HIV PROTEASE GENOTYPE AND VIRAL SENSITIVITY TO HIV PROTEASE INHIBITORS FOLLOWING SAQUINAVIR THERAPY

Objective: To examine the relationship between HIV protease genotype a nd altered protease inhibitor sensitivity of isolates from patients af ter therapy with saquinavir (SQV) in its hard gelatin formulation. Des ign: Forty-one post-therapy isolates and corresponding baseline sample s were obtained from 37 patients in four different clinical trials aft er therapy with SQV for 16-147 weeks. Post-therapy isolates were selec ted on the basis of preliminary sequence or drug sensitivity data. Res ults: Fifteen out of 17 isolates without detectable Val-48 or Met-90 m utations retained sensitivity to SQV. (The remaining isolates showed o nly a marginal increase in median inhibitory concentration.) In additi on, three out of 15 isolates with Met-90 retained sensitivity to ail o ther protease inhibitors tested (indinavir, ritonavir, amprenavir, nel finavir). Of the isolates showing reduced sensitivity to SQV, six out of 22 retained sensitivity to all other protease inhibitors, whereas o nly four out of 22 showed broad cross-resistance to all protease inhib itors tested. The reduction in sensitivity correlated closely with the presence of Val-48 or Met-90. Subsequent accessory substitutions were also linked to reduced sensitivity. However, significant linkage was observed only between mutations at residues 48 and 82 and between thos e at residues 82 and 74. Conclusions: Recruitment of Val-48/Met-90 mut ations was not found to be synonymous with cross-resistance. Indeed, t he majority of isolates with these mutations retained sensitivity to a t least one protease inhibitor (Val-48, 86%; Met-90, 77%). The recruit ment of accessory mutations may occur only after the selection of key resistance mutations. Furthermore, Met-90 was found to be a poor marke r of cross-resistance in SQV-treated patients. (C) 1998 Lippincott Wil liams & Wilkins.