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Objective: To identify accessory mutations associated with high levels of resistance to reverse transcriptase inhibitors (RTI)., Design: HIV pol sequences from routine resistance tests from over 3000 patients who were treatment experienced and infected with subtype B HIV-1 were analysed. Changes relative to the wild-type amino acid for codons 1-400 of reverse transcriptase were determined in two series: (i) samples showing the accumulation of thymidine analogue mutations (TAMs); and (ii) samples showing the accumulation of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations., Methods: Accessory mutations were identified as occurring in those codons in which there was a statistically significant association between the distribution of amino acids and the number of TAMs/NNRTI resistance mutations. Positions already established as drug resistance positions by the International AIDS Society - USA Panel were not included in this analysis., Results: Twenty-four positions were identified where accessory mutations were associated with the accumulation of TAMs (20, 35, 39, 43, 60, 83, 98, 101, 122, 135, 179, 196, 203, 208, 218, 223, 228, 284, 322, 356, 359, 360, 371 and 381). Likewise changes at 25 positions (6, 20, 35, 39, 43, 53, 68, 90, 98, 101, 122, 179, 200, 203, 208, 218, 221, 223, 228, 284, 318, 320, 348, 359 and 371) were associated with NNRTI mutations. The accumulation of accessory mutations correlated with increasing numbers of TAMs and NNRTI mutations., Conclusion: The development of high-level resistance to RTI is associated not only with the accumulation of recognized mutations but also with accessory mutations.