patrizia farci. hepatitis delta virus hepatitis b surface antigen (hbsag) hdv rna genome hepatitis...
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Patrizia FARCI
Hepatitis Delta Virus
Hepatitis B surface antigen
(HBsAg)
HDV RNA genome
Hepatitis delta antigen (HDAg)
36 nm
From HDV: From HBV:From HDV: From HBV:
Features of the HDV RNA
I
Transcribed by host RNA Polymerase II
Self-cleavage of RNA by internal ribozyme elements
RNA Editing
Extensive base-pairing
1.7 kb, single-stranded, circular RNA
AHDAg gene
HDVHighly Pathogenic
HDV causes the least common but most severe form of chronic viral hepatitis
leading to cirrhosis in about 80% of the cases
Evolution of Hepatitis D Compared to Hepatitis B and C
HDV
HBV
HCV
0
Fib
rosi
s
C
irrh
osi
s
Years
Changing Epidemiology of HDV
• Although HDV incidence in Southern Europe has dramatically declined during the last 2 decades, new outbreaks are emerging in different areas of the world (Southern Russia, Albania, India, Japan, South America)
• In the face of a declining prevalence in areas of old endemicity, immigration poses a threat of resurgence
Hepatitis D Virus Infection-not a vanishing disease in Europe!
HH. Wedemeyer, B. Heidrich and
M.P. Manns
Hepatology 2007, in press
Therapy of Chronic Hepatitis D
Antiviral Therapy
Liver Transplantation
(12 months)
(12 months)
HDV RNA Quantification
End of Treatment vs. Baseline
n = 13 n = 12 n = 11
-3
-2
-1
0
Ch
an
ge
in
HD
V R
NA
Le
vels
(m
ea
n+
SE
)L
og
10
Ge
no
me
Eq
uiv
ale
nts
/ml
9 MU 3 MU Controls
p = 0.009
Farci et al., Gastroenterology, 2004
Changes from Baseline in HDV RNA Levels in Interferon Treated and Untreated Patients
Changes in HDV RNA Levels from Baseline According to Biochemical Response in Patients Treated with 9MU of IFN
-3
-2
-1
0
1
Ch
an
ge
in H
DV
RN
A L
ev
els
(m
ea
n+
SE
)L
og
10
Ge
no
me
Eq
uiv
ale
nts
/ml
Responders Non-responders
p = 0.003
Farci et al., Gastroenterology, 2004
End of Treatment vs. Baseline
(n = 4) (n = 9)
: 12 years)
Changes from Baseline in HDV RNA Levels in Interferon Treated and Untreated Patients
-3
-2
-1
0
1
Ch
ang
e in
HD
V R
NA
Lev
els
(mea
n+
SE
)L
og
10 G
eno
me
Eq
uiv
alen
ts/m
l
9 MU 3 MU Controls
End of Treatment vs. Baseline
Last Evaluation vs. Baseline
n = 13 n = 12 n = 11 n = 13 n = 11 n = 9
p = 0.008p = 0.009
Farci et al., Gastroenterology, 2004
-3
-2
-1
0
1
Ch
an
ge
in H
DV
RN
A L
ev
els
(m
ea
n+
SE
)L
og
10
Ge
no
me
Eq
uiv
ale
nts
/ml
Farci et al., Gastroenterology, 2004
Farci et al., Gastroenterology, 2004
Our long-term study provided evidence that high doses of interferon alpha significantly improved the long-term clinical outcome and survival of patients with chronic hepatitis D
Alpha-Interferon Therapy of Chronic Hepatitis D
Shortcomings
• Limited efficacy
• Relapses are common
• Treatment is often poorly tolerated at the doses needed
• Side effects are common
• Treatment is contraindicated in patients with decompensated cirrhosis
Treatment of Chronic Hepatitis DHow to Improve the Response Rate
Continuous therapy
Combination therapy
Pegylated Interferon
Pegylated Interferon Alpha
et al., 2006
20062006
2006
2006
2006
P. Farci , Hepatology 2006
Peg-IFN in Chronic Hepatitis D
• These preliminary studies indicate that Peg-IFN is well tolerated and effective in the treatment of CHD, even in the case of previous failure of standard IFN therapy
• In analogy with the superior results achieved with Peg-IFN in CHB and CHC, these studies, albeit limited, also support the use of Peg-IFN as first-line therapy for CHD
• Larger studies are needed to better evaluate the benefit of Peg-IFN and to define the optimal treatment schedule in patients with CHD
Alpha-Interferon Therapy of Chronic Hepatitis D
Summary
• Alpha IFN represents the only therapy of proven benefit for chronic hepatitis D
• IFN should be administered at high doses for at least one year
• HDV RNA quantification is needed for monitoring and treatment assessment
• Careful medical supervision is mandatory for the early detection of major medical and psychiatric complications
Alpha-Interferon Therapy of Chronic Hepatitis D
Summary
• In responders IFN should be continued as long as possible until serum HDV RNA and HBsAg are lost, titrating the dose according to tolerance and serum ALT levels
AcknowledgementsDepartment of Medical Sciences
University of Cagliari, ItalyEliana Lai
Rita StrazzeraStefania Farci
Alessandra CoianaAngelo Balestrieri
Luchino ChessaGiancarlo Serra
Cinzia Balestrieri Cristiana Cauli
Rosetta SciosciaMaurizio Loy
Department of Pathology, Leuven, BelgiumTania Roskams Valeer Desmet