Resistance to the HIV protease inhibitor amprenavir in vitro and in clinical studies - A review

Amprenavir (APV) is a highly active and selective HIV protease inhibitor (P I) that is used for the treatment of HIV infection in adults and children. In this review we present data from extensive resistance studies undertaken during the development of amprenavir. These include in vitro and clinical studies where the phenotype and genotype of HIV protease was determined aft er treatment with amprenavir either as the single PI [alone or with nucleos ide reverse transcriptase inhibitors (NRTIs)] or in combination with other PIs. In addition, cross-resistance with other PIs has been examined to help position use of amprenavir in the clinic. The key signature amino acid substitution associated with amprenavir resist ance that was identified from in vitro and subsequent ill vivo studies was isoleucine to valine at position 50 (I50V) in HIV protease. This was a new mutation not observed as a natural variant or in PI-experienced patients. A dditional mutations including M46I/L and I47V were required to produce high level resistance. Cross-resistance was limited and observed only with rito navir. In amprenavir/zidovudine/lamivudine combination therapy in PI-naive and lam ivudine-naive patients, therapy failure is associated frequently with the r everse transcriptase M184V mutation, and not with amprenavir resistance. Ho wever, when amprenavir was added to NRTI therapy in NRTI-experienced and PI -naive patients where treatment was compromised by baseline NRTI resistance , failure was more frequently associated with the development of amprenavir resistance. From these studies, four pathways of amprenavir resistance wer e identified, with the I50V pathway associated with the highest levels of r esistance. Alternative pathways to amprenavir resistance involved key subst itutions, either V32I + I47V, or I54L/M, or more rarely I84V. Limited cross -resistance was observed to other PIs with each of these genetic mechanisms . Similarly, in PI-experienced patients, cross-resistance to amprenavir is ma rkedly lower than for the other four approved PIs. Markers of cross-resista nce to amprenavir include the above mutations but not L90M or V82A/T/Y as o bserved for other PIs. These data suggest that amprenavir may have an impor tant part to play in rescue therapy regimens. In combination with other PIs, resistance development may be suppressed and key signature mutations, such as I50V (amprenavir), D30N (nelfinavir) and V82A/T/Y (ritonavir, indinavir) have not been observed in vitro. In additio n, passage with saquinavir may resensitise amprenavir-resistant variants to amprenavir. Hypersensitivity to amprenavir has been reported for N88S vari ants occasionally observed after nelfinavir therapy. Differences in the res istance profile of amprenavir from that of other PIs suggest that amprenavi r may add value to HIV combination therapy, particularly in PI combinations and in rescue therapy.