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.