Combination Therapy of Chronic Hepatitis Delta
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Combination Therapy of Chronic Hepatitis Delta Ulus Salih Akarca Ege University, Faculty of Medicine Izmir, Turkey
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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. - PowerPoint PPT Presentation
Transcript of Combination Therapy of Chronic Hepatitis Delta
Combination Therapy of Chronic Hepatitis Delta
Ulus Salih AkarcaEge University, Faculty of Medicine
Izmir, Turkey
Chronicity
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
Lower effect of immune modulator treatments
The logic of the combination treatment of chronic hepatitis delta
What are the choices?
●We have three major examplesHBVHCVHIV
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
Standart interferon + lamivudin combinations
Lamivudine 100 mg/dayLamivudine 100 mg/day
IFN α2a 9 MU tiwIFN α2a 9 MU tiwIFN α2a 9 MU/day
24 weeks 44 weeks
12 week FU12 week FU
Per protocol analysis ofresponse to therapy (baseline vs. end ofcombination therapy)
Lamivudine 100 mg/dayLamivudine 100 mg/day
IFN 9 MU tiwIFN 9 MU tiw
LAM+IFNLAM+IFNLAMLAM
Follow-upFollow-up
Follow-upFollow-up
Follow-upFollow-up
1 year
17
8
14
2 mo
6 mo
Virological and Biochemical responses in study groups
Yurdaydin et al. J Viral Hepat 2008;15:314-321
Viral kinetics
IFN/IFN+LAMLAM
Viral kinetics
HistologyN
umbe
r of p
atien
ts
IFN-α2b 10 MU tiwIFN-α2b 10 MU tiw
IFN-α2b 10 MU tiwLamivudine 100 mg/day
IFN-α2b 10 MU tiwLamivudine 100 mg/day Follow-upFollow-up
Follow-upFollow-up
48 week >96 week
12
14
8
11
Histological changes
0.11±0.11 0.00±0.30
-1.44±1.59 -5.27±1.08
Biochemical and virologic changes
Mean ALT level changes Loss of HDV RNA
5/12 9/14
p=0.024
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
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
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.
IFN-α2a 9 MU tiwIFN-α2a 9 MU tiw
IFN-α2a 9 MU tiwRBV 1000-1200 mg/day
IFN-α2a 9 MU tiwRBV 1000-1200 mg/day
10
21
5 (50%)5 (50%)
11 (52%)11 (52%)
2 (20%)2 (20%)
5 (24%)5 (24%)
HDV RNA negativityHDV RNA negativity
2 years 6 months FU
● 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
Pegylated interferon plus ribavirin
Peg-IFN α2b 1.5 μg/kg/weekPeg-IFN α2b 1.5 μg/kg/week
Peg-IFN α2b 1.5 μg/kg/weekRibavirin 800 mg/day
Peg-IFN α2b 1.5 μg/kg/weekRibavirin 800 mg/day
Peg-IFN α2b 1.5 μg/kg/week
Peg-IFN α2b 1.5 μg/kg/week
48 weeks 24 weeks
72 weeks
24 weeks
16
22
HEPATOLOGY 2006;44:713-720.
11
16
28 pts were treated with IFN, previously (74%)28 had cirrhosis (74%)
11 pts did not complete the study (2 adverse effects)
6 3 29 4 4 46
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 HEPATITISH. 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.
HIDIT I
Peg-IFN α2a 180 μg/weekPeg-IFN α2a 180 μg/week
Peg-IFN α2a 180 μg/weekAdefovir dipivoxil 10 mg/day
Peg-IFN α2a 180 μg/weekAdefovir dipivoxil 10 mg/day
Adefovir dipivoxil 10 mg/dayAdefovir dipivoxil 10 mg/day
Week 48 Week 72
32
29
30
HDV RNA negativity
7/31 7/29 8/31 9/29
1 (-) (+) 1 (-) (+)
5 (+) (-)
>1log decline in HBsAg titer
22 77 HBsAg negative
HBsAg levels at the onset and at the end of the treatment
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.
An ongoing trial: HIDIT IIPegIFN-alfa2a Plus Tenofovir in Chronic Delta
Hepatitis
●ClinicalTrials.gov Identifier: NCT00932971
Peg-IFN α2a 180 μg/wkPlacebo
Peg-IFN α2a 180 μg/wkPlacebo
Peg-IFN α2a 180 μg/wkTDF 300 mg/day
Peg-IFN α2a 180 μg/wkTDF 300 mg/day
96 wk 24 wk
70 pts
? ?
● 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.
Probable combinations in the near future
●Peg-IFN + potent antivirals●IFN-λ + potent antivirals●Long-term combination of potent antivirals
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.
