Targeting the hepatitis B virus precore antigen with a novel IgNAR single variable domain intrabody.

The Hepatitis B virus precore protein is processed in the endoplasmic reticulum (ER) into secreted hepatitis B e antigen (HBeAg), which acts as an immune tolerogen to establish chronic infection. Downregulation of secreted HBeAg should improve clinical outcome, as patients who effectively respond to current treatments (IFN-α) have significantly lower serum HBeAg levels. Here, we describe a novel reagent, a single variable domain (V(NAR)) of the shark immunoglobulin new antigen receptor (IgNAR) antibodies.

A systematic review of T-cell epitopes in hepatitis B virus: identification, genotypic variation and relevance to antiviral therapeutics.

Background: The immune response to hepatitis B virus (HBV) is important for both viral control and disease pathogenesis. A detailed understanding of the HBV-specific T-cell responses may potentially lead to novel therapeutic strategies for HBV.

Methods: All English language journal articles (including articles in press) up to October 2007 were retrieved using searches of MEDLINE, EMBASE and the Cochrane Controlled Trial Registry.

Genotype-specific genomic markers associated with primary hepatomas, based on complete genomic sequencing of hepatitis B virus.

We aimed to identify genomic markers in hepatitis B virus (HBV) that are associated with hepatocellular carcinoma (HCC) development by comparing the complete genomic sequences of HBVs among patients with HCC and those without. One hundred patients with HBV-related HCC and 100 age-matched HBV-infected non-HCC patients (controls) were studied. HBV DNA from serum was directly sequenced to study the whole viral genome.

Selection of hepatitis B virus (HBV) vaccine escape mutants in HBV-infected and HBV/HIV-coinfected patients failing antiretroviral drugs with anti-HBV activity.

Background: Given the overlap between envelope and polymerase in the hepatitis B virus (HBV) genome, changes in antigenic sites of the HBV surface antigen may occur as a result of selection of drug-resistance mutations.

Methods: Serum HBV-DNA was isolated from 71 patients with chronic hepatitis B receiving anti-HBV drugs for longer than 12 months, 52 of whom were HIV-positive. The reverse transcriptase/envelope gene from each HBV isolate was amplified using a nested polymerase chain reaction (PCR) covering 720 bp (aa 48 to 288), which includes all known nucleos(t)ide analogue resistance mutations in HBV.

Identification of a novel hepatitis B virus precore/core deletion mutant in HIV/hepatitis B virus co-infected individuals.

Objectives: Although HAART has resulted in improved health outcomes for most HIV-infected individuals, liver failure has emerged as a major cause of morbidity and mortality in people co-infected with hepatitis B virus (HBV). In HBV mono-infected individuals, core deletion mutants are associated with more aggressive liver disease. As HIV accelerates HBV liver disease progression, we hypothesized that HIV-HBV co-infected individuals have increased frequency of core mutations including deletions.

Lamivudine resistance in patients with chronic hepatitis B: role of clinical and virological factors.

Background: Lamivudine resistance is associated with long-term monotherapy for chronic hepatitis B and can lead to potentially serious clinical consequences. Scant information exists regarding the influence of hepatitis B virus variants in the development of resistance. The present study was designed to identify factors predictive of lamivudine resistance, with a particular focus on the role of precore and basal core promoter variants in the setting of hepatitis B e antigen-negative disease.

Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management.

Substantial advances have been made in the treatment of chronic hepatitis B in the past decade. Approved treatments for chronic hepatitis B include 2 formulations of interferon and 4 nucleos(t)ide analogues (NAs). Sustained viral suppression is rarely achieved after withdrawal of a 48-week course of NA therapy, necessitating long, and in many cases, indefinite treatment with increasing risk of development of drug resistance.

The L80I substitution in the reverse transcriptase domain of the hepatitis B virus polymerase is associated with lamivudine resistance and enhanced viral replication in vitro.

Long-term lamivudine (LMV) treatment of chronic hepatitis B almost inevitably engenders viral resistance. Mutations that result in the replacement of the methionine at position 204 of the deoxynucleoside triphosphate-binding site of the hepatitis B virus (HBV) reverse transcriptase (rt) by isoleucine, valine, or (rarely) serine (rtM204I/V/S) confer high-level resistance to LMV but reduce replication efficiency. The subsequent selection or coselection of secondary mutations that partially restore replication efficiency is common and may influence drug resistance.

SeqHepB: a sequence analysis program and relational database system for chronic hepatitis B.

SeqHepB is a combination of a HBV genome sequence analysis program and a relational database that houses data collected from multiple data sources. Registered users can access the sequence analysis component of SeqHepB online for rapid and detailed interrogation of HBV genomic sequences. Its main function is to determine the HBV genotype, identify key mutations associated with antiviral resistance, and identify clinically important HBV mutants.

Antiviral drug resistance: clinical consequences and molecular aspects.

Antiviral drug resistance now poses a major problem for the management of patients with chronic hepatitis B. In theory, resistance may be prevented if a sufficiently potent antiviral drug, or combination of antiviral agents, is used that prevents viral replication and thereby the ongoing selection of hepatitis B virus quasispecies. Emergence of drug resistance in patients with hepatitis B generally results in progression of liver disease and in some cases, significant clinical deterioration if hepatic reserve is compromised.

Characteristics of drug resistant HBV in an international collaborative study of HIV-HBV-infected individuals on extended lamivudine therapy.

Background: Little is known about the prevalence and pattern of hepatitis B virus (HBV) mutations in HIV/HBV co-infected individuals on long-term lamivudine (3TC) therapy.

Methods: HBV polymerase/envelope/basal core promoter/pre-core sequences from 81 HIV-HBV co-infected persons who received at least 6 months 3TC were compared to HBV reference sequences. Host and viral characteristics associated with HBV mutations were determined.

Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir.

Background: Tenofovir (TDF) is an adenosine nucleotide analogue that has been approved for the treatment of HIV-1 infection. It also shows activity against hepatitis B virus (HBV) in patients with or without lamivudine (LAM)-associated mutations. Development of clinical or virological HBV breakthrough during TDF therapy has not been reported so far.

Epidemiological and virological characteristics of 2 subgroups of hepatitis B virus genotype C.

Background: We aimed to investigate the characteristics of hepatitis B virus (HBV) genotype C subgroups in Hong Kong and their relationship with HBV genotype C in other parts of Asia.

Methods: Full-genome nucleotide sequences of 49 HBV genotype C isolates from Chinese patients with chronic hepatitis B were compared with the sequences of 69 HBV genotype C isolates and 12 non-genotype C isolates in the GenBank database. Phylogenetic analysis was performed to define the subgroups of HBV genotype C on the basis of >4% heterogeneity of the entire HBV genome.

Transmission of G145R mutant of HBV to an unrelated contact.

Household contacts of HBV-related chronic liver disease patients constitute a high-risk group for acquisition of HBV infection. Some of the HBsAg mutants are associated with liver disease and some are reported to be transmitted vertically. There is limited information on the horizontal transmission of Gly 145 Arg (G145R) mutant to related contacts.

Reduced hepatitis B virus (HBV)-specific CD4+ T-cell responses in human immunodeficiency virus type 1-HBV-coinfected individuals receiving HBV-active antiretroviral therapy.

Functional hepatitis B virus (HBV)-specific T cells are significantly diminished in individuals chronically infected with HBV compared to individuals with self-limiting HBV infection or those on anti-HBV therapy. In individuals infected with human immunodeficiency virus type 1 (HIV-1), coinfection with HBV is associated with an increased risk of worsening liver function following antiviral therapy and of more rapid HBV disease progression. Total HBV-specific T-cell responses in subjects with diverse genetic backgrounds were characterized by using a library of 15-mer peptides overlapping by 11 amino acids and spanning all HBV proteins.

Sexual transmission of hepatitis B infection despite the presence of hepatitis B virus immunity in recipients of allogeneic bone marrow transplantation.

Background: After hematopoietic cell transplantation (HCT), hepatitis due to hepatitis B virus (HBV) rarely occurred beyond the initial 12 months after transplantation.

Objectives: We investigated the cause of "late" hepatitis due to HBV infection in two recipients after allogeneic HCT.

Study Design: Two male patients with acute myeloid leukemia and light chain myeloma, respectively, developed HBV-related hepatitis more than 2 years after HCT.

Comparison of sequence analysis and a novel discriminatory real-time PCR assay for detection and quantification of Lamivudine-resistant hepatitis B virus strains.

We report a rapid and accurate real-time PCR-based method to quantify wild-type and lamivudine-resistant hepatitis B virus by using a common forward primer paired with different reverse primers. Excellent concordance was demonstrated between sequencing and the discriminatory real-time assay; however, a mixture of quasispecies was more frequently detected by discriminatory real-time PCR.

Comparisons of the HBV and HIV polymerase, and antiviral resistance mutations.

The antiviral treatment of chronic hepatitis B is limited by the selection of antiviral resistance mutations. Primary resistance to lamivudine occurs at rtM2041/V in the C Domain of the polymerase. Recently, resistance to adefovir has also been described in the D Domain at rtN236T.

Hepatitis B virus genotypes: comparison of genotyping methods.

There are eight genotypes of HBV designated A to H based on greater than 8% nucleotide variation over the entire genome. Hepadnaviruses infecting primates like the chimpanzee, orangutan and gibbon are very similar and can be regarded as genotypes of HBV. The eight genotypes of HBV show a distinct geographical distribution and influence the course of disease and the prognosis of treatment.

Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase.

Background & Aims: Adefovir dipivoxil effectively inhibits both hepatitis B virus (HBV) replication and disease activity in patients with chronic hepatitis B. Resistance to treatment was not observed in 2 recent large placebo-controlled 48-week studies with this drug. The aim of this study was to characterize adefovir resistance in a patient who developed clinical and virologic evidence of breakthrough during a 96-week course of treatment.

Prevalence and characterization of lamivudine-resistant hepatitis B virus mutations in HIV-HBV co-infected individuals.

Objective: To determine the prevalence of hepatitis B virus (HBV) genotypic resistance to lamivudine, identify risk factors associated with lamivudine resistance, and characterize the pattern of HBV polymerase mutations in patients co-infected with HIV.

Design: Retrospective cross-sectional study.

Methods: Thirty-three chronic HBV-infected patients were identified from a cohort of 1719 HIV-infected individuals.

Lamivudine and Famciclovir resistant hepatitis B virus associated with fatal hepatic failure.

Background: Lamivudine (LMV) is the only nucleoside analogue approved for the treatment of chronic hepatitis B (CHB). LMV, as with other nucleoside analogues including Famciclovir (FCV), suppresses the replication of hepatitis B virus (HBV) by targeting the viral polymerase. However, prolonged antiviral therapy results in the emergence of drug resistance HBV which can contribute to virological breakthroughs and recurrent hepatitis flares.