Mutations at positions 10, 20, 30, 36, 46, 48, 53, 54, 63, 71, 73, 77, 82, 84, 88, 90 and 93 may all contribute to some degree to nelfinavir resistance. The degree to which each individual mutation impacts nelfinavir varies greatly. D30N and to a lesser degree L90M are the key signature mutations developing with nelfinavir therapy.
Phenotypic resistance:
The single mutation D30N results in high-level phenotypic resistance to nelfinavir. Other major protease mutations also produce phenotypic resistance and combinations of major and minor mutations result in increasing levels of phenotypic resistance.
Cross-resistance:
Nelfinavir resistance associated with an isolated D30N mutation does not confer cross-resistance to other PIs. If additional mutations such as M46I/L accumulate, some degree of cross-resistance can be incurred. Not all patients failing nelfinavir develop the D30N as their key mutation. L90M and other mutations (such as V82A) may develop instead of D30N. Patients failing other PIs such as saquinavir or indinavir and who have accumulated resistance mutations will often have significant resistance to nelfinavir. Therefore, isolates showing resistance to one of the approved PIs will often demonstrate cross-resistance to nelfinavir.
Emergence of resistance in vivo:
In subtype B patients (the predominant subtype in Northern America and Western Europe), D30N develops in the majority of patients failing nelfinavir, whereas L90M and others develop significantly less commonly. Preliminary data suggest that for some non-B subtypes, mutations other than D30N may develop in the majority of cases. Further study is required.
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:
Since D30N does not result in cross-resistance to other PIs and is the most common mutation in patients failing nelfinavir, using nelfinavir as a first PI may often retain susceptibility to other drugs of the class in subsequent regimens. This may not be true for patients infected with non-B subtypes of HIV. Mutations associated with resistance to other PIs frequently confer cross-resistance to nelfinavir and therefore often make it a poor choice in patients failing other PIs.
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Nelfinavir (NFV), Viracept 
