hepatitis delta: anything new? - comtecmed - global ...€¦ · heiner wedemeyer: hepatitis delta ....
TRANSCRIPT
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
Heiner Wedemeyer: Hepatitis Delta
Epidemiology of Hepatitis D
Wedemeyer & Manns, Nat Rev
Gastroenterol
2010
Heiner Wedemeyer: Hepatitis Delta courtesy of Dr Carballo
Migration and viral hepatitis
Heiner Wedemeyer: Hepatitis Delta
HIV‐infected patients: anti‐HDV prevalence in HBsAg‐positive patients
Sorriano
et al., AIDS 2011
Overall prevalence: 14.5%!
Heiner Wedemeyer: Hepatitis Delta
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
Heiner Wedemeyer: Hepatitis Delta
Factors associated with clinical disease progession?
Heiner Wedemeyer: Hepatitis Delta
Baseline-Event-Association (BEA)-scorealgorithm
Calle Serrano et al. AASLD 2011
Heiner Wedemeyer: Hepatitis Delta
Survival according to the BEA-score
Calle Serrano et al. AASLD 2011
Heiner Wedemeyer: Hepatitis Delta
Survival according to the BEA-score
Barcelona: n=77
M. Homs, M. Buti et al.
Düsseldorf: n=58
A. Erhardt et al.
Calle Serrano et al. AASLD 2011
Heiner Wedemeyer: Hepatitis Delta
Hepatitis Delta: Diagnostics
Heiner Wedemeyer: Hepatitis Delta
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
PCR, aHDV-IgM ALT levels, Histology?
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
Heiner Wedemeyer: Hepatitis Delta
HBsAg+HBsAg+ Anti-HDV+Anti-HDV+
HDV-RNA-posHDV-RNA-pos
HDV-RNA-neg
HDV-RNA quantitativeHDV-RNA quantitative
Diagnostic Steps in Delta Hepatitis
Repeat
PCR, aHDV-IgM ALT levels, Histology?
Repeat
PCR, aHDV-IgM ALT levels, Histology?
Heiner Wedemeyer: Hepatitis Delta
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
Heiner Wedemeyer: Hepatitis Delta
HBsAg+HBsAg+ Anti-HDV+Anti-HDV+
HDV-RNA-posHDV-RNA-pos
HDV-RNA-neg
HDV-RNA quantitativeHDV-RNA quantitative
Repeat
PCR ALT levels, Histology?
Repeat
PCR ALT levels, Histology?
HDV GenotypeHDV Genotype
Diagnostic Steps in Delta Hepatitis
Heiner Wedemeyer: Hepatitis Delta
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
Heiner Wedemeyer: Hepatitis Delta
Different HDV genotypes are associated with different clinical outcomes
Su, Wu et al., Gastroenterology 2006
Heiner Wedemeyer: Hepatitis Delta
HBsAg+HBsAg+ Anti-HDV+Anti-HDV+
HDV-RNA-posHDV-RNA-pos
HDV-RNA-neg
HDV-RNA quantitativeHDV-RNA quantitative
Repeat
PCR ALT levels, Histology?
Repeat
PCR ALT levels, Histology?
HDV GenotypeHDV GenotypeHBeAg
HBV-DNA
HBeAg HBV-DNA
Diagnostic Steps in Delta Hepatitis
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
Heiner Wedemeyer: Hepatitis Delta
HBsAg+HBsAg+ Anti-HDV+Anti-HDV+
HDV-RNA-posHDV-RNA-pos
HDV-RNA-neg
HDV-RNA quantitativeHDV-RNA quantitative
Repeat
PCR ALT levels, Histology?
Repeat
PCR ALT levels, Histology?
HDV GenotypeHDV GenotypeHBeAg
HBV-DNA
HBeAg HBV-DNA
Diagnostic Steps in Delta Hepatitis
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
Heiner Wedemeyer: Hepatitis Delta
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
et al., J Viral Hepatitis 2008
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
et al., J Viral Hepatitis 2000
Niro, Aliment Pharmacol
Ther. 2005
; Niro
et al., J Viral Hepatitis 2008
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
… and entecavir?
Heiner Wedemeyer: Hepatitis Delta
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
Heiner Wedemeyer: Hepatitis Delta
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
et al., Hepatology 2006
Castelnau
et al., Hepatology 2006
Ormeci
et al., Hepatogastroenterology
2011
PEG‐Interferon alpha
•
48‐96 weeks HDV RNA SVR 17‐43%
Erhardt
Liver International 2006
Niro
et al., Hepatology 2006
Castelnau
et al., Hepatology 2006
Ormeci
et al., Hepatogastroenterology
2011
Heiner Wedemeyer: Hepatitis Delta
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
Heiner Wedemeyer: Hepatitis Delta
Treatment of Hepatitis Delta with PEG‐IFNa‐2a:~25% Sustained HDV RNA clearance
Wedemeyer et al. NEJM 2011
Heiner Wedemeyer: Hepatitis Delta
Combination Therapy shows more pronounced HBsAg decline!
Wedemeyer et al. NEJM 2011
Heiner Wedemeyer: Hepatitis Delta
Safety of treatment?
Heiner Wedemeyer: Hepatitis Delta
Decompensation in a patient with baseline platelet count of 74.000/µl
→ Caution in patients with advanced cirrhosis!
Wedemeyer et al. NEJM 2011
Heiner Wedemeyer: Hepatitis Delta
Renal Function during Treatment
PEG‐IFNa‐2a
PEG‐IFNa‐2a + ADV
Adefovir
Mederacke et al. J Viral
Hepatitis 2012
Heiner Wedemeyer: Hepatitis Delta
…
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
Heiner Wedemeyer: Hepatitis Delta
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
Heiner Wedemeyer: Hepatitis Delta
Liver
Transplantation for
Hepatitis D?
Heiner Wedemeyer: Hepatitis Delta
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
Heiner Wedemeyer: Hepatitis Delta
… but prolonged intrahepatic
persistence of HDAg
!
Mederacke et al., J Hepatol
2012
Heiner Wedemeyer: Hepatitis Delta
Suggested Treatment Algorithm for Hepatitis Delta
Wedemeyer & Manns, Nat Rev
Gastroenterol
2010
Heiner Wedemeyer: Hepatitis Delta
Future treatment
options?
Heiner Wedemeyer: Hepatitis Delta
Entry
Inhibitor
„Myrcludex“
Heiner Wedemeyer: Hepatitis Delta
Myrcludex B: HBV and HDV entry
inhibitor (Stephan Urban, Heidelberg)
Heiner Wedemeyer: Hepatitis Delta
Prenylation
inhibitor
(J. Glenn, USA)
Heiner Wedemeyer: Hepatitis Delta Bordier, Glenn et al. JCI 2003
Heiner Wedemeyer: Hepatitis Delta
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!
Heiner Wedemeyer: Hepatitis Delta
Michael P. Manns
Markus CornbergBeatrice Calle-Serrano, Benjamin Heidrich
Jan Grabowski, Ingmar Mederacke, Kalliopi
ZachouKerstin Port, Birgit Bremer, Janina Kirschner
Heiner Wedemeyer: Hepatitis Delta
And…
if
you
want
to
be more involved
in hepatitis delta: