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Treating Hepatitis C: Are Children the Same as Adults? Editorial
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Download the PDF here
Download the PDF here
Study below editorial
Gastroenterology 2010
AYMIN DELGADO-BORREGO
Department of Clinical Pediatrics
University of Miami Miller School of Medicine Miami, Florida
Significant progress has been made in the management of hepatitis C virus (HCV) infection over the last decade. Combination treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) represents the standard of care for the adult patient infected with chronic hepatitis C, producing sustained virologic response (SVR) in about half of persons treated. A number of host and viral factors that contribute to response to antiviral therapy have been identified in adults. Among viral factors, HCV genotype followed by pretreatment viral load are the most important predictors of SVR. Patients harboring genotypes 2 or 3 have substantially higher response rates than those with genotype 1, and those with pretreatment viral load levels <2 x 106 copies/mL (800,000 IU/mL) are more likely to experience SVR. Additional predictors of antiviral response include histology (absence of fibrosis and significant steatosis being more favorable), lower body mass index, and younger age.1 Comorbidities such as diabetes mellitus, insulin resistance, and HIV co-infection also negatively impact response rates.2, 3, 4 Race has been found to be an important determinant of response to therapy, with lower SVR rates among African Americans as compared with Caucasians. The recent identification of a polymorphism in the interleukin (IL)-28B locus on chromosome 19 as an exceptionally strong predictor of response to antiviral therapy, and may explain a large portion of the observed racial variation in response.5 However, we have learned also that, despite these advances, efforts to control HCV infection at a population level have been hampered by a lack of knowledge and awareness among health providers and the general public as well as by inadequate screening efforts leading to significant underdiagnsis.6
What is known about the management of HCV infection in children? The literature on pediatric hepatitis C is limited. In 1992, Ruiz-Moreno et al7 published their findings on a study of 12 children treated with recombinant IFN-alfa monotherapy. Later studies of pediatric HCV infection treatment with IFN were nonrandomized and included <50 patients each.8, 9, 10 In 2005, Gonzalez-Peralta et al11 studied 118 children treated with a combination of interferon alfa-2b plus RBV with 46% of patients achieving SVR. Subsequently, there have been studies evaluating the use of PEG-IFN for pediatric HCV infection, but the majority have been small in number and none have been randomized trials (Table 1). The results of one of the largest pediatric studies, an international multicenter trial, was recently published by Wirth et al.12 A total of 107 children 3-17 years of age were treated with PEG-IFN alfa-2b (60 μg/m2 per week) and RBV (15 mg/kg per day) for 48 weeks (genotype [G]1, G4, or G3 with high viral load) or 24 weeks (G2, G3 with low viral load) in an uncontrolled trial. SVR was attained in 65% of all patients, but only in 53% of those with genotype 1. Baseline viral load was the main predictor of response in the G1 cohort. No differences were noted based on patient age. There were no serious adverse events related to antiviral therapy.
However, none of these investigations evaluated whether combination therapy is superior to PEG-IFN monotherapy in the treatment of HCV infected children. This is an important question, because RBV, as the authors argue, has been found to be teratogenic13 and embryotoxic14 in animals. In this issue of Gastroenterology, Schwarz et al15 address this question by performing the only randomized, placebo-controlled trial of the safety and efficacy of PEG-IFN with and without RBV in children and adolescents with chronic hepatitis C, and did so in the largest pediatric treatment cohort published to date (PEDS-C). But perhaps even more significant is the fact that Schwartz et al explicitly ask whether children should be treated in the same manner as adults, highlighting the importance of potential differences and similarities in these 2 groups.
Schwarz et al compared children with chronic HCV infection, 5-18 years of age, who were randomly assigned for treatment with PEG-IFN alfa-2a (180 μg/1.73 m2 subcutaneously each week) and RBV (15 mg/kg per day in 2 divided doses) or PEG-IFN alfa-2a and placebo for 48 weeks. Most study participants had mild to moderate liver disease, 4% had bridging fibrosis, and 2% had cirrhosis. SVR was achieved in 59% of children treated with combination therapy versus 21% of those in the PEG-IFN alfa-2a plus placebo group. Among patients infected with HCV G1, 47% achieved SVR in the combination arm as opposed to only 17% in the PEG-IFN alfa-2a plus placebo group. When evaluating predictors of SVR, the investigators noted that combination therapy, HCV genotype other than 1, nonmaternal route of transmission, and female gender were strongly associated with response. A lower baseline HCV RNA level was among the most important predictors of response. No difference was observed between the combination and placebo groups for patients with HCV RNA <600,000 IU/L, although this group represented no more than 30% of the cohort. Response was associated also with the presence of moderate or marked hepatic inflammation and to the absence of steatosis. This investigation did not demonstrate an association between baseline fibrosis and SVR. Similarly, race or body mass index were not associated with SVR. However, it is important to note that this study was not designed to evaluate predictors of response; as such, the number of subjects within each of the relevant subgroups may have been insufficient to reach conclusions about certain variables. Details of the pathologic findings from children in this trial have been reported previously,16 demonstrating greater fibrosis among children who were overweight, which raises the question of the role of body mass index in the progression of HCV infection.
During the 2-year study period in PEDS-C, response proved to be durable. Durability of virologic response was 100% among the 82%-86% of SVR subjects who completed the 2-year follow-up evaluations. Interestingly, few children achieved viral clearance at 4 weeks of treatment, but all patients who did achieved SVR. There were 3 subjects who did not achieve viral clearance at week 12 of treatment (early virologic response), but did achieve SVR, in contrast with observations from the adult literature.17, 18 Dose reductions were necessary in about one third of the entire cohort, and somewhat more frequently in the combination therapy arm. Overall, therapy was well tolerated and there were few serious adverse events.
As eluded to by Schwarz et al, children are not small adults. Most new cases of pediatric HCV infection are the result of maternal-to-infant transmission. What it means for a developing fetus or for a newborn to acquire HCV infection remains largely unknown. There are some suggestions that this mode of acquisition may be associated with more aggressive disease.19 Schwarz et al's study showed infection acquired in this manner was a strong negative predictor of response. However, more studies are needed to learn the differences between this and other modes of HCV acquisition in pediatric populations. Potential effects on the developing body and brain should be considered, ideally balancing effects of therapy with those of the HCV itself. As we have learned from PEDS-C, discontinuation of treatment may not be indicated as a result of inability to achieve early virologic response in children, in stark contrast with adults, for whom this is a stopping rule. Female gender was significantly associated with SVR in PEDS-C; by contrast, the adult literature has not recognized this to be a major predictor of response to antiviral therapy. The basis for this difference in children may require further exploration. This investigation and others support the notion that children tolerate antiviral therapy better than adults, and this is an important factor to consider when making medical management decisions.
Understanding the differences between children and adults with respect to hepatitis C infection is not only relevant to pediatricians. Results of studies from HCV-infected adults are often confounded by comorbidities such as type 2 diabetes, alcoholic liver disease, cardiovascular diseases, and others.
Children, on the other hand, most often lack these comorbidities. They represent a natural cohort that can help to elucidate our understanding of the pathogenesis of hepatitis C through assessment of direct viral effects, which in turn may inform the adult literature. Thus, knowledge about pediatric hepatitis C infection is not only essential for the proper management of affected children, but can also serve the HCV-infected community at large.
Unfortunately, evidence on the subject of HCV infection in children is limited for the moment. Important, well-established concepts in the treatment of adults with HCV infection have not been documented in the pediatric literature. The negative associations between African-American race and advanced hepatic fibrosis with SVR were not observed by Schwarz et al and have not been reported in pediatric studies, likely as a result of insufficient power among available investigations to answer these questions. The role of obesity as a factor accelerating liver disease in HCV infection and as a negative predictor of response among children and adolescents20 should also be investigated in prospective trials. Despite a large body of literature on the metabolic consequences of HCV infection in adults, the answers to questions such as whether HCV induces insulin resistance, the role of insulin resistance in the natural history of HCV, or whether HCV leads to alterations in lipid metabolism in children have not been reported. Similarly, the effects of polymorphisms of the IL28B gene on response to antiviral therapy in children are not known.
Schwarz et al's investigation is an important step toward an improved understanding of pediatric HCV infection and its management, because it exemplifies the scientifically rigorous evidence that is much needed in the field. However, more work needs to be done. The fact that the only randomized, placebo-controlled trial of PEG-IFN and RBV in children is published a decade after this became the standard of care for adults speaks for itself. Upcoming advances in the management of adult HCV infection that are currently under investigation should provide an impetus for equivalent research in sufficiently large pediatric cohorts now rather than later. The notion by some that treatment should be delayed or postponed in HCV infected children is predicated more on opinion than fact. At present, there are likely more questions than answers in reference to pediatric HCV infection. As the Institute of Medicine recently reported, a large percentage of HCV infected individuals is unaware of their condition6; in addition the majority of HCV-infected children have not been diagnosed.21 To make progress in the medical treatment of pediatric HCV infection, we must first have a better understanding of the natural history of this disease and the effects it has on the developing child. Introducing efficacious therapies will be important, but improving the effectiveness of available treatments will be essential for the management of this condition of important public health concern not only for children, but also for adults. Efforts to improve identification of infected cases will be critical to achieve these goals and will aid in improving our knowledge of pediatric HCV.
In conclusion, PEDS-C is a well-designed, randomized, placebo-controlled trial that demonstrates superior SVR rates for PEG-IFN alfa-2a with RBV as compared with PEG-IFN alfa-2a alone for the treatment of children infected with hepatitis C. The other important contribution of this study is that it highlights the uniqueness of the pediatric patient. So, are children the same as adults? "Yes," in that they benefit from combined therapy for HCV. "No," in some ways, including altered viral kinetics. "We don't know" in most ways. Efforts to accelerate trials in children will be essential to understand the key host differences between children and adults.
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The Combination of Ribavirin and Peginterferon Is Superior to Peginterferon and Placebo for Children and Adolescents With Chronic Hepatitis C
Gastroenterology 2011
KATHLEEN B. SCHWARZ,* REGINO P. GONZALEZ-PERALTA, KAREN F. MURRAY, JEAN P. MOLLESTON, BARBARA A. HABER, MAUREEN M. JONAS,# PHILIP ROSENTHAL,** PARVATHI MOHAN, WILLIAM F. BALISTRERI, MICHAEL R. NARKEWICZ, LESLEY SMITH, STEVEN J. LOBRITTO, STEPHEN ROSSI,## ALEXANDRA VALSAMAKIS,*** ZACHARY GOODMAN, PATRICIA R. ROBUCK, and BRUCE A. BARTON for the Peds-C Clinical Research Network
Background & Aims
Although randomized trials of adults infected with hepatitis C virus (HCV) have shown that ribavirin increases the efficacy of pegylated interferon (PEG), such trials have not been performed in children. We conducted a randomized controlled trial of PEG and ribavirin, compared with PEG and placebo, in children 5 to 17 years old with chronic hepatitis C.
Methods
HCV RNA-positive children from 11 university medical centers were randomly assigned to receive either PEG alfa-2a (PEG-2a; 180 μg/1.73 m2 body surface area, subcutaneously each week; n = 55) and ribavirin (15 mg/kg orally in 2 doses daily) or PEG-2a and placebo (n = 59) for 48 weeks. The primary end point was sustained virologic response (SVR; lack of detectable HCV RNA at least 24 weeks after stopping therapy).
Results
SVR was achieved in 53% of children treated with PEG-2a and ribavirin, compared with 21% of children who received PEG-2a and placebo (P < .001). Early virologic response (HCV RNA reduction >2 log10 IU at 12 weeks) had a negative predictive value of only 0.89 in children with genotype 1, indicating that these children might benefit from 24 weeks of therapy before stopping treatment. Side effects, especially neutropenia, led to dose modification in 40% of children. Eighty-two percent of the PEG/ribavirin and 86% of the PEG/placebo group were in compliance with the year 2 follow-up visit; the durability of virologic response was 100% in both groups.
Conclusions
The combination of PEG and ribavirin is superior to PEG and placebo as therapy for chronic hepatitis C in children and adolescents.
Recently published data regarding the prevalence of chronic hepatitis C virus (HCV) infection in children in the United States have called attention to this important public health problem. In the 3rd National Health and Nutrition Evaluation Survey, the prevalence of antibody to HCV among children and adolescents was 0.2% to 0.4%, for an overall estimate of 132,000 antibody-positive children.1 More recent US census results have indicated that 23,048 to 42,296 children are chronically infected with HCV and 7200 new cases occur annually.2 In one study of infants infected with HCV at birth, 20% recovered, 50% developed mild asymptomatic chronic infection, and 30% developed progressive disease.3
Although chronic hepatitis C appears to run a more benign course in children compared with adults,4 significant histologic liver disease can occur.5 Although rare, liver transplantation may be needed during adolescence6 and cirrhosis may progress to hepatocellular carcinoma in the second decade of life.7 Treatment of chronic hepatitis C in adults has evolved from interferon alfa alone to the combination of interferon with ribavirin (RV) and, most recently, to the combination of pegylated interferon (PEG) with RV. A beneficial response is defined as clearance of detectable serum or plasma HCV RNA during therapy with a sustained absence of the viral RNA for at least 6 months after stopping treatment. Response rates vary by viral genotype, from 40% to 50% among patients with genotype 1 (representing 60%-70% of US patients) to 70% to 80% among patients with genotypes 2 or 3 (20%-30% of patients).8
Recommendations for treatment of HCV infection in children have been derived from trials in adults, although the efficacy and safety of these therapies may be different in children. The use of different treatment regimens in small uncontrolled clinical trials of thrice-weekly interferon for chronic hepatitis C in children makes direct comparisons to adults difficult. However, reported sustained responses are better in children (30%-60%) than adults (8%-35%).9 Addition of RV to interferon increased sustained response rates in adults to 30% to 40%.10 Studies in children have shown that standard interferon and RV yield response rates better than those in adults with fewer side effects.11, 12 These improved response rates in children may be secondary to the somewhat higher dose of interferon in children (3 MU/m2)11, 12 as opposed to that used in treating adults (3 MU/1.73 m2), the generally lower viral load in children, relatively mild liver disease, and/or other factors.
This combination therapy, which resulted in a sustained virologic response (SVR) of 46% (54/118 children) in a large multicenter pediatric study,11 is now approved by the Food and Drug Administration for children 3 years of age and older. In a small pilot study of long-acting, weekly PEG alfa-2a (PEG-2a) in children 2 to 8 years of age with chronic HCV infection, SVR was 43% (46% in genotype 1).13 In an open-label uncontrolled pilot study of the combination of PEG alfa-2b plus oral RV in children 2 to 17 years of age, Wirth et al14 reported an SVR in patients with genotype 1 of 48%. The combination of PEG alfa-2b with RV was recently approved for use in children in the United States, based largely on the results of this single uncontrolled trial.14 Results of larger uncontrolled trials of combination therapy in children were recently reported.15, 16, 17
A major purpose of the present proposal was to perform a prospective trial with placebo control for RV to investigate whether or not the addition of RV to PEG-2a is truly necessary to achieve the highest efficacy in young subjects. A major potential problem in the treatment of subjects with chronic hepatitis C who are younger than 18 years of age is that RV has been shown to be both teratogenic18, 19 and embryotoxic in animals.20 The Ribavirin Pregnancy Registry is an ongoing attempt to assess the effects of (accidental) RV exposure pregnancy in humans,21 which should clarify the consequences of maternal RV intake on the human fetus. Caution should be used when treating women of childbearing age with this drug. The need for a placebo-controlled trial was further supported by the data, detailed previously, that children appear to respond better to interferon-based therapies than adults and that PEG alone in young children resulted in almost identical SVR rates in children with genotype 1 compared with pediatric trials of the combination of interferon and RV and compared with the combination of PEG and RV. For all of these reasons, the Pediatric Study of Hepatitis C (PEDS-C) was conducted as an adequately powered, randomized, controlled, multicenter trial of the safety and efficacy of PEG-2a with and without RV in children and adolescents with chronic hepatitis C.
Results
Subject Characteristics
Supplementary Figure 1 shows the number of children randomized, treated, and followed up. Baseline characteristics were similar in the 2 treatment groups (Table 1). Most children had early-stage disease; only 5 (4%) had bridging fibrosis and 1 (2%) had cirrhosis.24
Treatment Responses
The primary end point, an SVR, was met by 29 children (53%; 95% confidence interval [CI], 40%-66%) in the PEG-2a plus RV group compared with only 12 (21%; 95% CI, 10%-32%) in the PEG-2a plus placebo group (P < .001). HCV RNA levels decreased in both treatment groups, but the average rate and degree of decline was greater among subjects receiving PEG-2a plus RV compared with PEG-2a plus placebo (Figure 1). Differences in HCV RNA decline became statistically significant by week 3 and remained significant to week 24.
HCV RNA was no longer detectable in a higher proportion of subjects treated with PEG-2a plus RV than with PEG-2a plus placebo at each time point from week 5 to week 48 of therapy as well as 24 weeks after stopping treatment (Figure 2). The higher SVR rate in the group treated with PEG-2a plus RV was related both to a higher end-of-treatment response (65% vs 37%; P = .002) and a lower relapse rate after stopping therapy (17% vs 45%; P = .02). Furthermore, the higher response rates with PEG-2a plus RV treatment occurred in both patients with genotype 1 (47% vs 17%) as well as patients with genotypes 2-4 (80% vs 36%). The higher response rate with PEG-2a plus RV versus PEG plus placebo therapy was present regardless of age, alanine aminotransferase level, or severity of liver histology (Table 2). The one exception to the increased SVR observed with PEG plus RV versus PEG plus placebo therapy was in the group with low HCV viral load, for whom both therapies resulted in high SVR rates (Table 2).
In post hoc multivariate analysis, significant predictors of SVR were therapy with PEG-2a plus RV (OR, 4.5; P = .013), female sex (OR, 4.5; P = .03), nonmaternal route of transmission of HCV (OR, 6.9; P = .02), genotype non-1 (OR, 6.1; P = .02), moderate or marked inflammation on liver histology (OR, 4.2; P = .04), absence of steatosis by liver histology (OR, 3.9; P = .04), and lower baseline HCV RNA levels (OR, 5.5; P = .0008). As shown in Supplementary Figure 1, 33 subjects treated with PEG-2a plus placebo who were HCV RNA positive after 24 weeks were considered nonresponders and were eligible for "open-label" therapy with PEG-2a plus RV. Of these 33 children, 28 began the open-label therapy; 13 (46%) became HCV RNA negative after 24 weeks and continued on therapy for another 24 weeks. Eleven of the 13 children (41% of the total) achieved an SVR. Thus, among the 57 children initially randomized to the PEG and placebo arm, 23 (40%) ultimately achieved an SVR; approximately half, however, failed to clear HCV RNA on PEG monotherapy and required re-treatment with both PEG and RV.
Patterns of Virologic Response During the First 12 Weeks as Predictors of SVR According to Genotype
Although only a small number of children had an RVR (9% of patients with genotype 1), 100% of those children with an RVR experienced an SVR (Table 3). Previous studies in adults have shown that the lack of an EVR is highly predictive of nonresponse and can be used as a means of stopping therapy early in patients in whom therapy is likely to be futile.28 In this study, 91 children or adolescents with genotype 1 infection were treated, among whom an EVR was achieved in 71% (32/45) of those treated with PEG plus RV versus only 40% (18/46) of recipients of PEG plus placebo. Among the 41 subjects with genotype 1 who did not achieve an EVR, 3 (7%) nevertheless had a SVR, including one on therapy with PEG plus RV and 2 receiving PEG plus placebo.
Durability of Response at Years 1 and 2 of Follow-up
As shown in Supplementary Figure 1, 48 (87%) of the 55 children originally randomized to PEG plus RV were followed up at year 1 and 45 (82%) at year 2. Of the 59 children originally randomized to PEG plus placebo, comparable numbers were 51 (86%) for both years. For those children achieving an SVR 72 weeks after initiation of therapy who were followed up for 2 years, durability of viral response was 100%.
Safety, Adverse Events, and Adherence
Influenza-like, headache, and gastrointestinal symptoms occurred in almost all children, and the frequency of all adverse events did not differ between treatment groups with the exception of the influenza-like adverse events, which were actually less frequent in the open-label group (Supplementary Table 2). Therapy led to significant declines in total white blood cell counts, absolute neutrophil counts, and hemoglobin levels, which returned to baseline when therapy was stopped (Figure 3A and B). Declines in white blood cell and neutrophil counts and hemoglobin levels were greater in patients treated with PEG-2a plus RV than in recipients of PEG-2a plus placebo. Overall, 27% of subjects required dose reduction for neutropenia as early as the first week of therapy. Neutropenia was not associated with increased rates of bacterial infections. Dose reductions of PEG-2a or RV were common (Supplementary Table 3) but appeared to have little effect on SVR rates in either group. In subjects treated with PEG-2a plus RV, the SVR was 44% in those with no dose reductions of PEG-2a versus 61% for those with one or more reductions (P = .23). In subjects treated with PEG-2a plus placebo, the SVR rate was 27% in those with no dose reduction of PEG-2a versus 16% for those with dose reductions (P = .32).
Adherence was excellent overall, with rates of 95% or higher for adherence to 90% of the prescribed doses of PEG/RV or PEG/placebo (Supplementary Table 3).
Therapy was discontinued early in 5 of 114 subjects (4%), including 4 treated with PEG-2a plus RV (one each for transient blindness, retinal exudates, suicide gesture, and new-onset type 1 diabetes mellitus) and one patient treated with PEG-2a plus placebo (withdrawn for aggressive behavior). These side effects were reported as possibly secondary to the drug therapy. The suicide gesture and diabetes both led to hospitalization and were thus considered serious adverse events, as was the one liver biopsy complication, which required hospitalization. The child with the liver biopsy complication had undergone percutaneous liver biopsy by a physician who referred the child to the study and the child was enrolled soon thereafter. The liver biopsy resulted in an initially occult perforation of the gallbladder, not evident at the time of enrollment, which eventually resulted in hospitalization and cholecystectomy. Given that the hospitalization occurred after enrollment, the hospitalization was technically considered a serious adverse event. Two children developed hypothyroidism by week 24 of therapy. One resolved off therapy; one did not and was treated with thyroxine.
Discussion
This prospective, randomized, controlled trial has shown that the addition of RV to PEG alfa-2a significantly increases early as well as sustained response rates. Therapy with PEG-2a plus RV was superior to PEG-2a plus placebo regardless of age, alanine aminotransferase levels, and degree of histologic severity. The single exception to the superiority of combination therapy was in the small group of children with HCV RNA levels <600,000 IU/mL who responded well regardless of whether RV was used. These results indicate that children with chronic hepatitis C should not receive PEG monotherapy. The response rates in this trial were comparable to those in uncontrolled clinical trials of PEG and RV in children14 and were similar to rates reported in adults.27, 28, 29, 30, 31, 32 The mechanism by which RV increases response rates in hepatitis C is unclear but may include effects on viral replication, error-prone mutagenesis, decreased intracellular inosine 5'-monophosphate dehydrogenase, and enhanced immune response.33, 34
Changes in HCV RNA levels early in the course of therapy have been reported to be useful in predicting ultimate sustained responses. In this study, SVR was achieved by all children treated with combination therapy who had an RVR at week 5 and 65% of those with an EVR at week 12. Importantly, however, 3 children who did not achieve an EVR nevertheless had a sustained response, so that the negative predictive value of EVR was not reliable enough to be used to stop therapy. These findings indicate that children should be given the benefit of 24 weeks of therapy before stopping therapy because of the futility of continuing treatment.
In multivariate analysis, the most important associations with sustained response were combination therapy versus PEG alone (P = .001) and lower versus higher baseline HCV levels. After adjustment for other factors, children with lower baseline HCV levels showed a higher probability of SVR (P = .0008). As in other studies, subjects with HCV genotype 1 had lower SVR rates compared with those with the other genotypes.29
Safety and Drug Dosage
In PEDS-C, the addition of RV to PEG-2a therapy increased response rates markedly, with little change in side effect profile. Decrease in hematocrit levels and neutrophil counts was greater in the children receiving both PEG and RV compared with those receiving PEG and placebo, but rates of dose modification and discontinuations and serious adverse events were similar. Because neutropenia occurred in one-third of subjects, children treated with this drug combination needed careful monitoring. Rates of depression were lower in children than in adults.34
Costs of HCV Infection
Chronic HCV infection is costly. Jhaveri et al2 projected that during the next decade, $26 million will be spent for screening, $117 to $206 million for monitoring, and $56 to $104 million for treating children with HCV. Although there have been only rare instances of hepatocellular carcinoma7 and end-stage liver disease requiring liver transplantation as a result of HCV infection in childhood,6 the proportion progressing to these end points will undoubtedly rise in adulthood in these patients infected early in life. The precise indications for treating the child with chronic HCV are evolving and are probably different than for adults, given that predictors of liver disease progression have not been elaborated for the child with chronic HCV. Eradication of the virus in an infected child has the dual benefits of eliminating social stigma as well as the progression of liver disease. As noted in the recent American Association for the Study of Liver Diseases Practice Guidelines on the Treatment of HCV, some would argue against routine treatment for children on the basis of the generally mild liver disease.27 However, others propose that treatment of children is equally reasonable given that the average child is likely to be infected for 5 decades or more. Chronic hepatitis C is also a costly disease in terms of medical and psychological consequences and social stigma.35 Thus, the identification of safe and effective treatments for children with HCV infection should proceed as rapidly as possible.
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