Resistance and cross-resistance with saquinavir and other HIV protease inhibitors: theory and practice

A mutation in HIV protease will arise less readily in patients treated with an HIV protease inhibitor if the mutation results in a substantial fall in viral replication fitness, and if the resulting decrease in viral drug sensitivity is modest, giving little advantage in exchange for the loss of fitness. An indicator of viral fitness can be obtained from a study of the incidence of variants in the pretreatment viral populations; those variants with a fitness similar to the wild-type virus will exist alongside the wild-type, while those that substantially disable the virus will not be seen. The key mutations for SQV resistance (G48V and L90M) are absent from pretreatment viral populations and give only modest decreases in viral drug sensitivity. This is consistent with the relatively low incidence of emergence of resistance to SQV at standard or higher dose levels. The key mutations to indinavir, ritonavir and nelfinavir have all been observed in pretreatment isolates (albeit at low frequencies). Secondary, compensatory mutations may occur subsequent and in addition to the primary mutations. These appear to arise in order to restore, at least in part, viral replicative fitness. The mutations typically seen to fulfil this role tend to arise at sites that are already polymorphic in the untreated virus population. For SQV and nelfinavir these additional mutations do not appear to further decrease viral sensitivity to these drugs. In contrast, for indinavir and ritonavir they give rise to a progressive decrease in drug sensitivity with increased numbers of mutations. Intuitively, cross-resistance is most likely to arise when a drug causes multiple mutations that substantially overlay with the mutation pattern of other protease inhibitors. Current data from studies with clinical isolates puts the rank order of frequency and breadth of cross-resistance as indinavir > ritonavir > SQV = nelfinavir. This is consistent with the intuitive hypothesis, although there are several unanswered questions in the detailed interpretation of genotype and cross-resistance profile.