Phenotypic impact of HIV reverse transcriptase M1841/V mutations in combination with single thymidine analog mutations on nucleoside reverse transcriptase inhibitor resistance

Objectives: To analyse the impact of the M1841/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. Design: 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 M1841 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 M1841/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. Conclusion: 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 M1841/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. (C) 2004 Lippincott Williams Wilkins.