2 Safety and efficacy of adefovir dipivoxil in patients with lamivudine-resistant chronic hepatitis B undergoing liver transplantation

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Thursday, 27 April

General Session 1

~-] MULTICENTER RANDOMIZED TRIAL OF HCV TREATMENT WITH P E G I N T E R F E R O N - A L P H A 2a AND RIBAVIRIN IN LIVER T R A N S P L A N T PATIENTS WITH ESTABLISHED R E C U R R E N T HEPATITIS C: INTERIM ANALYSIS C. Duvoux 1. D. Samuel 2, G. Pageaux 3, M. Messner4, R Wolf6, L. Rostaing 6, C. Vanlemmens7, Y.R Le Treut 8, S. Dharancy9, J. Gugenheim 11, E Durand 12, M. N~au-Cransac 13, O. Boilot 14, L. Samelson 15, K. Boudjema4, Y. Calmus 1~ 1Henri Mondo~ Creteil,

2paul Brousse, Villejuif, 3Saint Eloi, Montpellie~ 4pontehaillou, Rennes, 5Hautepierre, Strasbourg, 6Rangueil, Toulouse, 7Minjoz, Besanfon, 8La Conception, Marseille, 9Huriez, Lille, 1~ Paris', 11L'Arehet, Nice, 12Beaujon, Clichy, 13Pellegrin, Bordeaux, 14Edouard Herriot, Lyon, 15Roche Neuilly Sur Seine, France End-stage liver disease (ESLD) secondary to hepatitis C virus (HCV) infection is one of the most common indications for liver transplantation (OLT). Infection of the graft is universal, causing histologic injury and graft loss in 6 28% by the fifth postoperative year. Objective: to investigate whether a one year maintenance therapy of Ribavirin (RBV) could increase viral HCV eradication after a one year combination therapy with peginterferon alpha 2a (Pegasys| plus RBV (Copegus| Interim results of the one year combination therapy are presented. Methods: 101 patients with recurrent HCV and a minimum stage 1 fibrosis (Metavir score) on a liver biopsy obtained 1 to 5 years after OLT were included. The treatment with peginterferon alpha 2a and RBV was initiated at 90 gg/week and 600 mg/d respectively and then increased to 180 gg/week and 1000 mg/d according to biological parameters. Primary efficacy end point was virological response at 12 months and at the end of follow up (30 months) defined by negative qualitative HCV-RNA (Roche Amplicor TM test, lower limit of detection 50 UI/ml). A liver biopsy was performed at 12 months and at the end of follow up. Results: Among the 101 patients, 73% were male, the mean age was 53.2 years, the mean body weight was 74.4kg, 73% were genotype 1, 59% had a stage 1 fibrosis score and 2% a stage 4. At 12 months, 61% were negative by PCR in the intent to treat analysis (75% in per protocol analysis). Fibrosis remained unchanged before and after 12 months of therapy instead of histological activity which was significantly improved. Use of erythropoietin and G-CSF was necessary in 37% and 12% of the patients respectively. A low rate of side effects was observed including 2% of acute rejection and 2% of renal failure. Conclusions: Preliminary findings from this ongoing multicenter randomized trial reveal encouraging effect of a one year combination therapy with peginterferon alpha 2a and RBV. Virological response (HCV RNA <50 IU/L) was achieved in 61% of patients in intent to treat analysis and in 75% of patients in per protocol analysis with an acceptable safety profile.

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SAFETY AND EFFICACY OF ADEFOVIR DIPIVOXIL IN PATIENTS WITH LAMIVUDINE-RESISTANT CHRONIC HEPATITIS B U N D E R G O I N G LIVER TRANSPLANTATION

E. Schiff1, C.L. Lai 2, R Neuhaus 3, H. Tillman4, D. Samuel 5, J.E Villeneuve 6, S. Hadziyannis7, S. Arterburn 8, H. Mommeja-Marin8, S. Chuck 8. 1Centerfor Liuer Diseases, Uniuersity of Miami, Florida, USA,"

2Queen Mary Hospital, Hong Kong, China," 3Department of Surgery, Charite Campus' Virehow, Berlin, Germany," 4Gas'troenterology and Hepatology, Hannouer Medical School, Hannoue~ Germany," 5Hepatobiliary Centre, Paul Brousse Hospital, Villejuif, France," 6CHUM-Campus Saint-Luc, Montreal, Quebec, Canada," 7Henry Dunant Hospital, Athens, Greece," 8Gilead Sciences, Foster City, California, USA Background: Lamivudine and HBIg prevent reinfection of the graft following liver transplantation for chronic hepatitis B (CHB), however, lamivudine resistance can develop and HBIg is costly. The efficacy and safety of adefovir dipivoxil (ADV) and lamivudine in preventing reinfection in patients with lamivudine-resistant CHB were investigated. Methods: Fifty-seven patients with lamivudine-resistant CHB, who were being treated with ADV added to ongoing lamivudine, underwent transplantation. Serum HBV DNA was centrally assessed using the Roche Amplicor Monitor assay with a lower limit of quantification (LLQ) of 1000 copies/mL. Results: At baseline, the patients were median age 52 years, 88% male, 77% Caucasian, 19% Asian, 100% HBsAg positive, 42% HBeAg positive, with median serum HBV DNA 4.6 logl0 copies/mL, median ALT 1.0 times ULN, and 43%, 39% and 18% were CPT class A, B or C, respectively. The median duration of ADV therapy pre-transplantation was 15 weeks. Thirty-two patients (56%) also received HBIg. The median duration of follow-up post-transplantation was 36 weeks. Following transplantation, no patient was both HBsAg and HBV DNA positive. Four patients (7%) had HBsAg detected at their first measurement posttransplantation; of these, 2 patients had negative HBsAg on 5 and 2 subsequent measurements, and 2 patients had no additional HBsAg follow-up. Two of these 4 patients received HBIg. Four of 32 (13%) patients given HBIG had a single HBV DNA measurement >LLQ (max 3055 copies/mL) post-transplantation, and an additional 2/32 (6%) had confirmed detectable HBV DNA on the first two measurements post-transplantation with subsequent measurements LLQ (max 2088 copies/mL) during follow-up. Four patients (7%) discontinued ADV due to an adverse event; only one event (psychosis) was "possibly related" to ADV. The maximum serum creatinine post-transplantation was grade II or higher in 9/57(16%) patients. Conclusion: The combination of ADV and lamivudine, started prior to liver transplantation and continued afterward, was safe and efficacious in preventing reinfection of the graft in lamivudine-resistant CHB either with or without concomitant HBIg. Over 80% of patients never had detectable HBV DNA and 93% never had detectable HBsAg post-transplantation.