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Chronic Hepatitis C in Childhood: An 18-Year Experience
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Clinical Infectious Diseases Nov 15, 2005;41:1431-1437
"......In conclusion, this study indicates that chronic hepatitis C acquired in childhood is a mild disease with a slow progression of fibrosis. Despite the benign course of HCV infection in the majority of cases, spontaneous clearance of serum HCV RNA is rarely observed. In children with persistent viremia and hypertransaminasemia, IFN therapy may be effective in the presence of genotypes other than genotype 1, whereas lower response rates are expected for genotype 1infected children. Presently, combination therapy using pegylated IFN and ribavirin has dramatically improved the sustained virological response among adults with CHC; preliminary studies have confirmed the efficacy of this therapy for children as well. Therefore, it is probable that, in upcoming years, it will be used for children with CHC. At the present, it seems reasonable to not treat all children, but to treat only those with more-severe liver disease and/or with positive predictive factors of response...."
See reports on Peginterferon 2a (Pegasys) therapy in children at the end of this article. 14 children aged 2-8 yrs were treated with Pegasys with a 42% Sustained Viral Reponse rate.
Authors: Raffaele Iorio,1 Antonietta Giannattasio,1 Angela Sepe,1 Luigi Maria Terracciano,2 Raffaella Vecchione,2 and Angela Vegnente1
Departments of 1Pediatrics and 2Pathology, University of Naples "Federico II," Naples, Italy
Background. The long-term outcome of chronic hepatitis C (CHC) has not been well studied, both for untreated and interferon-treated children. The aim of this study was to evaluate the long-term outcome of disease in a large series of children with CHC.
Methods. Clinical, biochemical, virological, and histological features were evaluated in all children (age, 218 years) with CHC who did not have concomitant disease and who attended at our hospital's liver unit during the period of 19862004.
Results.
One hundred twenty-five children with CHC were studied. All patients remained free of symptoms throughout the period of observation. On the basis of transaminase levels during the first year of positivity for antibodies to hepatitis C virus (HCV), children were divided into 2 groups: patients with hypertransaminasemia (100 patients, all of whom had detectable HCV RNA), and those with normal transaminases (25 patients; 16 had viremia and 9 did not have viremia).
Sustained clearance of viremia (SVR) was achieved in 38% of the patients treated with interferon, compared with 12% of untreated children (P < .05).
A sustained response to therapy was obtained in 64.7% of children infected with an HCV genotype other than genotype 1 and in 24.2% of those infected with HCV genotype 1 (P < .05).
Histological lesions were mild in all 64 patients who underwent liver biopsy. No linear correlation was found between duration of disease and progression of fibrosis.
Examination of a follow-up liver biopsy specimen revealed cirrhosis only in 1 (4.7%) of 21 children.
Conclusions.
Children with CHC were symptom free and had a morphologically mild liver disease. Interferon therapy may be effective for patients infected with HCV genotypes other than genotype 1, whereas lower response rates are expected for HCV genotype 1infected children. The real impact of therapy on long-term outcome remains to be established.
DISCUSSION
This 18-year retrospective study of a large number of consecutive children with CHC who were observed at a single health care center confirms that, in the majority of cases, children with CHC are symptom free, experience normal growth, and do not show clinical signs of chronic liver disease. During the entire period of observation, no child had decompensated liver disease or required liver transplantation. Our results are in agreement with those of Casiraghi et al. [4], who described a benign course of HCV infection acquired early in life during the first 35 years after exposure. Our study differs from the study by Casiraghi and colleagues, which included subjects who had been exposed to HCV through blood transfusions involving blood collected from a single HCV-infected donor, and our study enrolled a larger number of patients who had been infected through different routes and with different genotypes.
Although the findings of clinical examinations were unremarkable, laboratory evaluation revealed hypertransaminasemia in 80% of patients, whereas the remaining 20% had normal transaminase levels ab initio. The prevalence of children with normal transaminase levels was similar to that reported for adults [26]. No differences were found between children with normal transaminase levels and those with hypertransaminasemia with regard to sex, age, route of infection, and genotype. Recently, it has been hypothesized that a relationship exists between polymorphisms in the promoter region of the osteopontin gene and transaminase levels in adults with CHC [27]; therefore, it is probable that genetic factors may also affect the behavior of transaminase levels in children. Mild liver disease is usually present at biopsy in the majority of adults with persistently normal transaminase levels, whereas few patients have severe histological damage [28, 29]. In our study, liver biopsy findings were not available for this group of patients, but because histological lesions were mild in the children with hypertransaminasemia, it seems reasonable to assume that necroinflammation and fibrosis were also mild in children with persistently normal transaminase levels.
It is noteworthy that almost all of the children with normal liver enzyme levels and viremia maintained their status during the follow-up period. Although adults with normal transaminase levels have rates of sustained response to therapy similar to those for adults with hypertransaminasemia [26, 30], these days, there is not a clear indication to treat such patients.
In this study, we identified a subgroup of children who, since they were first observed, were anti-HCV positive and had normal transaminase levels and the absence of viremia. It is likely that anti-HCV antibodies in these patients were the sign of a past HCV infection.
As for the group of 50 untreated patients with baseline hypertransaminasemia and viremia, the rate of spontaneous viral clearance (12%) was lower than that reported by Vogt et al. [5] (45%) and Locasciulli et al. [6] (26.8%). This discrepancy could be related to the peculiar characteristics of patients included in those studies: the first included children who had posttransfusion HCV infection without clear evidence of chronic hepatitis, and the second evaluated patients who had leukemia that was in remission and an atypical serological profile for HCV infection. Thus far, no predictive factor (including HCV genotype) of spontaneous viral clearance has been identified; it is likely that genetically determined immunological factors could be involved.
In the present study, treated patients had a rate of sustained virological clearance significantly higher than that for untreated children; in particular, this occurred in the presence of genotypes other than genotype 1. These findings confirm the previously reported favorable effects of IFN therapy [11]. In the analysis by Jacobson et al. [11], a sustained response was observed in 36% of treated patients and in 70% of patients infected with genotype other than 1b. Compared with the studies included in Jacobson and colleagues' analysis, our study had a longer period of observation, both for treated and untreated patients. Despite the longer posttreatment follow-up period, in our patients, the rate of relapse was lower (8% vs. 22%). This discrepancy is probably attributable to the very strict response criteria used in our study, in which frequent determinations of serum HCV RNA level were performed. In addition, our results confirmed that fibrosis may improve after IFN therapy in children, particularly if there is a treatment-induced HCV RNA clearance. In spite of the promising results of IFN therapy for children, at the present time, all children with CHC do not seem to be reasonable candidates for such therapy, because treatment is expensive and is associated to several adverse effects; furthermore, prolonged therapy is required, and a favorable response is achieved only in a subset of patients. Finally, in the vast majority of untreated children, no significant worsening is usually observed.
In contrast with adults with CHC, extrahepatic manifestations were rarely observed in the studied children. Although the presence of autoantibodiesparticularly LKM1 antibodieshas been associated with more-severe and -progressive liver disease [31], our LKM1-positive children had low fibrosis grades and a favorable response to IFN therapy [23].
The present study not only confirms that CHC in children is morphologically mild in most cases, but it also shows that fibrosis progression is relatively slow and that cirrhosis is extremely rare. Unlike what has previously been reported [32], no linear correlation between duration of disease and progression of fibrosis was found in the present study. In fact, 2 of the 3 children with moderate fibrosis (score, 4) at the time of the first biopsy had a short duration of disease (2.1 and 2.5 years). On the other hand, the only patient for whom fibrosis was absent had a disease duration of 13.9 years. Therefore, the severity of liver disease does not seem to depend on the duration of HCV infection; instead, a host-virus interplay might be involved.
Use of PEG-interferon alfa-2a plus ribavirin as treatment for chronic HCV hepatitis in a child cured of ALL
Letter to the Editor
Pediatric Blood & Cancer
Volume 43, Issue 2, Pages 185
17 May 2004
Luca Lo Nigro, MD 1 *, Paola Guardo, BD 2, Milena La Spina, MD 1, Elena Mirabile, PhD 1, Paola Pisana, MD 1, Gino Schilir, MD 1, Paola Guardo, BD 2
1Center of Pediatric Hematology and Oncology, University of Catania, Catania, Italy
2Clinical Pathology Service, M. Ascoli-Tomaselli Hospital, Catania, Italy
Article Text
To the Editor: The natural history of and the treatment options for chronic hepatitis C (HCV) infection, in long-term leukemia survivors, have not been well characterized. Several reports showed the efficacy of combination therapy with peginterferon (PEG-IFN) alfa-2a and ribavirin in immunocompetent adults with chronic HCV infection [1]. There are no data regarding the use of combination therapy with PEG-IFN in children [2]. We report on the administration of PEG-IFN alfa-2a in combination with ribavirin in a child who had chronic HCV infection acquired during treatment for acute lymphoblastic leukemia (ALL). She was treated for ALL in our institution at the age of 3. She had a 10-years history of high serum alanine aminotransferase concentration. She was subsequently diagnosed with HCV genotype-1b positive chronic active hepatitis. After a year of IFN-alfa administration, at the age of 14, she presented with high levels of both serum alanine aminotransferase concentration and baseline viral load. A percutaneous liver biopsy showed a moderate intralobular inflammation/necrosis. Therefore, according to a recently described treatment tailored for adults [1], we administered 180 ug of PEG-IFN alfa-2a subcutaneously once weekly, plus daily ribavirin 1,000 mg for a total of 48 weeks. We adopted this dosage based on the fact that she had almost adult size (height 165 cm; weight 48 kg). The Institutional review board of our center approved this treatment and an informed consent was signed by patient's parents. We assessed the efficacy of this combination therapy by measuring alanine aminotransferase concentration and by performing both qualitative and quantitative HCV RNA RT-PCR using the Cobas Amplicor HCV Monitor assay (Roche Diagnostics-LA Roche, Ltd., Basel, Switzerland). We evaluated therapy response after 1, 4, 8, 12, 24, and 48 weeks, respectively. We noted a dramatic decrease of serum alanine aminotransferase concentration (from 350 to 35 U/L), correlated with a significant decrement in viral load (from >5,000,000 to 50 IU/L). Although we used an adult dosage, no side effects related to the combination therapy have occurred. Three consecutive qualitative HCV-RNA RT-PCR assays have been performed at 3 and 6 months and 1 year from therapy withdrawal, each demonstrating an undetectable level of viral RNA.
Although the implementation of blood donor screening, the prevalence of anti-HCV seropositivity among leukemia survivors is still high [3]. Evidence of progression to liver failure in survivors of pediatric malignancies has been reported [3]. Because their previously immunocompromized status might have promoted more rapid viral replication, increasing the risk for a rapid disease progression, a more aggressive approach regarding the use of antiviral therapy in this population with chronic HCV is needed. Based on our experience, we suggest that administration of PEG-IFN in association with ribavirin should be considered as first line treatment in children with chronic HCV hepatitis who have been previously cured of malignancies.
Pegasys in Children in chronic hepatitis C: safety, efficacy and pharmacokinetics
Reported by Jules Levin. This is part of coverage from the Digestive Disease Week Conference in Orlando, Florida, May 2003:
http://www.natap.org/2003/DDW/day11.htm
Kathleen Schwarz (Johns Hopkins University School of Medicine) reported at the DDW Conference (May 17-22, 2003, Orlando, Fl) on a small pilot study of the safety, efficacy, and pharmacokinetics (blood levels) of Pegasys (peginterferon alfa-2a 40KD) in childfen with chronic hepatitis C.
Seroprevalence of HCV infection in children in the US is 0.2% aged less than 12 years and 0.4% in children aged 12 to 19 years. New infections are primarly acquired by perinatal transmission, by mother to newborn. Chronic HCV infection in children is typically asymptomatic with normal or near normal ALT levels. No therapies are currently approved by the FDA for treatment of chronic hepatitis C in children.
The role of antiviral therapy for chronic hepatitis C (CHC) in children remains unclear. Some studies have shown the safety and efficacy of standard interferon (IFN), with or without ribavirin (RBV), in children with CHC, but no data is available regarding the use of pegylated IFN in children.
The goal of this study is o investigate the safety, efficacy and pharmacokinetics (PK) of peginterferon alfa-2a (40KD) in children with CHC. This is a multicenter, open-label study of treatment-naive children with established chronic hepatitis C.
Children received Pegasys (peginterferon alfa-2a 40KD) once weekly for 48 weeks with a 24-week post-treatment follow-up. The dose was normalized for patient body surface area (BSA) ([180µg/1.73 m2)] x patient BSA). Multiple blood samples were obtained to determine single-dose and multiple-dose PK. Predose blood sampling was measured at weeks 1, 4, 8,12, 24, 40 and 48 weeks. Post-dose blood sampling was performed at weeks 1 and 24 at 24, 96, and 168 hours after dose. Adverse events (AEs) were assessed by clinical exam. HCV RNA was tested using Roche Amplicor Monitor HCV Test v. 2.0.
There were 14 patients, 8 males, 6 females, aged 2-8 (median = 4.5) years were enrolled; majority (13/14) were Caucasian and genotype 1 (12/13). Chronic hepatitis C was acquired by vertical transmission in 11 patients. The mean weight was 44 lbs, the mean height 106.9 cm. Mean ALT was 73.5and mean AST was 66.9. 10 children had viral load less than 850,000 copies/ml and 4 had greater than 850,000 copies/ml. All 14 children did not have cirrhosis.
In dosing, height, age, gender, body weight, and body surface area were assessed. After administration of the first peginterferon alfa-2a (40KD) dose, there was rapid and sustained absorption with mean concentrations of 22.3 ng/ml and 19.0 ng/ml at 24 and 96 hours postdose. The mean individual pediatric trough concentrations at week 24 ranged from 5 to 35 ng/ml, and the mean trough was 20 ng/ml which was insignificantly different from adult trough data which is 25 ng/ml for adults. AUC 0-168hrs varied from about 1000 to 9000 ng/ml for the children with a mean of 5700 ng/ml over the 168 hour dose interval and these were done at week 24, and was insiginificantly greater at 5700 ng.h/ml than for adults at 4548 ng.h/ml. Peginterferon alfa-2a (40KD) concentrations increased 1.5- 2.5-fold before reaching steady state by week 12.
At weeks 24, 48, and 72, 57% (8/14), 50% (7/14) and 42% (6/14) of patients, respectively, were HCV RNA negative. Most frequently reported AEs were pyrexia, headache, vomiting, injection site reactions, irritability, anorexia and abdominal pain; no serious AEs were observed. The majority of these AEs were mild in intensity. 5 patients had dose adjustments due to low absolute neutrophil counts; the lowest absolute neutrophil count for each patient was:
0.40 x 109/L
0.60 x 109/L
0.70 x 109/L
0.60 x 109/L
0.50 x 109/L
Characteristics of the 6 sustained responders: 5 male, 6 genotype 1, 5 viral load below 850,000 copies/ml, and 6 had ALT less than 3 times the upper limit of normal.
5 patients withdrew prematurely after completing 24 to 47 weeks of treatment. Reasons for withdrawal included: adverse events/intercurrent illness (2 for elevated ALT, 1 for elevated triglycerides); administrative error (last dose not taken; refusal to continue treatment.
The authors concluded that Pegasys dosing with a correction for body surface area is appropriate in children. A once weekly dose of 180 ug/1.73 m2 x BSA (104 ug/m2) provides a predicted Ctrough of about 20 ng/ml and AUC of about 5700 ng.h/ml after 24 weeks. Exposure values are generally similar to those in adults treated with the approved dose of Pegasys 180 ug/week. Pegasys produced sustained virologic responses in 42% of children aged 2 to 8 years, similar to that in adults. These results support further study of peginterferon alfa-2a (40KD), with and without RBV, in children with CHC.
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