impact of organ and non-organ-specific autoantibodies on the treatment outcome of patients with...

IMPACT OF ORGAN AND NON-ORGAN-SPECIFIC AUTOANTIBODIES ON THE TREATMENT OUTCOME OF

PATIENTS WITH HEPATITIS D VIRUS INFECTION

1Department of Gastroenterology, Hepatology and Endocrinology, Hanover Medical School, Hanover, Germany, 2Department of Medicine and Research

Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Thessaly, Greece, 3University of Ankara Medical School, Gastroenterology

Section, Ankara, Turkey, 4Institute of Pathology, University of Cologne, Cologne, Germany

Zachou Kalliopi1,2, Yurdaydin Cihan3, Drebber Uta4, Schlaphoff Verena1, DienesHans Peter4, Manns Michael1, Wedemeyer Heiner1, Dalekos GN2

for the HIDT-1 Study Group

INTRODUCTION

Chronic hepatitis delta virus (HDV) infection has been

associated with the production of autoantibodies.

More specifically, anti-LKM-3 autoantibodies (against

UGT1.1) have been detected in around 13% of patients

with chronic HDV infection

Buti et al, J Hepatol 1989

Strassburg et al, Gastroenterology 1996

Obermayer-Straub et al, J Autoimmun 2001

INTRODUCTION

It is well known that autoantibodies are also commonly found

in chronic HCV infection. We have shown that the presence of

some of them (ANA, PCA and SMA) before treatment or their

increase during IFN-α therapy may predict a worse response,

suggesting the need for a more intensive follow up during

treatment of HCV patients positive for these autoantibodies.

Gatselis et al, WJG 2005

We re-evaluated the production of organ and non-

organ specific autoantibodies in a large cohort of

patients with chronic HDV infection who participated

in the Hep-Net/ International Delta Hepatitis

Intervention Trial (HIDIT-1), as well as their impact

on treatment outcome.

AIM

PATIENTS & METHODS

87 HDV patients

PegIFN + AdefovirN= 30

PegIFN + PlaceboN= 29

AdefovirN= 28

48 weeks

PATIENTS & METHODS

Age (years) 38 (17-62)

Male /Female (%) 53 (61)/ 34 (39)

Hb (g/dl) 14.5 ± 1.61

WBC (109/L) 5.6 ± 1.63

PLT (109/L) 166.8 ± 54.1

AST (U/L, UNL:35 U/L) 82 ± 59

ALT (U/L, UNL:35 U/L) 120 ± 93

gGT (U/L, UNL:55 U/L) 80 ± 94

ALP (U/L, UNL:104 U/L) 89 ± 56

Bilirubin (mg/dl) 0.95 ± 1.5

Albumin (g/dl) (n=66) 4 ± 0.5

HDVRNA (copies/ml) 7.6 E5 (1080 -8.4 E7)

HBVDNA (IU/ml) 20 (0-18.9 E6)

HBsAg (IU/ml) 11798 (67-79590)

Baseline characteristics of the 87 patients included in the study

We investigated the presence of: • antinuclear Abs (ANA) • antimitochodrial Abs (AMA) • anti-smooth muscle Abs (SMA) • anti-liver kidney microsomal Abs (anti-

LKM) • anti-parietal cell Abs (PCA)

• anti-LKM-3

IIF: -HEp2 cells/ - rat liver-kidney-stomach sections (in-house method)

WB: - recombinant UGT 1.1

At baseline and at week 48 of treatment, in the sera of 87 patients with chronic HDV infection.

PATIENTS & METHODS

Quantitative determination of: • HDV-RNA (real-time PCR in-house)• HBV-DNA (Cobas TaqMan HBV test)• HBsAg (the Architect HBsAg assay)

PATIENTS & METHODS

At baseline, week 48 (end of treatment) and week 72 of treatment

Biopsies were available in 70 patients at baseline and 60 patients at w48

At baseline: • ANA→ 29/87 (33%)• SMA→ 24/87 (27%) • AMA→ 2/87 (2.3%) • anti-LKM→ 3/87 (3.4%)• PCA→ 4/87 (4.6%)

• anti-LKM-3→ 21/87 (24%)

• At least 1 autoantibody→ 56/87 (64.4%)

RESULTS

Week 48: • ANA→ 29/74 (39%)• SMA→ 20/74 (27%)• AMA→ 3/74 (4%)• anti-LKM→ 5/74 (7%)• PCA→ 18/74 (24%)

• anti-LKM-3→ 20/74 (27%)

• At least 1 autoantibody→ 54/74 (73%)

ANA

SMA

AMA

anti-LKM

PCA

anti-LKM 3

At least o

ne

0

10

20

30

40

50

60

70

80

90

100

Baseline Week 48

P < 0.001,

McNemar te

stNS

NS

NS NSNS

NS

RESULTS

RESULTS

PCA w48 was not induced by IFN therapy

P= 0.004

No correlation was found between baseline

epidemiologic, biochemical and histological

characteristics and autoantibodies positivity.

Anti-LKM-3 Abs positivity was associated with lower

baselineHDVRNA levels

RESULTS

p= 0.029

RESULTSAt baseline: • Presence of ANA was associated with HDVRNA (-) at w72

ANA (-) ANA (+)0

5

10

15

20

25

30

HDVRNA w72 (-)HDVRNA w72 (+)

p= 0.04

N o

f ca

ses

p= 0.05

At baseline: • Absence of SMA was associated with: lower HDVRNA at w72

amelioration of fibrosis

RESULTS

SMA (-) SMA (+)0

5

10

15

20

25

30

35

Better or same fi-brosis score

Worse fibrosis score

p= 0.05

N o

f ca

ses

At baseline: • Absence of PCA was associated with: amelioration of inflammation

RESULTS

PCA (-) PCA (+)0

5

10

15

20

25

30

35

40

45

Decrease in inflamma-tion screIncrease in inflamma-tion score

N o

f ca

ses

p= 0.03

Week 48: • Absence of PCA was associated with: lower HBsAg levels at w48 and w72

RESULTS

p= 0.01 p= 0.012

Week 48: • Absence of PCA was associated with: biochemical response at w72

RESULTS

PCA w48 (-) PCA w48 (+)0

5

10

15

20

25

30

35

ALT w72< UNLALT w72> UNL

P= 0.04

N o

f ca

ses

We found increased incidence of anti-LKM-3 as well as of

other autoantibodies in patients with chronic HDV infection.

Most patients had the same autoantibody profile before

and at the end of treatment. The only autoantibodies which

seemed to be increased in frequency were PCA.

Although anti-LKM-3 antibodies do not seem to affect

response to treatment, others may play a role in the

virological, biochemical or histological response.

CONCLUSIONS

Medical SchoolUniversity of Thessaly

University of Cologne