Potency of nonnucleoside reverse transcriptase inhibitors (NNRTIs) used in combination with other human immunodeficiency virus NNRTIs, NRTIs, or protease inhibitors.
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.
King
Robert W
RW
Virology Department, Bristol-Myers Squibb Pharma, The Experimental Station, Wilmington, Delaware 19880-0336, USA. robert.king@bms.com
Klabe
Ronald M
RM
Reid
Carol D
CD
Erickson-Viitanen
Susan K
SK
D000480:Alkynes; D048588:Benzoxazines; D002478:Cells, Cultured; D003521:Cyclopropanes; D004338:Drug Combinations; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000096:biosynthesis; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D019829:Nevirapine / Q000494:pharmacology; D009705:Nucleosides / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D009705:Nucleosides; D010078:Oxazines; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D054303:HIV Reverse Transcriptase; C098320:efavirenz