title: Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection.
abstract: OBJECTIVE
  Tenofovir alafenamide, a phosphonate prodrug of tenofovir with greater plasma stability than tenofovir disoproxil fumarate, provides efficient delivery of active drug to hepatocytes at reduced systemic tenofovir exposures.
  
  
  METHODS
  Non-cirrhotic, treatment-naïve subjects with chronic hepatitis B were randomized (1:1:1:1:1) to receive tenofovir alafenamide 8, 25, 40, or 120 mg, or tenofovir disoproxil fumarate 300 mg for 28 days and assessed for safety, antiviral response, and pharmacokinetics, followed-up by off-treatment for 4 weeks.
  
  
  RESULTS
  51 subjects were randomized and all completed study treatment. Groups were generally well matched (67% male, 57% Asian, 53% HBeAg-negative, mean HBV DNA approximately 6.0 log10 IU/ml) with HBV genotypes reflective of the population. No subject experienced an adverse event that was serious or severe (grade 3/4). Across the tenofovir alafenamide groups, similar mean changes in serum HBV DNA were found at Week 4 (-2.81, -2.55, -2.19, and -2.76 log10 IU/ml for the 8, 25, 40, and 120 mg groups, respectively) which were also comparable to the control (-2.68 log10 IU/ml for tenofovir disoproxil fumarate 300 mg). Kinetics of viral decline were also similar among groups. Tenofovir alafenamide pharmacokinetics were linear and proportional to the dose; doses⩽25 mg were associated with ⩾92% reductions in mean tenofovir area under the curve relative to tenofovir disoproxil fumarate 300 mg.
  
  
  CONCLUSIONS
  Tenofovir alafenamide was safe and well tolerated; declines in HBV DNA were similar to tenofovir disoproxil fumarate at all doses evaluated. Tenofovir alafenamide 25 mg has been selected for further hepatitis B clinical development.
authors.affiliation: Institute of Liver Studies, King's College Hospital, London, UK. Electronic address: kosh.agarwal@nhs.net.
authors.forename: Kosh
authors.initials: K
authors.lastname: Agarwal
authors.affiliation: Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Fung
authors.affiliation: T. Nguyen Research and Education, San Diego, CA, USA.
authors.forename: Tuan T
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Royal Perth Hospital, Perth, Western Australia, Australia.
authors.forename: Wendy
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Algorithme Pharma, Montreal, Quebec, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Sicard
authors.affiliation: Nottingham University Hospitals NHS Trust and Biomedical Research Unit, Nottingham, UK.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Ryder
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Flaherty
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Lawson
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: G Mani
authors.initials: GM
authors.lastname: Subramanian
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Auckland Clinical Studies, Auckland, New Zealand.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
authors.affiliation: Queen Mary's University of London, Barts Health, UK.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Foster
mesh_terms: D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000328:Adult; D000409:Alanine; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood; D005260:Female; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D000068698:Tenofovir / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000031:analogs & derivatives; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine
keywords: Antiviral; Clinical Trial; Treatment; Viral hepatitis