Tenofovir alafenamide demonstrates broad cross-genotype activity against wild-type HBV clinical isolates and maintains susceptibility to drug-resistant HBV isolates in vitro

• Published in: Antiviral research Vol. 139; pp. 25 - 31
• Main Authors: Liu, Yang, Miller, Michael D., Kitrinos, Kathryn M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2017
• Subjects: Adenine - analogs & derivatives; Adenine - chemistry; Adenine - pharmacology; Antiviral Agents - pharmacology; Drug Resistance, Viral; Drug susceptibility; Genotype; HBV genotype; HBV resistance; Hep G2 Cells; Hepatitis B - drug therapy; Hepatitis B - virology; Hepatitis B virus - drug effects; Hepatitis B virus - genetics; Hepatitis B virus - physiology; Humans; Mutagenesis, Site-Directed; Phenotype; Prodrugs - pharmacology; Tenofovir alafenamide (TAF); Virus Replication - drug effects; Tenofovir alafenamide (TAF); HBV genotype; Drug susceptibility; HBV resistance
• ISSN: 0166-3542; 1872-9096; 1872-9096
• DOI: 10.1016/j.antiviral.2016.12.012

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. •TAF in vitro antiviral activity was similar against wild-type genotype A-H HBV clinical isolates.•Drug-resistant HBV isolates were sensitive to TAF in vitro, as compared to the wild-type isolate.•Results support the use of TAF for treatment-naive and treatment-experienced HBV infected patients across genotypes.