title: Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial.
abstract: Tenofovir alafenamide is a novel prodrug formulated to deliver the active metabolite to target cells more efficiently than tenofovir disoproxil fumarate at a lower dose, thereby reducing systemic exposure. In patients with HIV, tenofovir alafenamide was as efficacious as tenofovir disoproxil fumarate, with reduced bone and renal toxic effects. We compared the efficacy and safety of the two drugs in patients with HBeAg-positive chronic hepatitis B virus (HBV) infection in a non-inferiority study.
  
  
  
  We did this ongoing double-blind, non-inferiority study in 161 outpatient centres in 19 countries. Patients with chronic HBV infection who were positive for the hepatitis B e antigen (HBeAg) were randomly assigned (2:1) to receive either 25 mg tenofovir alafenamide or 300 mg tenofovir disoproxil fumarate with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size six) stratified by plasma HBV DNA concentration and previous treatment experience. The primary efficacy endpoint was the proportion of patients with HBV DNA less than 29 IU/mL at week 48 in all patients who were randomly assigned and received at least one dose of study drug using a missing-equals-failed approach. The pre-specified non-inferiority margin was 10%. Key prespecified safety endpoints were bone and renal parameters at week 48. This study is registered with ClinicalTrials.gov, number NCT01940471.
  
  
  
  Of the 1473 patients screened from Sept 11, 2013, to Dec 20, 2014, 875 eligible patients were randomly assigned and 873 received treatment (581 with tenofovir alafenamide and 292 with tenofovir disoproxil fumarate). 371 (64%) patients receiving tenofovir alafenamide had HBV DNA less than 29 IU/mL at week 48, which was non-inferior to the 195 (67%) of patients receiving tenofovir disoproxil fumarate who had HBV DNA less than 29 IU/mL (adjusted difference -3·6% [95% CI -9·8 to 2·6]; p=0·25). Patients given tenofovir alafenamide had a significantly smaller decrease in bone mineral density at hip (mean change -0·10% [95% CI -0·29 to 0·09] vs -1·72% [-2·02 to -1·41]; adjusted difference 1·62 [1·27 to 1·96]; p<0·0001) and at spine (mean change -0·42% [-0·66 to -0·17] vs -2·29% [-2·67 to -1·92]; adjusted difference 1·88 [1·44 to 2·31]; p<0·0001) as well as smaller mean increases in serum creatinine at week 48 (0·01 mg/dL [0·00-0·02] vs 0·03 mg/dL [0·02-0·04]; p=0·02). The most common adverse events overall were upper respiratory tract infection (51 [9%] of 581 patients receiving tenofovir alafenamide vs 22 [8%] of 292 patients receiving tenofovir disoproxil fumarate), nasopharyngitis (56 [10%] vs 16 [5%]), and headache (42 [7%] vs 22 [8%]). 22 (4%) patients receiving tenofovir alafenamide and 12 (4%) patients receiving tenofovir disoproxil fumarate experienced serious adverse events, none of which was deemed by the investigator to be related to study treatment. 187 (32%) of 581 patients in the tenofovir alafenamide group and 96 (33%) of 292 patients in the tenofovir disoproxil fumarate group had grade 3 or 4 laboratory abnormalities, the most common of which were elevations in ALT (62 [11%] of 577 patients receiving tenofovir alafenamide and 36 [13%] of 288 patients receiving tenofovir disoproxil fumarate) and AST (20 [3%] of 577 patients receiving tenofovir alafenamide and 19 [7%] of 288 patients receiving tenofovir disoproxil fumarate).
  
  
  
  In patients with HBeAg-positive HBV infection, tenofovir alafenamide was non-inferior to tenofovir disoproxil fumarate, and had improved bone and renal effects. Longer term follow-up is needed to better understand the clinical impact of these changes.
  
  
  
  Gilead Sciences.
authors.affiliation: The Chinese University of Hong Kong, Hong Kong. Electronic address: hlychan@cuhk.edu.hk.
authors.forename: Henry L Y
authors.initials: HL
authors.lastname: Chan
authors.affiliation: Toronto General Hospital, Toronto, ON, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: Fung
authors.affiliation: Queen Mary Hospital, Hong Kong.
authors.forename: Wai Kay
authors.initials: WK
authors.lastname: Seto
authors.affiliation: Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wan-Long
authors.initials: WL
authors.lastname: Chuang
authors.affiliation: Chiayi Christian Hospital, Chiayi, Taiwan.
authors.forename: Chi-Yi
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Chung-Ang University Hospital, Seoul, South Korea.
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Alice Ho Miu Ling Nethersole Hospital, Hong Kong.
authors.forename: Aric Josun
authors.initials: AJ
authors.lastname: Hui
authors.affiliation: Toronto Centre for Liver Disease, Toronto, ON, Canada.
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.affiliation: Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Chowdhury
authors.affiliation: Princess Margaret Hospital, Hong Kong.
authors.forename: Tak Yin Owen
authors.initials: TY
authors.lastname: Tsang
authors.affiliation: Surat Institute of Medical Sciences, Surat, Gujarat, India.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Mehta
authors.affiliation: Auckland Clinical Studies, Auckland, New Zealand.
authors.forename: Edward
authors.initials: E
authors.lastname: Gane
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Flaherty
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Massetto
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Anuj
authors.initials: A
authors.lastname: Gaggar
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kitrinos
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Lanjia
authors.initials: L
authors.lastname: Lin
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: G Mani
authors.initials: GM
authors.lastname: Subramanian
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Lim
authors.affiliation: All India Institute of Medical Sciences, New Delhi, Delhi, India.
authors.forename: Subrat K
authors.initials: SK
authors.lastname: Acharya
authors.affiliation: Kings College Hospital, London, UK.
authors.forename: Kosh
authors.initials: K
authors.lastname: Agarwal
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine; D000998:Antiviral Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006513:Hepatitis B e Antigens / Q000097:blood*; D019694:Hepatitis B, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D000068698:Tenofovir / Q000627:therapeutic use* / Q000031:analogs & derivatives; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D006513:Hepatitis B e Antigens; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine