Impact of Stavudine Phenotype and Thymidine Analogues Mutations on Viral Response to Stavudine plus Lamivudine in Altis 2 Anrs Trial

Abstract

Objective

Stavudine-based antiretroviral combinations are less effective in zidovudine-experienced patients than in naive subjects and recently, mutations have been described to be associated to the use of both stavudine and zidovudine. In the ALTIS 2 trial, it was shown that a combination of stavudine and lamivudine is less effective in zidovudine-experienced patients than in naive patients. We conducted a retrospective genotypic and phenotypic resistance study (expressed as stavudine phenotypic index, calculated by dividing the inhibitory concentrations 50% [IC₅₀] by the mean value of the sensitive viruses) to evaluate the factors associated with decrease in plasma HIV-1 RNA.

Design

Associations with continuous variables were studied using non-parametric Spearman correlation coefficients. Associations with categorical variables were studied using non-parametric Mann–Whitney tests. Multivariate stepwise regression analyses were used to determine independent prognostic factors of the virological response.

Results

At baseline, most of the subjects harboured zidovudine-associated mutations in plasma and peripheral blood mononuclear cells. Zidovudine and stavudine IC₅₀ and IC₉₀ were strongly associated with response. It appears that a cut-off of stavudine phenotypic index of 1.8-fold of IC₅₀, much lower than the usually used value, could be clinically significant for response to stavudine. In the multivariate analysis, the stepwise model with the higher multiple correlation coefficient (R²=0.742) included the presence of a 215 Y/F mutation, the number of previously used nucleoside analogues and a resistant stavudine phenotype.

Conclusion

These results argue for a phenotypic and genotypic cross resistance between stavudine and zidovudine. Modest increases of IC₅₀ and IC₉₀ for stavudine had an important impact on the virological response during the trial and plead for a new definition of the threshold value for stavudine phenotypic index.