1. The Natural History of Delta Hepatitis Prof. Dr. Cihan Yurdaydin University of Ankara Medical School Gastroenterology Department EASL Monothematic Conference on DELTA HEPATITIS Istanbul, 24-26 September 2010

4. Delta Hepatitis Early chimpanzee experiments disclosed: Supression of HBV infection - Decline or disappearance of HBcAg in liver tissue - Decrease in HBsAg Typical patient with delta hepatitis: - HBeAg-negative, HBeAb-positive - HBV DNA low - High HDV RNA

5. Hepatitis D > Hepatitis B Hepatitis D = Hepatitis B Hepatitis D < Hepatitis B

6. Longutidinal follow-up of HBV DNA and HDV RNA patterns Both viruses were active in 15 (40.5%) patients and inactive in 4 (10.8%) HDV alone was active in 12 (32.4%) and HBV in 6 (16.2%) Considerable fluctuating activity of one or both viruses, including alternating predominance Schaper et al. J Hepatol 2010;

7. HBeAg-positive chronic delta hepatitis 534 patients; 71/534 (13%) HBeAg (+) Heidrich et al, AALD 2008 p <0.001

8. HBeAg-positive chronic delta hepatitis 534 patients; 71/534 (13%) HBeAg (+) Heidrich et al, AALD 2008 (%)

9. HBV-HDV co-infection

10. Europe 43/111 (39%) 101/532 (19%) <0.000001 Smedile et al 1982 USA 24/71 (34%) 5/118 (4%) 0.000016 Govindarajan et al 1984 Fulminant Acute Hepatitis B Hepatitis B p value Proportion of patients with evidence of HDV in acute self limited vs. fulminant hepatitis B Chronicity infrequent: 5/208 patients (2.4%) Caredda et al 1987

11. 138 acute hepatitis D 23 acute superinfection115 acute co-infection 104 resolution (90%) 10 chronic hepatitis (8%) Outcome of Acute Delta Hepatitis Buti et al, J Viral Hepat 2010 (in press) 23 chronic hepatitis (100%)

12. Chronic delta hepatitis

13. 1 4 3 2 5 10 15 Years FIBROSIS NATURAL HISTORY

14. 1977-19861987-1996 n= 162n= 122 Mild hepatitis9 (6%)9 (8%) Severe hepatitis105 (65%)21 (17%) Histologic cirrhosis46 (28%)38 (31%) Clinical cirrhosis2 (1%)54 (44%) Changing pattern of chronic hepatitis D in Southern Europe Rosina et al, Gastroenterology 1999

15. CLINICAL PRSENTATION OF DELTA HEPATITIS IN THE 90’s 0 1 2 3 4 5 6 7 8 9 10 Mild Hepatitis Severe Hepatitis Histologic Cirrhosis Clinical Cirrhosis Years Rosina et al, Gastroenterology 1999 40 80 60 100 Survival (%)

16. Delta hepatitis and HCC Early studies: infrequent association due to diminished life expectancy (Rizzetto & Verme, J Hepatol 1985) A European wide study reported a 3.2 fold increased risk compared to mono-infected pts (p<0.05); some risk for hepatic decompenstaion (2.2 fold, p= NS) (Fattovich et al, Gut 2000)

17. Romeo et al, Gastro 2009 HCC vs. hepatic decompensation in HDV cirrhosis: a 28 year follow-up study

18. HCC vs. decompensation in HDV cirrhosis Romeo et al, Gastroenterology 2009

19. 188 patierts enrolled 106 cirrhosis82 chronic hepatitis 21 cirrhosis61 chronic hepatitis 5 decomp. cirrh.+ 3 HCC 13 comp. cirrhosis 55 comp. cirrh. 37 decomp. cirrh.+ 14 HCC Follow up 59 Liver major complications Outcome of CDH in Italy (mean FU: 7.8 ± 4.1 years) Niro et al, J Hepatol 2010 (in press)

20. 158 chronic hepatitis D 114 stabile (72 %) 11 resolution (7 %) Buti et al, J Hepatol 2010 29 decompensation (18 %) 4 HCC (3 %) Outcome of CDH in Spain (median FU: 13.2 years)

21. Decompensation vs HCC in Cirrhotic HDV Patients (n=54) HCC Dec. p=0,2; HR=1,7 %95 CI(0,7 – 3,9) Decompensation [n=14 (25,9%)]: Median=59 mo(min-max=8,2 – 93,1) HCC [n=8 (14,8%)]: Median = 42,8 mo(min-max=17,5 – 87,8) Months

22. Chronic Delta Hepatitis Progression to Cirrhosis (n=97) Progression to Cirrhosis [n=19 (19,6 %)], Median 58,4 mo (min – max= 3,5 – 174,9) Months

23. Mortality in Cirrhotic HDV Cases (n=54)  Ex+Tx Median survival of cirrhotic HDV cases is 70 mo (min – max=15,5 – 99,8) (n=54) Mortality 16 cases (29,6 %); tx in 9 patients (17%)

24. 1. HBsAg clerance 2. Extrahepatic Malignancies in the Course of CDH HBsAg clearance in 14 patients after a median follow-up of 76 months (16/151- 11%). There were 7 (4.3 %) extrahepatic malignancies in the course of disease (4 adeno Ca of GI tract and 3 leukemia)

25. HDV-3 HDV-2 HDV-4 HDV-1 HDV genotypes- phylogenetic analysis (new classification) (Radjef et al, J Virol 2004) HDV-6 HDV-5 HDV-7

26. Effect of genotype on outcome HDV genotype affects outcome – Genotype I vs. genotype II 12 : – Higher incidence of fulminant or subfulminant hepatic failure in acute phase – Greater incidence of adverse outcome (cirrhosis, HCC, mortality) in chronic phase – Genotype III: – Frequently associated with fulminant hepatic failure Coinfecting HBV genotype can affect outcome – It is not always possible to genotype HBV as HBV DNA may be suppressed to low levels – HBV genotype C is significantly associated with adverse outcome (cirrhosis, HCC or mortality) in patients with CHD 3 1. Wu Lancet 1995; 2. Su et al. Gastroenterol 2006; 3. Wu Curr Top Microbiol Immunol 2006

27. Affect of HDV genotype on survival 0 5 10 15 Follow-up (yrs) Cumulative survival rate (%) P=0.0105 0 20 40 60 80 100 HDV genotype II HDV genotype I Patients at risk HDV genotype I: 46 29 25 10 HDV genotype II: 72 55 49 27 Su et al. Gastroenterol 2006 Taiwanese study of untreated patients with median median follow-up of 135 months

28. HBV- HDV genotype connection Su et al, Gastroenterology 2006 VariableRisk ratio95% Confidence p value Interval Genotype C HBV13.432.31- 78.160.004 Age > 6011.961.83- 78.010.009 Genotype I HDV9.741.94- 48.890.006

29. HBV genotypes D and F were associated with higher HDV viral load compared to HBV genotype A (Kiesslich D et al, JID 2009) High HDV viral load has been reported to be associated with poor prognosis (Smedile A et al, Hepatology 1991)

30. Natural history- open issues HBeAg (+) CDHGenotype III Other genotypes Is there change in the natural history of genotype III HDV Other HDV genotypes Other HBV genotypes Reason for different epidemiology of HDV

32. HBsAg Clearance in Chronic Hepatitis, and Cirrhotics (n=151) HBsAg Clearance was seen in 16 cases (10,6 %), in median 76,4 mo (min – max=11,9 – 248,5)

33. Mortality in Cirrhotic HDV Cases (n=54) Mortality [n=8 (14,8 %)]: Median 73,75 mo (min – max = 22,0 – 101,0)

34. Transplantation in Cirrhotic HDV Cases (n=54) Transplantation (n=9/54): Median 56,9mo (min – max=15,4 – 99,8)

35. Decompensation vs HCC in all HDV Patients p = 0,8, Hazard ratio 1,06 95% CI (0,5128 - 2,1990)

36. Decompensation vs HCC in all HDV Patients p = 0,8, Hazard ratio 1,06 95% CI (0,5128 - 2,1990) Decompensation Median: 58, 0 (min – max= 0 – 93,1) HCC Median: 62,6 (min – max=11,3 – 129,2) HCC Dec. Months

37. Cumulative Survival (all group) Mortality=16/161 (10%)

38. Figure 2 Source: Gastroenterology 2009; 136:1629-1638 (DOI:10.1053/j.gastro.2009.01.052 )Gastroenterology 2009; 136:1629-1638 Copyright © 2009 AGA Institute Terms and ConditionsTerms and Conditions

39. Chronic Delta Hepatitis HBsAg Clearance (n=97) HBsAg clearance [n=14 (14,4%)]; Median: 81,2 mo (min – max=11,9 – 248,5)

40. There is no difference between HBV, and D in means of HCC development HCC among HBV – Cirrhotics: n=4 (6,2 %) HCC among HDV – Cirrhotics: n= 8 (14,8%) p = 0,7570, Hazard ratio = 0,8 95% CI (0,2520 - 2,7248)

41. Decompensation vs HCC in Cirrhotic HDV Patients (n=54) p=0,2; HR=1,7 %95 CI(0,7 – 3,9) Decompensation [n=14 (25,9%)]: Median=59 mo(min-max=8,2 – 93,1) HCC [n=8 (14,8%)]: Median = 42,8 mo(min-max=17,5 – 87,8) HCC Dec.

42. Chronic Delta Hepatitis Progression to Cirrhosis (n=97) Progression to Cirrhosis [n=19 (19,6 %)], Median 58,4 mo (min – max= 3,5 – 174,9)

44. Figure 2 Source: Gastroenterology 2009; 136:1629-1638 (DOI:10.1053/j.gastro.2009.01.052 )Gastroenterology 2009; 136:1629-1638 Copyright © 2009 AGA Institute Terms and ConditionsTerms and Conditions

45. Figure 4 Source: Gastroenterology 2009; 136:1629-1638 (DOI:10.1053/j.gastro.2009.01.052 )Gastroenterology 2009; 136:1629-1638 Copyright © 2009 AGA Institute Terms and ConditionsTerms and Conditions