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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Baldick, Carl J. Tenney, Daniel J. Mazzucco, Charles E. Eggers, Betsy J. Rose, Ronald E. Pokornowski, Kevin A. Yu, Cheng F. Colonno, Richard J. |
| Description | Country affiliation: United States Author Affiliation: Baldick CJ ( Bristol-Myers Squibb Research and Development, Wallingford, CT 06492, USA.) |
| Abstract | UNLABELLED: Virologic resistance emerging during entecavir (ETV) therapy for hepatitis B virus (HBV) requires three substitutions in the viral reverse transcriptase (RT), signifying a high barrier to resistance. Two of these substitutions are associated with lamivudine resistance (LVDr) in the tyrosine-methionine-aspartate-aspartate (YMDD) motif (rtM204V and rtL180M), whereas the other occurs at one or more positions specifically associated with ETV resistance (ETVr): rtT184, rtS202, or rtM250. Although a variety of substitutions at these primary ETVr positions arise during ETV therapy, only a subset give rise to clinical virologic breakthrough. To determine the phenotypic impact of observed clinical and potential new ETVr substitutions, a comprehensive panel of clones containing every possible amino acid at the three primary ETVr positions in LVDr HBV was constructed and analyzed in vitro. A range of replication capacities was observed for the panel, but none of the mutations rescued replication of the LVDr mutant to the wild-type level. More clones with residue rtS202 substitutions were severely impaired than those at rtT184 or rtM250. A wide variety of ETV susceptibilities was observed, ranging from approximately eight-fold (no increase over the LVDr parent) to greater than 400-fold over the wild-type. A correlation was identified between clinically observed substitutions and those displaying higher in vitro replication and resistance, especially those from virologic breakthrough patients. CONCLUSION: The high number of tolerated and resistant ETVr substitutions is consistent with models predicting that the mechanism for ETVr is through enhancement of LVDr changes in the RT deoxyribonucleotide triphosphate (dNTP)-binding pocket. |
| File Format | HTM / HTML |
| ISSN | 02709139 |
| Issue Number | 5 |
| Volume Number | 47 |
| e-ISSN | 15273350 |
| Journal | Hepatology |
| Language | English |
| Publisher | Wiley |
| Publisher Date | 2008-05-01 |
| Publisher Place | United States |
| Access Restriction | Subscribed |
| Subject Keyword | Discipline Hepatology Amino Acid Substitution Antiviral Agents Pharmacology Guanine Analogs & Derivatives Hepatitis B Virus Enzymology Rna-directed Dna Polymerase Genetics Drug Effects Carcinoma, Hepatocellular Cell Line, Tumor Drug Resistance, Viral Enzyme-linked Immunosorbent Assay Hepatitis B Surface Antigens Humans Liver Neoplasms Mutagenesis, Site-directed Virus Replication Journal Article |
| Content Type | Text |
| Resource Type | Article |
| Subject | Hepatology |
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