Randomized, controlled trial of entecavir versus placebo in ... : Hepatology (original) (raw)
Viral Hepatitis
Randomized, controlled trial of entecavir versus placebo in children with hepatitis B envelope antigen–positive chronic hepatitis B
Jonas, Maureen M.*,1; Chang, Mei‐Hwei2; Sokal, Etienne3; Schwarz, Kathleen B.4; Kelly, Deirdre5; Kim, Kyung Mo6; Ling, Simon C.7; Rosenthal, Philip8; Oraseanu, Dumitru9; Reynolds, Laurie10; Thiry, Alexandra10; Ackerman, Peter10
1Boston Children's HospitalBostonMA
2National Taiwan University HospitalTaipeiTaiwan
3Cliniques Universitaires St Luc, Université Catholique de LouvainBrusselsBelgium
4Johns Hopkins Children's CenterBaltimoreMD
5Birmingham Children's HospitalBirminghamUK
6Asan Medical Center Children's Hospital, University of Ulsan College of MedicineSeoulRepublic of Korea
7The Hospital For Sick Children, and Department of PediatricsUniversity of TorontoTorontoCanada
8University of CaliforniaSan FranciscoCA
9Grigore Alexandrescu Emergency Hospital for ChildrenBucharestRomania
10Bristol‐Myers SquibbWallingfordCT
*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.
Abstract
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)
Erratum
We write to correct entecavir resistance (ETVr) data for the article titled “Randomized, Controlled Trial of Entecavir Versus Placebo in Children With Hepatitis B Envelope Antigen‐Positive Chronic Hepatitis B” (volume 63, pages 377‐387; doi: 1002/hep.28015), by Jonas, Chang, Sokal, Schwarz, Kelly, Kim, et al. The article reported cumulative emergent ETVr through years 1 (1 child) and 2 (3 children) of treatment, giving resistance rates of 0.6% and 2.6%, respectively. These genotypic resistance data were generated by a contract laboratory for the study sponsor Bristol‐Myers Squibb. Subsequently, these data were reassessed after the study sponsor discovered genotyping discrepancies and data nonreproducibility during its review of additional ETVr data from the same contract laboratory. When original laboratory specimens were retested at the in‐house Bristol‐Myers Squibb virology laboratory, only 2 children were found to have developed ETVr, both in year 2, giving a cumulative ETVr rate of 1.3%. Neither child had reported prior exposure to anti–hepatitis B virus therapy (including lamivudine) or evidenced detectable baseline resistance substitutions. Notably, both children had high baseline hepatitis B virus DNA (≥8 log10 IU/mL) and persistent viremia (≥3 log10 IU/mL) on‐treatment with ETV post–week 48.
We appreciate that in‐house retesting might be construed as having the potential to add bias to the study. However, we believe the corrected rate represents the most accurate ETVr point estimate based on study data. We chose to repeat this work at the Bristol‐Myers Squibb virology laboratory because ( ) results generated there have been verifiable and reproducible over many studies and ( ) ETVr data from this laboratory on six phase 2 and 3 trials have been previously published in Hepatology, where the findings were accepted without question. Another article describes in detail the methods and research on ETVr conducted by this laboratory.
Hepatology. 65(4):1427, April 2017.
© 2015 by the American Association for the Study of Liver Diseases