Natural History of HBV Infection

Transcription

1 Natural History of HBV Infection Joseph JY Sung MD PhD Institute of Digestive Disease Department of Medicine & Therapeutics Prince of Wales Hospital The Chinese University of Hong Kong

2 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

3 Natural Course of HBV Infection early data from 80 s Risk of HCC increased by 200 folds Beasley et al. Lancet 1981, Liaw et al. Liver 1989 Hepatitis Cirrhosis HCC 15-20% develop Cirrhosis in 5 years Liaw et al. Hepatology year survival 55% 40% of Asian men with CHB die of complications Beasley Lancet 1981

4 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)

5 What determine the outcome of CHB Host Factors Viral Factors Gender Age Immunological status Alcohol Genotypes HBeAg negative (Precore/Core promoter Mutant) HBV viral load

6 Genotype, PC/CP, Viral Load Genotypes HBeAg status (PC/CP mutation) Hepatitis Flare, Fibrosis in Liver & Cancer HBV DNA (serum, liver, ccc DNA)

7 Genotype, PC/CP, Viral Load Genotypes HBeAg status (PC/CP mutation) Hepatitis Flare, Fibrosis in Liver & Cancer HBV DNA (serum, liver, ccc DNA)

8 HBV Genotype and e seroconversion Retrospective studies of 323 Chinese patients Chu et al. Gastro 2002 Age-specific prevalence of HBV genotypes Cumulative spontaneous e seroconversion Of genotype B vs genotype C

9 Genotype B has a lower eag positive at presentation and higher rates of spontaneous e seroconversion % of patients * Genotype B 22 Genotype C 37 * 18 e Ag loss e conversion Chu et al. Gastro 2002

10 HBV Genotypes in Hong Kong Age of seroconversion C: 40 yr vs B: 34 yr C 62.5% B 32.5% Yuen et al. J Hepatol 2004

11 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

12 Genotype C has more aggressive disease Genotype B n=41 Genotype C n=105 P value Persistent positive HBeAg n=20 n=60 Age 37±16 32± % Male 55% 63% 0.69 FU (months) 25±15 30± % Active disease 50% 78% HBeAg seroconversion n=21 n=39 Age of seroconversion 33±9 34± % Male 68% 46% 0.21 FU (months) 39±8 38± Post-HBeAg seroconversion n=16 n=31 (Patients with >6 month FU) Post-seroconversion FU (months) 25±10 20± % Active disease 25% 45% % HBeAg reversion 38% 42% 1.00

13 Genotype C has more aggressive disease and cirrhosis Cirrhosis HCC (<50) HCC (>50) asymptomatic carrier 170 chronic liver disease % A B C D Others Kao et al. Gastro 2000

14 But genotype B associated with young HCC Control Cohort (N=100) HCC Cohort (N=80) C B B Kao et al. Gastroenterol 2000

15 HBV Genotype and HCC 426 pts recruited consecutively from 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

16 Cirrhosis and Genotype C is associated with development of HCC Independent Risk Factor of HCC Liver cirrhosis adjusted relative risk (95% confidence interval ; p < 0.001) Genotype C adjusted relative risk 2.84 (95% confidence interval ; p=0.040) Chan et al. Gut 2004

17 Cirrhosis and Genotype C are important factors of HCC development Log rank test p<0.001 Chan et al. Gut 2004

18 Genotype, PC/CP, Viral Load Genotypes HBeAg status (PC/CP mutation) Hepatitis Flare, Fibrosis in Liver & Cancer HBV DNA (serum, liver, ccc DNA)

19 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 ( ) HBsAg+/HBeAg+: 60.2 ( ) Yang et al. NEJM 2002

20 Genotypes and CP/PC mutants Majority of eag negative cases with PC variant have genotype B/D CP variant are found evenly in eag negative cases in all genotypes Chu et al. Gastro 2003

21 HBeAg negative CHB still have substantial risk Yang et al. NEJM 2002

22 Risk of HBeAg +/- CHB in Developing HCC Yang et al. NEJM 2002

23 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)

24 Cross-sectional study on PC/CP mutations and Hepatic Diseases HBeAg Negative Cases p=ns % of patients 100% 80% 60% 40% 20% 0% Overall N ALT Elev ALT Cirrhosis (128) (64) (40) (24) WT TA Both A1896 Chan et al., Hepatology 2000

25 PC/CP mutations and HBV DNA Levels 100% HBeAg Negative Patients p=ns % of patients 80% 60% 40% 20% bdnabdna+ 0% TA AG A1896 WT (83) (45) Basal CP (47) (81) PC Chan et al., Hepatology 2000

26 Prospective Cohort Study of 317 HBeAg- Patients HBeAg HBeAg Negative Negative Elevated Elevated ALT ALT (35%) (35%) Normal Normal ALT ALT (65%) (65%) Relapse Relapse (33%) (33%) Fluctuation Fluctuation (55%) (55%) Remission Remission (12%) (12%) Relapse Relapse (10%) (10%) Fluctuation Fluctuation (30%) (30%) Remission Remission (60%) (60%) Definition of hepatitis relapse ALT 200 ALT 3-fold from baseline Whichever higher Chan et al AJG 2000

27 Histology in HBeAg negative patients (Genotype and PC/CP Mutation) No. HAI-NI P HAI-F P Genotype B 11 4 (2-7) (1-4) Genotype C 31 6 (2-10) 3 (1-4) T1762/A1764* 31 5 (2-10) (1-4) 0.57 A1762/G (3-7) 3 (1-4) T1766/A1768# (4-10) (1-4) 0.85 C1766/T (2-10) 3 (1-4) C (2-10) (1-4) 0.96 T (2-10) 2.5 (1-4) A (2-10) (1-4) 0.78 G (2-10) 3 (1-4) Chan et al. AJG 2003

28 PC/CP Mutations and HCC 60 inactive CHB and 190 HCC patients T1762/1764 mutation Genotype C vs B [OR 5.18, 95%CI ] T1762/1764 associated with HCC [OR 10.60, 95%CI ] Independent of Genotype (B/C) Independent of Age (above or below 50) T1762/1764 CP mutation are at increased risk of HCC Kao et al. Gastroenterol 2003

29 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 ] Basal CP [OR 4.12, 95%CI ] Gender-related risk factor Basal CP [OR 4.35, 95%CI ] Basal CP might explain the gender difference in liver disease Lin et al. Liver Int 2005

30 Genotype, PC/CP, Viral Load Genotypes HBeAg status (PC/CP mutation) Hepatitis Flare, Fibrosis in Liver & Cancer HBV DNA (serum, liver, ccc DNA)

31 ALT, Mutant, DNA or genotype? Prospective cohort study Monitor 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

32 ALT, Mutant, DNA or genotype? Median (range) follow-up 70 (28-83) months 29.5% Active disease Remission Fluctuation Relapse 70.5 Sung et al. J Viral Hep 2002

33 HBV DNA and ALT (but not PC mutation) determines outcome Remission Active Disease P ALT ALT > HBV DNA ve HBV DNA +ve 0 12 PCR ve PCR +ve 4 19 T1762/A A1762/G A G C T

34 More severe necro-inflammation with high viral load No. HAI-NI P HAI-F P Male 41 5 (1-10) (0-4) 0.58 Female 14 5 (1-10) 1.5 (0-4) ALT > (2-10) (0-4) ALT (1-10) 1 (0-4) NAXCOR +ve 32 5 (2-10) (1-4) 0.23 NAXCOR -ve 23 3 (1-10) 2 (0-4) PCR positive 37 5 (2-10) (1-4) PCR negative 18 3 (1-10) 1 (0-4) Chan et al. AJG 2003

35 HBV genotype and DNA Levels in 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

36 Genotype, HBeAg, Viral Load are the important factors in HCC development Yu et al. JNCI 2005

37 In all age group, viral load is higher in patients with HCC Yu et al. JNCI 2005

38 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 ( ) HBeAg negative: 3.09 ( ) Anti-HBe positive: 1.55 ( ) Yu et al. JNCI 2005

39 Combined risk of HCC associated with DNA level and genotype Baseline HBV DNA levels (log 10 copies/ml) HBV genotype < >5.91 A, B or mix cases/control 8/81 34/113 33/48 Adjusted OR ( ) 6.99 ( ) C cases/control 11/15 18/13 42/16 Adjusted OR 6.55 ( ) 13.0 ( ) 26.5 ( ) Yu et al. JNCI 2005

40 HBV viral load and HCC 3,653 subjects in a cancer screening program follow up for 11.4 years, 164 cases of HCC diagnosed Chen et al. JAMA 2006

41 HBV Viral Load and HCC Chen et al. JAMA 2006