Aglaia Zellos

An analysis of published trials of interferon monotherapy in children with chronic hepatitis C.

Background Although no therapeutic regimen has received Food and Drug Administration approval for treating children with chronic hepatitis C viral infection (CHC), there have been a number of pediatric interferon-&agr; (IFN-&agr;) trials. The purpose of this study was to perform a critical review of these trials to determine 1) end-of-treatment (ETR) and sustained-response (SR) rates, 2) predictors of response to therapy, and 3) safety of and tolerance to IFN-&agr; in children with CHC. Methods Relevant studies in the English-language medical literature and abstracts (January 1990 through November 2000) were identified by searching for manuscripts that contained the key words “children,” “hepatitis C,” and “interferon.” Trials were considered eligible for inclusion in this analysis if criteria for treatment included positive serum polymerase chain reaction for hepatitis C virus RNA (HCV PCR). Results Twenty published manuscripts of the use of IFN-&agr; in children with CHC were found, of which 12 met our inclusion criteria. Twenty-two abstracts, of which seven met our inclusion criteria, were identified. In the 19 included trials, 366 treated and 105 untreated children were observed; five countries were represented. Average ETR was 54% (0%–91%) and average SR was 36% (0%–73%). The SR in children with genotype 1 was 27% versus 70% for nongenotype 1 (P = 0.001). Five of 105 (5%) untreated controls exhibited spontaneous viral clearance. Conclusions To date, there is no published large-scale, multicenter, prospective, placebo-controlled randomized trial of the use of IFN-&agr; in children with CHC. The data in this review suggest that IFN-&agr; in children with CHC does have reasonable efficacy and safety. This review highlights the need for a more systematic design of future pediatric CHC trials. Ideally, such trials would be large scale, prospective, and controlled, and would include HCV genotype and viral load, histology, quality of life measures, and systematic recording of adverse events and of effects of therapy on growth and development.

High viral load and mild liver injury in children with hemophilia compared with other children with chronic hepatitis C virus infection.

BACKGROUND In adults with hepatitis C virus (HCV) infection, the severity of liver disease may be influenced by the mode of transmission. The purpose of this study was to evaluate whether the mode of transmission affects liver injury and viral load in children with chronic HCV infection, independent of duration of infection and/or HCV genotype. METHODS Thirty-nine anti-HCV (EIA-2) positive patients, were divided into three groups: group 1, children with a history of blood transfusion (n = 9; age, 13.3+/-1.3 years), group 2, children with hemophilia (n = 19; age, 11.6+/-0.8 years); and group 3, children with maternal-fetal transmitted disease (n = 10; age, 4.7+/-1.1 years). Serum alanine aminotransferase, HCV viral load, HCV genotype, and liver histology were assessed. RESULTS Serum HCV viral load was higher in group 2 (4.27+/-1.0x10(6) copies/ml; p = 0.006) than in group 1 (0.73+/-0.3x10(6) copies/ml) and in group 3 (0.83+/-0.2x10(6) copies/ml). Conversely, group 2 had less severe liver injury compared with children of similar age in group 1 (p = 0.022). Despite a shorter duration of infection, group 3 had liver injury similar to that in group 1. Hepatitis C virus genotype did not influence the level of viremia or liver injury. CONCLUSIONS Although children with hemophilia exhibited a high HCV viral load, liver histopathology was less severe than in children who had acquired HCV by blood transfusion or maternal-fetal transmission. These observations support the need to investigate the role of host immune response rather than the virus per se in the pathogenesis of HCV infection in children.

Use of oral naltrexone for severe pruritus due to cholestatic liver disease in children.

Pruritus is a distressing and often debilitating symptom of many chronic cholestatic liver disorders. The severity of pruritus may interfere with normal daily activities and sleep and decreases the quality of life of affected patients (1,2). Intractable pruritus is difficult to manage and is an indi

Percutaneous liver biopsy in hemophiliac children with chronic hepatitis C virus infection

Objective: To develop a protocol for safe performance of percutaneous liver biopsies in children with deficiency of factor VIII (n = 12) or IX (n = 2) and chronic hepatitis C virus infection. Patients and Methods: Liver biopsies were performed after administration of factor VIII or IX, before and 24 weeks after cessation of antiviral therapy. To define the optimal means of providing replacement therapy, 10 children were enrolled in a randomized crossover design study of bolus versus continuous factor VIII for performance of the liver biopsy. For the crossover study, all of the patients were given a loading dose of 50 ± 5 IU recombinant factor (rF)VIII/kg; a minimum of factor VIII activity of ≥80% 30 to 60 minutes following factor VIII infusion was required for liver biopsy. For the bolus protocol, rFVIII 25 to 50 IU/kg was given 6, 14, 24, 36, 48, and 60 hours after completion of the loading dose. For the continuous protocol, rFVIII was given 3 to 4 IU/kg per hour for 48 hours, followed by a bolus of 25 IU/kg at 60 hours. In patients with factor IX deficiency, a loading dose of 100 IU/kg was followed by a bolus of 50 IU/kg at 3, 15, 27, and 48 hours after the loading dose. Results: Twenty liver biopsies were performed in children with factor VIII deficiency without major complications. One of the 3 biopsies in the patients with factor IX deficiency was complicated by a hemoperitoneum. Midazolam and fentanyl were used in the first 8 patients. However, postbiopsy pain, presumably secondary to hematoma in 2 patients and hemoperitoneum in 1, prompted us to use ultrasound to locate a suitable biopsy site and to change to propofol; this allowed us to better immobilize the liver, to minimize postbiopsy bleeding. The subsequent 15 biopsies were well tolerated without postbiopsy pain or other complication. Conclusions: Percutaneous liver biopsy in children with factor VIII deficiency can be safely performed using either bolus or continuous infusion of recombinant factor VIII. A brief general anesthetic and ultrasound guidance are recommended.

Nasobiliary drainage in an episode of intrahepatic cholestasis in a child with mild ABCB11 disease.

P rogressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive disorder, defined by conjugated hyperbilirubinemia with normal serum g-glutamyl transpeptidase (GGT) values and severe pruritus that progresses to fibrosis in the first months of life (1). Mutations in ATP8B1 are associated with PFIC type 1 (PFIC1) and with instability of the bile-canaliculus membrane (2,3). Mutations in ABCB11 are associated with PFIC type 2 (PFIC2) and with defective expression of bile salt export pump (BSEP) at the bile-canaliculus membrane (4,5). Mutations in ATP8B1 or ABCB11 also may result in ‘‘benign’’ recurrent intrahepatic cholestasis (BRIC; BRIC1 and BRIC2, respectively) marked by recurrent episodes of cholestasis and severe pruritus, with normal GGT values, that last from weeks to months without progression to chronic liver disease (2,6). Both ATP8B1 and ABCB11 disease of intermediate phenotypic expression between PFIC and BRIC are described (7,8). Endoscopic nasobiliary drainage (NBD) can rapidly resolve episodes of BRIC1 in adults (9); its use in adults with BRIC2 or children with BRIC has not been reported. We present a previously healthy 5-year-old child, a compound heterozygote for ABCB11 mutations associated with PFIC2/BRIC2, whose first episode of severe jaundice and pruritus ended shortly after initiation of NBD. A previously healthy 5-year-old boy, an only child, was admitted to Aghia Sophia Children’s Hospital with jaundice, acholic stools, and dark urine for 1 week. A month before admission, the patient developed severe pruritus, attributed to atopic dermatitis. There was no history of fever, diarrhea, or drug ingestion in the last month. There was no family history of consanguinity, autoimmune disease, chronic liver disease, or cystic fibrosis. Vaccinations against hepatitis A and B were complete. The patient was deeply icteric with severely excoriated extremities. His weight was 14.8 kg (less than 3rd percentile)