Is Interferon Therapy in Pediatric Chronic Hepatitis B Infection Warranted? (2000)

The mainstay of therapy for chronic hepatitis B infection is α interferon. Numerous studies have shown efficacy in adults with successful seroconversion from HBeAg to anti-HBeAg documented in about one-third of treated patients (Ann Intern Med 1993;119:312–23). The benefit of seroconversion already has been elucidated in adults: clinical, biochemical and histological improvement follow seroconversion. Outcome analyses have revealed a decreased incidence of hepatocellular carcinoma and improved survival amongst adults treated with α-interferon (Hepatology 1999;29:971–975). While the efficacy of interferon has been shown in adults, similar large studies have not been performed in children. Recently, two studies from Italy followed a total of 107 children with chronic hepatitis B over a period of 5 years following α-interferon therapy versus untreated controls (Gut 2000;46:591–594). Entrance criteria included: ages 2–16 years, HBsAg, HBeAg and HBV DNA positivity for at least 6 months, elevation of AST or ALT for at least six months, histologic evidence of chronic hepatitis without cirrhosis within 12 months, and exclusion of co-infection with HDV or HIV and of other causes of liver disease. Interferon therapy varied and consisted of either 3 MU/m2 three times a week for 6 months, 7.5 MU/m2 three times a week for 6 months, 5 MU/m2 for 12 weeks, or 5 MU/m2 preceded by 4 weeks of prednisolone. At the conclusion of the study, patients were categorized as responders or non-responders. Responders were defined as having persistent loss of Hepatitis B e antigen and Hepatitis B DNA within 12 months of therapy or spontaneous clearance in those without therapy. Of note, at five years of follow-up, there were an equal number of responders in both the untreated and treated groups. All of the interferon treated patients were analyzed collectively despite different therapeutic regimens. Comparison of the responders with the non-responders revealed elevated ALT and HBV DNA titers <1000 pg/mL in the responder group. These predictive factors of beneficial response to interferon corroborate prior study findings (Hepatology 1991;13:1035–9;Am J Gastroenterol 1991;86: 327–30). One interesting result noted in the Italian paper was evidence of HBsAg clearance in 17 responders during and following interferon therapy that was not noted in any of the untreated group. While Hepatitis B e antigen clearance was similar between interferon treated and untreated patients at five years, there was earlier Hepatitis B e antigen clearance in the interferon treated group. These two findings together may indicate the role of interferon in accelerating natural spontaneous clearance of hepatitis B virus. Previous studies on α-interferon performed in pediatric populations have revealed similar short-term improvements as defined by seroconversion of Hepatitis B e antigen to antibody. One multicenter randomized control study of 144 chronic hepatitis B patients revealed comparable early rates of seroconversion in the interferon treated group (Gastroenterology 1998;114:988–995). Another open randomized control study also revealed rates of 33% seroconversion at 6 month follow-up in children treated with 5 mega units/m2 thrice weekly for 6 months and of 60% seroconversion in children treated with 10 megaunits/m2 thrice weekly for 6 months (Pediatr Infect Dis J 2000;19:52–6). The recent long-term data from Italy bring into question current recommendations for treatment of children with chronic hepatitis B with interferon therapy. Should we be imposing such therapy for children without proven long-term benefits? The only benefit of interferon therapy was an earlier clearance of HbeAg—is this 3–4 year window of Hepatitis B e Antigen seroconversion worth it? While children often tolerate interferon therapy better than adults, the side effects are significant since these patients are often otherwise asymptomatic. Therapy is painful and consists of injections thrice weekly for six months. Flu-like symptoms from interferon can lead to significant anorexia and nutritional depletion. Finally, the cost of α-interferon therapy is substantial—up to US $10,000 for six months of treatment. There is only one analysis of the cost-benefit of interferon therapy in children with chronic active hepatitis B (J Pediatr Gastroenterol Nutr 1997;24:25–32). While this study found that interferon was cost-effective, this conclusion was based on the premise that the therapy prevented cirrhosis and hepatocellular carcinoma in a portion of children treated. Perhaps we should consider not treating children with chronic hepatitis B infection. One could argue that the only intervention in children for hepatitis B is limited to preventative measures i.e. vaccination. Should interferon therapy only be used in adult populations where efficacy has been demonstrated? If therapy of pediatric patients is in question, perhaps testing for chronic hepatitis B should not be performed at all in this age group (since effective interventions in this population have not been found). Long-term studies clearly are needed to determine whether interferon therapy in children will prove to be efficacious in preventing the long-term complications of HBV infection, including cirrhosis and hepatocellular carcinoma. In the meantime, perhaps there is a role for α-interferon in promoting early clearance of hepatitis B e antigen. If so, treatment criteria will need to be modified in order to achieve maximal efficacy by identifying those most likely to spontaneously clear hepatitis B e antigen. Hopefully, if α-interferon therapy does not have long-term benefit in chronic hepatitis B in children, lamivudine or even combination therapy of lamivudine with interferon will provide some early means of treatment.