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The effectiveness of a second protease inhibitor in patients who failed an initial protease inhibitor is unclear but believed to be low. It has been postulated, however, that patients who fail nelfinavir may respond differently. We therefore assessed the virologic response to a ritonavir-saquinavir-containing regimen in patients who had previously failed nelfinavir.A total of 26 patients enrolled in the nelfinavir clinical trials AG506 and AG511 at our two sites who failed (two consecutive HIV viral loads >5000 copies/ml; branched DNA assay) were switched to a combination of stavudine 40mg twice daily, lamivudine 150mg twice daily, ritonavir 400mg twice daily and saquinavir 400mg twice daily.The mean viral load at enrollment in this study was 46674 copies/ml (range, 1075-146400 copies/ml). The median CD4 cell count was 222×106/l (range, 82-448×106/l). The median duration of nelfinavir use with a detectable viral load before the switch occurred was 48 weeks. Two patients discontinued the study at 3 weeks. All of the remaining patients (n=24) reached undetectable viral loads (<500 copies/ml) that were sustained at week 24 in 17 (71%) out of 24 subjects. The most frequent baseline mutations in the protease gene prior to switching were D30 N (13 out of 18), N88 D (eight out of 18) and M36 I (eight out of 18). The presence or absence of these mutations was not predictive of a short-term virologic response.Most patients who failed a nelfinavir-containing regimen responded to a switch to a combination regimen with saquinavir-ritonavir.