Thymidine analogue reverse transcriptase inhibitors resistance mutations profiles and association to other nucleoside reverse transcriptase inhibitors resistance mutations observed in the context of virological failure

Abstract

During ZDV or d4T exposure, mutations at codons 41, 67, 70, 210, 215, and 219 can be selected and were named thymidine analogue mutations (TAMs). Some previous results suggested that different TAMs patterns could exist and that the kind of TAMs pattern could influence the virological response to some nucleoside reverse transcriptase inhibitors (NRTIs). In order to get more data about the relative prevalence of these patterns, their associations with other NRTI resistance mutations and the identification of the different stages observed during the acquisition of TAMs under treatment by NRTIs, we collected 1,098 RT sequences harbouring at least one TAM from patients failing to antiretroviral regimen. Sequences were stored in a database designed specifically to allow the retrieval of sequences that met specific criteria such as the occurrence and frequency of a particular mutation, the nature and frequency of the amino acid substitution at a given codon, and/or the rate of association between resistance mutations. Two pathways of TAMs can be identified: profile #1 (T215Y mutation linked) and profile # 2 (T215F mutation linked). The frequency of selection of profile # 1 is two times higher than profile # 2. The E44D/A + V118I complex, 69 insertions, and L74V mutation are associated to profile #1, whereas the Q151M complex and M184V mutation are associated to both profiles. As some NRTI resistance mutations were associated preferentially with profile #1, further studies are needed to explore if, the weaker efficacy observed on viruses harbouring this profile using some NRTIs, could be explained by the TAMs profile itself or the other associated NRTI resistance mutations.