Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study. APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings. CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.

Less is more: The use of a single biodegradable stenting to treat biliary anastomotic strictures in pediatric liver transplantation.

OBJECTIVE: To report our experience of using biodegradable biliary stents for anastomotic biliary strictures in pediatric liver transplant patients. METHODS: Analysis of a retrospective data collection from January 2014 to January 2023, including all pediatric liver transplant recipients in our center treated for anastomotic biliary strictures with biodegradable biliary stents (BBS). In phase 1 (2014-2019), there was an initial percutaneous transhepatic cholangiography (PTC) with anastomotic dilatation followed two weeks after by a second PTC with BBS insertion. In phase 2 (2019-2023), the BDS were placed shortly after anastomotic biliary strictures dilatation, requiring only one PTC. All patients were followed up with routine tests and ultrasound. RESULTS: Forty-six anastomotic biliary strictures were diagnosed in 43 pediatric liver transplant recipients with a median of 6.7 months post-liver transplantation (0.1-246.8 months). Eight out of 46 anastomotic biliary strictures (17.4%) treated with biodegradable biliary stents relapsed (median recurrence time: 6.5 months; 1.6-17.0 months). Four resolved with further BBS placement; only four needed surgical revision (8.7%) after a median follow-up time of 43.9 months (0.3-106.3). There were no differences in anastomotic biliary strictures recurrence rate, time between stent placement and recurrence, or the presence of cholangitis based on whether the BBS was deployed in one or two steps. Patients with end-to-end anastomosis had a higher anastomotic biliary strictures recurrence (or 10.8; 1.4-81.3, p=0.008) than those with bilioenteric anastomosis. CONCLUSION: The use of biodegradable stents stents could be good option for treating anastomotic biliary strictures in pediatric liver transplant patients, with our series showing a success rate of over 90% and an average follow-up of 43.9 months.

Opinion paper on the diagnosis and treatment of progressive familial intrahepatic cholestasis.

Background & Aims: Progressive familial intrahepatic cholestasis (PFIC) relates to a group of rare, debilitating, liver disorders which typically present in early childhood, but have also been reported in adults. Without early detection and effective treatment, PFIC can result in end-stage liver disease. The aim of the paper was to put forward recommendations that promote standardisation of the management of PFIC in clinical practice. Methods: A committee of six specialists came together to discuss the challenges faced by physicians in the management of PFIC. The committee agreed on two key areas where expert guidance is required to optimise care: (1) how to diagnose and treat patients with a clinical presentation of PFIC in the absence of clear genetic test results/whilst awaiting results, and (2) how to monitor disease progression and response to treatment. A systematic literature review was undertaken to contextualise and inform the recommendations. Results: An algorithm was developed for the diagnosis and treatment of children with suspected PFIC. The algorithm recommends the use of licensed inhibitors of ileal bile acid transporters as the first-line treatment for patients with PFIC and suggests that genetic testing be used to confirm genotype whilst treatment is initiated in patients in whom PFIC is suspected. The authors recommend referring patients to an experienced centre, and ensuring that monitoring includes measurements of pruritus, serum bile acid levels, growth, and quality of life following diagnosis and during treatment. Conclusions: The algorithm presented within this paper offers guidance to optimise the management of paediatric PFIC. The authors hope that these recommendations will help to standardise the management of PFIC in the absence of clear clinical guidelines. Impact and implications: This opinion paper outlines a consistent approach to the contemporaneous diagnosis, monitoring, referral and management of children with progressive familial intrahepatic cholestasis. This should assist physicians given the recent developments in genetic diagnosis and the availability of effective drug therapy. This manuscript will also help to raise awareness of current developments and educate health planners on the place for new drug therapies in progressive familial intrahepatic cholestasis.

Erratum to "Opinion paper on the diagnosis and treatment of progressive familial intrahepatic cholestasis" [JHEP Reports 6 (2024) 100949].

[This corrects the article DOI: 10.1016/j.jhepr.2023.100949.].