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Natural History of HBV Infection
Joseph JY Sung MD PhDInstitute of Digestive Disease
Department of Medicine & TherapeuticsPrince of Wales Hospital
The Chinese University of Hong Kong
HBV Infection
• 2 billion people in world infected by HBV
• 350 million chronic carriers
• 75% are Asian
• 25-40% of them had cirrhosis or HCC
• 1.2 million death per year
Natural Course of HBV Infectionearly data from 80’s
Hepatitis Cirrhosis HCC
15-20% develop Cirrhosis in 5 yearsLiaw et al. Hepatology 1988
Risk of HCC increased by 200 foldsBeasley et al. Lancet 1981, Liaw et al. Liver 1989
5-year survival 55%40% of Asian men with CHB die of complications
Beasley Lancet 1981
HBV Infection in SE Asia
• Prevalence 5-15% (10% in Hong Kong) (Gut 1996)
• 10-25% HBeAg+ undergo e conversion per year (Liaw 1984, Lok 1987)
• Up to one-third of HBeAg- patients still develop
relapses of hepatitis (Lok 1987, Liaw 1987)
• Some even develop cirrhosis and HCC (Liaw 1988)
What determine the outcome of CHB
Viral Factors
• Genotypes• HBeAg negative
(Precore/Core promoter Mutant)
• HBV viral load
Host Factors
• Gender• Age• Immunological status• Alcohol
Genotype, PC/CP, Viral Load
Genotypes
HBV DNA(serum, liver, ccc DNA)
HBeAg status(PC/CP mutation)
Hepatitis Flare, Fibrosis in Liver & Cancer
Genotype, PC/CP, Viral Load
Genotypes
HBV DNA(serum, liver, ccc DNA)
HBeAg status(PC/CP mutation)
Hepatitis Flare, Fibrosis in Liver & Cancer
HBV Genotype and e seroconversion
Retrospective studies of 323 Chinese patientsChu et al. Gastro 2002
Age-specific prevalence of HBV genotypesCumulative spontaneous e seroconversion
Of genotype B vs genotype C
Genotype B has a lower eAg positive at presentation and higher rates of spontaneous e seroconversion
4037
2218
05
1015202530354045
e Ag loss e conversion
Genotype B Genotype C
% o
f pat
ient
s
* *
Chu et al. Gastro 2002
HBV Genotypes in Hong Kong
C 62.5%B 32.5%
Age of seroconversionC: 40 yr vs B: 34 yr
Yuen et al. J Hepatol 2004
HBV Genotype and disease activity
• 172 consecutive HBeAg positive patients
• Prospective follow-up at 6m intervals for at least 12m
• Co-infection by HCV, HDV and alcoholism excluded
• Active liver disease = ALT flare (>200 IU/l) OR ALT elevation plus positive HBeAg/HBV DNA
• Hepatocellular carcinoma (HCC) confirmed by combination of imaging and histology
Chan et al J Clin Microbiol 2003
Genotype C has more aggressive disease
1.0042%38%% HBeAg reversion
0.03045%25%% Active disease
0.05320±925±10Post-seroconversion FU (months)
n=31n=16Post-HBeAg seroconversion(Patients with >6 month FU)
0.7438±839±8FU (months)
0.2146%68%% Male
0.7634±1333±9Age of seroconversion
n=39n=21HBeAg seroconversion
0.03278%50%% Active disease
0.2430±1425±15FU (months)
0.6963%55%% Male
0.2432±1337±16Age
n=60n=20Persistent positive HBeAg
P valueGenotype Cn=105
Genotype Bn=41
Genotype C has more aggressive disease and cirrhosis
0
30
60
010
3
80
14
0 32
51
41
2 4
0
20
40
60
80
100
A B C D Others
Cirrhosis HCC (<50) HCC (>50)
100 asymptomatic carrier170 chronic liver disease
Kao et al. Gastro 2000
%
But… genotype B associated with young HCC
Kao et al. Gastroenterol 2000
Control Cohort (N=100)
B
HCC Cohort (N=80)
B
C
HBV Genotype and HCC
• 426 pts recruited consecutively from 1997-2000
• FU for 1664 person-year
• Median FU 225 (12-295) months
• HCC developed in 25 patients in 121 (14-236) months
Chan et al. Gut 2004
Cirrhosis and Genotype C is associated with development of HCC
Independent Risk Factor of HCC• Liver cirrhosis
– adjusted relative risk 10.24 – (95% confidence interval 4.39-23.89; p < 0.001)
• Genotype C– adjusted relative risk 2.84 – (95% confidence interval 1.05-7.72; p=0.040)
Chan et al. Gut 2004
Cirrhosis and Genotype C are important factors of HCC development
Log rank test p<0.001
Chan et al. Gut 2004
Genotype, PC/CP, Viral Load
Genotypes
HBV DNA(serum, liver, ccc DNA)
HBeAg status(PC/CP mutation)
Hepatitis Flare, Fibrosis in Liver & Cancer
HBeAg and Risk of HCC
• 111 cases of newly diagnosed HCC during 92,359 person-years of follow-up– HBsAg+/HBeAg+: 1169 per 100,000 p-y– HBsAg+/HBeAg-: 324 per 100,000 p-y– HBsAg-/HBeAg-: 39 per 100,000 p-y
• Relative Risk– HBsAg+: 9.6 (6.0-15.2)– HBsAg+/HBeAg+: 60.2 (35.5-102.1)
Yang et al. NEJM 2002
Genotypes and CP/PC mutants
Chu et al. Gastro 2003Majority of eAg negative cases with PC variant have genotype B/DCP variant are found evenly in eAg negative cases in all genotypes
HBeAg negative CHB still have substantial risk
Yang et al. NEJM 2002
Risk of HBeAg +/- CHB in Developing HCC
Yang et al. NEJM 2002
Core Promoter & Precore Stop Codon Mutation: More serious disease?
G→A at n1896 (PC)
A→T n1762 G→A n1764 (CP)
• Facilitate viral replication (Scaglioni 1997, Moriyama 1996, Buckwood
1996)
• Cause chronic active hepatitis (Liang 1991, Omata 1991, Hasegawa
1991, Sato 1995)
• Associate with fulminant hepatitis (Brunetto 1991, McMillan 1996)
• Associate with HCC (Baptista 1999, Fang 1998, Zhong 2000)
Cross-sectional study onPC/CP mutations and Hepatic Diseases
0%
20%
40%
60%
80%
100%
Overall N ALT Elev ALT Cirrhosis
WTTABothA1896
p=NS
(64) (40) (24)(128)
HBeAg Negative Cases
Chan et al., Hepatology 2000
% o
f pat
ient
s
PC/CP mutations and HBV DNA Levels
0%
20%
40%
60%
80%
100%
TA AG A1896 WT
bDNA-
bDNA+
p=NS
% o
f pat
ient
s
(47) (81)(83) (45)
HBeAg Negative Patients
Chan et al., Hepatology 2000Basal CP
PC
Prospective Cohort Study of 317 HBeAg- Patients
HBeAg Negative317
HBeAg Negative317
Elevated ALT111 (35%)
Elevated ALT111 (35%)
Normal ALT206 (65%)
Normal ALT206 (65%)
Relapse37 (33%)Relapse37 (33%)
Fluctuation61 (55%)
Fluctuation61 (55%)
Remission13 (12%)
Remission13 (12%)
Relapse20 (10%)Relapse20 (10%)
Fluctuation61 (30%)
Fluctuation61 (30%)
Remission125 (60%)
Remission125 (60%)
Definition of hepatitis relapse
• ALT ≥ 200
• ALT ≥ 3-fold from baseline
Whichever higher Chan et al AJG 2000
3 (1-4)5 (2-10)25G1896
0.782 (1-4)0.265 (2-10)17A1896
2.5 (1-4)5 (2-10)22T1858
0.963 (1-4)0.975 (2-10)20C1858
3 (1-4)5 (2-10)36C1766/T1768
0.852.5 (1-4)0.296.5 (4-10)6T1766/A1768#
3 (1-4)5 (3-7)11A1762/G1764
0.572 (1-4)0.355 (2-10)31T1762/A1764*
3 (1-4)6 (2-10)31Genotype C
0.0972 (1-4)0.00144 (2-7)11Genotype B
PHAI-FPHAI-NINo.
Histology in HBeAg negative patients(Genotype and PC/CP Mutation)
Chan et al. AJG 2003
• 60 inactive CHB and 190 HCC patients
• T1762/1764 mutation Genotype C vs B [OR 5.18, 95%CI 2.59-10.37]
• T1762/1764 associated with HCC [OR 10.60, 95%CI 4.92-22.86]– Independent of Genotype (B/C)– Independent of Age (above or below 50)
• T1762/1764 CP mutation are at increased risk of HCC
PC/CP Mutations and HCC
Kao et al. Gastroenterol 2003
PC/CP Mutations and Hepatic Diseases
• 174 HBeAg negative chronic HBV (including 62 inactive carriers)
• HBV genotypes, PC/CP sequence determined
• Risk of liver cirrhosis and HCC– Age>50 year [OR 9.09, 95%CI 3.22-25]– Basal CP [OR 4.12, 95%CI 1.41-12.03]– Gender-related risk factor
• Basal CP [OR 4.35, 95%CI 1.3-14.5]
• Basal CP might explain the gender difference in liver disease
Lin et al. Liver Int 2005
Genotype, PC/CP, Viral Load
Genotypes
HBV DNA(serum, liver, ccc DNA)
HBeAg status(PC/CP mutation)
Hepatitis Flare, Fibrosis in Liver & Cancer
ALT, Mutant, DNA or genotype?
Prospective cohort studyMonitor ALT, genotypes, CP/PC mutant and
HBV DNA levels• N=78, M:F 63:15• Age: Median 35 (16-66) years• Alcohol: 3• HCV, HDV negative• IFN therapy: 6 (7.7%) for 6 m
Sung et al. J Viral Hep 2002
ALT, Mutant, DNA or genotype?
70.5
12.8
16.7
RemissionFluctuationRelapse
29.5%Activedisease
Median (range) follow-up 70 (28-83) months
Sung et al. J Viral Hep 2002
HBV DNA and ALT (but not PC mutation) determines outcome
1.00129
43
C1858T1858
1.00615
25
A1896G1896
0.29183
43
T1762/A1764A1762/G1764
0.00419
514
PCR –vePCR +ve
0.001112
550
HBV DNA –veHBV DNA +ve
0.00617
4411
ALT ≤ 60ALT > 60
PActive DiseaseRemission
1 (0-4)3 (1-10)18PCR negative0.0563 (1-4)0.0055 (2-10)37PCR positive
2 (0-4)3 (1-10)23NAXCOR -ve0.232.5 (1-4)0.0395 (2-10)32NAXCOR +ve
1 (0-4)5 (1-10)21ALT ≤ 600.0653 (0-4)0.105 (2-10)34ALT > 60
1.5 (0-4)5 (1-10)14Female0.582 (0-4)0.965 (1-10)41Male
PHAI-FPHAI-NINo.
More severe necro-inflammation with high viral load
Chan et al. AJG 2003
HBV genotype and DNA Levelsin Hepatocellular Carcinoma
• Prospective Study 1988 to 1992• Cohort of 4841 Taiwanese HBV carrier• 154 developed HCC during follow up• 316 control subjects• Parameters
– Genotype– HBV DNA
• Unconditional logistic regress• Majority (86.7%-93.2%) HBeAg negative• Majority of HCC are genotype B (81.8%)
Yu et al. JNCI 2005
Genotype, HBeAg, Viral Load are the important factors in HCC development
Yu et al. JNCI 2005
In all age group, viral load is higher in patients with HCC
Yu et al. JNCI 2005
Effects of Viral Load on Risk of HCC
• Adjusted OR of HCC for an increase of 1 log10 HBV DNA copy/ml– HBeAg positive: 0.68 (0.39-1.16)– HBeAg negative: 3.09 (1.74-5.49)– Anti-HBe positive: 1.55 (1.30-1.85)
Yu et al. JNCI 2005
Combined risk of HCC associated with DNA level and genotype
42/1626.5 (10.4-67.4)
18/1313.0 (4.65-36.3)
11/156.55 (2.23-19.3)
Ccases/controlAdjusted OR
33/486.99 (2.97-16.5)
34/1132.95 (1.29-6.75)
8/811
A, B or mixcases/controlAdjusted OR
>5.914.23-5.90<4.22HBV genotype
Baseline HBV DNA levels (log10 copies/ml)
Yu et al. JNCI 2005
HBV viral load and HCC
Chen et al. JAMA 2006
3,653 subjects in a cancer screening program follow up for 11.4 years, 164 cases of HCC diagnosed
HBV Viral Load and HCC
Chen et al. JAMA 2006
