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Antimicrobial Agents and Chemotherapy, June 2002, p. 1640-1646, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1640-1646.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Potency of Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) Used in Combination with Other Human Immunodeficiency Virus NNRTIs, NRTIs, or Protease Inhibitors

Robert W. King,* Ronald M. Klabe, Carol D. Reid, and Susan K. Erickson-Viitanen

Virology Department, Bristol-Myers Squibb Pharma, The Experimental Station, Wilmington, Delaware 19880-0336

Received 16 July 2001/ Returned for modification 22 October 2001/ Accepted 11 February 2002

Efavirenz and a series of related quinazolinone nonnucleoside inhibitors of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) were evaluated in a series of two-drug combinations with several nucleoside RT inhibitors (NRTIs), nonnucleoside RT inhibitors (NNRTIs), and protease inhibitors (PIs). These combinations were tested in an established HIV-1 RT enzyme assay and a cell-based yield reduction assay with HIV-1 (replicative form [RF])-infected MT-2 cells. Synergy, additivity, and antagonism were determined in the two different assay systems by the method of Chou and Talalay (T.-C. Chou and P. Talalay, Adv. Enzyme Reg. 22:27-55, 1984). Efavirenz, DPC082, DPC083, DPC961, and DPC963 used in combination with the NRTIs zidovudine and lamivudine acted synergistically to inhibit RT activity in the HIV-1 RT enzyme assay and additively to slightly synergistically to inhibit HIV-1 (RF) replication in the yield reduction assay. The five NNRTIs in combination with the PI nelfinavir acted additively in the yield reduction assay to inhibit HIV-1 replication. Interestingly, efavirenz in combination with a second NNRTI acted additively to inhibit HIV-1 RT function in the enzyme assay, while it acted antagonistically to inhibit HIV-1 (RF) replication in the yield reduction assay. These data suggest that antiretroviral combination regimens containing multiple NNTRIs should be given thorough consideration before being used.

* Corresponding author. Mailing address: The Experimental Station, Bristol-Myers Squibb Pharma, P.O. Box 80336, Bldg. E336, Rm 205A, Wilmington, DE 19880-0336. Phone: (302) 695-9354. Fax: (302) 695-9420. E-mail: robert.king{at}bms.com.

Antimicrobial Agents and Chemotherapy, June 2002, p. 1640-1646, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1640-1646.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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