hepatitis delta: anything new? - comtecmed - global ...€¦ · heiner wedemeyer: hepatitis delta ....

Hepatitis Delta: Anything new?

Heiner Wedemeyer

Heiner Wedemeyer: Hepatitis Delta

Heiner Wedemeyer: Hepatitis Delta Calle

Serrano, Manns

& Wedemeyer, Seminars in Liver Disease 2012

The

HDV Life Cycle


Epidemiology of Hepatitis D

Wedemeyer & Manns, Nat Rev

Gastroenterol

2010

Heiner Wedemeyer: Hepatitis Delta courtesy of Dr Carballo

Migration and viral hepatitis


HIV‐infected patients: anti‐HDV prevalence in HBsAg‐positive patients

Sorriano

et al., AIDS 2011

Overall prevalence: 14.5%!


1980 1990 2000 2010

ACUTE HEPATITIS DELTA

CHRONIC HEPATITIS DELTA

% o

f HB

sAg+

pat

ient

sThe changing pattern of hepatitis delta

Romeo, Colombo; Gastroenterology 2009Niro, Rizzetto; Journal of Hepatology 2010Buti, Esteban; Journal of Viral

Hepatitis 2010

Romeo, Colombo; Gastroenterology 2009Niro, Rizzetto; Journal of Hepatology 2010Buti, Esteban; Journal of Viral

Hepatitis 2010

High frequency

of liver‐related

morbidity

High frequency

of liver‐related

morbidity


Factors associated with clinical disease progession?


Baseline-Event-Association (BEA)-scorealgorithm

Calle Serrano et al. AASLD 2011


Survival according to the BEA-score



Survival according to the BEA-score

Barcelona: n=77

M. Homs, M. Buti et al.

Düsseldorf: n=58

A. Erhardt et al.



Hepatitis Delta: Diagnostics


HBsAg+HBsAg+ Anti-HDV+Anti-HDV+

HDV-RNA-posHDV-RNA-pos

HDV-RNA-neg

Diagnostic Steps in Delta Hepatitis

Repeat

PCR, aHDV-IgM ALT levels, Histology?

Repeat


Heiner Wedemeyer: Hepatitis Delta Mederacke et al. Antiviral

Therapy

2011

Anti‐HDV

IgM‐levels

in HDV‐infected

patients before

and after

treatment

with

PEG‐IFNa‐2a




HDV-RNA-neg

HDV-RNA quantitativeHDV-RNA quantitative


Repeat


Repeat



Quantitative HDV‐PCR: Cobas‐TaqMan

Assay

Mederacke et

al. J Clin

Microbiol

2010

Participating Labs

Samples GenotypeWedemeyer Gordien Pawlotsky

German French French German Mix RocheG1 1 5.2 5.8 5.9 5.6 4.9 5.9G2 1 5.4 6.1 5.7 5.8 5.2 6.5G5 1 4.7 5.8 5.4 5.5 4.8 5.4G6 1 5.0 6.2 6.3 5.7 5.2 6.2G8 1 5.2 5.8 3.4 4.7 Neg 6.0G9 1 5.5 6.2 6.4 6.1 5.3 6.2G12 1 2.7 4.5 2.6 Neg Neg 5.0G15 1 3.5 4.8 Neg 4.0 Neg 4.9G17 1 3.2 4.1 Neg Neg Neg 4.3G18 1 3.4 4.5 Neg Neg Neg 4.0G20 1 2.5 Low

+ Neg Neg Neg 1.5G21 1 7.0 7.9 8.2 7.2 6.6 6.7B1033 7 5.9 7.7 6.1 6.3 5.7 2.2B2653 1+7 3.0 5.3 Neg Neg Neg 3.3B3105 1 4.8 7.4 5.3 6.0 5.3 6.2B2600 negative Neg Neg Neg Neg Neg NegB2703 5 4.5 6.0 5.0 4.7 4.6 4.8B2139 6 Neg 2.0 Neg Neg Neg NegB2736 8 3.2 4.3 Neg Neg Neg 2.4




HDV-RNA-neg


Repeat

PCR ALT levels, Histology?

Repeat


HDV GenotypeHDV Genotype



HDV and HBV genotypes

Region HDV genotype

HBV genotype

Europe 1 D / A

Brazil 1/3 F / A / D

China, Taiwan, Japan1/2/4 B/C

Turkey, Iran,Pakistan, India

1 D

Western Pacific 1 / 2 B/C/D

Africa 1, 5‐8 D / A / E


Different HDV genotypes are associated with different clinical outcomes

Su, Wu et al., Gastroenterology 2006




HDV-RNA-neg


Repeat


Repeat


HDV GenotypeHDV GenotypeHBeAg

HBV-DNA

HBeAg HBV-DNA


Heiner Wedemeyer: Hepatitis Delta Heidrich et al., Liver

International 2012

HBV DNA is

frequently

suppressed

even

in HBeAg+ Hepatitis Delta

Heiner Wedemeyer: Hepatitis Delta Heidrich et al., Liver

International 2012

The

outcome

of HBeAg‐positive

and HBeAg‐negative hepatitis

delta

is

not

different




HDV-RNA-neg


Repeat


Repeat


HDV GenotypeHDV GenotypeHBeAg

HBV-DNA

HBeAg HBV-DNA


Fluctuating Patterns of Viral Dominancemaybe observered over time

Heiner Wedemeyer: Hepatitis Delta Schaper, Buti et al.,

J Hepatol

2010

Fluctuating

Patterns of Viral

Dominancein Hepatitis D


HDV‐Infection Treatment Options

Nucleos(t)ide

Analogues

•

Famciclovir ineffective

Yurdaydin et al., J Hepatol

2002

•

Lamivudine ineffective

Wolters

et al., J Viral Hepatitis 2000

Niro, Aliment Pharmacol

Ther. 2005

; Niro


Yurdaydin et al., J Viral Hepatitis 2008

•

Ribavirin ineffective

Niro

et al., Hepatology 2006

Garripoli

et al., Liver 1994

Gunsar

et al., Antiv

Therapy 2005

Nucleos(t)ide

Analogues

•

Famciclovir ineffective

Yurdaydin et al., J Hepatol

2002

•

Lamivudine ineffective

Wolters


Niro, Aliment Pharmacol

Ther. 2005

; Niro


Yurdaydin et al., J Viral Hepatitis 2008

•

Ribavirin ineffective

Niro


Garripoli

et al., Liver 1994

Gunsar

et al., Antiv

Therapy 2005

… and entecavir?


13 Patients with HBV/HDV Infection1 year treatment with entecavir

8 patients HBV DNA positive at baseline

13 Patients with HBV/HDV Infection1 year treatment with entecavir

8 patients HBV DNA positive at baseline

All patients became HBV DNA negativeNo significant

overall HDV RNA decline

3 patients with low baseline HDV RNA levels were HDV RNA negative at year 1

All patients became HBV DNA negativeNo significant

overall HDV RNA decline

3 patients with low baseline HDV RNA levels were HDV RNA negative at year 1

Entecavir

to treat HDV‐Infection

Yurdaydin

et al. CID 2012


IFNa

to treat HDV‐Infection

Interferon alpha

• Sustained biochemical responses in 0‐36% of patients

Few Studies with virological endpoints

treatment >12 months may be required

Farci et al., NEJM 1994

Di Marco et al., J Viral Hepatitis 1996

Niro

et al., J Viral Hepatitis 2005; Yurdaydin et al., J Viral Hepatitis 2008

• Higher IFN doses were associated with better survival in small study cohort

Farci et al., Gastroenterology 2004

Interferon alpha

•

Sustained biochemical responses in 0‐36% of patients

Few Studies with virological endpoints

treatment >12 months may be required

Farci et al., NEJM 1994

Di Marco et al., J Viral Hepatitis 1996

Niro

et al., J Viral Hepatitis 2005; Yurdaydin et al., J Viral Hepatitis 2008

•

Higher IFN doses were associated with better survival in small study cohort

Farci et al., Gastroenterology 2004

PEG‐Interferon alpha

• 48‐96 weeks HDV RNA SVR 17‐43%

Erhardt

Liver International 2006

Niro


Castelnau


Ormeci

et al., Hepatogastroenterology

2011

PEG‐Interferon alpha

•

48‐96 weeks HDV RNA SVR 17‐43%

Erhardt

Liver International 2006

Niro


Castelnau


Ormeci

et al., Hepatogastroenterology

2011


The Hep‐Net/International Delta Hepatitis Intervention Trial (HIDIT‐1)

PEG-IFNa-2a (180 µg oiw) Adefovir dipivoxil 10 mg daily

PEG-IFNa-2a (180 µg oiw) Adefovir dipivoxil 10 mg daily

PEG-IFNa-2a (180 µg oiw) Placebo

PEG-IFNa-2a (180 µg oiw) Placebo

Adefovir dipivoxil 10mg dailyAdefovir dipivoxil 10mg daily

TW0 TW24 TW48 F24Screening

N=32*

N=29

N=30

N=91

Wedemeyer et al. NEJM 2011


Treatment of Hepatitis Delta with PEG‐IFNa‐2a:~25% Sustained HDV RNA clearance



Combination Therapy shows more pronounced HBsAg decline!



Safety of treatment?


Decompensation in a patient with baseline platelet count of 74.000/µl

→ Caution in patients with advanced cirrhosis!



Renal Function during Treatment

PEG‐IFNa‐2a

PEG‐IFNa‐2a + ADV

Adefovir

Mederacke et al. J Viral

Hepatitis 2012


…

and combination

with

tenofovir?

Screening/Baseline

R

0

Screening/Baseline

R

0

PEG-Interferon

alpha-2a 180µg oiw

+ Placebo

PEG-Interferon

alpha-2a 180µg oiw

+Tenofovir

disoproxilfumarat

245mg daily

Follow-up

Follow-up

96 weeks 5 years FU

The HIDIT‐2 Study:Germany, Romania, Greece, Turkey N = 120

The HIDIT‐2 Study:Germany, Romania, Greece, Turkey N = 120

Week 48 interim analysis: Yurdaydin, Wedemeyer et al., oral presentation AASLD 2012

Week 48 interim analysis: Yurdaydin, Wedemeyer et al., oral presentation AASLD 2012


Long‐Term Treatment with Nucleos(t)ides?

Sheldon, Soriano

et al, AVT 2008

16 Patients

with

HBV/HDV‐HIV Infection

15 aHCV+ (3/15 HCV‐RNA+)

13 IVDU; 4 HBeAg+

16 Patients

with

HBV/HDV‐HIV Infection

15 aHCV+ (3/15 HCV‐RNA+)

13 IVDU; 4 HBeAg+

ART median 6.1 years

(IQR 4.7‐8.7)ART median 6.1 years

(IQR 4.7‐8.7)

Median HDV‐RNA 7 → 5.8 log

10

‐copies/ml (p=0.011)

3 Patients

became

HDV‐RNA negative

Median HDV‐RNA 7 → 5.8 log10

‐copies/ml (p=0.011)

3 Patients

became

HDV‐RNA negative

Martin‐Carbonero

et al., AIDS 2011:HBsAg clearance rate of 2.6 per 100 patient/years in NUC‐treated

HIV/HBV/HDV infected patients

Martin‐Carbonero

et al., AIDS 2011:HBsAg clearance rate of 2.6 per 100 patient/years in NUC‐treated

HIV/HBV/HDV infected patients


Liver

Transplantation for

Hepatitis D?


HDV RNA

HBsAg

HDV RNA

HBsAg

HDV RNA

HBsAg

Rapid and Parallel Decline of HDV RNA and HBsAg after Liver Transplantation …

Mederacke et al., J Hepatol

2012


… but prolonged intrahepatic

persistence of HDAg

!

Mederacke et al., J Hepatol

2012


Suggested Treatment Algorithm for Hepatitis Delta

Wedemeyer & Manns, Nat Rev

Gastroenterol

2010


Future treatment

options?


Entry

Inhibitor

„Myrcludex“


Myrcludex B: HBV and HDV entry

inhibitor (Stephan Urban, Heidelberg)


Prenylation

inhibitor

(J. Glenn, USA)

Heiner Wedemeyer: Hepatitis Delta Bordier, Glenn et al. JCI 2003


Collaborators:C. Yurdaydin

(Ankara, Turkey),

G. Dalekos, K. Zachou

(Larissa, Greece), T. Bock (RKI, Berlin, Germany),

E. Herrmann (Frankfurt, Germany), E. Gordien, J.M. Pawtlosky

(Paris, France),

H.P. Dienes

(Cologne, Germany)A. Erhardt (Düsseldorf, Germany)

The

Hep‐Net

International Delta Hepatitis Study

Group!


Michael P. Manns

Markus CornbergBeatrice Calle-Serrano, Benjamin Heidrich

Jan Grabowski, Ingmar Mederacke, Kalliopi

ZachouKerstin Port, Birgit Bremer, Janina Kirschner


And…

if

you

want

to

be more involved

in hepatitis delta:

hepatitis delta: anything new? - comtecmed - global ...€¦ · heiner wedemeyer: hepatitis delta ....

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