HIV-1 reverse transcriptase thumb subdomain polymorphisms associated with virological failure to nucleoside drug combinations.

Methods: RT nucleotide sequences of 1893 HIV-1 isolates from 1680 persons with different treatment histories (including naive and treated patients) were analysed. chi(2) contingency tests were performed to detect mutations within positions 1-333 of HIV-1 RT, associated with therapy failure, and correlated mutations were identified using statistical methods.

Results: Thymidine analogue resistance mutations were strongly associated with therapy failure to all nucleoside analogue combinations analysed. Previously identified accessory mutations at positions 35, 39, 43, 90, 98, 101, 122, 178, 196, 203, 208, 221, 223 and 228 were associated with therapy failure with at least one of the drug combinations studied. Interestingly, several mutations affecting RT thumb subdomain polymorphisms were strongly associated (P 10(-3)) with therapy failure to abacavir/stavudine, stavudine/didanosine and abacavir/stavudine/didanosine. Mutations A272P, K277R and V293I were more prevalent in patients failing treatment with abacavir/stavudine than in naive individuals, while mutation frequencies of T286A, V292I and to a lesser extent E291D and E297K decreased in the treated population. These effects were also detected for A272P, T286A and V292I, when analysing didanosine/stavudine therapy failure, although statistical significance was higher for T286A.

Conclusion: Thymidine analogue resistance mutations were strongly associated with therapy failure to all nucleoside analogue combinations analysed. Previously identified accessory mutations at positions 35, 39, 43, 90, 98, 101, 122, 178, 196, 203, 208, 221, 223 and 228 were associated with therapy failure with at least one of the drug combinations studied. Interestingly, several mutations affecting RT thumb subdomain polymorphisms were strongly associated (P 10(-3)) with therapy failure to abacavir/stavudine, stavudine/didanosine and abacavir/stavudine/didanosine. Mutations A272P, K277R and V293I were more prevalent in patients failing treatment with abacavir/stavudine than in naive individuals, while mutation frequencies of T286A, V292I and to a lesser extent E291D and E297K decreased in the treated population. These effects were also detected for A272P, T286A and V292I, when analysing didanosine/stavudine therapy failure, although statistical significance was higher for T286A.