Document Detail


In vitro activity of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor (NRTI), against 215 HIV-1 isolates resistant to other NRTIs.
MedLine Citation:
PMID:  16245645     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
SPD754 (also known as AVX-754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor (NRTI) with antiretroviral activity against HIV-1 and HIV-2 in vitro and against recombinant viruses containing thymidine analogue mutations (TAMs). In order to better establish the activity of SPD754 against HIV-1 containing TAMs, twelve panels of up to twenty clinical isolates with defined TAM combinations were selected from the ViroLogic database. Phenotypic viral susceptibility to SPD754 and five other NRTIs was tested using the PhenoSense HIV assay and expressed as median fold-change compared with a reference strain. In total, 215 isolates were selected, representing four TAM patterns in both pathways by which TAMs accumulate clinically. The presence of five TAMs in the 41, 215 pathway, at codons 41, 67, 210, 215, and 219 of reverse transcriptase (RT), produced a median 1.8-fold reduction in SPD754 susceptibility, compared with fold reductions to zidovudine, lamivudine, abacavir, didanosine and tenofovir of 438, 4.8, 4.5, 1.4 and 3.6, respectively. Five TAMs in the 67, 70, 219 pathway (at codons 41, 67, 70, 215 and 219) reduced SPD754 susceptibility by a median 1.3-fold, compared with fold reductions for the aforementioned NRTIs of 108, 3.2, 3.0, 1.3 and 2.5, respectively. M184V addition reduced SPD754 susceptibility by 1.8-fold in the presence or absence of TAMs. SPD754 retains a substantial proportion of its antiviral activity against HIV-1 containing multiple TAMs, with or without the M184V mutation. These data suggest that SPD754 is a promising new NRTI for the treatment of NRTI-experienced HIV-infected patients.
Authors:
Richard C Bethell; Yolanda S Lie; Neil T Parkin
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Antiviral chemistry & chemotherapy     Volume:  16     ISSN:  0956-3202     ISO Abbreviation:  Antivir. Chem. Chemother.     Publication Date:  2005  
Date Detail:
Created Date:  2005-10-25     Completed Date:  2006-02-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9009212     Medline TA:  Antivir Chem Chemother     Country:  England    
Other Details:
Languages:  eng     Pagination:  295-302     Citation Subset:  IM    
Affiliation:
Shire BioChem Inc., Ville St. Laurent, Quebec, Canada. rbethell@lav.boeringer-ingelheim.com
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MeSH Terms
Descriptor/Qualifier:
Deoxycytidine / analogs & derivatives*,  pharmacology
Drug Resistance, Viral* / genetics
HIV-1 / drug effects*
Microbial Sensitivity Tests
Mutation
Reverse Transcriptase Inhibitors / pharmacology*
Chemical
Reg. No./Substance:
0/Reverse Transcriptase Inhibitors; 0/SPD754; 951-77-9/Deoxycytidine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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