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. 2005 Nov;49(11):4465-73.
doi: 10.1128/AAC.49.11.4465-4473.2005.

Anti-human immunodeficiency virus type 1 activity of the nonnucleoside reverse transcriptase inhibitor GW678248 in combination with other antiretrovirals against clinical isolate viruses and in vitro selection for resistance

Richard J Hazen  1 , Robert J Harvey, Marty H St Clair, Robert G Ferris, George A Freeman, Jeffrey H Tidwell, Lee T Schaller, Jill R Cowan, Steven A Short, Karen R Romines, Joseph H Chan, Lawrence R Boone
Affiliations

Anti-human immunodeficiency virus type 1 activity of the nonnucleoside reverse transcriptase inhibitor GW678248 in combination with other antiretrovirals against clinical isolate viruses and in vitro selection for resistance

Richard J Hazen et al. Antimicrob Agents Chemother. 2005 Nov.

Abstract

GW678248, a novel nonnucleoside reverse transcriptase inhibitor, has been evaluated for anti-human immunodeficiency virus activity in a variety of in vitro assays against laboratory strains and clinical isolates. When GW678248 was tested in combination with approved drugs in the nucleoside and nucleotide reverse transcriptase inhibitor classes or the protease inhibitor class, the antiviral activities were either synergistic or additive. When GW678248 was tested in combination with approved drugs in the nonnucleoside reverse transcriptase inhibitor class, the antiviral activities were either additive or slightly antagonistic. Clinical isolates from antiretroviral drug-experienced patients were selected for evaluation of sensitivity to GW678248 in a recombinant virus assay. Efavirenz (EFV) and nevirapine (NVP) had > or = 10-fold increases in their 50% inhibitory concentrations (IC50s) for 85% and 98% of the 55 selected isolates, respectively, whereas GW678248 had a > or = 10-fold increase in the IC50 for only 17% of these isolates. Thus, 81 to 83% of the EFV- and/or NVP-resistant viruses from this data set were susceptible to GW678248. Virus populations resistant to GW678248 were selected by in vitro dose-escalating serial passage. Resistant progeny viruses recovered after eight passages had amino acid substitutions V106I, E138K, and P236L in the reverse transcriptase-coding region in one passage series and amino acid substitutions K102E, V106A, and P236L in a second passage series.

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Figures

FIG. 1.
FIG. 1.
Structure of GW678248.
FIG. 2.
FIG. 2.
Isobolograms of the inhibition of HIV-1 by GW678248 in combination with several marketed anti-HIV agents in MT-4 cells. (a) In combination with NRTIs; (b) in combination with NNRTIs; (c) in combination with protease inhibitors (PIs). FIC, fractional inhibitory concentration.
FIG. 3.
FIG. 3.
Phenotypic susceptibilities to efavirenz, nevirapine, and GW678248 of 55 clinical isolate viruses obtained from NNRTI-experienced patients.
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