Treatment of Hepatitis C in children

Paloma Jara; Loreto Hierro

Disclosures

Expert Rev Gastroenterol Hepatol. 2010;4(1):51-61. 

In This Article

Treatment

There are different approaches to the treatment of children with chronic hepatitis C.[42] The main characteristic of chronic hepatitis C is its persistence over time with slow progression to fibrosis. Severe disease is rare in children, and therefore follow-up without treatment until adult life is a valid option for most pediatric patients. Treatment during childhood does not achieve increased rates of response compared with adult patients and adverse effects are frequent and, even in some cases, may be severe. Conversely, treatment may be justified, since it allows definitive resolution in a subgroup of patients. Quality of life is not affected in children with HCV infection, but parents are worried about the outcome and perceive the difficulties of social life, even when there is a negligible risk of horizontal transmission.[43,44] Adolescence and young adulthood are associated with high scholar or work demands, and more difficult compliance with medical visits. All those factors may lead to postponed treatment.

The decision to treat should consider several aspects in the individual patient: age, severity of disease, efficacy of the chosen therapy, its adverse effects, compliance to treatment and willingness. Children under 3 years old are not eligible for treatment (and treatment is not approved), as HCV infection may still spontaneously resolve and spastic diplegia has been reported in infants treated with IFN-α for hemangiomas.[45]

Over time, and in parallel with the results obtained in adults, experience has been gained in children with IFN-α monotherapy,[46–50] the combined use of IFN-α and ribavirin,[51,52] pegylated IFN (PEG-IFN) monotherapy[53] and, at present, the use of PEG-IFN with ribavirin, which was approved by the US FDA (in December 2008) and the EMEA (in December 2009) for children older than 3 years of age.

Baseline Patient Evaluation

Patients are excluded if they have comorbid medical conditions (i.e., moderate or severe depression, psychiatric conditions, seizures and renal insufficiency) that could compromise the tolerability of the drugs. Patients testing positive for autoimmunity markers – antinuclear antibody, smooth muscle antibody and LKM1 – are enrolled if other features do not suggest autoimmune hepatitis. Adolescents should be instructed in birth control during antiviral therapy and for 6 months after treatment cessation. Routine pregnancy testing is advised in girls of child-bearing potential.

The viral genotype involved must be known in order to assess the probability of response and to design the duration of therapy. Viral load must be quantified since the decision to maintain therapy will depend on the course of viraemia at week 12 of treatment in the case of genotypes other than 2 and 3. A biopsy is recommended before starting treatment. According to several studies performed on pediatric chronic HCV infection histology, showing mild lesions in most, the need for a biopsy to assess the disease is controversial, although it is the only method to identify severe cases. However, treatment decisions should not rely on histological findings.

Further workout should be carried out, especially in line with recent observations of genetic polymorphisms linked to response to treatment, which can be of value for treatment decisions in the future. Candidate studies are polymorphisms near the IL28B gene, encoding IFN-λ-3, which has been associated with an approximately twofold change in response to treatment.[54]

Treatment Design

Common terminology refers to 'rapid viral response' when viremia turns undetectable in week 4 of treatment, 'early viral response' when HCV RNA is negative in week 12 and 'end of treatment response' when viremia proves negative at the end of treatment. Sustained virologic response (SVR) is defined as undetectable serum HCV RNA 24 weeks after treatment cessation and is equivalent to resolution of infection.

In treatment-naive patients, the likelihood of achieving a SVR is best predicted by a more than 2 log10 unit decrease in HCV RNA by 12 weeks of therapy. Among naive populations, less than 2% of patients who fail to achieve an early virological response ultimately achieve a SVR.

Therapy aims to achieve negative conversion of HCV viremia to below the detection limit of the qualitative PCR technique employed (30–50 IU/ml). Once negativity has been achieved, treatment must continue long enough to ensure eradication of the infection in the liver. Different HCV genotypes exhibit different sensitivities to treatment. Genotypes 2 and 3 are more sensitive, with healing rates of 83–100% of all patients treated for 24 weeks. In the case of genotypes 1 and 4, the overall SVR rate is 50%, and 48 weeks of therapy are required. The high probability of a favorable response in the case of a sensitive genotype means all patients need treatment for 24 weeks. In the case of less-sensitive genotypes, re-evaluation is carried out after 12 weeks. If at this point there has been a decrease in viral load of at least 2 log10, treatment is continued up to 48 weeks. However, if such a decrease in viral load is not found, treatment is withdrawn, since healing is not likely to occur even if the full treatment course is administered.

Guidelines of treatment are well established in adults.[55] In these patients current studies aim to shorten the duration of therapy (to 16 weeks in the case of a sensitive or favorable genotype, and to 24 weeks in the case of genotype 1) for those subjects with rapid viral response, and to prolong therapy (48 weeks for genotype 3 and 72 weeks for genotype 1) for those subjects showing a drop in viremia, but with persistent positive HCV RNA at week 12. Other ongoing investigations aim to increase efficacy by adding antiviral agents, such as telaprevir or boceprevir, to the conventional PEG-IFN plus ribavirin treatment.[56]

Drugs

Pegylated IFN-α Pegylated IFN-α is created by covalently linking a polyethylene glycol moiety to the IFN-α protein. The addition of this moiety to IFN-α confers an extended serum half-life compared with native IFN-α, allows once-weekly dosing and significantly improves SVR rates. Two forms of PEG-IFN have been developed, PEG-IFN-α-2b and PEG-IFN-α-2a. PEG-IFN-α-2a uses a large (40 kD) branched polyethylene glycol molecule, while PEG-IFN-α-2b uses a smaller (12 kD) linear molecule. The overall results from controlled trials in adults suggest that they achieve a similar rate of SVR.

Adverse events of PEG-IFN occur in the same proportion of patients and are of the same quality as observed with IFN-α. PEG-IFN is more convenient because of the weekly administration and influenza-like symptoms being limited to one versus three doses per week with conventional IFN.

Dosing in Children A once-weekly dose of PEG-IFN-α-2a is calculated from each patient's body surface area according to the formula BSA (m2)/(1.73 m2) × 180 µg. This dosing achieves adequate therapeutic concentrations.[53]

PEG-IFN-α-2a 1–1.5 µg/kg once a week has been given to children after approval in adults. Another approach is to adjust the adult dosing of 1.5 µg/kg to the body surface of the child, so dosing for children results in 60 µg/m2 per week.

The PEG-IFN-α dose is transiently decreased in patients with a neutrophil count of less than 1–1.25 × 109 cells/ml to avoid significant neutropenia. PEG-IFN-α is temporarily discontinued if the neutrophil counts fall below 0.75–1.00 × 109 cells/ml; and it is resumed once the neutrophil counts recover.

Ribavirin Ribavirin is a guanosine analog. Ribavirin alone has a relatively minor antiviral effect in HCV-infected patients, but in combination with PEG-IFN-α it appears to enhance the second and third phases of viral decay, thereby reducing the chance of relapse.[57] Its suggested mechanisms of action include error catastrophe resulting from mutagenesis via incorporation of ribavirin into HCV RNA during replication, direct inhibition of HCV RNA replication, inosine-monophospatedehydrogenase inhibition and immunomodulation. A relationship between ribavirin dose and response to therapy with both IFN-α-2a and -α-2b has been established, especially in patients with HCV genotype 1.

Ribavirin is cleared by the kidneys, so it should be reduced in patients with decreased creatinine clearance and completely avoided in renal insufficiency. Its main toxicity is hemolytic anemia, directly related to the concentration of ribavirin in erythrocytes. Anemia is the most common reason for ribavirin dose reduction or treatment discontinuation.

Dosing in Children A study in children receiving IFN-α-2b plus ribavirin 8, 12 or 15 mg/kg/day demonstrated that those on 15 mg/kg had the maximum reduction in serum HCV RNA at treatment weeks 4 and 12, with an acceptable safety profile.[52]

On-therapy Assessments in Children

For assessment of efficacy, HCV RNA titers are measured at weeks 4, 12, 24 and 36, at the end of treatment, and every 12 weeks for another 6 months after the end of treatment. The assessment of safety should be planned in order to promptly detect adverse effects that require dose adjustment. Drugs cause influenza-like symptoms, neutropenia, anemia and weight loss especially during the first month of treatment. Clinical and analytical follow-up is performed every 2 weeks in the first phase of therapy. Monthly visits are advisable up to the sixth month, and scheduled every 3 months for the remaining period of treatment and for another 6 months after the end of treatment. Depression, thyroid disorders and growth velocity should be assessed. The long-term effects on thyroid function (if disturbed during treatment) and on growth would require an extended time (i.e., 2 years) of follow-up.

Efficacy of PEG-IFN Plus Ribavirin Treatment in Children

Combined therapy with PEG-IFN and ribavirin has improved sustained response rates compared with other treatments and currently represents the standard therapy in adult patients.

There are two ongoing trials in children with almost finished efficacy reports.[58–60] One international study investigates the pharmacokinetics, efficacy and safety of PEG-IFN-α-2b 60 µg/m2/week combined with ribavirin 15 mg/kg/day in 107 children. Another multicenter North American trial investigates PEG-IFN-α-2a plus ribavirin (55 children) compared with PEG-IFN-α-2a monotherapy (59 children) (Table 2).

Two European studies have been published with the data on the efficacy and adverse effects of the PEG-IFN plus ribavirin combination in children. One was conducted in a center in Spain; 30 children (24 naive) were enrolled to receive PEG-IFN-α-2a 1 µg/kg/week with ribavirin 15 mg/kg/day.[61] The other trial was carried out in several centers in Germany, and 61 children (51 naive) were given PEG-IFN-α-2a 1.5 µg/kg/week plus ribavirin 15 mg/kg/day.[62] In both studies the duration of treatment was 24 or 48 weeks in genotype 2/3 infections, and for 48 weeks in the case of genotype 1 or 4. The results were similar in both (Table 2), and showed a response equal to or slightly greater than that reported in children on conventional IFN-α given three-times per week plus ribavirin.

In the Spanish study, involving strict chronic infection inclusion criteria (over 3 years from infection), and with a patient age of 3.5–16 years, 69% of the cases were due to mother-to-child transmission, 86.6% corresponded to genotype 1, and baseline viral load was >5 log10 IU/ml in 66.6% of cases. SVR was achieved in 15 (50%) of 30 patients: in three (100%) out of three patients with HCV genotype 3, and in 12 (44%) out of 27 with HCV genotype 1. One patient with HCV genotype 4 did not respond. All patients who attained SVR remained HCV RNA-negative at further follow-up visits (up to 36 months) and had normal liver function.[61]

In the German study, the patients were between 2–17 years of age; 40.3% of the infections were the result of vertical transmission and 75.8% presented genotype 1. Of 46 patients with genotype 1, 22 (47.8%) showed SVR. All individuals with genotype 2 or 3 (n = 13) responded permanently, irrespective of the duration of treatment (i.e., 24 or 48 weeks) (p < 0.0003). One of two patients with genotype 4 had SVR.[62]

Predictors of Response

The study of baseline characteristics of treated patients may help to identify predictors for response, in order to select the candidates for therapy. Among adult patients, those aged less than 40 years without advanced disease show better response rates. However, overall results of treatment during childhood do not clearly offer significantly better results compared with adults.

The most important determinants of response in children are the viral genotype and viremia levels among those with genotype-1 infection. No baseline characteristic excludes response to therapy among those with genotype 1. On the other hand, the evolution of viremia after 12 weeks of therapy is of much help to identify future responders. In practical terms, all children may be eligible for treatment and early stopping rules according to week 12 viremia should be applied.

The HCV genotype is the main baseline predictor of response. Recent unpublished pediatric trials obtained a response in 93% of genotype 2 or 3, 80% of genotype 4 and 53% of genotype 1 HCV infections, and 47% of genotype 1 compared with 80% of genotype non-1, respectively.[58,60] In the international PEG-IFN-α-2a plus ribavirin study, response in genotype 1 was influenced by baseline viral load, as those showing HCV-RNA over 6 × 105IU/ml had 29% SVR compared with 72% SVR in genotype 1 with lower titers.[58]

Patient age does not seem to influence response (SVR: age < 12 years versus older children: 54.8 vs 63.3% in the German study and 45 vs 60% in the Spanish study). Responders show similar baseline ALT levels compared with nonresponders, and children with normal aminotransferase values display the same SVR rate as those with abnormal biochemistry prior to therapy. The baseline viral load and Knodell index did not influence the response in the Spanish study. However, in both experiences, the response in those children who developed the infection as a result of blood transfusions tended to be higher than in those with mother-to-child transmission (German children: 70.4 vs 48%; p = 0.087; Spanish children: 78 vs 38%; p = 0.1).[61,62]

Virological surveillance while on therapy appears to be the best predictor of response. In the Spanish study, only one patient showed negative HCV RNA at week 4. At week 12 of treatment, 51.7% showed undetectable HCV RNA, while 72% presented a greater than 2 log10 decrease compared with baseline viral load. A SVR was elicited in 87 and 71% of those presenting the above characteristics, respectively, at week 12. No cases with less than 2 log10 reduction at week 12 achieved sustained response. Continued therapy for 48 weeks in six children with positive HCV RNA at week 24 was ineffective in all cases.[61]

The German study reported that 62.3% of the treated children achieved negative HCV RNA at week 12. In turn, 91% of the patients with genotype 1 and 92.3% of those with genotypes 2/3 who showed a sustained response presented undetectable viremia at week 12 of therapy.[62]

Nonresponders to Therapy

Circumstances associated with a lack of response in children have not yet been elucidated.

Children with genotype 1 infection with mother-to-child transmission, currently representing the most numerous group, have shown SVR rates of 37.5 and 35% in the Spanish and German studies, respectively.[61,62] Thus, for many patients current therapy is inefficient.

Nonresponders can be retreated, but there is a very limited experience in children. According to studies in adults, the likelihood of response to retreatment depends on the type of response to prior therapy (relapsers achieve near 40% of SVR compared with 10% in nonresponders) and the differences in efficacy between the initial and the retreatment regimens. Very few children who failed to respond with IFN-α monotherapy were retreated with IFN-α plus ribavirin,[51] or PEG-IFN-α-2a plus ribavirin.[61,62] Using the highest efficacy PEG-IFN plus ribavirin, a sustained response was achieved in three out of 11 cases.

Adverse Effects

The adverse effects of PEG-IFN plus ribavirin are similar to those associated with conventional IFN, involving fewer injections and immediate injection reactions. Other adverse effects were of the same nature and intensity.

The toxicity of PEG-IFN plus ribavirin treatment must be carefully evaluated. It has been assessed in only two studies.[61,62]

In almost all children and adolescents, transient flu-like symptoms with variable intensity, including moderate fever, are observed during the first weeks of treatment. In most of them, the symptoms resolved or were of minor intensity during the second 6 months. Febrile convulsions are a hazard in younger children, but the problem did not occur in available series. Dose reduction by 20–30% of PEG-IFN was carried out because of considerable leukopenia in 5% of patients in the German series. Prolonged (>1 month) or permanent reductions in PEG-IFN-α-2b doses were required in 23% of Spanish children (Table 3).[61,62]

Owing to hemolysis induced by ribavirin, mean hemoglobin levels decrease within the first week of therapy, reaching a mean maximal decrease of 1.4 g/dl by week 12. Hemoglobin values are stable during the remaining period and return to normal when therapy is discontinued or completed. No reduction in ribavirin dose was required. Reticulocyte levels increased during therapy but returned to normal thereafter.

School performance is not grossly affected. Transient changes in character or mood have been recorded in 15–30% of the children, but severe psychological impairment was not observed.[61,62] Depression is a concern and should be looked for in adolescents, as suicidal ideation and even suicidal attempts have been reported during treatment with conventional IFN-α plus ribavirin.[52]

Patients with detectable LKM1 antibodies at baseline have shown either stable or varying titers during therapy. No patient developed LKM1 antibodies, although previous experiences have shown that LKM1 appear in 5% of children treated with IFN-α.[35] No specific liver function events occurred in antinuclear antibody-positive or LKM1 antibody-positive patients during or after therapy. Regarding the possibility of IFN facilitating autoimmune disease, one girl was reported to have developed diabetes mellitus after 9 months of treatment; therapy was continued without changing dosage and the patient showed SVR.[62]

The emergence of thyroid antibodies and thyroid-stimulating hormone elevation during treatment is significant. In the German study, five individuals received a weight-adjusted dose of l-thyroxine until the end of treatment. In three of these, l-thyroxine could be stopped during follow-up, and in two patients thyroid hormone supplementation was maintained 12 months after discontinuation of ribavirin and PEG-IFN.[62]

According to the Spanish study, four patients developed antithyroid antibodies. Two patients showed sudden decreases in thyroid-stimulating hormone values during therapy, accompanied by high T4 values and weight loss. Treatment was discontinued immediately in both patients. Anti-thyroid antibodies appeared in successive checkups. No specific therapy for hyperthyroidism was required and thyroid-stimulating hormone and T4 values returned to normal. The remaining two patients developed antithyroid antibodies during therapy and the condition persisted when off therapy. Mild elevation of thyroid-stimulating hormone or T4 values was observed in another additional six patients.[61]

Growth during the 48-week treatment period has been shown to be reduced in most patients by a mean of 1.6 cm compared with the average growth for age and gender. Growth velocity was normal in the 6-month period after the end of treatment; however, the modest decrease in height percentile observed during therapy was not recovered in the short term.[61]

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