title: Tenofovir alafenamide demonstrates broad cross-genotype activity against wild-type HBV clinical isolates and maintains susceptibility to drug-resistant HBV isolates in vitro.
abstract: Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir (TFV). This study evaluated the antiviral activity of TAF against wild-type genotype A-H HBV clinical isolates as well as adefovir-resistant, lamivudine-resistant, and entecavir-resistant HBV isolates. Full length HBV genomes or the polymerase/reverse transcriptase (pol/RT) region from treatment-naïve patients infected with HBV genotypes A-H were amplified and cloned into an expression vector under the control of a CMV promoter. In addition, 11 drug resistant HBV constructs were created by site-directed mutagenesis of a full length genotype D construct. Activity of TAF was measured by transfection of each construct into HepG2 cells and assessment of HBV DNA levels following treatment across a range of TAF concentrations. TAF activity in vitro was similar against wild-type genotype A-H HBV clinical isolates. All lamivudine- and entecavir-resistant isolates and 4/5 adefovir-resistant isolates were found to be sensitive to inhibition by TAF in vitro as compared to the wild-type isolate. The adefovir-resistant isolate rtA181V + rtN236T exhibited low-level reduced susceptibility to TAF. TAF is similarly active in vitro against wild-type genotype A-H HBV clinical isolates. The TAF sensitivity results for all drug-resistant isolates are consistent with what has been observed with the parent drug TFV. The in vitro cell-based HBV phenotyping assay results support the use of TAF in treatment of HBV infected subjects with diverse HBV genotypes, in both treatment-naive and treatment-experienced HBV infected patients.
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA. Electronic address: Yang.Liu@gilead.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kitrinos
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000409:Alanine; D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D005838:Genotype; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000188:drug therapy / Q000821:virology; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D011355:Prodrugs / Q000494:pharmacology; D000068698:Tenofovir / Q000031:analogs & derivatives; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine
keywords: Drug susceptibility; HBV genotype; HBV resistance; Tenofovir alafenamide (TAF)