viral proteins, and finally bring in the cancer development.
Chang MH
Chang MH
TREATMENT OF
HEPATITIS B
CURRENT THERAPY FOR HEPATITIS B IS NOT SATISFACTORY
Kao JH, Chen DS. Current Hepatitis Report 2006
Chang MH
No. of Children with Chronic HBV Infection
160
238
62
26
100%
HBV
C
80%
C
C
Genotype
C
Follow-up
A
60%
B+C
B→C
C→B
52.2% (12)
WX
0.73
21.7% (5)
SP or A
0.32
17.3% (4)
LW or V
0.29
0
SG
0.0032
0来自百度文库
SG
0.0032
0
AD
0.16
4.3% (1)
LP
0.015
21.6% (5)
TC or S
0.32
0
RS
0.0006
4.3% (1)
QX
0.0035
Ni YH, et al. Gut 2003;52:122-5
• HBeAg Negative & Normal ALT
Subjects : Relatively Stable Course with Low Rate of Progression.
• HBeAg Positive & Normal ALT
Subjects : May Progress , But No Effective Therapy.
* Approved for use in children
Effects of interferon in childhood hepatitis B
Place &
ALT
Authors at Rx
Barbera no limit
Gregorio > 1.5xN
Lai
no limit
Tsai, Hsu > 2xN
40%
B
B
B
B
Genotype C
Genotype B
20%
0% HBeAg(+/+) HBeAg(+/-) Anti-HBe(+)
HCC
Chang MH
Ni YH, Chang MH, et al. Gastroenterology 2004 ;127:1733-8.
Chang MH
HBeAg Seropositivity
1st HBeAg Last HBeAg 1st HBeAg Last HBeAg Positive Positive Negative Negative
PCR Neg. Mutant Only Mixed Wild Only
Chang MH
. Chang MH, et al. J Hepatol. 1998 ;28:915-22
Chang MH
NATURAL HISTORY OF HEPATITIS VIRUS INFECTION
Chang MH
Natural History of Hepatitis B
Chang MH
FACTORS AFFECTING THE CLINICAL COUSE OF
HEPATITIS VIRUS INFECTION