title: 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-drug-resistant 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.
authors.affiliation: Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. maedak@mail.nih.gov.
authors.forename: Kenji
authors.initials: K
authors.lastname: Maeda
authors.forename: Darshan V
authors.initials: DV
authors.lastname: Desai
authors.forename: Manabu
authors.initials: M
authors.lastname: Aoki
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Nakata
authors.forename: Eiichi N
authors.initials: EN
authors.lastname: Kodama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D003839:Deoxyadenosines / Q000737:chemistry / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D024921:Drug Resistance, Multiple, Viral; D000068679:Emtricitabine; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects*; D054298:Human Immunodeficiency Virus Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D008969:Molecular Sequence Data; D015394:Molecular Structure; D063065:Organophosphonates / Q000494:pharmacology; D000068698:Tenofovir; D013936:Thymidine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; C583040:BMS-986001; D003839:Deoxyadenosines; D054298:Human Immunodeficiency Virus Proteins; D063065:Organophosphonates; D003841:Deoxycytidine; D019259:Lamivudine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; C558823:islatravir; D013936:Thymidine