patrizia farci. hepatitis delta virus hepatitis b surface antigen (hbsag) hdv rna genome hepatitis...

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