One of the first clinical trials to ascertain the efficacy of pegylated interferon with the antiviral drug, ribavirin, in children with hepatitis C has reached positive results.1
"This combination treatment has some advantages, so I guess that this combination will replace conventional treatment very soon analogous to the adults' treatment," said Stefan Wirth, MD, of Children's Hospital at Witten-Herdecke University in Wuppertal, Germany, the study's chief investigator. Yet Wirth stressed that pegylated interferon/ribavirin treatment hasn't yet been approved for hepatitis in children.
Pegylated Interferon for Children: A Topic of Debate
In the study, more than half of the children who took part achieved a sustained virologic response, or SVR, defined as undetectable levels of the hepatitis C virus for at least 6 months following the end of therapy.2 The combination of pegylated, or longer-lasting, interferon and ribavirin is considered the gold standard treatment today for people with hepatitis C.3 But there have been no definitive studies published previously to determine if this therapy protocol was also effective in children infected with the virus, wrote Wirth and his associates.
Interferon alfa-2b and ribavirin is the currently approved treatment for children with HCV between ages 3 and 18, but "the indication for therapy in children and adolescents is still debated in many countries," wrote the research team.
More Tolerable Side Effects in Children
Why treat children at all? Liver disease is not very progressive in the first 15 to 20 years of life, Wirth and his colleagues wrote. Nonetheless, "severe liver disease occasionally occurs during childhood" and "because treatment at an early age is better tolerated than in adulthood, individuals who were infected very early in their lifetime, particularly by vertical transmission, should be offered treatment," the investigators stressed.
"You do not find the most severe complication, which is neurological impairment, such as depression" in children, Wirth explained. "Also, flu-like symptoms are not that serious. It is quite common that children do bear some clinical symptoms easier than adults (e.g. fever)."
Scrutinizing Pegylated Interferon
To find out whether pegylated interferon and ribavirin might be effective, Wirth's group tested the efficacy and tolerability of the treatment combination in a group of 62 children chronically infected with HCV ranging in age from 2 to 17 years. HCV genotype, liver enzyme tests, and route of disease transmission were also taken into account in this trial.
Once HCV genotype (the various strains of the virus), method of infection, and liver enzyme levels were determined, Wirth and his team initiated therapy consisting of weekly injections of pegylated interferon alfa-2b (PEG-Intron/Schering-Plough) combined with oral doses of ribavirin once per day. One child—who developed an injection site reaction—quit the study.
After 1 year of treatment, the researchers found that nearly two-thirds of the children (39 of 61) had undetectable levels of HCV RNA—the virus' genetic material that serves as evidence of infection. Three of these initial responders later relapsed during a 6-month follow-up period, but nearly 60 percent remained HCV-free, meaning they achieved sustained virologic responses.
In responders who had increased liver enzyme levels before treatment, all had normal levels afterwards.
Response Rates by Viral Strain
When the results were broken out by viral strain, all those with genotypes 2 or 3 achieved a persistent SVR, compared to fewer than half of the children infected with the genotype 1 strain of the virus. This strain is the most common among people with hepatitis C and the most difficult to treat.4 Of those with genotypes 2 and 3 who achieved viral responses after only 6 months of treatment, all of them continued to remain viral-free 1 year later, Wirth's team found.
The findings also showed that children who had been infected by contact with a needle (such as in a blood transfusion) responded better to this therapy than those who had been infected by their mothers at birth, though the differences weren't significant. Those with normal levels of liver enzymes before treatment similarly responded better to the PEG-Intron/ribavirin combination treatment than those with increased levels, but the difference here was also not significant. (These enzymes are typically measured by doctors to confirm whether a person's liver is damaged or not. Higher blood levels of the enzymes is a clear indicator of such damage.)5
"The data of this uncontrolled study confirms that treatment with recombinant peginterferon alfa-2b plus ribavirin in children and adolescents with chronic hepatitis C was well tolerated and yielded an encouraging result with 59 percent sustained viral response," wrote Wirth and his colleagues. "It is particularly remarkable that all patients infected by genotype 2 and 3 showed permanent response."
As a result of the findings, Wirth said children with genotypes 2 and 3 can be treated to a maximum of 6 months.
They also stressed that even children with normal liver enzymes had high viral responses, suggesting that they should not be excluded from therapy. Additionally, the lower response rates in those with genotype 1 and in those infected by their mothers warrants additional research, they stated.
More Research Needed
Despite the positive findings, the pilot study was not controlled; that is, it didn't randomly divide children into one group receiving the combination treatment or a control group receiving another type of therapy or a non-therapeutic intervention, such as a placebo. This type of trial is considered of higher quality because the differences in the results between the two groups can be directly compared. Additionally, the response rates found in this study were not substantially higher than those reported in trials of standard interferon and ribavirin, the authors pointed out, especially in those with genotype 1. However, the dose with pegylated interferon is once per week, less often than what is indicated for pediatric hepatitis using standard interferon, Wirth's team noted.
"Further studies with larger numbers of patients have to elucidate whether there is a different response rate in relation to mode of transmission," Wirth and his colleagues wrote. Additional future research "should focus on treatment duration for genotype 2 and 3 patients, and particularly on vertically infected children with genotype 1."
The researchers have future research plans of their own. "I think we will join an international controlled study with more patients, also focusing on this issue," Wirth told Priority Healthcare.
1. Wirth S, Pieper-Boustani H, Lang T et al. Peginterferon alfa-2b plus ribavirin treatment in children and adolescents with chronic hepatitis C. Hepatology 2005 May;41(5):1013-8.
2. Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002 Sep 26;347(13):975-82.
3. Strader DB, Wright T, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Hepatology 2004 Apr;39(4):1147-71.
4. NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements 2002 Jun 10-12;19(3):1-46.
5. New Definitions for Healthy Ranges of Alanine Aminotransferase, a Blood Test of Liver Function. Summaries for Patients. Annals of Internal Medicine. Available at: http://www.annals.org/cgi/content/full/137/1/I-37. Accessed May 5, 2005.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
