Hepatitis-B viral variants with reduced susceptibility to nucleoside analogs and uses thereof
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Publication Number
US-7422848-B2
Publication Date
2008-09-09
Expiration Date
Abstract
The present invention relates generally to the field of Hepatitis B variants exhibiting a reduced sensitivity to nucleoside analogues, both in vivo and in vitro. More in particular, reverse transcriptase mutant rtA181S is provided. Present invention provides assays and methods for detecting such variant, which assays are useful in monitoring anti-viral therapeutic regimes and adjusting patient therapy. A diagnostic kit for detecting the presence of an HBV variant in a biological sample has also been described.
Core Innovation
The invention relates to HBV variants in which at least one nucleotide mutation in the DNA polymerase gene at codon 181 results in an alanine to serine amino acid substitution rtA181S. These HBV variants are characterized by reduced susceptibility and/or resistance to nucleoside analogues, including cross-resistance to lamivudine and adefovir dipivoxil. The document places rtA181S in the context of known HBV drug-resistance codons in the reverse-transcriptase/polymerase region, including rtM204I/V/S, rtL180M, and rtN236T.
The invention further provides HBV polynucleic acids, including fragments, encoding the rtA181S variants, and expression products derived from such polynucleic acids. The disclosed diagnostic approaches are based on detecting the presence of the HBV polynucleic acid and/or detecting codon-specific polymorphisms associated with codon 181, including serine versus alanine/valine, and optionally additional codons including codon 180, codon 204, and codon 236.
In addition, the disclosed detection is used to monitor therapy, select non-cross-resistant drugs, and detect resistance patterns. The document describes diagnostic methods that use nucleic-acid sequencing and/or hybridization with discriminating oligonucleotides that distinguish codon 181 outcomes, with optional discrimination at additional codons. A corresponding diagnostic kit is described including discriminating oligonucleotides and components configured for the codon-specific detection and inference of resistance-related variants.
Claims Coverage
The document includes two independent methods. One method detects an HBV variant defined by the DNA polymerase gene mutation rtA181S at codon 181 in a biological sample, and the other method detects resistance of an HBV virus in a biological sample to an antiviral drug by detecting the same rtA181S-associated polynucleic acid mutation.
Detecting rtA181S HBV variant presence in a biological sample
A method for detecting the presence of an HBV variant in a biological sample by detecting the presence of an HBV polynucleic acid, wherein the HBV variant comprises at least one nucleotide mutation in the DNA polymerase gene at codon 181 resulting in an alanine to serine amino acid substitution rtA181S, and wherein the HBV polynucleic acid comprises the nucleotide mutation that results in rtA181S or a fragment of the polynucleic acid comprising the nucleotide mutation.
Indicating resistance via detection of rtA181S HBV polynucleic acid
A method for detecting the resistance of an HBV virus present in a biological sample to an antiviral drug by detecting the presence of an HBV polynucleic acid comprising a nucleotide mutation that results in an amino acid substitution rtA181S of the DNA polymerase gene in the HBV variant, or a fragment comprising the nucleotide mutation, wherein the presence of the HBV polynucleic acid indicates resistance of the HBV virus present in the biological sample to the antiviral drug.
Across both independent claims, detection is anchored on identifying an HBV polynucleic acid mutation in the DNA polymerase gene at codon 181 that produces rtA181S. The first independent claim uses this detection to determine the presence of the HBV variant, while the second independent claim uses the same detection to indicate resistance to an antiviral drug, with dependent claims further refining codon-context detection and discriminatory nucleic-acid detection/inference.
Stated Advantages
Reduced susceptibility/resistance to nucleoside analogues for HBV variants comprising rtA181S.
Cross-resistance to lamivudine and adefovir dipivoxil for HBV variants comprising rtA181S.
Monitoring of therapy by detecting the presence of HBV variant-associated mutations and resistance patterns.
Selection of non-cross-resistant drugs based on detecting resistance patterns.
Detection of resistance by determining the presence of HBV polynucleic acid mutations associated with rtA181S and optionally additional codons.
Documented Applications
Monitoring therapy using detection of HBV variant-associated resistance patterns.
Selecting non-cross-resistant drugs based on detected resistance patterns.
Detecting resistance of an HBV virus in a biological sample by detecting the presence of an HBV polynucleic acid comprising the rtA181S mutation.
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