Saquinavir (SQV), Invirase (hardgel cap) and Fortovase (softgel cap)
Peptidomimetic inhibitor of HIV-1 protease
Mutations associated with drug resistance:
Mutations at positions 10, 20, 36, 46, 48, 53, 54, 63, 71, 73, 77, 82, 84, 90 and 93 may all contribute to some degree to saquinavir resistance. The degree to which each individual mutation impacts saquinavir varies greatly. L90M and G48V are considered the key signature mutations developing with saquinavir therapy.
Phenotypic resistance:
L90M is the most common key mutation seen in isolates from patients treated with saquinavir. Much less common, and possibly related to higher exposures, is G48V. V82A can appear as a late mutation after prolonged use. Patients who have accumulated multiple mutations demonstrate substantially increased phenotypic resistance in association with L90M, I84V, V82A and G48V, and often numerous minor mutations.
Cross-resistance:
Patients failing saquinavir often demonstrate some degree of reduced susceptibility to other PIs if mutations have developed. Depending on which mutations have been acquired (L90M, G48V + V82A, I54V) and how many have accumulated, other PIs may still retain clinical activity. This may require ritonavir boosting to achieve higher levels. Patients who have failed other PIs may retain some degree of susceptibility to saquinavir and benefit clinically if used with ritonavir boosting. Once again, this depends on which and how many mutations have developed, but may be more useful after initial failure with nelfinavir or amprenavir.
Emergence of resistance in vivo:
Subjects receiving saquinavir monotherapy, or failing combinations of saquinavir and NRTIs develop L90M and less often G48V in addition to frequent multiple minor mutations.
Clinical correlates of resistance:
Failure of PI therapy can be multifactorial. Not all patients failing therapy containing a PI demonstrate protease mutations. Still, the presence of protease mutations is strongly correlated with therapeutic failure, and changing therapy based on the mutations determined improves virologic response.
Other comments:
Saquinavir's utility is primarily limited by its low bioavailability, with only a small fraction of the orally administered drug absorbed. This requires TID administration and a high pill burden. Saquinavir levels are increased 4- to 20-fold when boosted with ritonavir. Concomitant saquinavir/ritonavir (in various dosage combinations) may be the most potent method of administration to insure high blood levels and less frequent dosing. BID and QD regimens have been studied.
Zolopa, A. R., K. Hertogs, R. Shafer, P. Dehertogh, V. De Vroey, B. Efron, S. Bloor, and B. Larder 1999a.
A comparison of phenotypic, genotypic, and clinical / treatment history predictors of virologic response to saquinavir / ritonavir salvage therapy in a clinic-based cohort [abstract 68].
Antivir. Ther. 4(Supplement 1):47-48.
Saquinavir (SQV), Invirase (hardgel cap) and Fortovase (softgel cap)
