Phenotypic impact of HIV reverse transcriptase M184I/V mutations in combination with single thymidine analog mutations on nucleoside reverse transcriptase inhibitor resistance.
OBJECTIVE
To analyse the impact of the M184I/V mutation and individual thymidine-associated mutations (TAM) on nucleoside reverse transcriptase inhibitor (NRTI) phenotypic susceptibility and compare these results with those obtained using commercial and public algorithms.


METHODS
An HIV genotypic/phenotypic database with over 27 000 samples was used to obtain the median fold change (5-95th percentile) in NRTI phenotypic susceptibility for viruses from patients containing individual TAM with or without the M184I or V mutation and for wild-type patient viruses.


RESULTS
The resulting data indicated that in vitro, individual TAM do not have an equivalent impact on NRTI resistance, with some individual TAM having little or no impact on NRTI resistance (e.g. M41L or K219Q/E/H/R). In the presence of the M184I/V mutation, re-sensitization to some drugs, including zidovudine, stavudine and tenofovir was observed despite the presence of a TAM. For didanosine and abacavir, the presence of the M184V mutation and a single TAM did not result in a fold-change increase associated with decreased drug susceptibility. Analysis of public and commercial algorithms revealed a lack of concordance regarding the impact of these mutations, and with the observed phenotypic data.


CONCLUSIONS
These analyses should assist in the creation of rules for genotypic drug resistance algorithms for a better reflection of the impact of individual TAM and also the impact of M184I/V on resistance. These data provide additional evidence that retaining lamivudine in those treatment regimens in which TAM can be selected may provide some therapeutic benefit by maintaining the M184V mutation.
Department of International Clinical Virology at GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.
Lisa
L
Ross
Neil
N
Parkin
Colombe
C
Chappey
Robin
R
Fisher
Marty St
MS
Clair
Michael
M
Bates
Margaret
M
Tisdale
Ernest Randall
ER
Lanier
D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000465:Algorithms; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D030541:Databases, Genetic; D016049:Didanosine / Q000627:therapeutic use; D015224:Dideoxynucleosides / Q000627:therapeutic use; D024921:Drug Resistance, Multiple, Viral; D006678:HIV / Q000235:genetics; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D009154:Mutation; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000627:therapeutic use; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D018119:Stavudine / Q000627:therapeutic use; D000068698:Tenofovir; D013936:Thymidine / Q000031:analogs & derivatives / Q000235:genetics*; D016047:Zalcitabine / Q000627:therapeutic use; D015215:Zidovudine / Q000627:therapeutic use; D000099227:Abacavir
D000225:Adenine; D019380:Anti-HIV Agents; D016049:Didanosine; D015224:Dideoxynucleosides; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D000068698:Tenofovir; D013936:Thymidine; D016047:Zalcitabine; D015215:Zidovudine; D000099227:Abacavir