title: In Vitro Virology Profile of Tenofovir Alafenamide, a Novel Oral Prodrug of Tenofovir with Improved Antiviral Activity Compared to That of Tenofovir Disoproxil Fumarate.
abstract: Tenofovir alafenamide (TAF) is an investigational oral prodrug of the HIV-1 nucleotide reverse transcriptase inhibitor tenofovir (TFV). Tenofovir disoproxil fumarate (TDF) is another TFV prodrug, widely used for the treatment of HIV-1 infection. TAF is converted mostly intracellularly to TFV and, in comparison to TDF, achieves higher tenofovir diphosphate (TFV-DP) levels in peripheral blood mononuclear cells. As a result, TAF has demonstrated potent anti-HIV-1 activity at lower doses than TDF in monotherapy studies. Here, the in vitro virology profile of TAF was evaluated and compared to that of TDF. TAF displayed potent antiviral activity against all HIV-1 groups/subtypes, as well as HIV-2. TAF exhibited minimal changes in the drug concentration needed to inhibit 50% of viral spread (EC50) upon removal of the prodrug, similar to TDF, demonstrating intracellular antiviral persistence. While TAF and TDF exhibited comparable potencies in the absence of serum pretreatment, TAF maintained activity in the presence of human serum, whereas TDF activity was significantly reduced. This result demonstrates TAF's improved plasma stability over TDF, which is driven by the different metabolic pathways of the two prodrugs and is key to TAF's improved in vivo antiviral activity. The activity of TAF is specific for HIV, as TAF lacked activity against a large panel of human viruses, with the exception of herpes simplex virus 2, where weak TAF antiviral activity was observed, as previously observed with TFV. Finally, in vitro combination studies with antiretroviral drugs from different classes showed additive to synergistic interactions with TAF, consistent with ongoing clinical studies with TAF in fixed-dose combinations with multiple other antiretroviral drugs for the treatment of HIV.
authors.affiliation: Clinical Virology, Gilead Sciences, Inc., Foster City, California, USA christian.callebaut@gilead.com.
authors.forename: Christian
authors.initials: C
authors.lastname: Callebaut
authors.affiliation: High Throughput Biology, Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: George
authors.initials: G
authors.lastname: Stepan
authors.affiliation: High Throughput Biology, Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Clinical Virology, Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000409:Alanine; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D002460:Cell Line; D003470:Culture Media / Q000494:pharmacology; D004355:Drug Stability; D005838:Genotype; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000473:pathology / Q000821:virology; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology; D008826:Microbial Sensitivity Tests; D061251:Primary Cell Culture; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D044967:Serum / Q000737:chemistry; D000068698:Tenofovir / Q000378:metabolism / Q000494:pharmacology* / Q000031:analogs & derivatives; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D003470:Culture Media; D011355:Prodrugs; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine