Combination of pegylated interferon and lamivudine is superior to lamivudine monotherapy in the treatment of chronic hepatitis B — a randomized trial

General Session 4: Viral Hepatitis Methods: 181 patients with serum HBVDNA > lOMEq/mL (Quantiplex assay) after at least 24 weeks of LVD therapy or YMDD mutation and serum ALT <10x ULN were randomized to ETV 0.1, 0.5, or 1.0 mg, or LVD 100 mg daily for up to 52 weeks. Results: Treatment groups were comparable for baseline demographics, HBeAg status (67% positive), mean HBVDNA (8.1 log10 copies/ml PCR), and median ALT (71 u/L). Mean decrease from baseline in HBVDNA for all ETV doses was superior to LVD at 48 weeks. For HBeAg-negative patients in the ETV 0.1, 0.5, and 1.0 mg groups, mean log10 HBVDNA reductions were 2.9, 4.0 and 5.6, respectively, versus 0.7 for LVD; whereas ALT normalization occurred in 5/10, 10112, and 900 ETV patients, respectively, versus 0113 LVD. For HBeAg-positive patients, mean log10 HBVDNA reductions were 2.8, 4.6 and 4.7 respectively, versus 1.8 for LVD; whereas ALT normalization occurred in 6/l 1, 702, and 905 ETV patients, respectively, versus 200 LVD. Preliminary analysis demonstrates durable virologic suppression and ALT normalization through 6 months off treatment follow-up in a substantial proportion of ETV patients. Conclusion: In patients previously failing LVD therapy, HBVDNA reduction and ALT normalization after 48 weeks of ETV therapy were comparable in HBeAg-positive and negative patients. HBeAg-negative patients who responded to ETV treatment frequently demonstrated a durable posttreatment response.

I

94

THE EFFECT

OF PEGINTERFERON

HISTOLOGY

IN CHRONIC

HEPATITIS

INDIVIDUAL

PATIENTS DATA

ALFA-2A

(40 KD) ON LIVER

C: A META-ANALYSIS

OF

C. Camma’,2,

D. Di Bona’, F. Schepis3, E.J. Heathcote4, S. Zeuzem’, P.J. Pockros6, l? Marcellin7, A. Alberti’, A. Craxi’. ‘Cattedra Di Gastroenterologia, Istituto Di Clinica Medica, University Of Palermo, Palermo; 21BIM, Consiglio Nazionale Delle Ricerche, Palermo; ‘Dipartimento Di Medicina Sperimentale E Clinica, University Of Magna Graecia, Catanzaro, Italy; 4Department Of Medicine, University Health Network, Toronto Western Hospital, Toronto, Canada; ‘Klinikum Der Johann Wolfgang Goethe University, Frankjiut, Get-many; 6Scripps Clinic, La Jolla, CA, USA; 71NSERM U481, Service D’Hepatologie Hospital Beaujon, Clichy, France; ‘Dipartimento Di Medicina Clinica E Sperimentale, University Of Padova, Padova, Italy The benefit of peginterferon alfa-2a (40KD) on liver histology has been extensively studied however, the results are still equivocal. Methods: We performed a MIPD on 1013 naive patients with pre- and post-treatment biopsies from 3 RCTs in order to assess the differences between peginterferon alfa-2a (40KD) and interferon alfa-2a in liver histology, to determine if the histological benefit of peginterferon alfa-2a is related to virological response and to identify predictors of histological improvement. We used a random-effects model to quantify the average effects of peginterferon alfa-2a (40KD) on liver histology and identify predictors of fibrosis improvement by logistic regression. Results: Peginterferon alfa-2a (40KD) compared to interferon alfa-2a significantly reduced fibrosis (net change -0.14; 95% confidence interval [CI] from -0.27 to -0.01, p: 0.04). An impressive reduction in fibrosis after treatment was observed in sustained virological responders (SVR) (-0.59; 95% CI from -0.89 to -0.3O;P
I

95

33

COMBINATION LAMIVUDINE

OF PEGYLATED IS SUPERIOR

IN THE TREATMENT A RANDOMIZED

INTERFERON

TO LAMIVUDINE

OF CHRONIC

AND MONOTHERAPY

HEPATITIS B -

TRIAL

J.J.Y. Sung, H.L.Y. Chan, A.Y. Hui, F.K.L. Chan, A.M.L.

Chim, M.L. Wong, N.W.Y. Leung. Department of Medicine & Therapeutics, Chinese University of Hong Kong, Hong Kong

Background: Previous studies combining interferon with lamivudine failed to prove additional benefit in clearance of HBV infection. We aimed to study the anti-viral effects of pegylated interferon (Peg-IFN) and lamivudine combination. Patients and Methods: Treatment-naive chronic hepatitis B patients who had positive HBeAg, HBV DNA >l,OOO,OOO copies/ml and ALT 1.3. 5x upper limit of normal were recruited into an open-labeled, randomized study. Patients received either combination treatment (Combo group) with Peg-IFN 1.5 mcg/kg for 8 weeks, then Peg-IFN plus lamivudine 1OOmg daily for 24 weeks followed by lamivudine alone for 28 weeks, or lamivudine monotherapy 1OOmg daily for 52 weeks (Lam group). Endof-treatment and sustained (24.week post-treatment) virological response (VR, defined as HBeAg seroconversion and undetectable HBV DNA) and biochemical response (BR, defined as normalization of ALT) were analyzed. Results: The interim results of first 40 patients who finished treatment and follow-up were analyzed. There was no difference in the gender, age and ALT levels between the two groups. The proportion of patients achieving end-of-treatment and sustained VR in Combo group was significantly higher than that of Lam group (75% vs 25%, p=O.O005 and 50% vs lo%, p=O.O2 respectively). There was no significant difference in the end-oftreatment and sustained BR between the Combo and Lam groups (95% vs 70%, p=O.l and 50% vs 30%, p=O.3 respectively). Four patients receiving Peg-IFN had premature termination of treatment due to serious adverse events. Conclusion: Combination of Peg-IFN and lamivudine has superior antiviral effect to lamivudine monotherapy in the treatment of chronic hepatitis B infection.

I 96

EFFICIENCY LAMIVUDINE

OF DNA VACCINE FOR CHRONIC

IN ASSOCIATION

HEPATITIS

WITH

B THERAPY

A. Thermet’, J. Rhodes2, C. Trepo’, F. Zoulim’, L. Cova’. ‘INSERM Unit271, Lyon, France; 2GlaxoSmithKline, Stevenage, UK Combination of antiviral drugs with immunotherapeutic approaches may be a promising new strategy for treatment of chronic hepatitis B. We have used the duck HBV (DHBV) infection model and explored whether combination therapy associating a lamivudine treatment with DNA-immunization to viral structural proteins may lead to the complete viral clearance. Pekin ducklings chronic DHBV-carriers received intraperitoneal lamivudine treatment alone or followed by DNA-immunization. The DNAimmunization consisted in intramuscular injections of either a plasmid encoding viral large envelope and/or a plasmid encoding core protein. The viremia and anti-preS humoral response evolution were followed during 9 months. During the lamivudine administration period, a decrease by 70% in mean viremia titers was observed in the drug-treated as compared with the untreated duck groups, which was followed by persistence of viral replication. DHBV DNA analysis of autopsy liver samples showed no viral DNA clearance within the lamivudine only treated duck group. Importantly, 7/30 (23%) of animals that received specific DNA-based therapy, in association or not with lamivudine, have completely cleared intrahepatic DHBV DNA including the cccDNA form. Combination therapy associating lamivudine and DNA vaccine to envelope protein appeared as more effective since 38% of ducks have undetectable viral DNA in their livers as assessed by real time PCR.