Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: Efficacy, safety, and pharmacokinetics

Abstract

Chronic hepatitis C virus (HCV) infection is usually asymptomatic in children, but significant liver disease may occur. We evaluated the efficacy, safety, and pharmacokinetics of interferon alfa-2b and ribavirin in children with chronic HCV. We determined the optimal ribavirin dose in an initial cohort of a phase 1 study and then subsequently used it, in combination with interferon alfa-2b, in a second cohort of this study and a phase 3 trial. The primary efficacy endpoint in all studies was sustained virological response, defined by undetectable serum HCV RNA 24 weeks after completion of therapy. All efficacy and safety analyses were performed on the intent-to-treat population. Children receiving interferon alfa-2b plus ribavirin 15 mg/kg/d in the phase 1 study had the maximum reduction in serum HCV RNA at treatment weeks 4 and 12 with an acceptable safety profile. This ribavirin dose was selected as optimal and used in all subsequent studies. In all, 46% (54/118) of optimally treated children achieved sustained virological response. Sustained virological response was significantly higher in children with HCV genotype 2/3 (84%) than in those with HCV genotype 1 (36%). Adverse events led to dose modification in 37 (31%) and discontinuation in 8 (7%). Multiple-dose interferon alfa-2b and ribavirin peak and trough concentrations and area-under-the-curve were similar between children and adults. In conclusion, interferon alfa-2b in combination with ribavirin is effective and safe in children with chronic hepatitis C virus. (HEPATOLOGY 2005;42:1010-1018.) H epatitis C virus (HCV) infection is a global health problem affecting an estimated 170 million individuals worldwide. Although our understanding about the natural history and pathobiology of HCV infection in children is incomplete, it has been associated with significant liver disease, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma in this population. 1-4 Approximately 10% to 20% of adults 5 and 36% of children 6 treated with interferon alone achieve long-term virological remission. The addition of ribavirin to interferon-based regimens markedly improves virological responses in adults. 7,8 Limited data are available regarding the use of interferon alfa with ribavirin in children. Therefore, the aim of our studies was to evaluate the efficacy, safety, and pharmacokinetics of interferon alfa-2b in combination with ribavirin for the treatment of chronic HCV infection in children. Patients and Methods Study DesignA clinical program consisting of two studies was initiated to evaluate the efficacy, safety, and pharmacokinetics of interferon alfa-2b (Intron A, Schering-Plough, KenAbbreviations: HCV, hepatitis C virus; MIU, million international units; PCR, polymerase chain reaction; TSH, thyroid-stimulating hormone; ALT, alanine aminotransferase; SVR, sustained virological response. From the

Comparison of the Safety Profiles of Pegylated Interferon α-2a and α-2b Administered in Combination with Ribavirin for Chronic Hepatitis C Infection: A Real-World Retrospective Cohort Study

“…The age criterion was included as disease prognosis is different in children and adults. 17) Study Outcome The primary outcome measure was defined as difference in time to withdrawal from treatment due to adverse events between patients receiving PEG-IFN α-2a combined with ribavirin and those receiving PEG-IFN α-2b combined with ribavirin. The variables used to evaluate the outcome were treatment performance (completion or withdrawal), reasons for withdrawal, and treatment period.…”

Controversies in the management of pediatric liver disease: Hepatitis B, C and NAFLD: Summary of a single topic conference

“…35,36 Because of the observed synergy in adults, several trials have assessed IFN plus ribavirin in children. [37][38][39][40] Overall, SVR occurred in 73 of 144 (51%) children treated with IFN plus ribavirin in these trials. Several randomized clinical trials in adults verify considerably better virologic response rates (50%-60%) with the use of pegylated (peg) interferons, particularly when combined with ribavirin.…”

“…In one small study, children younger than 12 years of age appeared to fare better. 40 As in adults, African-American children had poorer response rates to combination treatment than Whites but the small number of patients enrolled limited the analysis. 40 Sustained virologic response rates are similar between HCV-infected children with normal and abnormal pre-treatment serum AT levels.…”

“…40 As in adults, African-American children had poorer response rates to combination treatment than Whites but the small number of patients enrolled limited the analysis. 40 Sustained virologic response rates are similar between HCV-infected children with normal and abnormal pre-treatment serum AT levels. 36,40,41 Important factors that may forecast response early in the course of treatment and in individualizing therapy in adults, such as early virologic response and 'duration of undetectability' have not been studied in children.…”

Hepatitis C virus infection in children and adolescents

“…Currently, the only Food and Drug Administration‐approved options for children with chronic HCV infection are ribavirin (RBV) and pegylated‐interferon (PEG‐IFN). While sustained viral responses (SVRs) have improved over the last several decades from ∼16% with IFN monotherapy to >50% with the combination of RBV and PEG‐IFN, multiple studies have shown that SVR rates remain frustratingly low compared to adults with access to DAA regimens 6, 13, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116. Consequently, in the absence of approved DAA therapies in the United States, the chance of attaining SVR in HCV‐infected children and adolescents is little more than 50% (Table 4).…”