Pediatric Hepatitis C Medication

Alpha interferon (IFN) results in a sustained response in fewer than 20% of patients, and adverse effects are often problematic. More recently, the addition of oral ribavirin to IFN therapy has improved the sustained response rate to 40-50%. Some research suggests that the dose of interferon might be lowered in genotypes 2 and 3, if ribavirin is used in combination. However, adverse effects remain a problem, and the response rate is lower for individuals infected with genotype 1, the most common genotype that causes infection, and the less common genotype 4.

For patients with HCV genotype 1 who do not have a sustained response to therapy with peginterferon–ribavirin, a new treatment option is emerging. Though its role in pediatric HCV needs to be further defined, studies show that the potent oral HCV-protease inhibitor boceprevir is an effective treatment option for previously treated patients as well as untreated patients when used in addition to standard therapy as compared to standard therapy alone.

Pegylated IFN (the addition of polyethylene glycol to the drug) results in significantly higher rates of response, especially with non–genotype 1 hepatitis C virus (HCV) infections.

Peginterferon alfa-2b (PEG Intron) plus ribavirin (Rebetol) is approved for children aged 3 years or older, whereas peginerferon alfa-2a (Pegasys) plus ribavirin (Copegus) is approved for children aged 5 years or older.

One long-term study found that peginterferon was associated with significantly lower height, weight and BMI, which largely recovered when therapy was discontinued. However, height remained significantly lower for age in children treated for 48 weeks or more.^[8]

Class Summary

Interferons (IFNs) are synthetically derived from a class of proteins that is produced and released by cells after viral invasion. They stimulate the production of another protein that inhibits viral replication. The nucleoside analogue ribavirin has some antiviral activity against hepatitis C virus, although improvements are not typically sustained after monotherapy is discontinued. However, the use of ribavirin in combination with IFN alpha is more effective than either drug alone and provides sustained responses. The newly approved protease inhibitor boceprevir is specific to HCV genotype 1 and has been shown to improve virologic response when added to IFN and ribavarin.^{[9, 10]}

Ribavirin (Rebetol, Copegus)

Ribavirin inhibits viral replication by inhibiting DNA and RNA synthesis. It is administered as combination therapy with IFN alpha-2b. Ribavirin may potentiate the effects of IFN alpha, improving sustained-response rates with HCV.

Peginterferon alfa-2a (Pegasys)

Pegylated IFN is used in combination with ribavirin to treat patients with chronic HCV infection who have compensated liver disease and have not previously received IFN alfa. Pegasys consists of IFN alfa-2a attached to a 40-kd branched PEG molecule (alfa-2b has a smaller 12-kd PEG molecule and is made from IFN alpha-2b). It is predominantly metabolized by the liver.

Several recent small clinical trials have shown that PEG-IFN used in combination with ribavirin is superior to standard IFN therapy. Which populations these recommendations can be extended to (the trials involved mostly HIV/HCV co-infected individuals) and whether alfa-2a is better than alfa-2b or vice versa is not yet clear.

Peginterferon alfa-2b (PEG Intron)

E coli recombinant product. Used to treat chronic hepatitis C in patients not previously treated with interferon alfa who have compensated liver disease. Exert cellular activities by binding to specific membrane receptors on cell surface, which in turn may suppress cell proliferation and may enhance phagocytic activity of macrophages. May also increase cytotoxicity of lymphocytes for target cells, and inhibit virus replication in virus-infected cells.

Interferon alfa-2b (Intron A)

INF alfa-2b is a protein product manufactured with recombinant DNA technology. Its mechanism of antiviral activity is not clearly understood. However, modulation of host immune responses enhances cytolytic T-cell activity, stimulates natural killer cell activity, and amplifies HLA class I protein on infected cells. Its direct antiviral activity activates viral ribonucleases, inhibits viral entry to cells, and inhibits viral replication. A direct antifibrotic effect has been postulated.

Prior to initiation of therapy, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cells, and bone marrow hairy cells; monitor periodically (eg, monthly) during treatment to determine response to treatment; if patient does not respond within 4 mo, discontinue treatment. If a response occurs (as measured by clinical improvement, a reduction in HCV viral load, or histologic improvement on liver biopsy), continue treatment until no further improvement is observed.

Whether continued treatment after that time is beneficial remains unknown. Some studies have found some salvage regimens with PEG-IFN to be of benefit.

Boceprevir (Victrelis)

Boceprevir is a NS3/4A protease inhibitor specific to HCV genotype 1a and 1b. It is metabolized by the liver and has many drug interactions through interference of the CYP3A4/5 enzyme. In combination with ribavarin and IFN, it has been shown to increase rates of virologic response, especially in African American patients (who typically fare poorly with regard with HCV genotype 1).