Mutations at positions: 10, 20, 32, 36, 46, 47, 48, 50, 53, 54, 63, 71, 77, 82, 84 and 90 may all contribute to some degree to amprenavir resistance. The degree to which each individual mutation impacts amprenavir varies greatly. Although I50V is considered the key signature mutation developing with amprenavir therapy, other pathways to resistance are seen. Mutations at position 54, as well as those at 32, 46, 47 and 84 have a substantial effect on amprenavir.
Phenotypic resistance:
The I50V mutation is associated with 2- to 3-fold resistance to amprenavir. The triple mutation M46I/I47V/I50V has been associated with a 20-fold reduction in susceptibility to amprenavir.
Cross-resistance:
The degree of cross-resistance between amprenavir and other PIs is very dependent on the specific mutational pattern present. If a patient has developed only the I50V mutation as a result of amprenavir failure, susceptibility to other PIs should be preserved. Lopinavir susceptibility is reduced by the I50V mutation but in isolation it may not preclude use of the drug. If other mutations such as 32, 46, 47, 54 or 84 have developed, this will reduce susceptibility to the other PIs and may preclude their use depending on which and how many are present. Patients who have failed other PIs may often show various degrees of reduced susceptibility to amprenavir. This will depend on the specific mutations and the number present. Mutations at positions 46, 54, 84, as well as others often seen in patients failing other PIs, are known to influence amprenavir susceptibility.
Emergence of resistance in vivo:
Four distinct pathways to amprenavir resistance are seen in clinical practice. These patterns evolve around one of the following key mutations: I50V or I54L/M or V32I + I47V or I84V. Some data suggest that higher drug levels of amprenavir favor the I50V pathway, whereas lower exposures favor I54L/M.
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 virological response.
Other comments:
The clinical utility of a second PI after amprenavir failure is dependent on which of the above resistance pathways has developed and how many mutations have accumulated. The I50V pathway leaves the most options. Likewise, in PI-experienced patients the response to amprenavir will also depend on the specific mutations that have accumulated, and possibly to the dosing of amprenavir used (boosted or not and at what dose). Additional studies to determine clinical phenotypic cut-offs and more specific mutational patterns will help guide amprenavir use in the salvage setting.
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Resistance during early virologic rebound on amprenavir plus zidovudine plus lamivudine triple therapy or amprenavir monotherapy in ACTG 347.
Antivir. Ther. 3(Supplement 1):50-51. Abstract 71.
Descamps, D., B. Masquelier, J. P. Mamet, C. Calvez, A. Ruffault, F. Telles, A. Goetschel, P. M. Girard, F. Brun-Vezinet, and D. Costagliola 2001.
A genotypic sensitivity score for amprenavir based genotype at baseline and virological response.
Antivir. Ther. 6:103.
Klein, A., M. Maguire, D. Paterson, P. Nacci, N. Mustafa, J. Yeo, W. Snowden, and J. P. Kleim 2000.
Virological response to amprenavir combination therapy in PI-experienced paediatric patients: association with distinct baseline HIV-1 protease variants - study PROAB3004 [abstract].
Antivir. Ther. 5 Supplement 2:4.
Maguire, M., S. MacManus, P. Griffin, C. Guinea, W. Harris, N. Richard, J. Wolfram, M. Tisdale, W. Snowden, and J.-P. Klein 2001.
Interaction of HIV-1 protease and gag gene mutations in response to amprenavir-selective pressure exerted in amprenavir-treated subjects - contribution of gag p6 changes L449F and P453L.
Antivir. Ther. 6:48.
Prado, J. G., T. Wrin, J. Beauchaine, L. Ruiz, C. Petropoulos, B. Clotet, R. D'Aquila, and J. Martinez-Picado 2001. Lopinavir resistance of amprenavir-selected, replication-impaired mutants of HIV-1.
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Snowden, W., D. Shortino, A. Klein, W. Harris, V. Manohitharajah, R. Elston, M. Tisdale, and M. Maguire 2000. Development of amprenavir resistance in NRTI-experienced patients: alternative mechanisms and correlation with baseline resistance to concomitant NRTIs [abstract 108].
Antivir. Ther. 5(Supplement 3):84.
Amprenavir (APV), Agenerase, 141W94
