Titre du document / Document title

Impact of stavudine phenotype and thymidine analogues mutations on viral response to stavudine plus lamivudine in ALTIS 2 ANRS trial

Auteur(s) / Author(s)

CALVEZ Vincent ⁽¹⁾ ; COSTAGLIOLA Dominique ⁽²⁾ ; DESCAMPS Diane ⁽³⁾ ; YVON Anne ⁽¹⁾ ; COLLIN Gilles ⁽³⁾ ; CECILE Agnes ⁽¹⁾ ; DELAUGERRE Constance ⁽¹⁾ ; DAMOND Florence ⁽²⁾ ; MARCELIN Anne-Geneviève ⁽¹⁾ ; MATHERON Sophie ⁽²⁾ ; SIMON Anne ⁽⁴⁾ ; VALANTIN Marc-Antoine ⁽¹⁾ ; KATLAMA Christine ⁽¹⁾ ; BRUN-VEZINET Francoise ⁽³⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Departments of Virology and Infectious Diseases and Pitie-Salpetrière Hospital, Paris, FRANCE
⁽²⁾ INSERM SC4 School of Medicine, Saint Antoine Hospital, Paris, FRANCE
⁽³⁾ Departments of Virology and Infectious Diseases, Bichat Claude Bernard Hospital, Paris, FRANCE
⁽⁴⁾ Department of Internal Medicine, Pitie-Salpetrière Hospital, Paris, FRANCE

Résumé / 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.

Revue / Journal Title

Antiviral therapy   ISSN 1359-6535 

Source / Source

2002, vol. 7, n^o3, pp. 211-218 [8 page(s) (article)] (23 ref.)

Langue / Language

Anglais

Editeur / Publisher

International Medical Press, London, ROYAUME-UNI  (1996) (Revue)

Mots-clés anglais / English Keywords

Virus ; Retroviridae ; Lentivirus ; Human immunodeficiency virus ; Pyrimidine nucleoside ; Dideoxynucleoside ; HIV-1 virus ; Resistance ; Antiviral ; Genotype ; Phenotype ; Clinical trial ; Drug interaction ; Drug combination ; Mutation ; Analog ; Thymidine ; Lamivudine ; Zidovudine ; Stavudine ;

Mots-clés français / French Keywords

Virus ; Retroviridae ; Lentivirus ; Virus immunodéficience humaine ; Nucléoside analogue ; Pyrimidine nucléoside ; Didésoxynucléoside ; Virus HIV1 ; Résistance ; Antiviral ; Génotype ; Phénotype ; Essai clinique ; Interaction médicamenteuse ; Association médicamenteuse ; Mutation ; Analogue ; Thymidine ; Lamivudine ; Zidovudine ; Stavudine ;

Mots-clés espagnols / Spanish Keywords

Virus ; Retroviridae ; Lentivirus ; Human immunodeficiency virus ; Pirimidina nucleósido ; Didesoxinucleósido ; HIV-1 virus ; Resistencia ; Antiviral ; Genotipo ; Fenotipo ; Ensayo clínico ; Interacción medicamentosa ; Asociación medicamentosa ; Mutación ; Análogo ; Timidina ; Lamivudina ; Zidovudina ; Estavudina ;

Localisation / Location

INIST-CNRS, Cote INIST : 27047, 35400010687771.0090