John,
Thanks for the St. Petersburg link. While it is very informative to read the whole report, I think the following two paragraphs are key for evaluating nelfinavir:
Ronald Swanstrum, University of North Carolina at Chapel Hill, used increasing concentrations of various protease inhibitors in vitro to select for resistant HIV-1 strains, and assessed the ability of other protease inhibitors to inhibit these resistant strains7. At higher drug concentrations, i.e., higher selective pressure, greater the numbers of protease inhibitor resistant mutations were seen.
These experiments were formed in step wise manner for saquinavir, ritonavir, and indinavir. In all cases, cross resistance to the other two inhibitors was similar to that seen to the protease inhibitor used for selection of the resistant strains. These experiments support concerns that resistance to any single protease inhibitor will affect subsequent regimens using other drugs in this class.
....
Genotypic analysis of HIV from patients treated with nelfinavir-containing combinations for up to one year were presented by Amy Patick from Agouron Pharmaceuticals in San Diego. Patients who failed this regimen were found to predominately have the D30N mutation, without detection of amino acid changes associated with ritonavir or indinavir resistance. The L90M mutation associated with saquinavir resistance was only rarely observed. This may be related to the sensitivity of assays for genotypic resistance detection, since in other presentations, it was observed that selection for protease inhibitor mutations not specific for resistance to the inducing drug may occur at fairly low abundance and may not be detected until increased selective pressure is exerted by starting the new therapy. Subsequent therapies may also result in increased abundance of mutations selected for in initial therapies.
In several studies the L90M mutation associated with saquinavir resistance was often not seen in patients failing saquinavir until additional selection pressure was provided by subsequent therapy with indinavir. Nonetheless, the order of protease inhibitor use will certainly influence the pathway toward resistance by providing higher selective pressure for certain protease inhibitor mutations.
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My conclusion from the report of this conference is as follows:
If you start with any of the other PI's and become resistant (which might happen even if you maintain good viral suppression) you will likely also be resistant to Viracept.
If you start with Viracept, and you become resistant, there is no evidence _yet_ that you will likely be resistant to the other three.
Whether this conclusion is going to hold up must await trials of the other PI's on Viracept-resistant patients.
Based on what we know today, it seems to me that Viracept should clearly be the first PI tried for new patients.
Peter |
