1 / 24

NAs Induced Immune Response and Antiviral Therapy in Chronic Hepatitis B

NAs Induced Immune Response and Antiviral Therapy in Chronic Hepatitis B. Gui-Qiang Wang Department of Infectious Diseases Center for Liver Diseases Peking University First Hospital. Chronic hepatitis B is hard to treat. liver. immunity. HBV. Other organs. Control of infection.

faith
Download Presentation

NAs Induced Immune Response and Antiviral Therapy in Chronic Hepatitis B

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. NAs Induced Immune Response and Antiviral Therapy in Chronic Hepatitis B Gui-Qiang Wang Department of Infectious Diseases Center for Liver Diseases Peking University First Hospital

  2. Chronic hepatitis B is hard to treat liver immunity HBV Other organs Control of infection Persistance of Infection Virus Host immunity Impaired immunity DCs, CTL, cytokines PD-1 in active T cells regulatory T lymphocytes cccDNA High viral load Mutation Replication out of liver Host immunity Viral replication

  3. Acute Chronic 50 40 30 20 10 0 60 45 30 15 0 CD8 and CD4 response: Acute hepatitis B vs. Chronic hepatitis B Specific lysis % Ferrari C et al. J Immunol. 1990; Penna A et al. J Exp. Med. 1991; Bertoletti A et al. Proc. Natl.Acad. Sci. USA,1991; Rehermann B et al. J Exp. Med. 1995; Jung C et al. Virology 1999;Maini et al. J Exp. Med. 2000

  4. Goals of CHB therapy: Sustained immune control HBsAg clearance Reduction of HCC and cirrhosis, and improve survival rate Sustained immune control After the end of therapy HBeAg (+) patients: sustained HBeAg seroconversion HBeAg (-) patients: permanent HBV suppression lower quantitation of HBsAg Antiviral therapy Permanent suppression of HBV DNA replication ALT normalization Perrillo et al. Hepatology 2006; 17. EASL guidelines 2009;van Zonneveld et al. Hepatology 2004; 19. Marcellin et al. APASL 2010

  5. Treatment Options Immuno-modulators Aiming for sustained remission IFNα Peg IFN Nx cytokines Vaccine therapy Antivirals Maintained remission Lamivudine Adefovir EntecavirTelbivudine Tenofovir CD8+ HBV Treatment combinations

  6. Immune response during NAs treatment

  7. Lamivudine Boni C, et al. J Hepatol, 2003, 39: 595-605.

  8. CTL responses to individual HBV peptides containing the HLA-A2 binding motif Boni C, et al. HEPATOLOGY 2001;33:963-971

  9. Lamivudine induced the restoration of anti-viral T cell responses is transient  40 P<0.002 Number of IFN-γ+ lymphocytes/100,000 T cells Treatment initiation Treatment termination 30 20 10 0 -24-0 2-12 16-24 28-36 40-52 52-56 weeks Boni C, et al. J Hepatol, 2003, 39: 595-605.

  10. HBV specific CTL response for Sustained HBeAg seroconversion after LAM treatment Lee CK, et al. Korea J Hepatol 2005; 11:34-42

  11. Entecavir Zhang J, et al. PLoS ONE 2010Nov 30; 5(11): e13869.

  12. Entecavir yields transient decrease of Treg cells and ratios of Treg cells to Th17 cells Treg/TH17ratios and HBV DNA levels Frequency of Treg cells months P=0.016 P=0.002 P=0.042 12 3.0 0 1 3 6 9 12 10 2.4 8 *§ Treg/Th17 ratios %FoxP3+ CD4+ T cells 1.8 6 *§ * 1.2 4 0.6 2 r=1.00 0 0.0 0 1 3 6 9 12 8 6 4 2 0 HBV DNA, log10 IU/mL months During treatment of entecavir in HBeAg-positive patients, Treg cells and Treg/Th17 ratios decreased and bottomed out at 3 months and then increased, exhibiting a reverse ‘‘V’’-type change. These transient changes of Treg cells and Treg/Th 17 ratios correlate with suppression of HBV DNA. Zhang J, et al. PLoS ONE 2010Nov 30; 5(11): e13869.

  13. Adefovir Dipivoxil .Jeroen N. et,al. Virology 361 (2007) 141–148

  14. Adefovir induces transient decrease in expression of Treg cells in chronic hepatitis B patients Jeroen N. et,al. Virology 361 (2007) 141–148

  15. Comparison of CD4 T-cell reactivity to HBcAg in patients receiving ADV or the placebo • ADV N=13 • PLB N=6 Cooksley H, et al. Antimicrobial agents & chemotherapy, 2008, 312–320

  16. HBcAg-specific T-cell proliferation according to virological response Group1: HBeAg seroconversion Group2: non-responder Group3: placebo Cooksley H, et al. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2008, 312–320

  17. Telbivudine preserves Th1 cytokine production and down regulates PD-L1in a mouse model of viral hepatitis

  18. Telbivudine enhances the production of TNF-α in MHV-3-infected macrophages compared to lamivudine Vitro study 350 * * 300 * 250 200 TNF-α (pg/ml) 150 100 50 0 0 100 10 50 0 5 25 50 Lamivudine (ug/ml) Telbivudine (ug/ml) Q.Ning et al. J Viral Hepat., 2010, 17 (Suppl. 1), 24–33.

  19. Effects of antiviral therapy with telbivudine on peripheral iNKT cells in HBeAg-positive chronic hepatitis B patients Shi TD, et al. Clin Exp Med. 2012 Jun;12(2):105-13.

  20. Telbivudine continuously increased frequencies of IFN-γ iNKT cellsin chronic hepatitis B patients P<0.05 CHB cells 0.4 0.3 0.2 0.1 0.0 0.3 0.2 0.1 0.0 P<0.05 IFN+iNKT cells frequency (%) iNKT cells frequency (%) Healthy controls Baseline12weeks24weeks52 weeks Baseline12weeks24weeks52 weeks *P<0.05 (vs. healthy controls) P<0.05 (vs. baseline) This study included 29 HBeAg-positive and HBsAg-positive CHB patients. Telbivudine was orally administered at a dose of 600 mg per day, and heparinized venous blood was taken at four study visits: baseline and treatment weeks 12, 24 and 52 to detect the frequencies, function and PD-1 expression ofperipheral iNKT cells. Shi TD, et al. Clin Exp Med. 2012 Jun;12(2):105-13.

  21. Continually decreased PD-1 expression of iNKT cells in CHB patients was found during telbivudine treatment 50 40 30 20 10 0 * P<0.05(vs. healthy controls) P<0.05(vs. baseline) PD-1+ iNK cells (%) Baseline12weeks24weeks52weeks Healthy controls CHB patients This study included 29 HBeAg-positive and HBsAg-positive CHB patients. Telbivudine was orally administered at a dose of 600 mg per day, and heparinized venous blood was taken at four study visits: baseline and treatment weeks 12, 24 and 52 to detect the frequencies, function and PD-1 expression ofperipheral iNKT cells. .Shi TD, et al. Clin Exp Med. 2012 Jun;12(2):105-13.

  22. The frequencies of PD-1+ CD4+ and CD8+ T cells during treatment with LDT 29 HBeAg positive CHB treated with LDT for 52 weeks, 19 patients achieved virological response with HBV DNA less than 60IU/ml. Unpublished data

  23. Conclusion • CHB is characterized by an impaired immune response to HBV.  • The host immune response is crucial to control HBV infection, Neither IFN nor NAs will not work without host immune response • The immune modulatory effects of telbivudine have been broadly investigated because its higher HBeAg seroconversion rates, and shown promising data • We need further study on immunological profiles with NAs based treatment to elucidate the whole story

  24. Thank you! Gui-Qiang Wang wanggq@hotmail.com

More Related