As with all other anti-HIV drugs, strains of HIV that are resistant to saquinavir (Invirase) may emerge after a period of treatment. The emergence of drug-resistant strains coincides with a fall in the effectiveness of the drug.

Two primary mutations in the protease gene, L90M and G48V, reduce susceptibility to saquinavir^[1][2][3][4]. The effect of these mutations can be enhanced by the secondary mutations L10I/V, K20R, M36I/L, A71T, V82X or I84V. However, virological failure of ritonavir (Norvir)-boosted saquinavir-based regimens occurs very rarely, at least in first-line therapy. In the Staccato study, ten of 258 patients had experienced virological failure after 30 weeks of treatment, but none of these had any major protease mutations^[5].

Virus that is resistant to other protease inhibitors, particularly indinavir (Crixivan) and ritonavir, may show some degree of cross-resistance to saquinavir^[6][7][8]. Saquinavir may not therefore be a useful option after failure of an indinavir-based combination.

Conversely, HIV with certain mutations that can cause resistance to atazanavir (Reyataz), amprenavir (Agenerase) or nelfinavir (Viracept) has been shown to be hypersusceptible to saquinavir. Using saquinavir after failure of these drugs may be beneficial, although this has not been established in clinical studies.