Impact of HIV-1 Reverse Transcriptase Polymorphism at Codons 211 and 228 on Virological Response to Didanosine

Abstract

To determine the potential impact of reverse transcriptase (RT) mutations, other than those currently known to confer nucleoside reverse transcriptase inhibitors (NRTIs) resistance, on the virological response to didanosine (ddl). In the placebo-controlled Jaguar trial, 168 patients were randomly assigned to receive ddl (n=111) or placebo (n=57) in addition to their currently failing regimen for 4 weeks. The virological response was a reduction of HIV-1 RNA from baseline to week 4. In an univariate analysis, we investigated the impact on the virological response to ddl of all the mutations in the RT gene (codons 21-236), except those known to confer NRTI resistance. Using the removing procedure, with a test for trend (Jonckheere's test), a new potential score was calculated incorporating all potential mutations associated to the week 4 virological response. Two RT polymorphisms were associated with a reduced virological response to ddl, R211A/D/G/K/S and L228H/M/R, and one with a better virological response: F214L. A mutation score (M41L+D67N+T69D-K70R +L74V-M 1 84V/I+T21 5Y/F+ K219Q/E+ R211A/D/G/K/S+ L228H/M/R), including two RT polymorphisms not previously described to be associated with ddl resistance (211 and 228) and RT mutations previously described, was associated with a continuum of virological response and increased the predictability of virological response to ddl. RT polymorphisms should be taken into account to define algorithms able to correctly define resistance to NRTIs and more specifically ddl.