Abstract | BACKGROUND: METHODS: In this ongoing randomised, double-blind, phase 3, non-inferiority study in 105 centres in 17 countries, patients with HBeAg-negative chronic HBV were randomly assigned (2:1) by a computer-generated allocation sequence (block size six), stratified by plasma HBV DNA concentration and previous treatment status, to receive once-daily oral doses of tenofovir alafenamide 25 mg or tenofovir disoproxil fumarate 300 mg, each with matching placebo. Participants, investigators, and those assessing outcomes were masked to group assignment. Eligible patients were aged at least 18 years with HBeAg-negative chronic HBV infection (with plasma HBV DNA concentrations of >20 000 IU/mL), serum alanine aminotransferase concentrations of greater than 60 U/L in men or greater than 38 U/L in women and at no more than ten times the upper limit of normal, and estimated creatinine clearance of at least 50 mL/min (by the Cockcroft-Gault method). The primary efficacy endpoint was the proportion of patients who had HBV DNA less than 29 IU/mL at week 48 in those who received at least one dose of study drug; the study was powered to show non-inferiority with a 10% efficacy margin of tenofovir alafenamide compared with tenofovir disoproxil fumarate. Bone and renal safety, and key secondary safety endpoints were assessed sequentially. The study will be conducted for a total of 3 years as a double-blind comparison to assess the longer term response to treatment. This study is registered with ClinicalTrials.gov, number NCT01940341. FINDINGS: Between Sept 12, 2013, and Oct 31, 2014, 426 patients were randomly assigned (285 assigned to tenofovir alafenamide and 141 assigned to tenofovir disoproxil fumarate; one patient assigned to tenofovir disoproxil fumarate did not receive the treatment. 268 (94%) of 285 patients receiving tenofovir alafenamide had HBV DNA less than 29 IU/mL at week 48 versus 130 (93%) of 140 patients receiving tenofovir disoproxil fumarate (difference 1·8% [95% CI -3·6 to 7·2]; p=0·47), which demonstrates non-inferiority. Patients receiving tenofovir alafenamide had significantly smaller mean percentage declines in bone mineral density than those receiving tenofovir disoproxil fumarate (hip -0·29% [95% CI -0·55 to -0·03] vs -2·16% [-2·53 to -1·79], adjusted percentage difference 1·87% [95% CI 1·42 to 2·32; p<0·0001]; spine -0·88% [-1·22 to -0·54] vs -2·51% [-3·09 to -1·94], adjusted percentage difference 1·64% [95% CI 1·01 to 2·27]; p<0·0001). At week 48, mean change in serum creatinine was small in both groups ( tenofovir alafenamide 0·01 mg/dL [95% CI 0·00 to 0·02] vs tenofovir disoproxil fumarate 0·02 mg/dL [0·00 to 0·04], adjusted percentage difference -0·01 mg/dL [95% CI -0·03 to 0·01]; p=0·32), but patients receiving tenofovir alafenamide had a smaller reduction in creatinine clearance (median change in estimated glomerular filtration rate -1·8 mL/min [IQR -7·8 to 6·0] vs -4·8 mL/min [-12·0 to 3·0]; p=0·004). Most adverse events were mild to moderate in severity in the two treatment groups. The most common adverse events overall were headache ( tenofovir alafenamide 40 [14%] patients vs tenofovir disoproxil fumarate 14 [10%] patients), nasopharyngitis (30 [11%] vs 15 [11%]), and upper respiratory tract infection (35 [12%] vs ten [7%]). 14 (5%) patients receiving tenofovir alafenamide and nine (6%) patients receiving tenofovir disoproxil fumarate had serious adverse events, none of which was deemed by investigators to be related to study treatment; one patient in the tenofovir disoproxil fumarate group died, but this was not deemed to be related to study treatment. INTERPRETATION: FUNDING: Gilead Sciences.
|
Authors | Maria Buti, Edward Gane, Wai Kay Seto, Henry L Y Chan, Wan-Long Chuang, Tatjana Stepanova, Aric-Josun Hui, Young-Suk Lim, Rajiv Mehta, Harry L A Janssen, Subrat K Acharya, John F Flaherty, Benedetta Massetto, Andrea L Cathcart, Kyungpil Kim, Anuj Gaggar, G Mani Subramanian, John G McHutchison, Calvin Q Pan, Maurizia Brunetto, Namiki Izumi, Patrick Marcellin, GS-US-320-0108 Investigators |
Journal | The lancet. Gastroenterology & hepatology
(Lancet Gastroenterol Hepatol)
Vol. 1
Issue 3
Pg. 196-206
(11 2016)
ISSN: 2468-1253 [Electronic] Netherlands |
PMID | 28404092
(Publication Type: Clinical Trial, Phase III, Equivalence Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2016 Elsevier Ltd. All rights reserved. |
Chemical References |
- Antiviral Agents
- Biomarkers
- Hepatitis B e Antigens
- Tenofovir
- tenofovir alafenamide
- Adenine
- Alanine
|
Topics |
- Adenine
(analogs & derivatives, therapeutic use)
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Alanine
- Antiviral Agents
(therapeutic use)
- Biomarkers
(blood)
- Double-Blind Method
- Female
- Follow-Up Studies
- Hepatitis B e Antigens
(blood)
- Hepatitis B, Chronic
(diagnosis, drug therapy, immunology, virology)
- Humans
- Male
- Middle Aged
- Tenofovir
(therapeutic use)
- Treatment Outcome
- Viral Load
- Young Adult
|
|
Join CureHunter, for free Research Interface BASIC access!
Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease.
Find out why thousands of doctors, pharma researchers and patient activists
around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!
|