188 Posters • NOVEL MECHANISM OF HepeX-B ANTIBODIES IN PROLONGED BLOCKING OF RELEASE OF HEPATITIS B VIRUS AND HBsAg PARTICLES FROM INFECTED CELLS INDICATED BY VIRAL DYNAMICS IN-VIVO A.U. Neumann 1, I. Levine 1, S. Dagan2, R. Eren 2 . :Bar-Ilan University, Ramat-Gan, Israel; 2XTL Biopharmaceuticals Ltd., Rehovot, Israel Background: The accepted mechanisms of action of antibodies against viral pathogens are acceleration of clearance arid neutralization of infec- tion. Recently, findings in-vitro suggested that anti-HBsAg antibodies may enter infected cells and block the release of hepatitis B virions (HBV) and HBsAg particles (Na~mmv et al., 2003). Objectives: To analyze HBV-DNA arid HBsAg in-vivo kinetics daring infusion of HepeX-B, a mixture of two human monoclonal antibodies against HBsAg, and test by mathematical models its mechanism of action. Methods: Fifteen chronic HBV infected patients received a sin- gle HepeX-B infusion (026-40mg) and 12 patients 4 weekly in- fusions (10-80mg). HBV-DNA was frequently quantified by PCR (LD=400IU/ml) and HBsAg by a modified Abbott IMx assay (LD = 125pg/ml). A mathematical model of viral dynamics (Nenmann et al., Science, 1998) modified to include acceleration of serum clearance and/or blocking production or release and/or blocking infection, was used to fit the data. Results: Viral decline during HepeX-B infusion was close dependent. A significant decline in HBV-DNA (mean 2.5±0.61ogIU/rnl) and in HBsAg (mean 4.1±0.31ogpg/rnl) was observed at 4 hours of infusion in 8/10 patients dosed with 40 or 80rng. Decline slope in HBV-DNA and HBsAg was rapid (mean tl/2=0.45±0.10h and t1/2=0.26±0.03h, respectively). These half-lives clearly indicate acceleration in serum clear- ance of virions (mean 24 fold) and HBsAg particles (minimal estimate 40 fold). However, the model of acceleration of clearance predicts only 1.4 (2.4) log decline in HBV-DNA (HBsAg). Fitting the kinetics is possible only by assuming that HepeX-B also causes partial blocking of release of virions (mean effectiveness 92.6±5.0%) and of HBsAg particles (minimal estimate 98.2± 1.5%). Furthermore, HBV-DNA and HBsAg rebound to baseline within 72 hours post infusion. Fitting indicates that blocking of release continues after end of infusion with a half-life of 6.4 hours. Conclusion: A potential novel mechanianl of action of anti-HBsAg antibodies suggests partial blocking of release of virions and HBsAg partides from infected cells in addition to acceleration of clearance from serum. These in-vivo results are supported by in-vitro findings and suggest quantitative predictions. Further studies are important to assess clinical implications and relevance to other viruses. [ • I F N IMPACT ON LIVER DISEASE PROGRESSION IN HBeAg NEGATIVE CHRONIC HEPATITIS B (CHB): A LONG TERM ITALIAN MULTICENTER AISF STUDY F. Oliveri ~, M. Puoti 2, T. Santantonio 3, P. Lampertico 4, G. Colloredo 5, G. Niro 6, G. Fattovich 7, E Morisco 8, A. Marrone 9, E Costa 1°, M. Felder 1~, R Cacciatore 12, A. Srnedile ~3, M.R. Brunetto 1 . : U.O. Gastroenterologia edEpatologia, Azienda Ospedaliera Unioersitaria Pisana, Pisa, Italy," 2Cliniea Malattie Infettive e Tropicali, AO Spedali CiviB, Brescia, Italy," s Clinica Malattie Infettive, Azienda Ospedaliera Policlinico Consorziale, Bari, Italy," 4Divisione di Epatologia, IRCCS Ospedale Maggiore Policlinieo, Milano, Italy," 5Divisione Medicina, Polielinico San Pietro, Ponte San Pietro, Italy," 6 Gastroenterologia Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy," 7 Dipartimento di Gastroenterologia, Universit~ di Verona, Verona, Italy," ~Cattedra Di Gastroenterologia, Dipartimento di Scienza degli Alimenti, Unioersit~ di Napoli 'Federico H', Napoli, Italy," 9Divisione di Medicina Interna ed Epatologia, Seconda Universit~ di Napoli, Napoli, Italy, :°Dioisione Malattie Infettive Ospedale "C. Poma ', Mantova, Italy," 11Dioisione di Gastroenterologia, Ospedale Centrale Bolzano, Italy," 12Clinica Malattie Infettive, Universit?~ Di Chieti, Italy, 13U0 Gastroenterologia Ospedaliera, Ospedale S. Giovanni Battista 'Molinette ', Torino, Italy, Italy HBeAg negative CHB is a progressive disease with low spontaneous and drug induced resolution rates. We evaluated sustained response (SR) to IFN and factors influencing treatment and disease olttcome in a large series of patients. Patients and Methods: We followed up prospectively 558 anti-HBe posi- tive CHB patients (451 males, 107 females; mean age 41, range 12-66 y) from 13 Italian Centers. Patients received at least 3 months (too) of IFN41 from 1985 to 2001:437 (78%) experienced single courses whereas 121 (22%) 2 or more courses. Mean follow up after end of treatment (EOT) 54rn (1-205rno). SR = normal ALT, HBV-DNA < 10pg/ml, IgM anti- HBc < 0.2 IMx index for at least 12 mo after EOT. Results: At baseline 150 (27%) patients had cirrhosis, 49 (9%) moderate~ severe steatosis. At first IFN treatment 319 (57.2%) patients achieved EOT response, 96 (17.2%) were SR; after relapse 14 (2.5%) developed persistently normal ALT and undetectable HBV-DNA (PRR Persistent Remission after Relapse). Long Term Response (LTR SR + PRR) rate in naives (19.7%) was the same of that in retreated (19.8%). At multivariate analysis (MVA) age younger than 40y (p 0.011) and treatment duration (p < 0.000001) were independently associated with SR, observed in 6.8%, 15.9% and 30.7% of patients treated 3-6mo, 7-12mo and more than 1 y (mean 19rno), respectively. HBsAg clearance was observed in 47 (35%) of 134 LTR (anti-HBs seroconversion in 32). During follow up 43 (7.7%) patients developed End Stage Complications (ESC) (jaundice, ascites, var. bleeding, encephalopathy) and/or Hepatocelhflar Carcinoma (HCC in 27, 4.8%). Four patients were transplanted because of HCC and 1 for terminal cirrhosis (t.c.); 14 (2.5%) (tied 15 100too after EOT because of HCC (10), t.c. (3) and extrahepatic tumor (1). Among 43 ESC patients 31 had baseline cirrhosis, only 1 was female. At MVA female sex, younger age, absent-mild steatosis, absence of cirrhosis and LTR to IFN were independently associated with a better outcome. In cirrhotics LTR was independently associated with the absence of ESC except HCC. Conclusions: In HBeAg negative CHB standard IFN warrants a 20% LTR associated with a better clinical outcome. In cirrhotics IFN may avoid clinical decompensation, but not HCC.