PEDIATRICS Vol. 106 No. 4 October 2000, p. e53

ELECTRONIC ARTICLE:
Interferon- and Ribavirin in Treating Children and Young Adults With Chronic Hepatitis C After Malignancy

Herwig Lackner, MD^*, Andrea Moser, MD^*, Johann Deutsch, MD^*, Harald H. Kessler, MD, Martin Benesch, MD^*, Reinhold Kerbl, MD^*, Wolfgang Schwinger, MD^*, Hans-Jürgen Dornbusch, MD^*, Karl-Heinz Preisegger, MD^*, and Christian Urban, MD^*

From the ^* Division of Pediatric Hematology/Oncology, Department of Pediatrics; and the  Institute of Hygiene, Karl-Franzens-University, Graz, Austria.

	ABSTRACT

Top Abstract Methods Results Discussion Conclusion References

Objective.  Chronic hepatitis C is a major long-term problem for children who survive cancer. Interferon (IFN)- has been shown to be effective in treating patients with chronic hepatitis C; however, the rate of sustained response is low. Combining IFN- and ribavirin (RBV) has been shown to significantly improve the response in adult patients with chronic hepatitis C. The aim of this pilot study was to evaluate the efficacy and safety of a combined virostatic treatment with IFN- and RBV in a small cohort of children and adolescents with chronic hepatitis C and previous malignancy.

Methods.  Twelve patients with a history of a hematooncologic disease (median follow-up: 13.5 years; range: 7-14.7 years) and chronic hepatitis C were treated with recombinant IFN--2a (6 megaunits/m² body surface area, 3 times a week, subcutaneously) combined with RBV (15 mg/kg body weight/day, orally) for 12 months. They were tested monthly for blood counts and liver function, and for serum virus concentrations (hepatitis C virus RNA by polymerase chain reaction) every 3 months.

Results.  At the end of the treatment, hepatitis C virus RNA could not be detected in the serum of 8 of the 12 patients; 2 of these patients relapsed soon after therapy withdrawal, whereas 6 patients maintained in sustained virologic and biochemical remission (follow-up: 12 months). Treatment-induced toxicity was moderate and reversible with influenza-like symptoms and a decrease in blood counts in all 12 patients, alopecia in 5 of the 12, hemolysis in 4 of the 12, and weight loss of >10% in 2 of the 12.

Conclusions.  As demonstrated in adults with chronic hepatitis C, treatment with IFN- and RBV also seems to be an effective and safe therapeutic option for children and adolescents with chronic hepatitis C after malignancy.  Key words:  children, hepatitis C, malignancy, interferon-, ribavirin, treatment.

Infection with hepatitis C virus (HCV) is one of the major long-term problems of pediatric patients treated for malignancy before 1990, because blood donors were not screened for HCV at that time. A 12% to 43% prevalence of exposure to HCV has been reported for these patients.^1-7

Spontaneous remissions associated with clearance of HCV RNA from serum occur in 2.5% to 11% of children who acquired HCV infection during treatment for malignancies.^1,8 The number of spontaneous remissions in children with HCV infection and nonmalignant diseases ranges between 16% and 45%.^8,9 The definitive prognosis in the remaining patients is still a matter of debate.¹⁰ There are some reports describing a relatively benign clinical course of childhood chronic hepatitis C.^1,9 However, a recent study of liver histology in children with chronic hepatitis C showed a high risk of fibrosis and cirrhosis similar to that observed in adults.¹¹ In addition, progression to hepatocellular carcinoma attributable to long-lasting persistence of HCV in the liver cannot be excluded and treatment with interferon (IFN) seems to reduce this risk in adult patients.¹² Considering this doubtful prognosis, effective antiviral treatment seems to be justified, not only in adults, but also in children with chronic hepatitis C.

IFN has been shown to be effective in adult patients with chronic hepatitis C, but sustained response, defined by persistent viral clearance and normalization of the aminotransferases 6 months after withdrawal of therapy, is observed in only 15% to 20% of patients.¹³ There are few data regarding the use of IFN in the treatment of HCV infection in children and the response rates to IFN monotherapy were similar to those observed in adults.^14-23 Complete sustained remissions on IFN monotherapy in children with an underlying malignant disease range between 0% and 38%.^16,20

Ribavirin (RBV), an oral nucleoside analog with activity against several RNA viruses, has been shown to lower aminotransferase levels in adult patients with chronic HCV infection.²⁴ However, oral RBV has not been used as monotherapy for children with chronic hepatitis C until now. Combination therapy of IFN and RBV has been found to significantly improve the sustained biochemical and virological response in adult patients with chronic hepatitis C.^13,24-26 So far there are no reported data on combination therapy with IFN and RBV in children with chronic HCV infection.

The aim of the present pilot study was to evaluate the safety and efficacy of IFN/RBV therapy for children, adolescents, and young adults with chronic hepatitis C after a previous malignancy.

	METHODS

Top Abstract Methods Results Discussion Conclusion References

Patients

Twelve children or young adults (7 males and 5 females) who were cured of a malignant pediatric hematooncologic disease (median follow-up: 13.5 years: range: 8-15.7 years) entered the present study. Median age at diagnosis of the underlying disease was 4.6 years (range: .1-14.7 years), median age at study entry was 17.1 years (range: 10.6-31 years). All patients had chronic HCV infection defined by detectable circulating HCV RNA for >6 months. None had signs of concomitant infection with human immunodeficiency virus, hepatitis B virus, cytomegalovirus, or Epstein-Barr virus. Other causes of liver damage (such as ₁-antitrypsin deficiency, Wilson's disease, and autoimmune hepatitis) were also excluded. Liver biopsies were performed percutaneously by the Menghini technique before study entry but were not performed at completion of therapy. Determination of fibrosis score and hepatitis activity index was performed according to the criteria and recommendations by Chevallier et al²⁷ and Bianchi et al,²⁸ respectively. The HCV subtype was determined by genotyping and serotyping in 11 of 12 patients. All patients had HCV subtype 1, including genotype 1a in 4 patients, genotype 1b in 6 patients, and mixed genotype 1a/1b in 1 patient. None of the patients had received IFN before entering the study. Treatment results were updated on March 31, 2000.

Treatment Protocol

The patients received recombinant IFN--2a (Roferon, Hoffmann-La Roche SA, Basel, Switzerland) at a dose of 6 megaunits/m² body surface area, subcutaneously 3 times a week, combined with RBV (Distri Drug, Morschwiller Le Bas, France) at a dose of 15 mg/kg body weight/day orally. The duration of treatment was 12 months. Clinical evaluation, complete blood count, and liver function tests were performed before, monthly during therapy, and then every 3 months during follow-up. The presence of serum HCV RNA by polymerase chain reaction (PCR) was tested before IFN/RBV therapy, 1 month after the start of therapy, and then every 3 months during therapy and during the follow-up period. Sustained response was defined by normalization of aminotransferases and by negativity of HCV RNA by PCR at the end of the treatment and for >6 months after withdrawal of the IFN/RBV therapy. Because RBV carries a possible risk of teratogenecity, pregnancy tests were performed monthly in all female study patients of childbearing age. The study was approved by the University of Graz Ethics Review Committee. Informed consent from the parents and/or patients was obtained before liver biopsy and at the beginning of the IFN/RBV therapy.

Liver Function and Virologic Testing

The serum alanine aminotransferase (ALT) values were determined by a standard autoanalyzer. The upper limit of normal ALT was 23 IU/L. For quantitation of serum HCV RNA, the Cobas Amplicor HCV Monitor Test (Roche Diagnostic Systems, Pleasanton, CA) was used. Qualitative PCR was performed using the Cobas Amplicor HCV Test (Roche Diagnostic Systems). For genotyping, the Inno-LiPA HCV II assay (Innogenetics NV, Zwijndrecht, Belgium) was used.

To exclude false-negative results because of inhibitors, Amplicor assays include an internal control (IC) with primer binding regions identical to those of the target sequence, a randomized internal sequence of similar length and base composition as the target sequence, and a unique probe-binding region that differentiates the IC product from the target product. The IC is introduced into each amplification reaction and is coamplified with target nucleic acid from the clinical specimen. After amplification, the products are hybridized to target-specific and in parallel to IC-specific probe-coated magnetic particles.

	RESULTS

Top Abstract Methods Results Discussion Conclusion References

Response to Treatment

At study entry all patients had histologic features of active hepatitis with mild disease activity, the ALT values were abnormal in 5/12 patients (median: 22; range: 9-70 IU/L). At the end of treatment, ALT values were normal in all patients (median: 10: range: 5-20 IU/L). HCV RNA was detected in the baseline sera of all patients with a median level of 2.0 × 10⁵ copies/mL (range: .2-5.6 × 10⁵ copies/mL). Table 1 shows the serum HCV RNA profiles before, during, and after IFN/RBV treatment. Three months after the start of treatment serum HCV RNA was no longer detectable in 9/12 patients (75%), while 3 patients never cleared HCV RNA. One patient (patient 12) cleared HCV RNA from serum within 3 months, but HCV RNA reappeared during treatment. At the end of IFN/RBV treatment 8/12 patients were HCV RNA-negative: 2 relapsed soon after therapy withdrawal, whereas 6 remained negative for at least 12 months after cessation of therapy. Sustained response was, therefore, obtained in 6/12 patients (50%).

Complications

IFN/RBV treatment was well tolerated and all side effects were transient and reversible. All patients exhibited a mild influenza-like syndrome during the first weeks of treatment. There were decreases in leukocyte and platelet counts and hemoglobin levels after the beginning of IFN/RBV therapy in all patients. However, none of the patients showed a leukocyte count below 1.500/µL, a platelet count below 100 × 10³/µL, or a hemoglobin below 11 g/dL. Five patients complained about transient hair loss, which required a 10% reduction of IFN in 3 of them. Additional side effects were mild hemolysis in 4/12 patients and a >10% loss of body weight in 2 patients. Neurological or psychological side effects, aseptic bone necrosis, or reactions at injection sites were not observed in our patients.

	DISCUSSION

Top Abstract Methods Results Discussion Conclusion References

Little information is available about the efficacy of IFN in the treatment of children or adolescents with chronic hepatitis C. There are only a few pilot studies with small patient numbers, heterogeneous viral HCV populations, and different treatment protocols.^15-23 The achieved sustained response rates ranged between 0% and 56% of the patients.^15-23 However, Pensati et al²³ recently observed a low virological response of only 8% in 25 children treated with IFN monotherapy for chronic hepatitis C. The most important factors in predicting IFN response seem to be HCV genotype, pretreatment HCV RNA titers, an underlying hematooncologic disease, and absence of cirrhosis.^14,16,17,19 In view of these results, and because controlled trials with sufficient numbers of patients are lacking, many pediatricians are reluctant to use IFN as monotherapy for chronic hepatitis C in children.

RBV inhibits the replication of many different viruses including HCV.²⁴ Pilot studies of adult patients suggested that combining IFN with RBV is more effective than using IFN alone.^13,24,25 McHutchison et al²⁶ randomly assigned 912 adult patients with chronic hepatitis C to receive standard dose IFN alone or in combination with RBV (1000 or 1200 mg orally per day) for either 24 weeks or 48 weeks, respectively. The rate of sustained response was higher among patients who received combination therapy for 24 weeks (31%) or 48 weeks (38%), compared with patients receiving IFN monotherapy for 24 weeks (6%) or 48 weeks (13%). Combination treatment was generally well tolerated, and the observed side effects (including nausea, fatigue, hemolysis, pancytopenia, anorexia, and emotional lability) were acceptable and reversible.^13,25,26 Because there were no data in the literature on IFN/RBV therapy in children with chronic hepatitis C, a similar regimen as in adults was used in the present study.

The results of the present pilot study suggest that, as in adult patients, the combination therapy with IFN and RBV may also be beneficial in children and adolescents with chronic HCV infection. In fact, 50% of the patients achieved a sustained response with HCV RNA negativity for >12 months after completion of therapy. This response rate is of note because all patients were survivors of previous malignant hematooncologic diseases and all patients had HCV genotype 1, factors usually predicting a poor response to IFN treatment. It was interesting to observe that of the 6 sustained responders, 4 had cleared HCV from serum by month 1 and 2 by month 3. The observed adverse effects were mild and reversible in all patients; only 3 of 12 patients required a 10% dose reduction of IFN.

	CONCLUSION

Top Abstract Methods Results Discussion Conclusion References

The results of this small pilot study are encouraging and prompt further investigation. However, 50% of the patients did not respond to combination therapy with IFN and RBV. Whether these patients will respond to higher doses or longer courses of treatment or new antiviral drug combinations needs to be investigated.

	FOOTNOTES

Received for publication Jan 21, 2000; accepted Apr 25, 2000.

Reprint requests to (H.L.) Division of Pediatric Hematology/Oncology, Department of Pediatrics, Auenbruggerplatz 30, A-8036, Graz, Austria. E-mail: herwig.lackner{at}kfunigraz.ac.at

	ABBREVIATIONS

HCV, hepatitis C virus; IFN, interferon; RBV, ribavirin; PCR, polymerase chain reaction; ALT, alanine aminotransferase; IC, internal control.

	REFERENCES

Top Abstract Methods Results Discussion Conclusion References

1. Cesaro S, Petris MG, Rossetti F, Chronic hepatitis C virus infection after treatment for pediatric malignancy. Blood 1997; 90:1315-1320 [Abstract/Free Full Text]
2. Locasciulli A, Cavalletto D, Pontisso P, Hepatitis C virus serum markers and liver disease in children with leukemia during and after chemotherapy. Blood 1993; 82:2564-2567 [Abstract/Free Full Text]
3. Aricò M, Maggiore G, Silini E, Hepatitis C virus infection in children treated for acute lymphoblastic leukemia. Blood 1994; 84:2919-2922 [Abstract/Free Full Text]
4. Fink FM, Höcker-Schulz S, Mor W, Association of hepatitis C virus infection with chronic liver disease in paediatric cancer patients. Eur J Pediatr 1993; 152:490-492 [CrossRef][Medline]
5. Paul IM, Sanders J, Ruggiero F, Andrews T, Ungar D, Eyster ME Chronic hepatitis C virus infections in leukemia survivors: prevalence, viral load, and severity of liver disease. Blood 1999; 93:3672-3677 [Abstract/Free Full Text]
6. Januszkiewicz D, Wysocki J, Nowak J Hepatitis B and C virus infection in Polish children with malignancies. Eur J Pediatr 1997; 156:454-456 [CrossRef][Medline]
7. Dibenedetto SP, Ragusa R, Sciacca A, Incidence and morbidity of infection by hepatitis C virus in children with acute lymphoblastic leukaemia. Eur J Pediatr 1994; 153:271-275 [Medline]
8. Fujisawa T, Komatsu H, Inui A, Spontaneous remission of chronic hepatitis C in children. Eur J Pediatr 1997; 156:773-776 [CrossRef][Medline]
9. Vogt M, Lang T, Frösner G, Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med 1999; 341:866-870 [Abstract/Free Full Text]
10. Thaler MM Hepatitis C virus in infants and children. Curr Opin Pediatr 1997; 9:508-512 [Medline]
11. 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 [CrossRef][Medline]
12. Imai Y, Kawata S, Tamura S, Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Ann Intern Med 1998; 129:94-99 [Abstract/Free Full Text]
13. Schalm SW, Hansen BE, Chemello L, Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C. J Hepatol 1997; 26:961-966 [CrossRef][Medline]
14. Jonas MM Interferon- for viral hepatitis. J Pediatr Gastroenterol Nutr 1996; 23:93-106 [CrossRef][Medline]
15. Ruiz-Moreno M, Rua MJ, Castillo I, Treatment of children with chronic hepatitis C with recombinant interferon-: a pilot study. Hepatology 1992; 16:882-885 [Medline]
16. Cesaro S, Rossetti F, De Moliner L, Crivellaro C, Zanesco L, Bortolotti F Interferon for chronic hepatitis C in patients cured of malignancy. Eur J Pediatr 1994; 153:659-662 [CrossRef][Medline]
17. Fujisawa T, Inui A, Ohkawa T, Komatsu H, Miyakawa Y, Onoue M Response to interferon therapy in children with chronic hepatitis C. J Pediatr 1995; 127:660-662 [CrossRef][Medline]
18. Bortolotti F, Giacchino R, Vajro P, Recombinant interferon- therapy in children with chronic hepatitis C. Hepatology 1995; 22:1623-1627 [CrossRef][Medline]
19. Iorio R, Pensati P, Porzio S, Fariello I, Guida S, Vegnente A Lymphoblastoid interferon- treatment in chronic hepatitis C. Arch Dis Child 1996; 74:152-156 [Abstract]
20. Komatsu H, Fujisawa T, Inui A, Efficacy of interferon in treating chronic hepatitis C in children with a history of acute leukemia. Blood 1996; 87:4072-4075 [Abstract/Free Full Text]
21. Matsuoka S, Mori K, Nakano O, Efficacy of interferons in treating children with chronic hepatitis C. Eur J Pediatr 1997; 156:704-708 [CrossRef][Medline]
22. Sawada A, Tajiri H, Kozaiwa K, Favorable response to lymphoblastoid interferon- in children with chronic hepatitis C. J Hepatol 1998; 28:184-188 [Medline]
23. Pensati P, Iorio R, Botta S, Low virological response to interferon in children with chronic hepatitis C. J Hepatol 1999; 31:604-611 [CrossRef][Medline]
24. Reichard O, Schvarcz R, Weiland O Therapy of hepatitis C: alpha interferon and ribavirin. Hepatology 1997; 26:108-111 [CrossRef]
25. Reichard O, Norkrans G, Frydén A, Braconier JH, Sönnerborg A, Weiland O Randomised, double-blind, placebo-controlled trial of interferon -2b with and without ribavirin for chronic hepatitis C. Lancet 1998; 351:83-87 [CrossRef][Medline]
26. McHutchison JG, Gordon SC, Schiff ER, Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998; 339:1485-1492 [Abstract/Free Full Text]
27. Chevallier M, Guerret S, Chossegros P, Gerard F, Grimaud JA A histological semiquantitative scoring system for evaluation of hepatic fibrosis in needle liver biopsy specimens: comparison with morphometric studies. Hepatology 1994; 20:349-355 [CrossRef][Medline]
28. Bianchi L, Gudat F. Chronic hepatitis. In: McSween RNM, Anthony PP, Scheuer PJ, Burt AD, Portmann BC, eds. Pathology of the Liver. Edinburgh, Scotland: Churchill Livingstone; 1994:349-396