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Antimicrobial Agents and Chemotherapy, November 2005, p. 4465-4473, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4465-4473.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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,1 Marty H. St. Clair,2 Robert G. Ferris,1 George A. Freeman,3 Jeffrey H. Tidwell,3 Lee T. Schaller,3 Jill R. Cowan,3 Steven A. Short,4 Karen R. Romines,5 Joseph H. Chan,3,{dagger} and Lawrence R. Boone1

Departments of Virology,1 Clinical Virology,2 Medicinal Chemistry,3 Viral Diseases, Metabolic and Viral Diseases Center of Excellence for Drug Discovery,5 Department of Gene Expression and Protein Bichemistry, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 277094

Received 10 March 2005/ Returned for modification 26 May 2005/ Accepted 16 August 2005

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 ≥10-fold increases in their 50% inhibitory concentrations (IC50s) for 85% and 98% of the 55 selected isolates, respectively, whereas GW678248 had a ≥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.

* Corresponding author. Mailing address: Department of Virology, GlaxoSmithKline, 5 Moore Dr., P.O. Box 13398, Research Triangle Park, NC 27709. Phone: (919) 483-9179. Fax: (919) 315-5243. E-mail: richard.j.hazen{at}gsk.com.

{dagger} Present address: Discovery Research Kinase Chemistry, GlaxoSmithKline K.K., Ibaraki, Japan.

Antimicrobial Agents and Chemotherapy, November 2005, p. 4465-4473, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4465-4473.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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