Randomized, controlled trial of entecavir versus placebo in children with hepatitis B envelope antigen–positive chronic hepatitis B
Maureen M. Jonas1,*, Mei-Hwei Chang2, Etienne Sokal3, Kathleen B. Schwarz4, Deirdre Kelly5, Kyung Mo Kim6, Simon C. Ling7, Philip Rosenthal8, Dumitru Oraseanu9, Laurie Reynolds10, Alexandra Thiry10 andPeter Ackerman10
Volume 63, Issue 2, pages 377–387, February 2016
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1 Boston Children's Hospital, Boston, MA
2 National Taiwan University Hospital, Taipei, Taiwan
3 Cliniques Universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium
4 Johns Hopkins Children's Center, Baltimore, MD
5 Birmingham Children's Hospital, Birmingham, UK
6 Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea
7 The Hospital For Sick Children, and Department of Pediatrics, University of Toronto, Toronto, Canada
8 University of California, San Francisco, CA
9 Grigore Alexandrescu Emergency Hospital for Children, Bucharest, Romania
10 Bristol-Myers Squibb, Wallingford, CT
*Address reprint requests to: Maureen M. Jonas, M.D., Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115. E-mail: [email protected]; fax: +1-617-730-0716.
Potential conflict of interest: Dr. Jonas consults for and received grants from Gilead. She received grants from Bristol-Myers Squibb and Roche. Dr. Chang received grants from Bristol-Myers Squibb and Gilead. Dr. Schwarz consults for and received grants from Roche. Dr. Kelly consults for and received grants from Bristol-Myers Squibb. Dr. Ling received grants from Bristol-Myers Squibb. Dr. Rosenthal consults for and received grants from Gilead. He consults for Hyperion and AbbVie and received grants from Roche, Vertex, and Bristol-Myers Squibb. Dr. Reynolds is employed by and owns stock in Bristol-Myers Squibb. Dr. Ackerman is employed by and owns stock in Bristol-Myers Squibb. Dr. Thiry is employed by and owns stock in Bristol-Myers Squibb.
This work is registered under study registration number: ClinicalTrials.gov NCT01079806.
This ongoing, randomized phase III study assesses the safety and efficacy of entecavir versus placebo in nucleos(t)ide-naïve children (2 to <18 years) with hepatitis B envelope antigen (HBeAg)-positive chronic hepatitis B (CHB). Blinded treatment was administered for a minimum of 48 weeks. After week 48, patients with HBeAg seroconversion continued blinded treatment; those without switched to open-label entecavir. The primary endpoint was HBeAg seroconversion and HBV DNA <50 IU/mL at week 48. A total of 180 patients were randomized (2:1) and treated. Baseline median age was 12 years, with approximately 50% of children ages >12 to <18, and 25% each ages ≥2 to ≤6 and >6 to ≤12. Rates for the primary endpoint at week 48 were significantly higher with entecavir than placebo (24.2% [29 of 120] vs. 3.3% [2 of 60]; P = 0.0008). Furthermore, higher response rates were observed with entecavir compared with placebo for the key week 48 secondary endpoints: HBV DNA <50 IU/mL (49.2% [59 of 120] vs. 3.3% [2 of 60]; P < 0.0001); alanine aminotransferase normalization (67.5% [81 of 120] vs. 23.3% [14 of 60]; P < 0.0001); and HBeAg seroconversion (24.2% [29 of 120] vs. 10.0% [6 of 60]; P = 0.0210). Among entecavir-randomized patients, there was an increase in all efficacy endpoints between weeks 48 and 96, including an increase from 49% to 64% in virological suppression. The cumulative probability of emergent entecavir resistance through years 1 and 2 of entecavir was 0.6% and 2.6%, respectively. Entecavir was well tolerated with no observed differences in adverse events or changes in growth compared with placebo.
Conclusion: In childhood CHB, entecavir demonstrated superior antiviral efficacy to placebo with a favorable safety profile. These results support the use of entecavir as a therapeutic option in children and adolescents with CHB. (Hepatology 2016;63:377–387) 作者: StephenW 时间: 2016-1-20 21:41