HBV-associated Severe Liver Diseases: Progress on Pathogenesis and Treatment

1. HBV-associated Severe Liver Diseases: Progress on Pathogenesis and Treatment Yuming Wang Institute for Infectious Diseases of PLA Southwest Hospital Third Military Medical University Chongqing, P. R. China

2. The Progress of Pathogenesis Viral Factors

3. Evidence for the role of viral factors • Long-term follow-up studies demonstrated the close relationship between disease severity and viral factors • NA has been showed to be effective in prevention and treatment of hepatitis exacerbation • HBV mutation and genotypes are closely related to disease severity • Immune suppressed ALF: overwhelming viral replication and immune paralysis

4. HBV mutation and genotyping is closely related to disease severity • Precore (G1896A) mutation /core-promoter (G1762T/G1764A) mutations • PreS2 mutations • HBV genotypes

5. Fig. Frequencies of Precore/C-promoter mutations compared between pts. with FH and self-limited acute hepatitis who were infected with HBV/Bj or Ce Ozasa A, et al. Hepatology. 2006, 44: 326-334

6. Outcome of acute hepatitis B virus infection • Pts with FH were older (>34y) • FH was frequent (13%) and associated with Bj and Ce • Lack of HBeAg • High replication due to precore mutation Ozasa A, et al. Hepatology. 2006, 44: 326-334

7. Pathogenesis of Special Fulminant Hepatitis---- Immunosuppression-induced ALF(Fibrosing Cholastatic Hepatitis, FCH)

8. Death ALF Chronic hepatitis Liver cirrhosis Acute hepatitis HBV DNA ALT Immuno- suppression Immuno-rebound Recover Fig. Hepatitis reactivation after chemotherapy chemotherapy 0 4 8 12 16 24 28 32 52 100 20 36 Actually there are 2 kinds of responses: immune rebound and immune paralysis Time after exposure (w) Meuleman P, et al. J Virol, 2006, 80(6):2797-2807.

9. Extensive hepatocyte injury and inflamation Severe architectural disruption with fibrosis and necrosis Extensive Positive HBsAg HBcAg HBsAg HBcAg Fig. Overwhelming HBV infection with immnosuppression A-D ALF after chemotherapy in 1 case of non-Hodgkin lymphoma E, F a case with CHB Ocama P, et al. Am J Med, 2005, 118, Dec:e15-1413.e22

10. Why do the pts. in tolerance stage have no FCH manifestations? • Immune tolerance≠ immune paralysis • Immune tolerance：virus and host have a relationship of mutually restriction • immune paralysis: host loses its restriction to the virus

11. Medical strategy for two categories of ALF • Immune suppression induced ALF - Inhibition of virus • Immune mediated ALF - Immune suppression by using steroids - Inhibition of virus, ceasing of Immune mediated liver necrosis

12. The Progress of TreatmentAntiviral therapy by NA

13. (人) 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Hospitalized pts. with HBV-associated hepatic failure in Our Dept. through 1991-2005

14. Fig. Hospitalized liver failure patient of hepatitis B and nucleoside analogue usage in South-West hospital Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

15. Outcome of severe hepatitis patients after LAM treatment Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

16. Fig. Patient’scondition and prognosis of anti-HBV therapy within 1 week after onset of symptoms *P=0.000 张绪清，等，待发表

17. Tab. Curative effect of 810 liver failure patients of hepatitis B after nucleoside analogue treatment Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

18. Fig.1 Survival Curve of 215 liver failure of hepatitis B after lamivudine treatment Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

19. Fig. liver failure of Chronic Hepatitis B Virus Infection After Withdrawal of Lamivudine Therapy in South-West hospital Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

20. Fig. Anti-HBV therapy by NA of 276 liver failure patients of Hepatitis after anti-HBV therapy by NA Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

21. admission LAM peritonitis liver failure death Fig. The disease cause of 1 patients with severe hepatitis B after treatment 38y male； HBsAg (+) 4 years, jaundice for 2 weeks was transferred to our department after 8 weeks treatment from local hospital Zhang X, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

22. 停药后复发 LAM ADV LAM 50mg/d ETV 6m LAM 100mg/d 36m IU/ml HBV DNA (log10 copies/ml) 800 YVDD 700 600 500 400 300 200 100 month Fig. One pts. with decompensated liver cirrhosis showed multi-drug resistance Wang Y, et al. unpublished data

23. Target sequence: 394 bp. located in the Rt region of the polymerase gene in HBV genome • All known mutation loci associated with nucleoside analog resistance were included Fig. Nested-PCR for the amplification of P Rt sequence Xia J, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

24. Agarose gel electrophoresis of PCR products TA cloning PCR verification of white colonies Xia J, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

26. Patient I ‘VM’ breakthrough Quasispecies memory Dynamics of serum HBV DNA, ALT and HBV quasispecies population Liu L et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

27. Patient J ‘VM’ breakthrough Quasispecies memory Dynamics of serum HBV DNA, ALT and HBV quasispecies population Liu L et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

28. Antiviral therapy before and After OLTx in Pts. with Severe Hepatitis

29. Fig. Prevention and Treatment of HBV Reinfection in OLTx Patients Terrault N, et al. Liver Transpl, 2005, 11: 716-732

30. HBV recurrence rate between HBV DNA(+) and HBV DNA(-) pre-OLT patients （％） 51.4（19/37） 31.5（17/54） 20.6（7/37） 12.7（7/55） 8.2（7/85） 2.3（2/88） P＜0.01 (post-OLT) Xia J, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

31. Mechanism for HBV recurrence post-OLTx • Without anti-virus treatment pre-OLT in HBV DNA(-) patients • Insufficient anti-viral treatment pre-OLT • HBV mutations (LAM-R) pre-OLT has not been detected by real-time PCR • Be short of profession doctor’s guidance, and insufficient follow-up system • The problem in compliance of patients Xia J, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

32. Conclusion: Progress of Pathogenesis • viral factors are emphasized now, which have been demonstrated by the efficacy of antiviral therapy by nucleoside analogues • Immunosuppression induced liver failure is associated with immune polarization and viral replication

33. Conclusion: the Progress of Antiviral Therapy by NA (1) • NA has been shown to be effective and safe in patients with hepatitis B including fulminant hepatitis and decompensated liver cirrhosis • could effectively suppress HBV-induced liver inflammation and necrosis in short term, and prevent hepatitis flares • more experience has been accumulated in LAM and ADV, latter is suitable for the patients with slow progression

34. Conclusion: the Progress of Antiviral Therapy by NA (1) • ETV and LdT will have potential application owing to their strong potency; iii) antiviral indication can be extended to acute course • viral load can be flexible, and duration is indefinite (except for patients with acute infection) • viral resistance is not common and multi-drug resistance is rare, but more attention should be paid, due to the resistance related hepatitis reactivation

35. 50-year Anniversary of Dept. of Infectious Diseases, TMMU in 2005