May 7, 2012

Durability of Sustained Response Shown in Paediatric Patients With Chronic Hepatitis C Who Were Treated With Interferon Alfa-2b Plus Ribavirin

From Journal of Viral Hepatitis

D. A. Kelly; B. Haber; R. P. González-Peralta; K. F. Murray; M. M. Jonas; J. P. Molleston; M. R. Narkewicz; F. R. Sinatra; T. Lang; A. Lachaux; S. Wirth; M. Shelton; H. S. Te; H. Pollack; W. Deng; S. Noviello; J. K. Albrecht

Posted: 05/07/2012; J Viral Hepat. 2012;19(4):263-270. © 2012 Blackwell Publishing

Abstract and Introduction
Abstract

Summary. Long-term studies in adults indicate that sustained virologic response (SVR) after combination treatment for chronic hepatitis C (CHC) predicts long-term clearance. Although peginterferon plus ribavirin is now standard care for children with CHC, long-term follow-up studies are not yet available. This study evaluated durability of virologic response over 5 years in children previously treated with interferon alfa-2b plus ribavirin (IFN/R). Ninety-seven of 147 children with CHC, who were treated with IFN/R and completed the 6-month follow-up in two previous clinical trials, participated in this long-term follow-up study. All were assessed annually for up to 5 years; patients with SVR were assessed for durability of virologic response. Children with SVR (n = 56) and those with detectable hepatitis C virus (HCV) RNA 24-week post-treatment (n = 41) were followed for a median of 284 weeks. Overall, 70% (68/97) of patients completed the 5-year follow-up. One patient with genotype 1a CHC had SVR and relapsed at year 1 of follow-up with the same genotype. Kaplan–Meier estimate for sustained response at 5 years was 98% (95% CI: 95%, 100%). Six patients with low-positive HCV RNA levels (n = 4) or missing HCV RNA at the 24-week follow-up visit (n = 2) in the initial treatment studies had virologic response during this long-term follow-up study. Linear growth rate was impaired during treatment with rapid increases in the immediate 6 months post-treatment. Mean height percentile at the end of the 5-year follow-up was slightly less than the mean pretreatment height percentile. Five patients experienced serious adverse events; none related to study drug exposure. SVR after IFN/R predicts long-term clearance of HCV in paediatric patients; growth normalized in the majority of children during the long-term follow-up. Similar long-term results could be expected after peginterferon alfa-2b plus ribavirin treatment.

Introduction

The World Health Organization estimates the prevalence of hepatitis C virus (HCV) infection between 1.3% and 1.7% in Europe and the Americas.[1] Seroprevalence of HCV among children is lower than in adults, with estimated rates of 0.1–0.4% in developed countries.[2,3] Although chronic hepatitis C (CHC) is often benign in young children, the occurrence of fibrosis increases with age and duration of the disease.[4] Thus, effective treatment of children with CHC may reduce the progression of liver disease in young adulthood.[5] Studies using interferon (both nonpegylated and pegylated) plus ribavirin for 48 or 52 weeks in children and adolescents with CHC have yielded sustained virologic response (SVR) rates of 46–65%.[6–11] However, the long-term safety of interferon (both nonpegylated and pegylated) plus ribavirin and durability of the virologic response in children are unknown and are essential outcome measures.

In a long-term follow-up study of adults with CHC who attained SVR after treatment with interferon alfa-2b with or without ribavirin, 99% remained virus free during the subsequent 5-year period.[12] Similar findings were seen in adults previously treated with peginterferon alfa-2b plus ribavirin.[13] These findings indicate that sustained loss of serum HCV RNA for 6 months after the end of treatment is an excellent predictor of long-term viral clearance in adult patients with CHC.

The durability of response has not been formally studied in the paediatric population. Although peginterferon plus ribavirin is currently the standard of care for the treatment of paediatric patients with CHC, there are no long-term data on safety or durability of virologic response. Thus, long-term data on children treated with interferon alfa-2b plus ribavirin are uniquely relevant. This study was designed to confirm long-term safety and durability of virologic response in paediatric patients with CHC who were previously treated with interferon alfa-2b plus ribavirin for 48 weeks.[8]

Materials and Methods
Study Design

A phase 3b, multicentre, long-term, follow-up study of paediatric patients with CHC who were previously treated with interferon alfa-2b (Intron A®; Schering-Plough Corporation, now Merck & Co., Whitehouse Station, NJ, USA) 3 MIU/m2 three times per week plus ribavirin (Rebetol®; Schering-Plough Corporation, now Merck & Co.) 8, 12, or 15 mg/kg/day for 48 weeks in two international clinical trials was conducted.[8] The initial treatment studies allowed patients who had detectable HCV RNA levels at treatment week 24 to discontinue as treatment failures at the discretion of individual investigators. Patients who completed 24 weeks of follow-up after the end of treatment in the two clinical trials were eligible for enrolment. No study medications were administered to patients during the 5-year follow-up study.

Baseline data, including gastrointestinal/liver examinations, weight and height measurements, haematology, blood chemistry, and HCV RNA, were obtained from the 24-week follow-up visit in the initial treatment studies. Annual assessments for clinical evidence of liver disease progression and safety in all patients as well as virologic relapse in those who attained SVR in the initial treatment studies were performed for up to 5 years. A patient was considered to have an enduring SVR at a given time point if serum HCV RNA [by quantitative polymerase chain reaction (PCR)] was undetectable at that time point. A patient was considered to have relapsed if a single serum sample had detectable HCV RNA.

Polymerase chain reaction testing for HCV RNA was performed by Schering-Plough Research Institute using a proprietary TaqMan reverse transcriptase–PCR assay (lower limit of detection, <125 IU/mL) and by Quest Diagnostics, Nichols Institute, using the Roche COBAS TaqMan assay (lower limit of quantitation, <50 IU/mL).

The study was conducted in accordance with Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies.

Study Population

Paediatric patients (3–16 years of age) from 24 study sites (17 in the United States and seven international) who participated in one of two clinical trials were invited to enrol in the long-term, follow-up study.[8] Patients who completed 24 weeks of follow-up in the initial treatment studies and whose parents or legal guardians provided informed consent prior to any study-related procedures were included. Patients were excluded if they were currently participating in any other clinical trial for treatment of CHC, if they had received antiviral retreatment for CHC after completing 24 weeks of follow-up in the initial treatment studies or if the investigator determined that the patient had any condition which would make him or her unsuitable for participation in the study. Patients were discontinued from the study if antiviral retreatment for CHC was administered, if the investigator determined that it was in the best interest of the patient or if the patient wished to withdraw.

Efficacy End Point

The primary efficacy end point was the assessment of the durability of SVR in paediatric patients with CHC who were previously treated with interferon alfa-2b plus ribavirin. Durability of SVR was assessed at 1 year after the week-24 follow-up visit of the initial treatment studies and then annually for the next 4 years.

Safety Assessments

Signs of clinical disease progression and safety were assessed for patients at 1 year after the week-24 follow-up visit of the initial treatment studies and then annually for the next 4 years. To assess for clinical disease progression, investigators examined patients for ascites, hepatomegaly, splenomegaly and liver tenderness. In addition to the physical exams and laboratory evaluations, height and weight measurements were collected. Growth measurements were converted electronically to an age- and gender-specific percentile according to the method developed by the Centers for Disease Control and Prevention.[14] Growth velocities during the different study periods were compared with age- and gender-standardized norms for the US population. Growth velocity was calculated by regressing assessed height during the period over the day of assessed height from randomization. At least two height assessments at least 90 days apart were required in any period to calculate growth velocity. Growth velocity percentiles relative to those norms were determined to assess the impact of treatment on growth.[14,15]

Results
Patient Disposition

Of the 166 patients who received interferon alfa-2b plus ribavirin in the two initial treatment studies, 147 (78 sustained responders and 69 treatment failures) completed 24 weeks of follow-up and were eligible for enrolment in the long-term follow-up study (Fig. 1). Enrolled patients (N = 97) had been treated with interferon alfa-2b (3 MIU/m2) three times per week plus ribavirin 8 mg/kg/day (n = 11), 12 mg/kg/day (n = 10) or 15 mg/kg/day (n = 76) at 16 study centres. Owing to the timing of the initial treatment studies and long-term study enrolment, the majority of the enrolled patients (54%, 52/97) were initially treated in the second study, the phase 3 trial.[8] Of those enrolled in this long-term follow-up study, 58% (56/97) had attained SVR and 42% (41/97) of them had not attained SVR (Table 1). Therefore, 72% of sustained responders and 59% of treatment failures from the initial treatment studies entered this long-term follow-up study. In genotype 1, infected patients were 77% (75/97) of the study population, of whom 47% (35/75) had achieved SVR.

762506-fig1

Figure 1. Patient disposition. Study 1, a phase 1 trial, includes patients who were treated with IFN alfa-2b plus RBV 8, 12 or 15 mg/kg/day and Study 2, a phase 3 trial, includes patients treated with IFN alfa-2b plus RBV 15 mg/kg/day.8

Duration of Long-term Follow-up

Overall, 70% (68/97) of patients completed the 5 years of long-term follow-up (Table 2). More patients who attained SVR (75%, 42/56) than those who did not attain SVR (63%, 26/41) in the initial treatment studies completed the long-term follow-up. One patient with detectable HCV RNA at the end of the initial treatment study was subsequently retreated with peginterferon alfa-2b and ribavirin and was therefore withdrawn from the long-term follow-up study.

Efficacy Evaluation

Durability of Response Of 56 patients who attained SVR, only one had virologic relapse during long-term follow-up, with detectable serum HCV RNA level of 3.6 million copies/mL at the year-1 annual evaluation. HCV genotype was 1a at initial infection and at relapse. This patient had received interferon alfa-2b plus ribavirin (15 mg/kg/day) and completed 48 weeks of treatment without any known dose reductions. The Kaplan–Meier point estimate (95% confidence intervals) for the likelihood of maintaining SVR at 5 years after the initial treatment studies was 98% (95%, 100%).

Alanine Aminotransferase Levels The majority (98%, 51/52) of patients who attained SVR and had normal alanine aminotransferase (ALT) levels at the 24-week follow-up of the initial treatment studies maintained normal ALT levels throughout their long-term follow-up visits. The remaining patient with SVR had an elevated ALT level during long-term follow-up (67 U/L at the year-5 visit) with hepatomegaly, possibly caused by obesity (body mass index of 37.1 kg/m2). The investigator did not consider this finding to be clinically significant. In addition, three patients who attained SVR but had abnormal ALT levels at week-24 follow-up visit had normalized ALT levels at their last long-term follow-up evaluation. ALT values in the long-term follow-up period were missing for one patient.

Treatment Failures Of the 41 patients who did not respond to therapy and who had detectable HCV RNA levels at the 24-week follow-up in the initial treatment studies, 26 (63%) completed the 5-year follow-up study. Among these 41 patients with treatment failure, 33 (80%) had ALT levels <2 times their baseline ALT level throughout the study; 7 (17%) had elevated ALT levels of at least two times their baseline level within the last 3 years of long-term follow-up, despite having ALT levels <2 times their baseline level at the 24-week follow-up visit in the initial treatment studies; and one had missing ALT levels.

Six patients who enrolled in the long-term follow-up study had been treated with interferon alfa-2b (3 MIU/m2) three times/week plus ribavirin 15 mg/kg/day in the initial treatment studies and were classified as treatment failures. Four of these patients had low detectable serum HCV RNA (125–250 copies/mL) at week-24 follow-up in the initial treatment studies although they had undetectable HCV RNA levels at week 24 during treatment and three of the four patients had undetectable HCV RNA levels at week 12 as well. These patients had undetectable serum HCV RNA and normal ALT values throughout the long-term follow-up study (4–5 years after completing treatment). The two remaining patients were defined as not having responded to therapy when they entered the long-term follow-up study because, although they had undetectable serum HCV RNA at their last visit in the initial treatment protocol, they did not have HCV RNA results available for the 24-week follow-up visit. However, their serum HCV RNA remained undetectable throughout the 5 years of long-term follow-up.

Safety Evaluation

In this long-term follow-up study, 5% (5/97) of patients reported a serious adverse event, all of which were considered unlikely to be related to previous treatment with interferon alfa-2b and ribavirin. The serious adverse events included a cardiac catheterization in a patient with a history of congenital heart disease, injury with loss of consciousness after tipping an all-terrain vehicle, contrast media reaction during magnetic resonance imaging, tooth abscess and depression with self-injurious ideation and drug abuse after an alleged sexual assault. No patients died during the study. During the initial treatment studies, 23 of the 118 patients reported severe adverse events, which included mainly neutropenia as well as more significant events of suicidal ideation (n = 3), attempted suicide (n = 1) and hypothyroidism requiring treatment (n = 3); one patient with hypothyroidism also developed diabetes mellitus.[8] Of these seven patients with more significant events, five patients were followed for up to 5 years in this long-term follow-up study without further serious adverse events reported. Mean changes in haematologic parameters (haemoglobin, platelet and white blood cell counts) during treatment returned to normal levels at the end of the 24-week follow-up period and remained stable during the long-term follow-up study. No patient showed signs of clinical progression of hepatic disease.

Body Weight and Height During the initial treatment studies, weight loss occurred during treatment with compensatory weight gain during the 24-week follow-up and long-term follow-up (Table 3). The mean weight percentile, 60th percentile, for all patients at the end of the long-term follow-up was above their mean baseline weight percentile, 54th percentile, as well as the median for the US population.[14]

The mean height percentile, 44th percentile, for all patients at the end of the long-term follow-up was slightly below the patients' mean pretreatment baseline height percentile, 48th percentile, and below the median for the US population (Table 3). Twenty (21%) patients had >15 height percentiles decrease from baseline to their last visit in the long-term follow-up period. Of these 20 patients, 10 patients had >30 percentiles decreases. Decreases in height of >15 percentiles were most common in patients treated with interferon alfa-2b plus ribavirin during their estimated period of peak growth velocity based on age [girls 9–12 years old (6/15, 40%) vs girls 3–8 and 13–16 years old (1/31, 3%); P = 0.001 and boys 11–14 years old (9/19, 47%) vs boys 3–10 and 15–16 years old (4/32, 13%); P = 0.006]. In contrast, 15 (15%) patients (girls 4–12 years old and boys 5–16 years old) had increases in height of >15 percentiles from baseline to their last visit in the long-term follow-up study.

Mean growth velocity (2.46 ± 2.48 cm/year) and mean growth velocity percentile (11 ± 22) were at their lowest during treatment (Table 3). During the 24-week follow-up period of the initial studies, both growth velocity and growth velocity percentile increased to levels above the median for the US population. Mean growth velocity during this period was 5.40 ± 4.13 cm/year, and mean growth velocity percentile increased to 62 ± 40. During the long-term follow-up period, mean growth velocity was 3.29 ± 2.74 cm/year, and mean growth velocity percentile was 36.7 ± 37.6.

Discussion

Chronic hepatitis C is a significant cause of liver disease and a frequent indication for liver transplantation in adults.[16] 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.[12,17–26] 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.[8] 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.[27] 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.[9] In addition, Wirth et al.[10] 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.[28] 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.[5] The disease course varies, but most children show at least mild or moderate hepatic inflammation and a small proportion have steatosis.[29] Rare cases of children with hepatitis C-related bridging fibrosis, decompensated cirrhosis and hepatocellular carcinoma have been reported.[4,30–33] 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.[8] 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.[10,11]

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.

References
  1. Perz JF, Farrington LA, Pecoraro C et al. Estimated global prevalence of hepatitis C virus infection. Presented at: 42nd Annual Meeting of the Infectious Diseases Society of America; September 30–October 3, 2004; Boston, MA, USA. Abstract 154.
  2. Committee on Infectious Diseases. Hepatitis C virus infection. Pediatrics 1998; 101: 481–485.
  3. Wirth S, Kelly D, Sokal E et al. Guidance for clinical trials for children and adolescents with chronic hepatitis C. J Pediatr Gastroenterol Nutr 2011; 52: 233–237.
  4. Guido M, Rugge M, Jara P et al. Chronic hepatitis C in children: the pathological and clinical spectrum. Gastroenterology 1998; 115: 1525– 1529.
  5. Bortolotti F, Verucchi G, Camma C et al. Long-term course of chronic hepatitis C in children: from viral clearance to end-stage liver disease. Gastroenterology 2008; 134: 1900– 1907.
  6. Wirth S, Lang T, Gehring S, Gerner P. Recombinant alfa-interferon plus ribavirin therapy in children and adolescents with chronic hepatitis C. Hepatology 2002; 36: 1280–1284.
  7. Lackner H, Moser A, Deutsch J et al. Interferon-alpha and ribavirin in treating children and young adults with chronic hepatitis C after malignancy. Pediatrics 2000; 106: E53.
  8. Gonzalez-Peralta RP, Kelly DA, Haber B et al. Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. Hepatology 2005; 42: 1010–1018.
  9. Jara P, Hierro L, de la Vega A et al. Efficacy and safety of peginterferonalpha2b and ribavirin combination therapy in children with chronic hepatitis C infection. Pediatr Infect Dis J 2008; 27: 142–148.
  10. Wirth S, Ribes-Koninckx C, Calzado MA et al. High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin. J Hepatol 2010; 52: 501–507.
  11. Schwarz KB, Gonzalez-Peralta RP, Murray KF et al. Peginterferon with or without ribavirin for chronic hepatitis C in children and adolescents: final results of the PEDS-C trial. Hepatology 2008; 48: 418A.
  12. McHutchison JG, Shiffman ML, Gordon SC et al. Sustained virologic response (SVR) to interferon-alfa- 2b+/- ribavarin therapy at 6 months reliably predicts long-term clearance of HCV at 5-years follow up. J Hepatol 2006; 44: S275.
  13. Manns M, Lindsay KL, Gordon SC et al. Sustained virologic response after peginterferon alfa-2b and ribavirin treatment predicts long-term clearance of HCV at 5-year followup. J Hepatol 2008; 48: S300.
  14. National Center for Health Statistics. CDC Growth Charts for the United States: Methods and Development. Centers for Disease Control and Prevention website. 2000. Available at: http://www.cdc.gov/growthcharts/(accessed 28 February 2008).
  15. Tanner JM, Davies PS. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 1985; 107: 317– 329.
  16. Gordon FD, Kwo P, Vargas HE. Treatment of hepatitis C in liver transplant recipients. Liver Transpl 2009; 15: 126–135.
  17. Veldt BJ, Saracco G, Boyer N et al. Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy. Gut 2004; 53: 1504–1508.
  18. Lau DT, Kleiner DE, Ghany MG, Park Y, Schmid P, Hoofnagle JH. 10-Year follow-up after interferon-alpha therapy for chronic hepatitis C. Hepatology 1998; 28: 1121–1127.
  19. Marcellin P, Boyer N, Gervais A et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med 1997; 127: 875–881.
  20. Chemello L, Cavalletto L, Casarin C et al. Persistent hepatitis C viremia predicts late relapse after sustained response to interferon-alpha in chronic hepatitis C. TriVeneto Viral Hepatitis Group. Ann Intern Med 1996; 124: 1058–1060.
  21. Manesis EK, Papaioannou C, Gioustozi A, Kafiri G, Koskinas J, Hadziyannis SJ. Biochemical and virological outcome of patients with chronic hepatitis C treated with interferon alfa-2b for 6 or 12 months: a 4-year follow-up of 211 patients. Hepatology 1997; 26: 734–739.
  22. Fontaine H, Chaix ML, Lagneau JL, Brechot C, Pol S. Recovery from chronic hepatitis C in long-term responders to ribavirin plus interferon alfa. Lancet 2000; 356: 41.
  23. Sim H, Yim C, Krajden M, Heathcote J. Durability of serological remission in chronic hepatitis C treated with interferon-alpha-2B. Am J Gastroenterol 1998; 93: 39–43.
  24. Collier JD, Adams PA, Feinman V et al. Long term follow-up of patients with chronic hepatitis C treated with interferon alpha. Can J Gastroenterol 2000; 14: 77B–80B.
  25. Reichard O, Glaumann H, Fryden A, Norkrans G, Wejstal R, Weiland O. Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon. J Hepatol 1999; 30: 783–787.
  26. Camma C, Di Marco V, Lo Iacono O et al. Long-term course of interferontreated chronic hepatitis C. J Hepatol 1998; 28: 531–537.
  27. Comanor L, Minor J, Conjeevaram HS et al. Impact of chronic hepatitis B and interferon-alpha therapy on growth of children. J Viral Hepat 2001; 8: 139–147.
  28. Sokal EM, Bourgois A, Stephenne X et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in children and adolescents. J Hepatol 2010; 53: 170–178.
  29. Goodman ZD, Makhlouf HR, Liu L et al. Pathology of chronic hepatitis C in children: liver biopsy findings in the Peds-C Trial. Hepatology 2008; 47: 836–843.
  30. Badizadegan K, Jonas MM, Ott MJ, Nelson SP, Perez-Atayde AR. Histopathology of the liver in children with chronic hepatitis C viral infection. Hepatology 1998; 28: 1416– 1423.
  31. Rumbo C, Fawaz RL, Emre SH et al. Hepatitis C in children: a quaternary referral center perspective. J Pediatr Gastroenterol Nutr 2006; 43: 209– 216.
  32. Strickland DK, Jenkins JJ, Hudson MM. Hepatitis C infection and hepatocellular carcinoma after treatment of childhood cancer. J Pediatr Hematol Oncol 2001; 23: 527–529.
  33. Gonzalez-Peralta RP, Langham MR, Andres JM et al. Hepatocellular carcinoma in 2 young adolescents with chronic hepatitis C. J Pediatr Gastroenterol Nutr 2009; 48: 630–635.

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