Sustained virological and biochemical responses to lamivudine and adefovir dipivoxil combination in a chronic hepatitis B infection despite mutations conferring resistance to both drugs

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Sylvie Larrat*, Marie-Noëlle Hilleret, Raphaele Germi, Julien Lupo, Sandrine Nicod, Jean-Pierre Zarski, Jean-Marie Seigneurin and Patrice Morand

Background: Sequential monotherapies of nucleotide analogs used in chronic hepatitis B treatment can lead to the selection of a resistance mutation to each antiviral drug.

Case presentation: A patient with chronic hepatitis B was successively treated with lamivudine monotherapy, lamivudine-adefovir dual therapy, adefovir monotherapy and again with an adefovirlamivudine dual therapy. Lamivudine-associated mutations (rtL180M and rtM204V/I) followed by adefovir-associated mutations (rtN236T and rtA181V) emerged during the two monotherapy regimens. Despite the presence of rtM204V/I, rtA181V, and rtN236T mutations at the beginning of the second dual therapy, sustained biochemical and virological responses have been observed thus far after 23 months.

Conclusion: This case illustrates that rtM204V/I, rtA181V, and rtN236T resistance mutations can coexist in a patient but do not preclude the recycling of lamivudine and adefovir in combination therapy, when no other therapeutic choices are available.

Detection and identification of NAP-2 as a biomarker in hepatitis B-related hepatocellular carcinoma by proteomic approach

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Min He*, Jian Qin, Rihong Zhai, Xiao Wei, Qi Wang, Minhua Rong, Zhihua Jiang, Yuanjiao Huang and Zhiyong Zhang

Background: A lack of sensitive and specific biomarkers is a major reason for the high rate of Primary hepatocellular carcinoma (HCC)-related mortality. The aim of this study was to investigate potential proteomic biomarkers specific for HCC.

Methods: 81 patients with hepatitis B-related HCC and 33 healthy controls were randomly divided into a training set (33 HCC, 33 controls) and a testing set (48 HCC, 33 controls). Serum proteomic profiles were measured using Surface-enhanced laser desorption/ionization-time-offlight mass spectroscopy (SELDI-TOF-MS).) A classification tree was established by Biomarker Pattern Software (BPS). Candidate SELDI peaks were isolated by tricine-SDS-PAGE, identified by HPLC-MS/MS and validated by immunohistochemistry (IHC) in liver tissues.

Results: A total of 6 proteomic peaks (3157.33 m/z, 4177.02 m/z, 4284.79 m/z, 4300.80 m/z, 7789.87 m/z, and 7984.14 m/z) were chosen by BPS to establish a classification tree with the highest discriminatory power in the training set. The sensitivity and specificity of this classification tree were 95.92%, and 100% respectively in the testing set. A candidate marker of about 7984 m/z was isolated and identified as neutrophil-activating peptide 2 (NAP-2). IHC staining showed that NAP- 2 signals were positive in HCC tissues but negative in adjacent tissues.

Conclusion: The NAP-2 may be a specific proteomic biomarker of hepatitis B-related HCC.

HBVRegDB: Annotation, comparison, detection and visualization of regulatory elements in hepatitis B virus sequences

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Nattanan Panjaworayan, Stephan K Roessner, Andrew E Firth and Chris M Brown*

Background: The many Hepadnaviridae sequences available have widely varied functional annotation. The genomes are very compact (~3.2 kb) but contain multiple layers of functional regulatory elements in addition to coding regions. Key regions are subject to purifying selection, as mutations in these regions will produce non-functional viruses.

Results: These genomic sequences have been organized into a structured database to facilitate research at the molecular level. HBVRegDB is a comparative genomic analysis tool with an integrated underlying sequence database. The database contains genomic sequence data from representative viruses. In addition to INSDC and RefSeq annotation, HBVRegDB also contains expert and systematically calculated annotations (e.g. promoters) and comparative genome analysis results (e.g. blastn, tblastx). It also contains analyses based on curated HBV alignments. Information about conserved regions – including primary conservation (e.g. CDS-Plotcon) and RNA secondary structure predictions (e.g. Alidot) – is integrated into the database. A large amount of data is graphically presented using the GBrowse (Generic Genome Browser) adapted for analysis of viral genomes. Flexible query access is provided based on any annotated genomic feature. Novel regulatory motifs can be found by analysing the annotated sequences.

Conclusion: HBVRegDB serves as a knowledge database and as a comparative genomic analysis tool for molecular biologists investigating HBV. It is publicly available and complementary to other viral and HBV focused datasets and tools http://hbvregdb.otago.ac.nz. The availability of multiple and highly annotated sequences of viral genomes in one database combined with comparative analysis tools facilitates detection of novel genomic elements.