Delayed emergence of HIV-1 variants resistant to 4'-ethynyl-2-fluoro-2'-deoxyadenosine: Comparative sequential passage study with lamivudine, tenofovir, emtricitabine and BMS-986001

Abstract

Background: 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) contains an ethynyl moiety and the 3'-hydroxyl and exerts highly potent activity against various HIV type-1 (HIV-1) strains including multi-drug-resistant variants. Methods: Comparative selection passages against EFdA, lamivudine (3TC), tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) or BMS-986001 (Ed4T) were conducted using a mixture of 11 highly multi-drugresistant clinical HIV-1 isolates (HIV11MIX) as a starting virus population. Results: Before selection, HIV11MIX was sensitive to EFdA with a 50% inhibitory concentration (IC50) of 0.032 μM, less susceptible to TDF and Ed4T with IC50s of 0.57 and 2.6 μM, respectively, and highly resistant to 3TC and FTC with IC50s>10 μM. IC50s of TDF against HIV11MIX exposed to EFdA and TDF for 17 (HIV11MIX EFdA-P17) and 14 (HIV11MIX TDF-P14) passages were 8 and >10 μM, respectively, while EFdA remained active against HIV11MIX EFdA-P17 and HIV11MIX TDF-P14 with IC50s of 0.15 and 0.1 μM, respectively. Both selected variants were highly resistant against zidovudine, 3TC, Ed4T and FTC (IC50 values >10 μM). Conclusions: The present data demonstrate that HIV11MIX developed resistance more rapidly against 3TC, FTC, TDF and Ed4T than against EFdA and that EFdA remained substantially active against TDF- and EFdA-selected variants. Thus, EFdA has a favourable resistance profile and represents a potentially promising new-generation nucleoside reverse transcriptase inhibitor. © 2014 International Medical Press 1359-6535.