Emergence of Resistance to Protease Inhibitor Amprenavir in Human Immunodeficiency Virus Type 1-Infected Patients: Selection of Four Alternative Viral Protease Genotypes and Influence of Viral Susceptibility to Coadministered Reverse Transcriptase Nucleoside Inhibitors

Abstract

Previous data have indicated that the development of resistance to amprenavir, an inhibitor of the human immunodeficiency virus type 1 protease, is associated with the substitution of valine for isoleucine at residue 50 (I50V) in the viral protease. We present further findings from retrospective genotypic and phenotypic analyses of plasma samples from protease inhibitor-naïve and nucleoside reverse transcriptase inhibitor (NRTI)-experienced patients who experienced virological failure while participating in a clinical trial where they had been randomized to receive either amprenavir or indinavir in combination with NRTIs. Paired baseline and on-therapy isolates from 31 of 48 (65%) amprenavir-treated patients analyzed demonstrated the selection of protease mutations. These mutations fell into four distinct categories, characterized by the presence of either I50V, I54L/I54M, I84V, or V32I؉I47V and often included accessory mutations, commonly M46I/L. The I50V and I84V genotypes displayed the greatest reductions in susceptibility to amprenavir, although each of the amprenavir-selected genotypes conferred little or no cross-resistance to other protease inhibitors. There was a significant association, for both amprenavir and indinavir, between preexisting baseline resistance to NRTIs subsequently received during the study and development of protease mutations (P ‫؍‬ 0.014 and P ‫؍‬ 0.031, respectively). Our data provide a comprehensive analysis of the mechanisms by which amprenavir resistance develops during clinical use and present evidence that resistance to concomitant agents in the treatment regimen predisposes to the development of mutations associated with protease inhibitor resistance and treatment failure.

A randomized study investigating the efficacy and safety of amprenavir in combination with low‐dose ritonavir in protease inhibitor‐experienced HIV‐infected adults

“…D30N, G48V, I54V, V82A/T/S/F and L90M) are not selected by APV in vivo or in vitro [1]. Data from clinical studies [3][4][5] have confirmed that the incidence of cross-resistance to APV following treatment with other PIs is markedly lower than that observed with other PIs.…”

“…Mutations key for resistance to other PIs (e.g. D30N, G48V, V82A/T/S/F or L90M) are not selected with APV in vivo or in vitro [1], and the incidence of cross-resistance to APV in PI-experienced subjects is markedly lower than that observed with other PIs [3,4]. The distinct resistance profile of APV may help to make available another treatment option for PI-experienced patients.…”

“…APV resistance develops through four alternative mutation pathways that are distinct from those observed with other PIs [1]. The pathways are characterized by the presence of mutations I50V, I54L or M, V32I 1 I47V and less commonly I84V in combination with other secondary protease and p1/p6 cleavage-site mutations [2].…”

Ninety-Nine Is Not Enough: Molecular Characterization of Inhibitor-Resistant Human Immunodeficiency Virus Type 1 Protease Mutants with Insertions in the Flap Region

“…We show that PR insertions, particularly those between residues 32 and 42, have become more prevalent since 1999. These insertions are positively correlated with PR codons associated with resistance to PIs whose usage has increased in recent years, including atazanavir (position 16) (38), lopinavir and amprenavir (position 47) (21,17), and tipranavir (positions 13, 36, and 47) (11). Additionally, a mutation at position 57 is a predictor of early virologic failure (23), and codon 91 mutations are more common in patients on long-term nonsupressive PI therapy (16).…”

Mutation Patterns and Structural Correlates in Human Immunodeficiency Virus Type 1 Protease following Different Protease Inhibitor Treatments

“…Most of the published sequence data on protease inhibitorassociated mutations are based on isolates obtained from persons treated for no more than 1 year with a single inhibitor (4,17,(19)(20)(21). Few published data are available from persons with carefully characterized treatment histories who have received more than one inhibitor (12), and the genetic mechanisms by which HIV-1 protease develops resistance to multiple inhibitors have not been explored.…”