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Guidance for Clinical Trials for Children and Adolescents ÃStefan Wirth, yDeirdre Kelly, zEtienne Sokal, Socha, jjGiorgina Mieli-Vergani, jjAnil Dhawan, e Lacaille, Agne`s Saint Raymond, Olivier, and Taminiau be compared with present therapy. Safety measures should include the Most children with chronic hepatitis C are infected vertically, have a low standard recommended laboratory investigations, growth parameters, qual- natural seroconversion rate, and carry a lifetime risk of cirrhosis and cancer.
ity-of-life or psychological measures, and a requirement for long-term Affected children are usually asymptomatic, and histological findings are mild with a low risk of progression, although 5% develop significant liverdisease in childhood. The use of combination treatment with pegylated Key Words: children and adolescents, chronic hepatitis C, clinical trials, interferon-a and ribavirin has changed the outcome and prognosis for this disease, with approximately 60% of children achieving sustained viralclearance. Combination therapy is not ideal for children because pegylated interferon is administered subcutaneously, impairs growth velocity, and bothinterferon and ribavirin have significant adverse effects that affect com-pliance. In addition, approximately 50% of children infected with genotype 1 do not respond to therapy. Thus, additional treatment options are requiredincluding improvement in dosing, reduction in the length of treatment, andevaluation of new drugs, such as protease inhibitors, which could be more In adults, treatment guidelines for chronic hepatitis C virus (HCV) infection are based on a large number of published effective for patients infected with genotype 1. The primary goal of natural history studies and randomized controlled trials. There treatment is to eradicate the infection. The future clinical trial design should are fewer data available regarding the epidemiology, spontaneous ensure that any new drugs demonstrate noninferiority to the present standard course, and treatment of chronic hepatitis C in children and regimen in both children and adults. The measure for documenting sub- adolescents. Initially, most guidelines recommended children to stantial improvement above present therapy should be increased viral be managed and treated in a similar way as adults, although recent clearance rate or the same clearance rate, with a shorter duration of treatment data suggest that this may no longer be appropriate. Some experts and/or fewer adverse effects. We do not believe there is any need for a recommend postponing treatment until adulthood because children placebo arm because approved therapy is available and new treatments can are asymptomatic and have mild liver disease. Recently, severalpublished open-label treatment trials have demonstrated significantefficacy and safety of HCV infection therapy in children and Received May 22, 2010; accepted July 20, 2010.
adolescents using either interferon-a 2b or peginterferon-a 2b in From the ÃClinic for Children and Adolescence, HELIOS Klinikum Wuppertal, Witten-Herdecke-University, Germany, yThe Liver Unit, combination with ribavirin, which resulted in official approval of Birmingham Children’s Hospital NHS Trust, Birmingham, UK, the this treatment regimen by the US Food and Drug Administration zService de He´patologie Pe´diatrique, Cliniques Universitaires St Luc, (FDA) and the European Medicines Agency (EMA) In the §Department of Gastroenterology, Hepatology and Immunology, addition, there is now considerable experience with peginter- The Children’s Memorial Health Institute, Warsaw, Poland, the jjKing’s feron-a 2a in combination with ribavirin in children As in College London School at King’s College Hospital, London, UK, the adults, sustained viral response (SVR) depends on genotype.
ôHoˆpital Necker-Enfants Malades Service de Gastroente´rologie Pe´dia- Patients infected with genotype 2 and 3 respond significantly trique, Paris, France, and the #European Medicines Agency, London, better than those with genotype 1 or 4 who only have response rates of 50% Therefore, half of the treated patients remain Address correspondence and reprint requests to Prof Dr Stefan Wirth, Clinic for Children and Adolescence, HELIOS Klinikum Wuppertal, chronic virus carriers with a risk of progressive liver disease Witten-Herdecke-University, Heusnerstr. 40, D-42283 Wuppertal, so there are compelling reasons to improve the present treatment The views expressed in this article are the personal views of the authors and should not be understood or quoted as being made on behalf of or reflecting the position of the EMA or one of its committees or workingparties.
This Guidance is the result of a consensus meeting of a working group in The prevalence of HCV infection in children in developed November 2009 consisting of members and experts of the ESPGHAN countries ranges between 0.1% and 0.4% During the last Hepatology Committee and the EMA: Stefan Wirth, Deirdre Kelly, 10 years the predominant mode of viral hepatitis C transmission has Etienne Sokal, Piotr Socha, Giorgina Mieli-Vergani, Anil Dhawan, become vertical infection. In developed countries, contamination and Florence Lacaille for ESPGHAN; Agne`s Saint Raymond, Sophie through transfusion or health care is exceedingly rare, but it may remain frequent in developing countries. The rate of perinatal The authors report no conflicts of interest.
transmission from an infected mother to her child ranges from Copyright # 2011 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric 2% to 5% and is now the nearly exclusive mode of infection in Gastroenterology, Hepatology, and Nutrition Western countries In the United Kingdom the prevalence of HCV infection in pregnant women was 0.16% In Scotland the JPGN  Volume 52, Number 2, February 2011 Copyright 2011 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN  Volume 52, Number 2, February 2011 prevalence ranged between 0.29% and 0.4% depending on age Peginterferon-a 2b (60 mg Á mÀ2 Á weekÀ1) and ribavirin From France a 0.53% HCV infection RNA prevalence of the young (15 mg Á kgÀ1 Á dayÀ1) were approved by the FDA (2008) and the population was reported Seroprevalence of antibody to HCV EMA (2009). Recommendations are that patients with genotype 1 infection in the United States was 0.4% Given a perinatal and 4 should be treated for 48 weeks, with treatment discontinued at transmission rate of approximately 4% in HCV infection, RNA- 6 months if there has been no viral response. Patients with genotype positive mothers, and an annual birth rate of 4.4 million newborns in 2 and 3 should be treated for 24 weeks. The majority of treated North America and 5 million in Europe, there could be an estimated children and adolescents will tolerate peginterferon and ribavirin 530 to 600 new unavoidable infections annually in infants for these well. Most adverse events were mild to moderate, although dose industrialized regions. In cases of vertical infection, the chronicity reductions of both drugs were required; the rates of discontinuation rate is extremely high Spontaneous viral clearance after HCV were low in all published trials. Severe psychiatric adverse effects infection in children seems higher in parenterally infected individ- were rare in prepubertal individuals, but thyroid dysfunction and uals and may reach 35% to 45% up to adolescence transient growth impairment were reported Follow-up studies However, viral clearance in vertically infected children seems to to evaluate long-term sequelae are in progress.
be dependent on the genotype and was found to range from 2.4% to In summary, despite considerable progress in the treatment of 25% In contrast, children infected with genotype 3 had a children with chronic hepatitis C, in approximately half of the patients higher spontaneous clearance rate than those infected with genotype with genotype 1, which represents the vast majority of infected 1. Beyond age 4 years spontaneous viral clearance became unlikely individuals, treatment remains unsuccessful. The need for subcu- taneous administration of pegylated interferon and the range ofsignificant adverse effects with both interferon and ribavirin meanthat further improvement in terms of dosing, reducing the length of treatment, and evaluating new drugs such as protease inhibitors It is well documented that HCV infection in children is clinically asymptomatic. Histological findings are usually mildand the risk of severe complications is low. Nevertheless, despitethe favourable prognosis during the first and second decades of life, approximately 4% to 6% of children have evidence of advanced liver fibrosis or cirrhosis Large liver transplantation units Present treatment is demanding with respect to parenteral have reported on children who needed liver transplantation due to administration, the range of adverse effects, and patients’ compli- progressive HCV infection In a lifetime, the risk of developing ance, and its efficacy against genotype 1 is suboptimal.
cirrhosis is about 20%, which is influenced by alcohol consumption, Eradication of childhood HCV infection is desirable because whereas the risk of hepatocellular carcinoma is based on developing children with chronic hepatitis C carry a lifetime risk of cirrhosis cirrhosis at 2% to 5% However, these data are from adults and and cancer. The risk is probably not linear and may be strongly there is no valid information about the long-term course of verti- influenced by environmental factors. However, affected children cally infected children. A recent study in pediatric patients cured of further expand the pool of hepatitis C carriers in the population and malignancy with chronic hepatitis C documented liver cirrhosis in hence participate in viral transmission. Importantly, children may feel stigmatized by their friends and develop serious psychologicalproblems, resulting in reduced quality of life. In addition, edu- cational problems may rise with the risk of restricting their careerchoices by the infection, especially in the health field.
Initially, treatment of chronic hepatitis C in children and Moreover, therapy may be more efficient in children due to adolescents was based on an a-interferon monotherapy with multiple the general absence of comorbidities or intoxications. The present dosing regimen yielding an SVR rate from 0% to 76% Nineteen standard of care regimens using peginterferon in combination with studies using a-interferon have been published between 1992 and ribavirin are long, relatively toxic, and expensive. New protocols, 2003 With increasing experience a-interferon monotherapy either shorter or with different drugs, are thus desirable.
(injections thrice weekly) showed a rather poor response, and riba-virin was added. Six studies were published between 2000 and 2005and demonstrated an SVR from 27% to 64% Thestratification according to genotypes revealed a good response (>80%) in patients with genotype 2 and 3 and an SVR of approxi- mately 36% to 53% in those with genotype 1. FDA and EMA The primary goal of treatment is to eradicate the infection approved interferon-a 2b (3 Mio U, thrice per week) in combination to prevent late complications. Hence, the aim is not the treatment of with ribavirin (15 mg Á kgÀ1 Á dayÀ1).
an ongoing liver disease, but the prevention of a future one. All Peginterferon in combination with ribavirin became the children with chronic hepatitis C with active infection with a standard of care for adults with chronic hepatitis C. Advantages measurable level of HCV-RNA should be considered for treatment.
were better SVR, reduced injection frequency to once per week, and Although neither the level of aminotransferases nor of HCV-RNA a better adverse effect profile. Subsequently, the therapy was predicts the long-term outcome, these criteria should be included in evaluated in children and adolescents and the results of 6 trials the analysis of the results because SVR may be better in individuals have been reported SVR in patients with genotype 1 with genotype 1 who have a lower viral load from 5 trials with >30 patients ranged from 44% to 59%. SVR in Histology: We do not feel that liver histology is a useful entry children with genotype 2 and 3 was >90%. Three trials used criterion because children generally do not have severe lesions.
peginterferon-a 2b, and 2 used peginterferon-a 2a. The level of However, because steatosis is a prognostic factor for treatment aminotransferases or histological findings by liver biopsy did not response in adults and is partly related to HCV infection itself as correlate with SVR. In 1 study, 32% of children with genotype 1 and well as to body weight, it would be desirable to perform a liver high viral load (>600,000 U/L) and 73% with low viral load biopsy at the beginning of a trial as a baseline and to include measures of fibrosis/steatosis in the analysis of the results Copyright 2011 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN  Volume 52, Number 2, February 2011 Guidance for Clinical Trials for Children and Adolescents With Chronic HCV Endpoints: The primary endpoint should be SVR, which is TABLE 1. Recommended baseline investigations before HCV defined as persistent HCV-RNA loss more than 6 months after cessation of treatment, anticipating eradication of the chronic HCVinfection. A secondary endpoint should be normalization of amino- Physical and neuropsychiatric examinationTanner pubertal stage Evaluation of growth parameters, z scores for height and weight, The drug to be tested should have demonstrated noninfer- iority to the present standard treatment in adults and children (pegylated interferon-a in combination with ribavirin). We do Liver histologyassessed by Ishak or Metavir scores not feel that there is a need for a placebo arm because approved effective therapy for children and adolescents is available and new treatments could be compared with present therapy. The test drug Complete red and white blood cell count, reticulocytes could be used in triple combination with pegylated interferon andribavirin or as monotherapy.
ALT, AST, g-GT, AP, bilirubin, Alb, coagulation New treatment options should focus primarily on patients infected with genotype 1 because of the relative lack of efficacy of present therapy. Improved efficacy could be evaluated as an Immunoglobulins, autoantibodies (ANA; LKM 1), increased viral clearance rate (eg, >65%) in those patients. Alter- natively, new treatment regimens could achieve the same viral clearance rate, but with a shorter duration of treatment or with less Alb ¼ albumin; ALT ¼ alanine aminotransferase; ANA ¼ anti-nuclear antibody; AP ¼ alkaline phosphatase; AST ¼ aspartate aminotransferase;BMI ¼ body mass index; BUN ¼ blood urea nitrogen; g-GT ¼ gamma- All of the children with chronic hepatitis C, defined as glutamyl transferase; HCV ¼ hepatitis C virus; HOMA ¼ homeostasis persistence of viral replication with positive HCV-RNA for more model assessment; LKM ¼ liver-kidney microsomal antigen; TSH ¼thyroid-stimulating hormone.
than 6 months, are eligible independent of the mode of transmissionand the level of aminotransferases before treatment. Treatment isnot indicated before age 3 years because of safety reasons and to Surrogate markers of steatosis such as findings of ultrasono- allow for the possibility of spontaneous viral clearance. Trial graphy, magnetic resonance imaging, or Fibroscan are not generally protocols should stratify patients according to genotype 1 and 4 available and are not standardized. Thus, for a more reliable and 2 and 3, respectively. Two age groups (3–10 years and 10–18 analysis of the results it is desirable to have a liver biopsy at the years) should be separately documented and analysed. In view of beginning of a clinical trial. Because insulin resistance is also a the effect on final height, treatment during rapid growth spurts or factor associated with response to treatment in adults, determination puberty should be avoided if possible. Additional factors influen- of homeostatic model assessment index is useful at the beginning cing SVR such as mode of infection; sex; aminotransferase levels; and end of the treatment. Iron load has been related in adults to a and histolological grading of fibrosis, inflammation, and steatosis more severe disease Therefore, the determination of serum should be recorded. Female adolescents should be advised ferritin levels is a meaningful marker for the analysis of results.
Because of possible transient growth inhibition of interferons and Children with previous treatment failure could be included 2 evaluation of growth parameters including z scores for height and years after the end of treatment to allow for delayed seroconversion weight, growth velocity needs to be performed regularly. Bone age and/or the effects of the previous medication. Individuals with in children older than 7 years at the beginning and the end of significant comorbidities interfering with liver function, such as treatment may be a guide to estimated final height.
co-infection with HIV, chronic hepatitis B, hepatotoxic treatments, The recommended investigations and repeat frequency or other liver diseases, should not be treated in clinical trials.
during treatment are shown in The decrease of HCV- The recommended necessary baseline investigations before RNA during 4, 8, and 12 weeks after the initiation of treatment are treating patients with chronic hepatitis C in a clinical trial are evaluated and included in the analysis of the results. Patients with summarized in A baseline liver biopsy is recommended, persistence of positive HCV-RNA at 6 months, irrespective of although histological inflammatory activity and fibrosis are likely genotype, should stop treatment because SVR is unlikely.
to be mild, but measures of steatosis may be useful as discussed Five-year follow-up after cessation of treatment is recom- above. demonstrates 2 internationally established scores mended and includes the measurement of standard blood tests, liver that could be used to assess fibrosis and inflammation function tests, and quantitative HCV-RNA at 6 months and then TABLE 2. Comparison of histological staging using Ishak and Metavir scores Copyright 2011 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN  Volume 52, Number 2, February 2011 TABLE 3. Recommended investigations during HCV treatment Physical and neuropsychiatric examination Evaluation of growth parameters, z score for height and weight, BMI, waist circumference Complete red and white blood cell count, Alb, ALT, AST, g-GT, AP, bilirubin, coagulation Reticulocytes, Alb, BUN, creatinine, immunoglobulins, autoantibodies (ANA; LKM 1), Alb ¼ albumin; ALT ¼ alanine aminotransferase; ANA ¼ anti-nuclear antibody; AP ¼ alkaline phosphatase; AST ¼ aspartate aminotransferase; BMI ¼ body mass index; BUN ¼ blood urea nitrogen; g-GT ¼ gamma-glutamyl transferase; HCV ¼ hepatitis C virus; HOMA ¼ homeostasis model assessment;LKM ¼ liver kidney microsomal antigen; TSH ¼ thyroid-stimulating hormone.
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