1st International Workshop on HIV Drug Resistance & Treatment Strategies 25-28 June 1997, St. Petersburg, Florida, USA

SELECTION OF SAQUINAVIR-RESISTANT MUTANTS BY INDINAVIR FOLLOWING A SWITCH FROM SAQUINAVIR

Antiviral Therapy 1997;2 (Suppl 5):11 (abstract no. 16)

A Dulioust¹, S Paulous², L Guillemot², F Bouè¹, P Galanaud¹ and F Clavel^2
1Hôpital A Béclère, Clamart; and ²Institut Pasteur, Paris, France

The treatment of HIV infection with saquinavir often does not result in detectable selection of saquinavir-resistant variants. Since saquinavir-resistant viruses only have limited cross-resistance to indinavir, a switch from saquinavir to indinavir may be beneficial whether or not saquinavir-resistant variants have been selected before the switch.

In this study, we have selected 11 patients initially treated with saquinavir (mean time of treatment 9 months), who were switched to indinavir because of a poor virological response. Plasma viraemia, as well as protease genotypes and resistance phenotypes were determined before saquinavir treatment, before the introduction of indinavir and on average 4 months after introduction of indinavir.

The mean change in viraemia between the start of saquinavir therapy and the introduction of indinavir was +0.2 log, while the mean response to indinavir was -0.8 log. Before the introduction of indinavir, saquinavir-resistance mutations (always including L90M) were detected in five patients. In these five patients, the mutations were maintained under indinavir, while a limited number of other resistance mutations were added, none of them involving codon 82. A previously uncharacterized mutation, G73S, was observed in all post-indinavir sequences: it was present before indinavir in two patients and emerged after indinavir in three patients.

In the other six patients, no saquinavir resistance mutations were detected before the introduction of indinavir. Surprisingly, in all six patients, the switch to indinavir resulted in the rapid selection of typical saquinavir-resistance mutations L90M or G48V, while mutation of codon 82 (V82A) was only found in two patients. The emergence of saquinavir-resistance mutations following introduction of indinavir strongly suggests that in these six patients, saquinavir-resistant variants were present as a minority in the population of virus quasi-species following saquinavir treatment, and that their full selection was subsequently reinforced by indinavir.

Phenotypic evaluation of HIV resistance to protease inhibitors by a single-cycle recombinant virus assay showed that the mutant viruses selected under saquinavir, which displayed an average 10-fold increase in IC₉₀ to saquinavir compared to pre-saquinavir virus, had a limited (threefold) cross-resistance to indinavir. Similarly, the mutant viruses that emerged under indinavir treatment, with the exception of the two viruses mutated at codon 82, displayed strong resistance to saquinavir and limited cross-resistance to indinavir. These findings reveal that in spite of a relatively modest cross-resistance, indinavir can actively select saquinavir-resistant HIV variants, a process that might preclude full response to indinavir when administered after saquinavir treatment.

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1997-06-25
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