Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial

Abstract

Importance: Biliary atresia is the most common cause of end-stage liver disease in children. Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome.

Objective: To determine whether the addition of high-dose corticosteroids after hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and survival with the native liver.

Design, setting, and patients: The multicenter, double-blind Steroids in Biliary Atresia Randomized Trial (START) was conducted in 140 infants (mean age, 2.3 months) between September 2005 and February 2011 in the United States; follow-up ended in January 2013.

Interventions: Participants were randomized to receive intravenous methylprednisolone (4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for 2 weeks) followed by a tapering protocol for 9 weeks (n = 70) or placebo (n = 70) initiated within 72 hours of hepatoportoenterostomy.

Main outcomes and measures: The primary end point (powered to detect a 25% absolute treatment difference) was the percentage of participants with a serum total bilirubin level of less than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy. Secondary outcomes included survival with native liver at 24 months of age and serious adverse events.

Results: The proportion of participants with improved bile drainage was not statistically significantly improved by steroids at 6 months posthepatoportoenterostomy (58.6% [41/70] of steroids group vs 48.6% [34/70] of placebo group; adjusted relative risk, 1.14 [95% CI, 0.83 to 1.57]; P = .43). The adjusted absolute risk difference was 8.7% (95% CI, -10.4% to 27.7%). Transplant-free survival was 58.7% in the steroids group vs 59.4% in the placebo group (adjusted hazard ratio, 1.0 [95% CI, 0.6 to 1.8]; P = .99) at 24 months of age. The percentage of participants with serious adverse events was 81.4% [57/70] of the steroids group and 80.0% [56/70] of the placebo group (P > .99); however, participants receiving steroids had an earlier time of onset of their first serious adverse event by 30 days posthepatoportoenterostomy (37.2% [95% CI, 26.9% to 50.0%] of steroids group vs 19.0% [95% CI, 11.5% to 30.4%] of placebo group; P = .008).

Conclusions and relevance: Among infants with biliary atresia who have undergone hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded. Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia.

Trial registration: clinicaltrials.gov Identifier: NCT00294684.

Conflict of interest statement

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bezerra reported receiving grants from Molecular Genetics Laboratory of Cincinnati Children’s Hospital Medical Center outside the submitted work. Dr Shneider reported serving on data monitoring committes for Bristol-Myers Squibb and Vertex on hepatitis B and C, respectively; serving as associate editor for the American Association for the Study of Liver Diseases; and receiving royalites from PMPH-USA for a pediatric gastrointestinal textbook. Dr Rosenthal reported receiving grants from Roche, Bristol-Myers Squibb, Vertex, and Gilead; and receiving consulting fees from General Electric and Hyperion. Dr Haber reported receiving grants from the National Institutes of Health during the conduct of the study while with Children’s Hospital of Philadelphia, University of Pennsylvania. In January 2012, Dr Haber changed employment and now works at Merck in the area of viral hepatitis; however, her current work does not overlap or effect any aspect of the article. Dr Loomes reported receiving book royalties from Lippincott Williams & Wilkins and payment for an article on biliary atresia from Up-to-Date. Dr Molleston reported receiving grants from Schering, Roche, and Vertex outside the submitted work. Dr Schwarz reported serving as a consultant to Roche/Genentech; providing expert testimony for the State of Pennsylvania; and receiving institutional grants from the National Institute of Diabetes, Digestive and Kidney Diseases, Bristol-Myers Squibb, Roche/Genentech, and Vertex. Dr Sokol reported receiving grants from National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health; receiving nonfinancial support from Mead Johnson Nutrition during the conduct of the study; receiving consulting fees from Yasoo Health Inc, Ikaria Pharmaceuticals, Roche Products, and Cardax Pharmaceuticals; and having a patent for use of antioxidants for treatment of cholestasis licensed to Yasoo Health Inc. No other disclosures were reported.

Figures

Figure 1. Enrollment, Randomization, and Follow-up of Participants in START Through 24 Months of Age

START indicates Steroids in Biliary Atresia Randomized Trial. aDefined as participants who did not receive at least 80% of their protocol-prescribed study medication.

Figure 2. Kaplan-Meier Analysis of Key Secondary End Points by Treatment Group

Vertical tick marks indicate censored observations. Participants were censored at time of earlier withdrawal from the study or at the age of 24 months. aDefined as period when total bilirubin level of less than 1.5 mg/dL achieved for the first time to the first time total bilirubin increased to 1.5 mg/dl or higher, participants underwent liver transplant, or died. Participants that never achieved good bile drainage were considered treatment failures at time 0.

Figure 3. Time to First Serious Adverse Event

Vertical tick marks indicate censored observations. aDefined as the time from initiation of study medication to the earliest first serious adverse event or liver transplantation, exit from the study, or last day taking study medication (censored). Serious adverse events occurred significantly earlier in participants receiving steroids compared with placebo. bDefined as the time from the end of study medication to the earliest first serious adverse event after completion of study drug or placebo (event) or liver transplantation, or exit from the study (censored).