This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hepatitis C affects approximately 170 million people worldwide and is an established cause of chronic liver disease in adults and children. The exact number of chronically infected children is unknown. However, based on data from the Centers for Disease Control and Prevention (CDC)/National Health and Nutritional Evaluation Study (NHANES), the United States (US) prevalence of hepatitis C virus (HCV) infection in the pediatric population is 0.1 to 0.2% (compared with 1.8% of adults in the US), translating to approximately 150,000 infected children. The prevalence of HCV infection in children is between 0.1to 0.9% in Western countries. The clinical features of HCV infection are similar in adults and children. Acute HCV infection is typically subclinical in all age groups with fulminant hepatitis being an extremely rare presentation of disease. Most patients remain asymptomatic. Based on retrospective assessment of patients infected during childhood through transfusion, approximately 40 to 55% of children will progress to chronic hepatitis C, compared with rates of up to 80 to 90% in adults. A previous clinical study (on file with the sponsor) established the comparability of pediatric pharmacokinetics of INTRON A (interferon alfa 2b) and REBETOL (ribavirin) to that reported in the adult population. Interferon alfa 2b pharmacokinetic parameters in pediatric subjects were approximately twice that of the corresponding adult values. This is consistent with the fact that the dose administered to children was approximately twice that given to adult subjects on a body surface area basis. When these data were dose normalized to 1.875 MIU/m2, AUC and Cmax measurements were similar in adults and children. Pediatric pharmacokinetic parameters for REBETOL 8, 12, and 15 mg/kg/day corresponded to that seen in adults receiving doses of 800, 1000, and 1200 mg/day, respectively. Two pediatric hepatitis C open label studies on file with the sponsor evaluated the safety and efficacy of INTRON A 3 MIU/m2 twice a week plus REBETOL. A total of 118 subjects from these studies received INTRON A 3 MIU/m2 twice a week and 15 mg/kg/day REBETOL. Overall, sustained virologic response (SVR) was achieved in 46% of subjects; in these subjects, 36% SVR was reported for Genotype 1 subjects and 84% for Genotype 2/3 subjects. The pediatric response rates were comparable to published adult hepatitis C literature for subjects that receive a comparable regimen. These published adult data sets report an overall range of SVR between 41 to 47%, with SVR in 29 to 33% of Genotype 1 subjects and 65 to 79% of Genotype 2/3 subjects. Wirth et al. reported results of an open label study of 41 children aged 3 to 16 years with chronic hepatitis C. Approximately half of the children received interferon alfa 2b at a dose of 3 MIU/m2 twice a week and the remainder received 5 MIU/m2 twice a week. All subjects received 15 mg/kg/day of ribavirin. Overall, SVR was achieved in 61% (25/41). Response by genotype was reported as follows: 53% (18/34) SVR in Genotype 1 subjects and 100% (7/7) in Genotype 2/3 subjects. At present, the optimal therapy for adult patients is peginterferon alfa in combination with ribavirin. The pegylated form of interferon alfa 2b, peginterferon alfa 2b (PEG Intron ), when combined with REBETOL represents a further enhancement both in efficacy and in the convenience of once weekly dosing. PEG Intron 1.5 g/kg once weekly plus weight based REBETOL has been significantly more effective than INTRON A plus REBETOL in adults. Sixty-one percent of adult subjects overall achieved SVR, with 48% SVR in Genotype 1 subjects and 88% in Genotype 2/3 subjects. PEG Intron plus REBETOL use in children has not been evaluated by a major clinical study. Because both pharmacokinetics and response rates to INTRON A plus REBETOL are comparable in the pediatric and adult populations, it is reasonable to expect that treatment of children with PEG Intron plus REBETOL will result in further enhancements in treatment efficacy. This global, multicenter, open label Phase 1 b/3 study is designed to evaluate this hypothesis.
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