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Background: Approximately 3.5 million children and adolescents worldwide are chronically infected with HCV. This study uses pharmacokinetic modeling to identify pediatric doses of elbasvir/grazoprevir (EBR/GZR) that achieve plasma concentrations similar to those seen in adults receiving the approved fixed-dose combination regimen of EBR/GZR. Patients and Methods: We conducted a nonrandomized, single-arm, multicenter, open-label phase 2b trial in children and adolescents aged 3 to <18 years with chronic HCV genotype 1 or 4 infection (NCT03379506). Pharmacokinetic data were used to bridge efficacy and safety data from adults to children in a stepwise (oldest to youngest) manner. A total of 57 participants were enrolled: cohort 1 (aged 12 to <18 y), n = 22; cohort 2 (aged 7 to <12 y), n =17; and cohort 3 (aged 3 to <7 y), n =18. Results: Steady-state plasma exposures were achieved by week 4 for EBR and GZR in all cohorts and daily dosing achieved geometric mean steady-state area under the concentration-time curve at 0-24 hours that fell within comparability bounds established for adults. All participants achieved sustained virologic response 12 weeks after completing treatment (ie, undetectable HCV RNA 12 wk following completion of treatment). Headache (n =4), fatigue (n =4), and nausea (n =2) were the most common treatment-related adverse events (all mild or moderate); no participant discontinued because of an adverse event. Conclusions: Pediatric EBR/GZR pharmacokinetic models were successfully developed based on complex adult population pharmacokinetic models. At appropriate age-related doses, EBR/GZR is safe and effective in pediatric and adolescent participants with HCV infection. [ABSTRACT FROM AUTHOR]

The etiology of portal hypertension (pHTN) in children differs from that of adults and may require different management strategies. We set out to review the etiology, management, and natural history of pHTN at a pediatric liver center. From 2008 to 2018, 151 children and adolescents with pHTN were identified at a free‐standing children's hospital. Patients were stratified by etiology of pHTN (intrahepatic disease [IH], defined as cholestatic disease and fibrotic or hepatocellular disease; extrahepatic disease [EH], defined as hepatic vein obstruction and prehepatic pHTN). Patients with EH were more likely to undergo an esophagoduodenscopy for a suspected gastrointestinal bleed (77% vs. 41%; P < 0.01). Surgical interventions differed based on etiology (P < 0.01), with IH more likely resulting in a transplant only (65%) and EH more likely to result in a shunt only (43%); 30% of patients with IH and 47% of patients with EH did not undergo an intervention for pHTN. Kaplan‐Meier analysis revealed a significant increase in mortality in the group that received no intervention compared to shunt, transplant, or both and lower mortality in patients with prehepatic pHTN compared to other etiologies (P < 0.01 each). Multivariate analysis revealed increased odds of mortality in patients with refractory ascites (odds ratio [OR], 4.34; 95% confidence interval [CI], 1.00, 18.88; P = 0.05) and growth failure (OR, 13.49; 95% CI, 3.07, 58.99; P < 0.01). Conclusion: In this single institution study, patients with prehepatic pHTN had better survival and those who received no intervention had higher mortality than those who received an intervention. Early referral to specialized centers with experience managing these complex disease processes may allow for improved risk stratification and early intervention to improve outcomes. [ABSTRACT FROM AUTHOR]

Background: The safety and efficacy of sofosbuvir-velpatasvir in children aged 3-17 years with chronic hepatitis C virus (HCV) infection of any genotype were evaluated., Methods: In this Phase 2, multicenter, open-label study, patients received once daily for 12 weeks either sofosbuvir-velpatasvir 400/100 mg tablet (12-17 years), 200/50 mg low dose tablet or oral granules (3-11 years and ≥17 kg), or 150/37.5 mg oral granules (3-5 years and <17 kg). The efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Dose appropriateness was confirmed by intensive pharmacokinetics in each age group., Findings: Among 216 patients treated, 76% had HCV genotype 1% and 12% had genotype 3. Rates of SVR12 were 83% (34/41) among 3-5-year-olds, 93% (68/73) among 6-11-year-olds, and 95% (97/102) among 12-17-year-olds. Only two patients experienced virologic failure. The most common adverse events were headache, fatigue, and nausea in 12-17-year-olds; vomiting, cough, and headache in 6-11-year-olds; and vomiting in 3-5-year-olds. Three patients discontinued treatment because of adverse events. Four patients had serious adverse events; all except auditory hallucination (n = 1) were considered unrelated to study drug. Exposures of sofosbuvir, its metabolite GS-331007, and velpatasvir were comparable to those in adults in prior Phase 2/3 studies. Population pharmacokinetic simulations supported weight-based dosing for children in this age range., Interpretation: The pangenotypic regimen of sofosbuvir-velpatasvir is highly effective and safe in treating children 3-17 years with chronic HCV infection., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background and Aim: Weight loss is an effective treatment for children with nonalcoholic fatty liver disease (NAFLD), but it is extremely difficult to achieve outside of an intensive weight management program. We hypothesized that one can achieve success in improving NAFLD and weight-related outcomes in a structured and focused multidisciplinary clinical program feasible to implement in a gastroenterology clinic., Methods: We prospectively tracked the clinical status of our patients enrolled in a multidisciplinary program of dietary and exercise advice through an institutional review board-approved NAFLD registry. Each patient met with a gastroenterologist and dietitian every 3 months for 30 minutes to set individualized goals and monitor progress., Results: A total of 108 children have been enrolled in the registry, and of the 83 that were eligible for 1-year follow-up and included in the analysis, 39 patients returned, resulting in a 47% follow-up rate. These 39 patients showed statistically significant improvements in mean BMI z score (-0.1 U, P < 0.05), total (-11 mg/dL, P < 0.05) and low-density lipoprotein (9 mg/dL, P < 0.05) cholesterol, and serum alanine aminotransferase levels (-36 U/L) and aspartate aminotransferase levels (-22 U/L) levels., Conclusions: A clinically feasible multidisciplinary program for obese pediatric patients with NAFLD stabilized BMI z score and significantly improved aminotransferase levels at 1-year follow-up.

Objectives: Autoantibodies were studied in a well-characterized cohort of children with chronic hepatitis C during treatment with pegylated interferon and ribavirin to assess the relation with treatment and development of autoimmune disease., Methods: : A total of 114 children (5-17 years), screened for the presence of high-titer autoantibodies, were randomized to pegylated interferon with or without ribavirin. Anti-nuclear, anti-liver-kidney-microsomal, anti-thyroglobulin, anti-thyroid peroxidase, insulin, anti-glutamic acid decarboxylase (GAD) antibodies were measured after trial completion using frozen sera., Results: At baseline, 19% had autoantibodies: anti-nuclear antibodies (8%), anti-liver-kidney-microsomal antibodies (4%), and glutamic acid decarboxylase antibodies (4%). At 24 and 72 weeks (24 weeks after treatment completion), 23% and 26% had autoantibodies (P=0.50, 0.48 compared with baseline). One child developed diabetes and 2 hypothyroidism during treatment; none developed autoimmune hepatitis. At 24 weeks, the incidence of flu-like symptoms, gastrointestinal symptoms, and headaches was 42%, 8% and 19% in those with autoantibodies versus 52%, 17%, and 26% in those without (P=0.18, 0.36, and 0.20, respectively). In children with negative hepatitis C virus polymerase chain reaction at 24 weeks, there was no difference in the rate of early virologic response/sustained virologic response, respectively, in those with autoantibodies 76%/69% vs 58%/65% in those without (P=0.48)., Conclusions: Despite screening, we found autoantibodies commonly at baseline, during treatment for chronic hepatitis C and after. The presence of antibodies did not correlate with viral response, adverse effects, or autoimmune hepatitis. Neither screening nor archived samples assayed for thyroid and diabetes-related antibodies identified the 3 subjects who developed overt autoimmune disease, diabetes (1), and hypothyroidism (2).

Objective: To determine whether portoenterostomy (PE) revision in patients afflicted with biliary atresia (BA) is a viable treatment option and, if so, identify which patients may benefit., Background: BA, the most common cause of neonatal liver disease, results in biliary tract obstruction and hepatic fibrosis. Kasai PE is the initial surgical intervention performed and, if successful, restores drainage and preserves the native liver. Portoenterostomy failure warrants liver transplantation, but because of complications related to transplantation, treatment strategies to salvage the native liver may be beneficial. Using uniformly applied criteria, we have revised PEs to delay or avoid transplantation., Methods: A retrospective review of medical records of patients diagnosed with BA since 1983 was performed. Patient demographics, symptoms, indications for revision, laboratory values, and outcomes were recorded. A cohort of patients who underwent revision after initial PE was identified. Survival rates were assessed using the Kaplan-Meier method. For patients who required transplantation, operative data from the revised PE cohort were compared with those from the unrevised PE cohort. A Cox proportional hazards model was used to determine covariates predictive of a favorable outcome., Results: Of 181 children who underwent PE, 24 underwent revision. Adequate biliary drainage, as evidenced by normalized conjugated bilirubin levels, was achieved in 75% of revised patients. Overall survival in patients who underwent revision, regardless of transplantation, was 87%. Among patients who underwent PE revision, 46% have survived with their native liver., Conclusion: Experience at our center suggests that with appropriate patient selection, PE revision may delay the need for liver transplanation yielding encouraging patient outcomes.

Objective: Alpha-1-antitrypsin (A1AT) deficiency is the most common genetic cause of liver disease in children; however, the role of polymorphic heterogeneity in the A1AT gene as a modifier of other forms of pediatric liver disease is not clear. We hypothesized that non-M A1AT allele variants are more common in children with chronic liver disease than in the general population., Methods: A retrospective, single-center study was performed in which A1AT phenotypes were obtained by reviewing charts of children with chronic liver disease. Chi-square analysis was used to compare allele frequencies in the population of children with liver disease with published epidemiologic data and to compare allele frequencies among disease subgroups., Results: The frequency of A1AT Z and other alleles was increased in children with chronic liver disease (n = 241) when compared with the published reference database (P < 0.001). This increase remained significant when the population was divided into disease subsets: biliary atresia (n = 67) and other liver disease (n = 174) (P < 0.001 for both). Among children with biliary atresia referred for liver transplant evaluation, the presence of a non-M allele was associated with a lower mean age at transplant listing than the MM phenotype (235 vs 779 days, P = 0.036) and more frequent loss of native liver by 24 months of age (90% vs 65%, P = 0.04)., Conclusions: A1AT non-M alleles are more frequent in children with chronic liver disease than in the general population. We speculate that these non-M alleles may act as genetic modifiers in pediatric liver disease in general and modulate disease progression in children with biliary atresia in particular.

Background: Previous studies have suggested an increased risk of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder (EBV-PTLD) in patients receiving tacrolimus for immunosuppression. We hypothesized that after correction for confounding variables, immunosuppression with tacrolimus is not associated with an increased risk of EBV-PTLD., Methods: Potential cases of EBV-PTLD, identified by chart review, were independently ascertained by three clinicians and defined using published criteria. Agreement in diagnosing EBV-PTLD was measured using Kappa coefficients. Unadjusted and adjusted relative risk estimates were determined using proportional hazards regression., Results: Twenty-three cases of EBV-PTLD were identified in 221 patients, a proportion of 10.4% (95% confidence interval [CI]: 6.4%-14.4%). Multivariable analysis revealed that immunosuppression with tacrolimus was associated with an increased risk of EBV-PTLD (relative risk 3.10: 95% CI: 1.21-7.92), as was age at transplantation as a continuous variable (parameter estimate -0.15, P=0.03). Kappa coefficients in diagnosing EBV-PTLD and subclassifying as neoplastic and non-neoplastic EBV-PTLD were 0.73 (95% CI: 0.54-0.93) and 0.54 (95% CI: 0.40-0.68), respectively. Patients with neoplastic PTLD demonstrated a lower probability of survival than patients with non-neoplastic PTLD and non-cases., Conclusions: Immunosuppression with tacrolimus and young age at transplantation are associated with an increased risk of EBV-PTLD in children undergoing liver transplantation, although we cannot exclude detection bias as an explanation for this observed increase. Good agreement between observers can be achieved using previously published criteria for defining EBV-PTLD. Patients with neoplastic EBV-PTLD may have a worse prognosis, and thus identification of risk factors for the development of this subtype of the disorder may be more important.