INTERFERON-ALPHA-2b TREATMENT OF CHRONIC HEPATITIS C IN CHILDREN WITH HEMOPHILIA

Abstract

A high proportion of boys with hemophilia are infected with the hepatitis C virus (HCV) as a result of exposure to virus-contaminated coagulation factor concentrates.1 These children are at risk for progression to cirrhosis, end stage liver disease and hepatocellular carcinoma.2-4 Interferon alpha-2b (IFN) is approved for the treatment of chronic HCV infection in adults.5, 6 In a preliminary study adults with hemophilia and HCV infection responded similarly to IFN therapy when compared with HCV-infected adults without hemophilia.7 However, more recent studies, in which elimination of HCV RNA from serum was the treatment endpoint, were less encouraging.8-10 Limited data exist regarding the efficacy and toxicity of IFN treatment of children with chronic HCV infection, but recent studies suggest that response rates are similar to those of adults and that adverse effects may be less severe.11, 12 No information about interferon treatment is available regarding the large subset of children with hemophilia and chronic HCV infection. This paper reports the results of a pilot trial of IFN treatment for young hemophiliacs. Methods.Patients. A child was eligible for this study if he had Factor VIII or IX deficiency and was followed at our center. The diagnosis of chronic HCV infection was based on positive tests with the second generation enzyme-linked immunosorbent assay and the confirmatory HCV matrix assay (Abbott Laboratories, Abbott Park, IL), alanine aminotransferase (ALT) elevation for at least 1 year (see below) and no other explanation for liver dysfunction. Boys were candidates for IFN therapy if they had serum ALT ≥1.5 times the upper limit of normal on at least three occasions at least 1 month apart during the year before study entry and liver histology consistent with chronic viral hepatitis. Children were excluded from the IFN treatment protocol if they had HIV coinfection with a CD4 count <200/mm3, a high titer Factor VIII or IX inhibitor, decompensated liver disease, thrombocytopenia, anemia, neutropenia, autoimmune liver or thyroid disease, renal insufficiency, cardiomyopathy or any other liver disease. HCV RNA reverse transcriptase-PCR. Serum was stored at -70°C from samples obtained at intervals throughout the study period. Qualitative nested PCR amplification of extracted RNA from serum was done by standard protocols with modifications.13 (Primer sequences and specific conditions are available on request.) HCV genotypes were determined at the National Genetics Institute, Los Angeles, CA, under the direction of Dr. Andrew Conrad. Liver biopsy. A percutaneous liver biopsy was performed within 3 months before starting IFN treatment. Coagulation factor concentrate was given to achieve a factor level of 100% immediately before the biopsy and maintained above 50% for 72 h thereafter. An 18-gauge spring-loaded biopsy needle (Monopty Biopsy Instrument; Bard Inc., Covington, GA) was used to obtain tissue. Factor concentrate doses were adjusted according to factor levels measured daily. The children were hospitalized for 48 to 72 h after the biopsy. An experienced pediatric hepatopathologist blinded to the patients' identities scored each biopsy according to the Knodell method for the assessment of chronic hepatitis.14 Interferon treatment. Interferon-alpha-2b (Intron A, Schering-Plough Corp., Kenilworth, NJ) was administered to the first three patients in a dosage of 3 million units/m2 (maximum, 5 million units/dose) three times weekly for 24 weeks by subcutaneous injection. For the subsequent three patients, the dosage was reduced to 1.75 million units/m2 (maximum, 3 million units/dose) for 24 weeks by subcutaneous injection at the recommendation of the manufacturer, to be more consistent with the recommended adult dosage of 3 million units. The parents were taught to administer the medication at home. During IFN therapy clinic visits for interval history, physical examination and laboratory monitoring occurred regularly. Informed consent. The study protocol was approved by the Institutional Review Board of the University of Texas South-western Medical Center at Dallas. Informed consent was obtained from the parents of the enrolled children. Results. One hundred twelve patients with hemophilia (101 with Factor VIII deficiency and 11 with Factor IX deficiency) <21 years of age who had been exposed to plasma-derived coagulation factor concentrates were tested for HCV. Forty-five (40%) were confirmed to be seropositive for HCV. Twenty-three of these boys had normal or only slightly elevated serum ALT values. The remaining 22 seropositive patients had elevations of the serum ALT that qualified them for further consideration for liver biopsy and IFN therapy. Of these 22 patients 14 were ineligible for study entry for the following reasons: refusal to give consent (4); history of poor compliance (3); residence a long distance from Dallas, precluding their receiving regular follow-up monitoring in our center (3); HIV infection with CD4 count below 200/mm3 (2); or the presence of a high titer Factor VIII inhibitor (2). Pretreatment evaluation and liver biopsy. The pretreatment characteristics of the eight patients who ultimately underwent percutaneous liver biopsy are summarized in Table 1. None of the patients had physical findings of liver disease. There were no complications of liver biopsy, including hemorrhage, in any of the patients. The histologic hepatic lesions ranged from mild to moderate hepatitis; two patients had mild bridging fibrosis but no patient had cirrhosis. Only one patient (Patient 3) was infected with more than one HCV genotype. Interferon therapy. Six of the patients (Patients 1 to 6) who underwent liver biopsy were treated with IFN. One patient (Patient 6) did not complete IFN therapy; the drug was discontinued after 3 weeks when the CD4 count decreased from a pretreatment value of 434/mm3 to 100/mm3 in this HIV-coinfected patient. Patient 7 was not treated with IFN because of minimal histologic evidence of hepatitis and a borderline CD4 count (267/mm3) complicating HIV infection. Patient 8 decided against IFN treatment when learning of the very mild histologic hepatitis on his biopsy. Figure 1 summarizes the responses to IFN. None of the patients treated with IFN permanently lost HCV RNA, although Patients 1 and 2 had transient loss of detectable HCV RNA at the end of treatment. The changes in serum ALT with IFN treatment varied but there was no predictable or persistent response. Toxicity of interferon. The only serious adverse effect possibly attributable to IFN was the decline in the CD4 count in the HIV coinfected patient (Patient 6). He did not develop opportunistic infections or have other untoward consequences. The CD4 count increased to >200/mm3 within 3 months of discontinuing IFN and substituting didanosine for zidovudine. Four of six patients developed an influenza-like syndrome consisting of fever, chills and arthralgias after the first few injections of IFN. These symptoms lasted no longer than 1 week in any case, and no patient's symptoms were severe enough to warrant IFN dosage reduction. Three patients had mild abdominal pain lasting for 1 to 2 weeks which resolved spontaneously. One patient had mild injection site erythema throughout the treatment period. No patient developed hematomas or external hemorrhage at IFN injection sites. There was no increase in spontaneous bleeding or use of coagulation factor concentrate. Discussion. Among adults with blood coagulation disorders, data are limited regarding response rates and toxicity of IFN therapy for chronic HCV infection. Several small trials in adults with hemophilia show a clinically significant improvement in the serum ALT value in 45 to 60% of subjects. However, relapse after completion of treatment is common so that sustained normalization of serum ALT and sustained loss of HCV RNA occurs in only 22 to 33% and 0 to 7%, respectively.7-10 Our data suggest that the initial response to IFN in boys with hemophilia and chronic hepatitis C is similar to that noted in adults with hemophilia and chronic hepatitis C. However, there were no patients with a sustained response after treatment. Factors contributing to this observation include the small numbers in this pilot trial and the fact that all the patients were infected with the relatively interferon-resistant genotypes, 1a and 1b.15-18 One patient was coinfected with both genotype 1a and genotype 1b; there was nothing distinctive about this child's response to IFN.19 Relatively little is known regarding HIV coinfection in the patient with chronic HCV infection. Recent information in hemophiliacs suggests that HIV infection may accelerate the development of cirrhosis resulting from HCV.20 Limited data suggest that IFN therapy is useful for the treatment of HCV in this population and does not lead to worsening of the immune status in HIV infected subjects.21, 22 Nevertheless the one HIV-infected patient whom we treated exhibited a decline in CD4 cell count during a brief period of IFN therapy. In conclusion liver biopsy can be performed safely and IFN is well-tolerated with minimal toxicity in young hemophilic patients. However, of the six boys treated with IFN, none had a sustained normalization of the serum ALT or clearance of HCV RNA from serum. Therefore IFN therapy of chronic HCV infection in young hemophiliacs cannot be recommended except in the setting of a controlled clinical trial. Acknowledgments. This work was supported by Schering-Plough Corp. and by Grant MCJ-482006 from the Maternal and Child Health Branch, Department of Health and Human Services. R. Jeff Zwiener, M.D.; Barbara A. Fielman, M.S., R.N., C.P.N.P.; Cynthia Cochran, M.S.N., R.N., C.P.N.P.; Beverly Barton Rogers, M.D.; D. Brian Dawson, Ph.D; Charles F. Timmons, M.D., Ph.D.; George R. Buchanan, M.D. Divisions of Gastroenterology (RJZ, BAF) and Hematology-Oncology (CC, GRB) Department of Pediatrics Department of Pathology (BBR, DBD, CFT) University of Texas Southwestern Medical Center Children's Medical Center of Dallas Dallas, TXFIG. 1: Response to IFN in 6 boys with chronic HCV and hemophilia. The presence or absence of serum HCV RNA is designated by + or -, respectively. Patient 2 was hepatitis B surface antigen-positive but e antigen-negative. Patient 6 was coinfected with HIV. - - - -, upper limit of normal for serum ALT.