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Combination Therapy of Chronic Hepatitis Delta

Combination Therapy of Chronic Hepatitis Delta. Ulus Salih Akarca Ege University, Faculty of Medicine Izmir, Turkey. The logic of the combination treatment of chronic hepatitis delta. Chronicity. Lower effect of immune modulator treatments. Escape from immune system.

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Combination Therapy of Chronic Hepatitis Delta

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  1. Combination Therapy of Chronic Hepatitis Delta Ulus Salih Akarca Ege University, Faculty of Medicine Izmir, Turkey

  2. The logic of the combination treatment of chronic hepatitis delta Chronicity Lower effect of immune modulator treatments Escape from immune system Long-term treatment for the control of infection Resistance to drugs Need to target multiple points in viral life cycle Combination treatment

  3. What are the choices? • We have three major examples • HBV • HCV • HIV

  4. What is expected from NUCs? • They do not interfere with HDV replication. • Long-term NUCs treatment may decrease the cccDNA content of hepatocytes which goes parallel with the decline in HBsAg production. • HBsAg titer positively correlates with HDV RNA levels in pts with CHD • Decline in HBsAg levels or absence of HBsAg may decrease the infection of new hepatocytes and reinfection of the hepatocytes by precluding the viral assembly and viral entry into hepatocytes. • Powerful NUCs give hope for HBsAg loss

  5. Standart interferon + lamivudin combinations

  6. 24 weeks 44 weeks Lamivudine 100 mg/day 12 week FU IFN α2a 9 MU tiw IFN α2a 9 MU/day Per protocol analysis of response to therapy (baseline vs. end of combination therapy)

  7. 1 year 6 mo Lamivudine 100 mg/day Follow-up 17 IFN 9 MU tiw Follow-up 8 Follow-up LAM+IFN LAM 14 2 mo

  8. Virological and Biochemical responses in study groups Yurdaydin et al. J Viral Hepat 2008;15:314-321

  9. Viral kinetics IFN/IFN+LAM LAM

  10. Viral kinetics

  11. Histology Number of patients

  12. 48 week >96 week IFN-α2b 10 MU tiw Follow-up 12 8 IFN-α2b 10 MU tiw Lamivudine 100 mg/day Follow-up 14 11

  13. Histological changes -1.44±1.59 -5.27±1.08 0.11±0.11 0.00±0.30

  14. Biochemical and virologic changes Mean ALT level changes Loss of HDV RNA p=0.024 p=0.043 5/12 9/14

  15. Follow-up • Sustained response • IFN: 2/12 (16.7%) • IFN+LAM: 4/14 (28.6%) (p=0.47) • Mean survival (Kaplan-Meier) • IFN: 7.38±1.23 y • IFN+LAM: 11.38±1.03 y

  16. Ribavirin? • IMP dehydrogenase inhibition: GTP synthesis blockade. • Polymerase inhibition: Needs higher concentration than clinical use. • Mutagenesis: Cytidine  Uridine • Immunomodulator effect • RNA capping inhibition  inhibition of translation

  17. Ribavirin? • An in vitro study demonstrated anti HDV effect* • However, ribavirin monotherapy had no effect against HDV in a clinical study** • Yet, we may expect an antiviral activity, as in HCV infection. *: Choi SS, Rasshofer R, Roggendorf M. Inhibition of hepatitis delta virus RNA replication in primary woodchuck hepatocytes. Antiviral Res 1989;12:213-22. **: Garripoli A, Di Marco V, Cozzolongo R, et al. Ribavirin treatment for chronic hepatitis D: a pilot study. Liver 1994;14:154–157.

  18. 5 (50%) 2 (20%) IFN-α2a 9 MU tiw 10 2 years 6 months FU IFN-α2a 9 MU tiw RBV 1000-1200 mg/day 21 11 (52%) 5 (24%) HDV RNA negativity

  19. 19 patients (15 males; mean age standard deviation, 36.8 12.8 years) • 24 mo treatment with IFN-α2b 10 MU tiw + RBV 1000-1200 mg/day

  20. Pegylated interferon plus ribavirin

  21. HEPATOLOGY 2006;44:713-720. 72 weeks Peg-IFN α2b 1.5 μg/kg/week 16 11 24 weeks Peg-IFN α2b 1.5 μg/kg/week Ribavirin 800 mg/day Peg-IFN α2b 1.5 μg/kg/week 22 16 48 weeks 24 weeks 28 pts were treated with IFN, previously (74%) 28 had cirrhosis (74%) 11 pts did not complete the study (2 adverse effects)

  22. 6 9 3 2 4 4 6 4

  23. Pegylated interferon alfa-2a plus adefovir dipivoxil versus either drug alone in patients with hepatitis delta: an international randomised study (HIDIT) • Adevofir dipivoxil has been reported to have an effect on levels of cccDNA within infected hepatocytes, which acts as a template for HBsAg production. • A decrease in HBsAg level could potentially deprive HDV from the helper function of the HBV envelope protein and may therefore provide benefit. 72 WEEK DATA OF THE HIDIT-I TRIAL: A MULTICENTER RANDOMISED STUDY COMPARING PEGINTERFERON a-2a PLUS ADEFOVIR VS. PEGINTERFERON a-2a PLUS PLACEBO VS. ADEFOVIR IN CHRONIC DELTA HEPATITIS H. Wedemeyer, C. Yurdaydin, G. Dalekos, A. Erhardt, Y. Cakaloglu, H. Degertekin, S. Gurel, S. Zeuzem, T. Bockg, K. Zachou, H. Bozkaya, U. Drebber, S. Meyer, H.P. Dienes, M.P. Manns, J Hepatol 2006; 52:S4.

  24. HIDIT I Week 48 Week 72 Peg-IFN α2a 180 μg/week Adefovir dipivoxil 10 mg/day 32 Peg-IFN α2a 180 μg/week 29 Adefovir dipivoxil 10 mg/day 30

  25. HDV RNA negativity 5 (+)  (-) 1 (-)  (+) 1 (-)  (+) 7/31 7/29 8/31 9/29

  26. >1log decline in HBsAg titer 2 7 HBsAg negative

  27. HBsAg levels at the onset and at the end of the treatment

  28. Conclusions • Treatment with PEG-IFNα-2a ± ADV for 48 weeks results in sustained HDV RNA clearance in around one quarter of patients. • Addition of ADV to PEG-IFNα-2a may lead to improved HBsAg decline and may facilitate HBsAg clearance.

  29. An ongoing trial: HIDIT IIPegIFN-alfa2a Plus Tenofovir in Chronic Delta Hepatitis • ClinicalTrials.gov Identifier: NCT00932971 96 wk 24 wk Peg-IFN α2a 180 μg/wk Placebo 70 pts Peg-IFN α2a 180 μg/wk TDF 300 mg/day ? ?

  30. A 47 years -old male with chronic delta hepatitis • HBV-DNA >9 log copies/ml • HDV-RNA level=5.6 log copies/ml • Genotypes HBV/D and HDV-1 • The liver histology revealed chronic active hepatitis (Metavir score: A2F2). • The treatment was started with PegIFN (180g/week) for two months and then TDF (300 mg/day)(combined later with FTC) was added. • Sustained response was obtained after 10 months of treatment and was accompanied by the clearance of serum hepatitis B virus surface antigen with seroconversion to anti-HBs.

  31. Probable combinations in the near future • Peg-IFN + potent antivirals • IFN-λ + potent antivirals • Long-term combination of potent antivirals

  32. Summary • There has been no confirmed data that the combinations of interferon/peginterferon with lamivudine, ribavirin, and adefovir are superior to interferon/peginterferon monotherapies in delta hepatitis treatment. • Interferon/peginterferon plus entecavir/tenofovir combination may provide benefit. • The combinations with experimental drugs appears to be far from practice.

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