Delta Hepatitis: Treatment Options for a Largely Neglected Disease

Michael P. Manns and Heiner WedemeyerDept. of Gastroenterology, Hepatology und Endocrinology

Hannover Medical SchoolGermany

HEP-DART 2007, The Westin Maui, Lahaina, Hawaii, December 9 -13, 2007

The Hepatitis D Virus

Hepatitis D Virus (HDV)-Infection

HDV is the smallest known virus to infect men

HDV uses HBsAg as an envelope and thus can only beHDV uses HBsAg as an envelope and thus can only be found as a coinfection with HBV

HDV-infection affects approx. 15 Million people world-widepp p p

7-12% of HBsAg+ patients were anti-HDV+ at Hannover Medical between 1997 and 2006Wedemeyer et al., Hepatology 2007

HDV genotype 1 is found in Europe and the M dit A d i i t d ithMediterranean Area and is associated with more severe diseaseSu et al, Gastroenterology 2006

Simultaneous Co-Infection

95% recoveryAcute HBV

Acute HDV

95% recoveryMore frequent fulminant

HDV S I f tiHDV Super-Infection

Acute HDV90% chronic

More severe diseaseChronic Hepatitis Bp

Geographic Distribution of HDV infection

TaiwanMongolia:Pacific Islands

Mongolia:- 27% of acute hepatitis cases (Tsatsralt-Od J Med Virol 2006)

- >50% of HDV patients had triple infection (HBV/HCV/HDV) (Tsatsralt-Od J Med Virol 2005)

- 13 6% of HBsAg in children (Davaalkham Am J Trop Med Hyg 2006)HDV Prevalence

HighIntermediate

- 13.6% of HBsAg in children (Davaalkham Am J Trop Med Hyg 2006)

LowIntermediate

Very LowNo Data

Geographic Distribution of HDV infection

Genotype G t

Taiwan

Genotype (I)/II/IV

ypI

G t

Genotype I

Pacific Islands

Genotype III

Genotype V-VII

HDV Prevalence

HighIntermediate

III

LowIntermediate

Very LowNo Data

Radjef et al, J Virol 2004

Different HDV genotypes are associated with different clinical outcomesdifferent clinical outcomes

Su et alSu et al,

Gastroenterology 2006

35% fulminant hepatitis in an acute HDV genotype I outbreak in Samara Russiaoutbreak in Samara Russia

Flodgren, et al.J Clin Microbol 2000

C f / f l i t h titi i HDV t III i f tiCases of severe / fulminant hepatitis in HDV genotype III infection

Casey te al., J Infect Diseases 1996

Causes of Hepatocellular Carcinoma in Turkey

Cryptogenic(16.3%)

Alcohol(6.6%)

HBV/HDV(48%)

HCV+Alcohol(3.1%)

HCV(16.7%)

HBV+HCV(3.5%) HBV+Alcohol (6.2%)

Uzunalimoğlu et al, Dig Dis Sci 2001

Declining Prevalence of Hepatitis D Virus Infection in ItalyInfection in Italy

25

30

1987HB

sAg+

15

201992

1997-pos

itive

/ H

5

101997

% a

nti-H

DV-

00-29 30-49 >50

Age of Patients

%

Gaeta, Rizzetto et al., Hepatology 2000

Age of Patients

HDV-Infection: A problem in Germany?Anti-HDV-Prevalence inHBsAg+ Patients

Hannover Medical School: 1-1992 to 4-2006; n=2354+ 15

+ / H

BsA

g+

10

anti

HD

V+

5%

*

01992 1994 1996 1998 2000 2002 2004 2006

HDV-Infection: A problem in Germany?Anti-HDV-Prevalence inHBsAg+ Patients

Hannover Medical School: 1-1992 to 4-2006; n=2354

40

numbe

+

30

er of anti-H

15

+ / H

BsA

g+

20

HD

V+ patie

10

anti

HD

V+

10

nts [n/year

5%

*

0

r]

01992 1994 1996 1998 2000 2002 2004 2006

Emerging HDV Epidemiology: Migration

Taiwan

Pacific Islands

HDV Prevalence

HighIntermediateLowIntermediate

Very LowNo Data

HDV-Infection in Germany: Country of Birth

Origin of patients HDV diagnosis1989-1995N=8

HDV diagnosis1996-2002N=25

χ2p-level

Erhardt et al., Z Gastroenterologie 2003

N=8 N=25Germany [%] 12.5 (n=1) 14.3 (n=4) n.s.

Southern Europe[%] 75 (n=6) 32.1 (n=9) 0.03

Eastern Europe [%] 12.5 (n=1) 53.6 (n=15) 0.04

W d M t l MHH 1992 2006

Origin of patients HDV diagnosis1992-1996N=43

HDV diagnosis1997-2006N=101

χ2p-level

Wedemeyer, Manns et al., MHH 1992-2006

Germany [%] 23.2 (n=10) 17.8 (n=18) n.s.

Turkey [%] 41.8 (n=18) 19.8 (n=20) 0.006

Eastern Europe /NIS[%]

11.6 (n=5) 34.6 (n=35) 0.003

Factors associated with HDV infection

Anti-HDV positive household member OR 33.6Intravenous Drug Addiction OR 8 0Intravenous Drug Addiction OR 8.0Sexual Intercourse with a drug addiction OR 15.0

Residence South vs. North Italy OR 11.1Liver Cirrhosis OR 3.8

Gaeta, Rizzetto et al., Hepatology 2000

HDV: Conclusion I

HDV infection is not a vanishing disease in Europe!g p

The country of birth of delta hepatitis patients seen in y p pcentral Europe has significantly changed during the last 15 years

The migrational background may account for differences the clinical spectrum of HDV-associated liver disease

HDV-InfectionTreatment OptionsTreatment Options

Interferon alphaS stained biochemical responses in 0 36% of patients• Sustained biochemical responses in 0-36% of patientsFew Studies with virological endpointstreatment >12 months may be required

Farci et al., NEJM 1994Di Marco et al., J Viral Hepatitis 1996

Niro et al., J Viral Hepatitis 2005

• Higher IFN doses were associated with better survival in small study cohortFarci et al Gastroenterology 2004Farci et al., Gastroenterology 2004

HDV-InfectionTreatment OptionsTreatment Options

Interferon alphaS stained biochemical responses in 0 36% of patients• Sustained biochemical responses in 0-36% of patientsFew Studies with virological endpointstreatment >12 months may be required

Farci et al., NEJM 1994Di Marco et al., J Viral Hepatitis 1996

Niro et al., J Viral Hepatitis 2005

• Higher IFN doses were associated with better survival in small study cohortFarci et al Gastroenterology 2004Farci et al., Gastroenterology 2004

Nucleos(t)ide Analogues• Famciclovir ineffective Yurdaydin et al J Hepatol 2002• Famciclovir ineffective Yurdaydin et al., J Hepatol 2002• Lamivudine ineffective Wolters et al., J Viral Hepatitis 2000

Niro, Aliment Pharmacol Ther. 2005Niro et al., J Viral Hepatitis 2005

• Ribavirin ineffective Niro et al., Hepatology 2006Garripoli et al., Liver 1994

Gunsar et al., Antiv Therapy 2005

Trials using PEG-IFN in Delta Hepatitis3 studies published in September 2006

Castelnau, Gault et al. Hepatology 2006

14 patients, 12 months of PEG-IFNα-2b SVR in 6 patients (43%)

Niro, Rizzetto et al. Hepatology 200638 patients, 72 weeks PEG-IFNα-2b 16 pts monotherapy

Ribavirin had no additional effect

p py22 pts + ribavirin (first 48 weeks)

SVR: 8 patients (21%)Ribavirin had no additional effectRibavirin had no additional effectRibavirin had no additional effect

Erhardt, Häussinger et al. Liver Int 2006

12 patients, 48 weeks of PEG-IFNα-2b SVR in 2 patients (17%)

A Multicenter Randomised Study Comparing the Efficacy of

Pegylated interferon-alfa-2a plus Adefovir dipivoxil vs.

Pegylated interferon-alfa-2a plus Placebo vs.

Adefovir dipivoxilAdefovir dipivoxil

for the Treatment of Chronic Delta Hepatitis

“The HIDIT-1 Study”The HIDIT-1 Study

Heiner Wedemeyer*, Cihan Yurdaydın*, G D l k A E h dt Y Ç k l ğl H D ğ t ki S Gü lG. Dalekos, A. Erhardt, Y Çakaloğlu, H. Değertekin, S. Gürel,

S. Zeuzem, K. Zachou, H. Bozkaya, T. Bock, H.P. Dienes, Michael P. Manns

for the Hep Net/International Delta Hepatitis Study Groupfor the Hep-Net/International Delta Hepatitis Study Group *C. Yurdaydın and H. Wedemeyer contributed equally

funded by

Disclosures

This investigator-initiated trial was supported by

- Roche Basel

- Gilead Sciences

- The Hep-Net Study House

Acknowledgement

Clinical Investigator

M.P. Manns, H. Wedemeyer, A. Erhardt, S, Zeuzem, T. Berg, P. Buggisch, Germany

H. Hinrichsen, Manok, Herzog, Plein, W. Böcher, H.Hardt, Bohle, H. Porst

C. Yurdaydın, H. Bozkaya, Y. Çakaloğlu, S. Gürel, H Şentürk, F. Tabak, U.S. Akarca, G. Ersöz, H. Değertekin, K. Yalçın

Turkey

ğ ç

G. Dalekos, K. ZachouGreece

C t l H N t P th l i tCentral Hep-Net Pathologists U. Drebber, H.P. Dienes

Central Virology Hannover: K. Zachou, P. Magerstedt, R. RaupachTübingen: T. Bock

Study ManagementHep-Net Germany: S. Meyer, T. Müller & K. PeterMarkus Cornberg

SAE ManagementRoche Germany: U. AlshuthGilead Germany: C. Fischer

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

PEG-IFNa-2a (180 µg oiw)Adefovir dipivoxil 10 mg dailyN=32* p g y

PEG-IFNa-2a (180 µg oiw)Placebo

N=29N=91Placebo

Adefovir dipivoxil 10mg dailyN=30 p g y

TW0 TW24 TW48 F24Screening

* 1 patient withdrew informed consent after randomization

Inclusion Criteria

• Adults with chronic delta hepatitis• Compensated liver disease • HBsAg positive for at least 6 months • anti HDV positive for at least 3 months• HDV RNA positive by PCR • ALT ≥ ULN to ≤10x ULN. • Liver biopsy in the previous 12 months

N ti t t f HCV RNA & ti HIV• Negative tests for HCV-RNA & anti-HIV• No treatment for hepatitis D in the prior 6 months

Baseline Characteristics

PEG-IFN/ADVN=32

PEG-IFN/PN=29

ADVN=30

Median Age (yrs) 42 (23 59) 38 (17 62) 33 (21 55)*Median Age (yrs) 42 (23-59) 38 (17-62) 33 (21-55)

Sex M/F 21M / 11F 17M/ 12F 19M / 11F

HBeAG pos 5 (15 6%) 5 (17 2%) 4 (13 3%)HBeAG pos 5 (15.6%) 5 (17.2%) 4 (13.3%)

HBV-DNA log10 IU/ml 1.4 ** 2.6 2.1

HDV RNA cop/ml 1 25 x 106 7 x 105 3 x 105HDV-RNA cop/ml 1.25 x 106 7 x 105 3 x 105

Median ALT IU/l 96 87 108

Ci h i 4/29 (14%) 5/25 (20%) 7/29 (24%)Cirrhosis 4/29 (14%) 5/25 (20%) 7/29 (24%)

HDV genotype 1 100% 100% 100%

P i IFN T 12 (38%) 15 (52%) 12 (40%)Previous IFN-Tx 12 (38%) 15 (52%) 12 (40%)

•p<0.05 vs. Peg + AD and Peg + Plac** p <0.05 vs. Peg-IFN/Plac

Safety

91 patients randomized (32 PEG/ADV, 29 PEG, 30 ADV)

1 patient (PEG/ADV) withdrew IC before start of therapy

90 patients started treatment

10 patients stopped treatment (5 PEG+ADV; 3 PEG-IFN alone; 2 ADV)10 patients stopped treatment (5 PEG+ADV; 3 PEG IFN alone; 2 ADV)

6 patients due to disease progression including 1 death (HCC) and 1 LTx4 patients due to IFN-associated side effects

17 SAEs reported in 15 patients (17% of patients)

13 SAEs were considered as unrelated to study drug4 SAEs were considered as being related to PEG-IFNa-2a study drug

311 AEs reported in 69 patients (76% of patients)

80 patients completed treatment

Hematological ChangesADVPEG-IFN / PPEG-IFN / ADV

# #

Leucocytes/nl Platelets/nl7 200 # #

# #

4

5

6

80

120

160

2

3

4

TW0 TW24 TW48 F240

40

80

TW0 TW24 TW48 F24

# p<0 001 PEG IFN groups versus ADV mono

TW0 TW24 TW48 F24 TW0 TW24 TW48 F24

# p<0.001 PEG-IFN groups versus ADV mono

NS PEG-IFN / P versus PEG-IFN / ADV

Biochemical Response

PEG-IFNa-2a + Adefovir AdefovirPEG-IFNa-2a + Placebo

Median ALT

120

140Therapy

U/L

]

80

100

ALT

[IU

60

20

40

Study Week

00 10 20 30 40 50 60 70

Biochemical ResponseADVPEG-IFN / PPEG-IFN / ADV

120

Median ALT (IU/l)100Patients (%) with normal ALT

80

10060

80

60

80

20

40

40

TW0 TW24 TW48 F240

TW0 TW24 TW48 F24

Approx. 40% of patients treated with PEG-IFN achieved a biochemical response

HBV-DNA

Median HBV-DNA levels (log10 IU/ml)

3

2ADVPEG-IFN / PPEG-IFN / ADV

1

W0 W24 W48 F240

Significant decline of HDV-RNA with PEG-IFN

6HDV-RNA (copies/ml)

5

4 **

3

** *

2

ADVPEG-IFN / PPEG-IFN / ADV

2TW0 TW24 TW48 F24

*p<0.02 vs TW0; ** p<0.001 vs. TW0

PEG-IFN leads to sustained suppression of HDV-RNA in about 25% of patientsof HDV RNA in about 25% of patients

6Median HDV-RNA levels (copies/ml)

Patients (%) with negative HDV-RNA (ITT)

50 10 20 30 40 50 60

g ( )

4

TW48

3

F24

2

ADVPEG-IFN / PPEG-IFN / ADV

PEG-IFN / ADVPEG-IFN / PADV2

TW0 TW24 TW48 F24ADV

HDV-RNA levels in individual patients

PEG IFN 2 + Ad f i Ad f iPEG IFN 2 + Pl b

HDV-RNA (log10) copies/ml

PEG-IFNa-2a + Adefovir

78

AdefovirPEG-IFNa-2a + Placebo

567

234

012

TW0 TW24 TW48 F24 TW0 TW24 TW48 F24 TW0 TW24 TW48 F24TW0 TW24 TW48 F24 TW0 TW24 TW48 F24 TW0 TW24 TW48 F24

PEG-IFN & ADV combination resulted in a more pronounced decrease of HBsAg levelspronounced decrease of HBsAg levels

ADVHBs-Ag (IU/ml)

4 5

5ADVPEG-IFN / PPEG-IFN / ADV

HBs Ag (IU/ml)

4

4,5

3

3,5

2,5

3

W0 W24 W48 F24W0 W24 W48 F24

Clearance of HBs-Ag in 3 patients treated with PEG-IFN & ADV

Summary

PEG-IFNa-2a reduces HDV-RNA levels by at least 2logs in approx. 40% of patients with 25% becoming HDV-RNA negative after 48 weeks. 24 weeks after the end of therapy, HDV-RNA was negative in 27% of patients (ITT analysis)in 27% of patients (ITT-analysis).Adefovir dipivoxil does not effect HDV-replication but reduces HBV-DNA levels.Combination therapy of PEG-IFNa-2a plus adefovir was not superior in HDV-RNA suppression as compared to PEG IFN 2 lPEG-IFNa-2a alone.Combination therapy was superior to either monotherapy in reducing HBsAg levels in HBV-HDV-coinfected patientsreducing HBsAg levels in HBV HDV coinfected patients.

HDV: Conclusion II

PEG-IFNa-2a should be considered in the t t t f d lt h tititreatment of delta hepatitis.Longer therapies in patients with good tolerability need to be evaluated. Future trials need to confirm the increased HBsAg suppression of PEG-IFNa-2a plus nucleotide combination therapy.HIDIT II is coming soon: PEG-IFN alpha 2a + Tenofovir vs PEG-IFN alpha 2a for 96 weeks