title: Tenofovir alafenamide: A novel prodrug of tenofovir for the treatment of Human Immunodeficiency Virus.
abstract: Despite substantial progress in the development of antiretroviral regimens that durably suppress Human Immunodeficiency Virus (HIV) infection, new agents that maintain high efficacy while further optimizing the safety of lifelong, chronic therapy are needed. Tenofovir alafenamide (TAF; formerly known as GS-7340) is a novel prodrug of the antiviral acyclic nucleoside phosphonate tenofovir (TFV) with improved properties relative to tenofovir disoproxil fumarate (TDF). Although potent and generally well tolerated, TDF therapy has been associated with changes in markers of renal function, decreases in bone mineral density and a rare occurrence of serious renal adverse events, including Fanconi's Syndrome. The renal and bone toxicity observed with TDF is associated with high circulating plasma levels of TFV. TAF was discovered to be a more efficient prodrug able to further refine HIV therapy and better address life-long therapy in an older and increasingly comorbid HIV infected population. By enhancing stability in biological matrices while being rapidly activated in cells, TAF produces higher levels of intracellular TFV diphosphate, the pharmacologically active metabolite, in HIV-target cells at substantially reduced oral doses of TFV equivalents. All TFV released in the body is eventually eliminated renally; therefore, lowering the TFV equivalents administered reduces off-target kidney exposure. Effective therapy is thus achieved at approximately 90% lower systemic exposure to TFV, translating to statistically and clinically significant improvement in safety parameters associated with bone mineral density and markers of renal function.
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, USA. Electronic address: adrian.ray@gilead.com.
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, USA.
authors.forename: Marshall W
authors.initials: MW
authors.lastname: Fordyce
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, USA.
authors.forename: Michael J M
authors.initials: MJ
authors.lastname: Hitchcock
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000409:Alanine; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D015519:Bone Density / Q000187:drug effects; D004355:Drug Stability; D005198:Fanconi Syndrome; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007668:Kidney / Q000187:drug effects; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000068698:Tenofovir / Q000031:analogs & derivatives; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D011355:Prodrugs; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine
keywords: GS-7340; HAART; HIV; Nucleotide prodrug; PMPA; Viread