Medication Summary
The first direct-acting antiviral drugs were approved for adolescents in 2017. Sofosbuvir (Sovaldi) and the combination product, ledipasvir/sofosbuvir (Harvoni), are approved for chronic HCV infection in pediatric patients aged ≥12 years or who weigh at least 35 kg.
Sofosbuvir is indicated for HCV genotypes 2 or 3 and is used in combination with ribavirin. An open-label study was conducted in adolescents (n=52) who received sofosbuvir 400 mg once daily and weight-based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. Sustained virologic response at 12 weeks (SVR12) was achieved by 98% of patients (51/52; 95% confidence interval, 90%-100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for those with genotype 3. The single patient who did not achieve SVR12 was lost to follow-up after achieving SVR4. [9]
Ledipasvir/sofosbuvir is indicated for HCV genotypes 1, 4, 5, or 6. In an open-label study of adolescents (n=100) with HCV genotype 1, SVR12 was reached in 98%. The 2 patients who did not achieve sustained virologic response at 12 weeks were lost to follow-up either during or after treatment. [10] The safety and efficacy of ledipasvir/sofosbuvir for treatment of HCV genotypes 4, 5, or 6 infection in adolescents was based on data showing similar systemic exposures to ledipasvir/sofosbuvir in adults and adolescents with HCV genotype 1 infection, as well as similar efficacy and exposures across HCV genotypes 1, 4, 5, and 6 in adult. [11]
Glecaprevir/pibrentasvir was approved for adolescents in April 2019. The safety, efficacy, and pharmacokinetics of glecaprevir/pibrentasvir in HCV genotypes 1, 2, 3, or 4 infected pediatric patients aged 12 years and older or weighing at least 45 kg was based on data from an open label trial in 47 subjects without cirrhosis aged 12-18 years who were either treatment-naïve (n=36) or treatment experienced (n=11). [12]
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 peginterferon 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. [13]
Direct-acting antiviral drugs
Class Summary
Direct-acting antiviral (DAA) drugs interfere with specific steps in the HCV replication cycle through a direct interaction with the HCV genome, polyprotein, or its polyprotein cleavage products.
Sofosbuvir (Sovaldi)
Sofosbuvir is a nucleotide prodrug that undergoes metabolism to the active uridine analog triphosphate, an inhibitor of HCV NS5B RNA-dependent polymerase; its inhibition in turn suppresses viral replication. It is indicated for the treatment of chronic HCV genotypes 2 or 3 infection in pediatric patients aged ≥12 y or weighing at least 35 kg without cirrhosis or with compensated cirrhosis. It is used in combination with ribavirin.
Ledipasvir/sofosbuvir (Harvoni)
Ledipasvir inhibitors HCV NS5A protein, which is required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes metabolism to the active uridine analog triphosphate, an inhibitor of HCV NS5B RNA-dependent polymerase; its inhibition in turn suppresses viral replication. The combination is indicated for pediatric patients aged ≥12 y or weighing at least 35 kg with hepatitis C virus (HCV) genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis.
Glecaprevir/pibrentasvir (Mavyret)
Glecaprevir is a HCV NS3/4A protease inhibitor. NS3/4A protease is necessary for proteolytic cleavage of the HCV-encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. Pibrentasvir is a HCV NS5A inhibitor. NS5A is essential for viral RNA replication and virion assembly.
Glecaprevir/pibrentasvir is indicated for treatment-naïve adolescents who are 12-17 y old or weigh at least 45 kg (99 lb) with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis or with compensated cirrhosis. It is also indicated for treatment-experienced adolescents with HCV genotype 1 who have been previously treated with a regimen containing either an NS5A inhibitor or an NS3/4A protease inhibitor, but not both. An 8-week regimen is approved for treatment-naïve patients with any genotype and for treatment-experienced patients with genotypes 1, 2, 4, 5, or 6 who had prior treatment with peginterferon, ribavirin, and/or sofosbuvir.
Antiviral agents
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.
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 coinfected individuals) and whether alfa-2a is better than alfa-2b or vice versa is not yet clear.
It is indicated as part of a combination regimen with other HCV antiviral drugs in children aged >5 y with compensated liver disease.
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.
It is indicated combination with ribavirin in children aged ≥3-17 y with compensated liver disease.
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.
It is indicated in combination with ribavirin for treatment of chronic hepatitis C in children aged ≥3 y with compensated liver disease previously untreated with alpha interferon therapy and in patients aged ≥18 y who have relapsed following alpha interferon therapy.
