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 (ddI).
Design and patients
In the placebo-controlled Jaguar trial, 168 patients were randomly assigned to receive ddI (n=111) or placebo (n=57) in addition to their currently failing regimen for 4 weeks.
Methods
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 ddI 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.
Results
Two RT polymorphisms were associated with a reduced virological response to ddI, 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-M184V/I+T215Y/F+K219Q/E+R211A/D/G/K/S+ L228H/M/R), including two RT polymorphisms not previously described to be associated with ddI 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 ddI.
Conclusion
RT polymorphisms should be taken into account to define algorithms able to correctly define resistance to NRTIs and more specifically ddI.
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