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Discussion
Chronic hepatitis C is a significant cause of liver disease and a frequent indication for liver transplantation in adults. Long-term follow-up studies in adult patients with CHC have shown that attainment of SVR (defined as undetectable HCV RNA at 24 weeks after the end of therapy) following treatment with interferon (nonpegylated and pegylated) with or without ribavirin therapy is durable and predictive of long-term clinical benefit. Results of this 5-year follow-up study confirm that the long-term outcome for children who achieved SVR with interferon alfa-2b and ribavirin treatment for CHC is consistent with that observed in adults. Overall, 98% (55/56) of paediatric patients who attained SVR maintained undetectable HCV RNA levels during the long-term follow-up period. In addition to maintaining undetectable HCV RNA levels, 98% of paediatric patients who attained SVR and had normal ALT levels following treatment maintained normal ALT levels at their last long-term follow-up visit. The high percentage of patients who maintained long-term undetectable HCV RNA levels and normalization of ALT confirm the durability of virologic response in this population of paediatric patients, highlighting the success of this therapy in children.
Although nonpegylated interferon plus ribavirin is no longer the standard of care treatment for CHC in children, long-term data on safety and durability of response of any interferon in this population are not yet available. This study of long-term response in children treated with interferon alfa-2b plus ribavirin demonstrates similar durability to that reported in adults and suggests that similar outcomes are likely in children treated with peginterferon plus ribavirin. In addition, this study provides data on decreases in growth during combination therapy and recovery post-treatment, which is of value in selecting children for CHC therapy.
The initial treatment studies indicated that 8% and 20% of patients had haemoglobin level <10 g/dL and/or neutropenia (<1000 cells/L), respectively, while on treatment they recovered to pretreatment levels after therapy. No evidence of latent effects of treatment with interferon alfa-2b and ribavirin on haematologic parameters was apparent. Additionally, no delayed serious adverse events related to previous interferon alfa-2b and ribavirin treatment during the 5-year follow-up period were reported.
Treatment with interferon alfa-2b has been shown to cause a temporary slowing of growth in paediatric patients. Growth analyses of the initial and long-term follow-up studies showed that treatment with interferon alfa-2b and ribavirin slowed patients' growth during treatment and that some patients did not return to their baseline height percentile when treatment was completed. The mean height percentile observed during the 5 years of follow-up was slightly below the mean pretreatment height percentile and the median for the US population, but the mean last weight percentile was above the median for the US population and mean pretreatment weight percentile. Although the largest decreases in height percentiles were mainly seen in patients treated during their estimated peak height velocity based on age, there is much variability in the timing and rate of growth during puberty between individuals, and growth charts only capture a certain standard. In addition, a major limitation of our observations regarding growth is the absence of parental height data that would provide perspective on the patients' estimated final target heights.
Observations regarding a temporary reduction in growth velocity have also been made in paediatric patients receiving peginterferon alfa-2b plus ribavirin. Jara et al. reported a reduction in growth of 1.6 cm compared with the growth velocity 50th percentile for age and sex in 22 of 26 paediatric patients receiving peginterferon alfa-2b plus ribavirin. Despite a return to normal growth velocity after the end of treatment, the authors reported that the modest decrease in height percentile that occurred during treatment was not regained during the 6-month follow-up period. In addition, Wirth et al. reported that the mean height percentile after the 24-week post-treatment follow-up period for 107 paediatric patients treated with peginterferon alfa-2b plus ribavirin was slightly lower than the median of the US population and below the mean pretreatment height percentile. The 5-year long-term follow-up of this study is ongoing. However, Sokal et al. reported no influence of peginterferon alfa-2a plus ribavirin therapy on height in 65 paediatric patients. The trends seen in growth after interferon and ribavirin therapy are not consistent.
The risk/benefit ratio between the possible slowing of growth in paediatric patients receiving interferon products and the clinical consequences if treatment is withheld or delayed must be considered when treating a child with CHC with these agents. Much variability in growth was seen in this population, but supporting data including parental heights, nutritional status, concurrent disease status and medications were not available to firmly assess the impact of treatment on growth in this population. The long-term effect on growth is being further studied in patients who underwent treatment with peginterferon alfa-2b and ribavirin, and will be available in coming years.
Spontaneous resolution of chronic HCV infection is rare in untreated children, whereas persistent viremia after infection is almost universal. The disease course varies, but most children show at least mild or moderate hepatic inflammation and a small proportion have steatosis. Rare cases of children with hepatitis C-related bridging fibrosis, decompensated cirrhosis and hepatocellular carcinoma have been reported. Delaying therapy until early adulthood may have less impact on growth but increases the risk of liver disease progression or the need for liver transplantation in the interim, which may impede attainment of SVR in later years. In contrast, early treatment with interferon alfa-2b plus ribavirin results in an enduring clinical cure in almost half of all treated paediatric patients. The possibility of successful viral clearance needs to be weighed against the reported adverse events in children, which are largely consistent with the well-described tolerability profile among adult patients with hepatitis C receiving interferon alfa-2b (nonpegylated or pegylated) plus ribavirin. Thus, the arguments for withholding therapy from paediatric patients may be outweighed by the benefits of early viral eradication and the potential difficulties that may be incurred if treatment is delayed until the course of disease is further advanced. In addition, peginterferon alfa plus ribavirin treatment has shown improvement in therapeutic outcome among paediatric patients with CHC and is likely to demonstrate similar durability.
In conclusion, results of this 5-year follow-up study confirm that sustained loss of serum HCV RNA 24 weeks after the end of treatment with interferon alfa-2b plus ribavirin is predictive of long-term virologic response in paediatric patients. Most children had normalized (within 15 percentiles of pretreatment height) or improved growth during this 5-year long-term follow-up, although their mean height percentile at their last long-term follow-up visit was slightly below their mean pretreatment height. The findings of this study support the future treatment of paediatric patients with hepatitis C to prevent progression of liver disease.
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