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

Nelfinavir resistance is primarily associated with one key mutation at position D30N on the gene for the protease enzyme. This seems to cause greater resistance in sub-type C than sub-type B virus^[1][2]. However, the following mutations are also associated with nelfinavir resistance:

• M46I/L.
• G48V.
• I54V.
• V82A/T/F/S.
• I84V.
• N88D/S/T.
• L90M^[3].

When nelfinavir and saquinavir (Invirase) are taken together, the L90M mutation is most commonly associated with treatment failure^[4].

There is some evidence that nelfinavir-resistant strains of HIV do not reproduce efficiently and may not be as damaging to the immune system as other types of mutant virus. The implications of this are unclear, although it has been suggested that CD4 cell counts may continue to rise despite a rebound in HIV that is resistant to nelfinavir.

Following nelfinavir failure, there is a possibility that a patient will still benefit from indinavir (Crixivan), Kaletra or dual protease inhibitor therapy, but there is a reduced chance of benefiting from saquinavir (Invirase). One study found that people who took nelfinavir as their first-line protease inhibitor were much less likely to have cross-resistance to other protease inhibitors compared with people who took another protease inhibitor in their first anti-HIV combination.

There is some evidence that patients whose treatment based on indinavir or saquinavir has failed may benefit from nelfinavir, although the saquinavir-associated L90M mutation may cause cross-resistance to nelfinavir^{[5][6][7][8][9]}. Patients whose treatment based on full-dose ritonavir (Norvir) has failed are also unlikely to benefit from nelfinavir.