DRUG-RESISTANCE PATTERNS OF SAQUINAVIR AND OTHER HIV PROTEINASE-INHIBITORS

Aim: To review available drug-resistance patterns of HIV proteinase in hibitors, in particular saquinavir (formerly known as Ro 31-8959), foc using on the implications for disease management. Results: Reduced sen sitivity to saquinavir appears to develop slowly and at low frequency even during prolonged therapy, with an incidence of approximately 45% in 1 year of monotherapy. This reduced sensitivity is consistently ass ociated with the presence of two independent mutations in the proteina se gene, glycine-->valine at position 48 and leucine-->methionine at p osition 90, with the latter predominating in vivo. Double mutants are rare, with a reported incidence of approximately 2% to date. There is no evidence that the incidence of resistance to saquinavir is increase d at doses two to four times higher than those used in clinical studie s. In fact, the opposite may be true. The incidence of zidovudine resi stance is decreased during combination therapy with saquinavir compare d to that during monotherapy, while the incidence of resistance to saq uinavir is decreased by combination with zidovudine and zalcitabine. C ross-resistance: According to the available genotype data, treatment w ith saquinavir is not associated with mutations at codons 46, 63 and 8 2, which are reported to induce cross-resistance to many other protein ase inhibitors. Saquinavir may be associated with mutations at positio n 84, but very rarely. Conclusions: Saquinavir appears to be well-suit ed to first-line monotherapy or combination therapy without prejudicin g subsequent or concurrent use of other proteinase inhibitors not affe cted by mutations at codons 48 and 90.