IMPACT OF ORGAN AND NON-ORGAN-SPECIFIC AUTOANTIBODIES ON THE TREATMENT OUTCOME OF PATIENTS WITH HEPATITIS D VIRUS INFECTION 1 Department of Gastroenterology, Hepatology and Endocrinology, Hanover Medical School, Hanover, Germany, 2 Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Thessaly, Greece, 3 University of Ankara Medical School, Gastroenterology Section, Ankara, Turkey, 4 Institute of Pathology, University of Cologne, Cologne, Germany Zachou Kalliopi 1,2, Yurdaydin Cihan 3, Drebber Uta 4, Schlaphoff Verena 1, DienesHans Peter 4, Manns Michael 1, Wedemeyer Heiner 1, Dalekos GN 2 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 + Adefovir N= 30 PegIFN + Adefovir N= 30 PegIFN + Placebo N= 29 PegIFN + Placebo N= 29 Adefovir N= 28 Adefovir N= weeks

PATIENTS & METHODS Age (years)38 (17-62) Male /Female (%)53 (61)/ 34 (39) Hb (g/dl) 14.5 ± 1.61 WBC (10 9 /L) 5.6 ± 1.63 PLT (10 9 /L) ± 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 ( E7) HBVDNA (IU/ml)20 ( E6) HBsAg (IU/ml)11798 ( ) 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%)

P < 0.001, McNemar test NS 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

RESULTS At baseline: Presence of ANA was associated with HDVRNA (-) at w72 p= 0.04 N of cases

p= 0.05 At baseline: Absence of SMA was associated with: lower HDVRNA at w72 amelioration of fibrosis RESULTS p= 0.05 N of cases

At baseline: Absence of PCA was associated with: amelioration of inflammation RESULTS N of cases 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 P= 0.04 N of cases

 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.  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 School University of Thessaly University of Cologne