M. Buti

Is telbivudine superior to lamivudine for the treatment of patients with chronic hepatitis B

This practice point commentary discusses the findings and limitations of a prospective, double-blind, phase III trial conducted by Lai et al. in which patients with chronic hepatitis B (CHB) were randomly allocated to receive telbivudine 600 mg daily or lamivudine 100 mg daily. The trial showed that telbivudine was superior to lamivudine in terms of mean reduction in number of HBV DNA copies/ml from baseline, the number of patients with a reduction in serum HBV DNA to undetectable levels, and rate of HBV drug resistance. This commentary highlights the issues to consider when interpreting and generalizing these results, including the fact that lamivudine is no longer recommended as first-line therapy for patients with CHB and that head-to-head comparisons between telbivudine and its two alternatives—entecavir and adefovir dipivoxil—have not been performed. The importance of selecting patients for treatment according to predictive factors of a good response is also highlighted.

800 UTILITY OF ITPA GENOTYPING TO PREDICT EARLY SEVERE ANEMIA IN CHRONIC HEPATITIS C PATIENTS RECEIVING TRIPLE THERAPY

Serious adverse events (SAEs) 33 (32.4%) Premature discontinuation 33 (32.4%) Due to SAEs 10 (9.8%) Discontinuing patient care 3 (2.9%) Virological failure 20 (10.6%) Death Septic shock, Multi-organ failure secondary to pneumonia 2 (1.96%) Dose modification (PegIFN) 8 (7.8%) Infection Grade 3–4 5 (4.9%) Hepatic decompensation (Grade 3/4) 4 (3.9%) Anaemia Hg <10.0 g/dL 29 (28.4%) Hb <8.0 g/dL 3 (2.9%) EPO use 26 (25.5%) Blood transfusion 9 (8.8%) Ribavirin dose adjustment 27 (26.4%) Neutropenia N < 1,000/mm3 44 (43.1%) N < 500/mm3 5 (4.9%) Use G-CSF 2 (2.0%) Thrombopenia Platelets <50,000 18 (17.6%) Platelets <25,000 1 (0.98%)

379 ULTRA-DEEP PYROSEQUENCING OF BASIC CORE PROMOTER, PRECORE AND CORE REGIONS OF HEPATITIS B VIRUS TO STUDY VIRAL VARIABILITY AND QUASISPECIES COMPLEXITY

Methods: HepaRG and PHH were either infected with HBV or transfected with either purified viral nucleocapsid or recombinant HBc protein. Moreover engineered HepaRG cell lines, which express HBV proteins, were also used to analyse the role of individual proteins. Ligands of PRRs were used to engage innate receptor and analyse the inhibitory effect of HBV proteins. HBV replication was analysed with standard procedures, whereas the effect of viral proteins on the expression of various interferons (a, b, l. . . ), interferon-induced (ISG) and pro-inflammatory cytokines genes was analysed by RT-qPCR, WB and ELISA. ChIP experiments were also performed to analyse the binding of HBc to target promoters as well as to analyse the recruitment of epigenome-modifying enzymes to target promoters. Results: HBV is capable to inhibit dsRNA-mediated interferon response after only few hours of infection. This inhibition occurs also with Dane-depleted and UV-inactivated virus suggesting that neo-synthesis of HBV protein is not mandatory. Using engineered cell lines we demonstrate that HBc is responsible for this very early inhibition. The transfection of purified nucleocapsid or recombinant HBc leads to the same inhibitory phenotype. HBc needs to be located in the nucleus to inhibit the transcription of targeted genes (i.e. IFNs, ISG), as inhibition of its trafficking, revert the phenotype. ChIP analyses with anti-HBc revealed that HBc is capable to bind to target promoters and to recruit epigenome-modifying enzymes to establish a negative mark on target promoters. Conclusion: Our results demonstrate that HBc is responsible for the very early inhibition of IFN response by HBV. The precocity of this inhibition is instrumental for the establishment of a persistent infection in vitro and is possible because HBc from incoming virions is capable to inhibit gene expression in the nucleus of infected cells by either direct interference with transcriptional machinery or by recruiting epigenome-modifying enzymes leading to repressive marks.

1108 ULTRA-DEEP-PYROSEQUENCING OF PRECORE REGION OF HEPATITIS B VIRUS

1107 PRIME/BOOST IMMUNIZATION WITH DNA AND ADENOVIRAL VECTORS PROTECTS WOODCHUCKS FROM HEPATITIS D VIRUS INFECTION M. Fiedler, A. Schumann, A. Kosinska, M. Lu, L. Johrden, O. Wildner, M. Roggendorf. Institut fur Virologie, Abt. fur Klinische Chemie, Universitatsklinikum Essen, Essen, Institut fur Virologie, Universitat Bochum, Bochum, Paul-Ehrlich-Institut, Langen, Germany E-mail: melanie.fiedler@uni-due.de