Improved Interpretation of Genotypic Changes in the HIV‐1 Reverse Transcriptase Coding Region That Determine the Virological Response to Didanosine

Abstract

Consensus on the interpretation of mutations in the human immunodeficiency virus (HIV)-1 reverse transcriptase (RT) gene that predict the response to didanosine treatment is needed. Baseline HIV-1 RT genotypes and 12-week virological outcomes for patients undergoing didanosine-containing salvage regimens were extracted from prospective studies. Existing didanosine genotypic-resistance interpretation rules were validated in the entire-patient data set. Mutations were given weighted positive or negative scores according to their coefficient of correlation with virological response in a derivation set. The score resulting from the algebraic sum of the mutations was then validated in an independent data set. A total of 485 patients were analyzed. The didanosine-resistance scores derived from the Jaguar and Gesca studies predicted virological outcome. The best correlation with response was found with the derived score (M41L x 2) + E44D/A/G + T69D/S/N/A + (L210W x 2) + T215Y or revertants + L228H/R - D123E/N/G/S, by use of which viruses were categorized as being susceptible (score < or =0), as having intermediate resistance (1-3), and as being resistant (> or =4) to didanosine. In the validation set, the adjusted mean difference in 12-week virological response was +0.34 log(10) copies/mL (95% confidence interval, +0.11 to +0.57; P=.004) per higher resistance category. Correlation with virological response constantly outperformed that obtained with the previous interpretation. The improved genotypic-resistance interpretation score can be applied to better guide the use of didanosine in treatment-experienced individuals.