TREATING CHILDREN WITH CHRONIC HEPATITIS C AFTER MALIGNANCY IN A SINGLE CENTER

Patients who are treated for pediatric malignancy prior to donor screening for the hepatitis C virus (HCV) are at a high risk of acquiring HCV from the blood product transfusions that they receive [1]. Moreover, hepatitis C is symptomatic in 10% of cases; the acute illness is generally asymptomatic and 70–80% of patients develop chronic infection [[1], [2]]. HCV could make the outcome of successfully treated pediatric oncology patients worse, because they receive a hepatotoxic drug during therapy [[1], [3], [4]]. It has recently been shown that antimetabolite chemotherapy exposure leads to a more rapid progression to fibrosis [[1], [5]]. At present, the management of patients with hepatitis C focuses largely on combination antiviral treatment using a 24- or 48-week course of peg interferon and ribavirin [[6], [7]].

Our clinics follow 408 patients who were treated for malignancy (leukemia and lymphoma) and blood product transfusions before 1990 when there were no tests available for detecting HCV in blood products. These patients have been screened for HBV and HCV. Patients were tested for antibody to HCV and HBV and for serum PCR-RNA and genotype at the follow-up.

Seven children (5 males and 2 females) of 408 patients who were cured of a pediatric malignancy disease (median follow-up 11 years, range 7–15 years) entered the present study. All patients received at least 3 blood products (range 3–60) by transfusion with a median 14 ± 2.9 transfusions.

All patients had chronic HCV infection defined by detectable circulating HCV-RNA. One patient had hepatitis B, C. Liver biopsies were performed. Determination of fibrosis score and hepatitis activity index was performed. The HCV subtype was determined by genotyping and serotyping in 6 of 7 patients. All patients had HCV subtype 1, including genotype 1a in 3 patients, genotype 3a in 1 patient, and mixed genotype 1a/1b in 2 patients.

The patients received recombinant IFN 2a at a dose of 6 megaunits/m² body surface subcutaneously 3 times a week combined with RBV at a dose of 15 mg/kg/body weight/day orally. For all of the patients, monthly complete blood count and liver function tests were performed every 3 months during treatment and the follow-up period.

Sustained response was defined by normalization of aminotransferases by negativity of HCV-RNA by PCR at the end of the treatment and for more than 6 months after withdrawal of the INF/RBV therapy. At study entry all patients had histologic features of active hepatitis with mild disease activity. The ALT values were abnormal in 6/7 patients (median 37 IU/L, range 30–67 IU/L), HCV-RNA was detected in the baseline sero of all patients with median level 3.0 × 10⁵ copies/mL. At the end of INF/RBV treatment, 5/7 patients were HCV-RNA negative; 3 relapsed soon after therapy withdrawal, whereas 2 remained negative for at least 24 months after cessation of therapy. Sustained response was, therefore, obtained in 2/7 patients (28%) (Table 1).

TABLE 1 Serum HCV RNA Profiles During Therapy and Follow-up

	Age (years)	Sex	HCV subtype	HAI	INF RBV therapy	Response
1	24	Male	1a, 1b	CH-MOA	12 month	Relapse
2	28	Female	1a	CH-MOA	24 month	Relapse
3	22	Male	1a	CH- MOA	6 month	Yes
4	16	Male	1a	MH	6 month	Yes
5	11	Female	ND	CH-MOA	36 month	Relapse
6	14	Male	1a, 1b	ND	ND	Follow up
7	15 month	Male	3a	CH MOA	12 month	Sustained

Note. HAI, hepatitis activity index; CH-MOA, chronic hepatitis with moderate activity; MH, minimal hepatitis.

Little information is available about the efficacy of INF and ribavirin in the treatment of hepatitis C in children with malignancies. Pensati et al. recently observed a low virological response of only 8% in 25 children treated with INF for chronic hepatitis C.

The most important factors in predicting IFN response seem to be HCV genotype, pretreatment HCV-RNA titers in underlying hematooncological disease, and absence of cirrhosis [[5], [9]]. The pathogenesis of liver damage is most likely due to a combination of direct cytopathic effects of viral proteins and of immune mechanisms, including cytolytic and noncytolytic reactions that are mediated by cytotoxicity [1].

McHutchison et al. showed that the rate of sustained response was higher among patients who received combination therapy for 24 or 48 weeks. The combination therapy with INF and RBV (ribavirin) may also be beneficial in children with chronic HCV infection. In fact, 50% of patients achieved a sustained response with HCV-RNA negativity for >12 months after therapy [8].

Patients with underlying malignant diseases are not good candidates for interferon therapy [10]. Because all patients were survivors of previous malignant hematooncologic diseases and had HCV genotype 1, they usually had a poor response to INF treatment [8]. It was interesting that in our study 2 patients were sustained responders (follow-up 24 months) and >50% of the patients did not respond to combination therapy with INF and RBV.

The results of this small study show that the patients did not respond to RBV and INF. These patients may respond to higher doses and/or longer courses of treatment. More study is needed.