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nelfinavir resistance after saquinavir
Aug 27, 1997

I had sent you a message about my husband last week signing it K-please don't bother to answer it as we know which drug gave him the rash (the Viracept- he has been restarted on an escalating dose with no rash so far after a week). I am concerned about an article I read from the St. Petersburg conference that they have found people with prior saquinavir use have resistance to nelfinavir and that they do better when failing saq. to switch to crixivan. He has only been on viracept a few weeks after 3 months saq.use-should he switch to Crixivan (with new D4T/3TC) now before he blows his P.I. option? As in prior message his V.L.=6000,CD4=350--Thanx--K

Response from Dr. Cohen

At the St. Petersburg resistance conference, there were several interesting (and discouraging) reports looking at response to second protease inhibitors after the development of saquinavir (Invirase) resistance. In one, patients who had developed resistance to saquinavir who were switched to nelfinavir (Viracept) failed nelfinavir despite the fact that they didn't develop a mutation at codon 30, which is usually the first and most important mutation associated with nelfinavir resistance.

In another study, patient who had become resistant to nelfinavir developed mutations associated with cross-resistance to indinavir and ritonavir, despite not having taken either of those two drugs.

The implications of these studies are that:

Cross-resistance is more extensive among protease inhibitors than was originally believed Resistance to second protease inhibitors may occur in a different pattern than when the same PIs are used first, because of the presence of mutations associated with resistance to the first PI Genotypic analyses may not be very helpful in determining the most appropriate salvage regimens because of these alternate pathways.

We did not hear a lot of information about resistance to other PIs after the use of nelfinavir. While it may be true that these same principles apply to cross-resistance after nelfinavir failure, we cannot say that with certainty. If people fail nelfinavir with a single mutation at codon 30, will they still be sensitive to the other protease inhibitors? What we know about genotypic resistance patterns would indicate that they would, but perhaps the presence of that mutation will in turn promote resistance through alternate pathways. Thus, it remains to be seen whether claims that nelfinavir is a good first-line agent are true.

My approach to saquinavir failure has generally been to use ritonavir/saquinavir (along with a change in RT inhibitors) if I am catching the saquinavir failure early. That way I will be using a new PI as well as enhancing the drug levels of saquinavir, which presumably still has some activity. If saquinavir resistance is more extensive however (that is, if the viral load is high at the time of the switch), there may be no point in continuing the saquinavir.



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