The Discovery and Development of Islatravir (4′‐Ethynyl‐2‐fluoro‐2′‐deoxyadenosine [EFdA], MK‐8591)

4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA, islatravir [ISL], MK-8591) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) under development for the treatment and prevention of human immunodeficiency virus (HIV) infection. It acts through multiple mechanisms of action, inhibiting the translocation step of reverse transcription. EFdA is a promising antiviral due to its high potency, high barrier to resistance, and its potential to be included in future antiretroviral therapies (ARTs). In this review, we detail the history and development of EFdA from synthesis to its current place in Phase 3 clinical trials. Due to the favorable drug profile of EFdA, more antivirals that fall into the NRTTI class are currently in development.