Boceprevir and IFNL3

Boceprevir (Victrelis ®) is currently used for the treatment of patients with chronic hepatitis C virus (HCV), specifically the genotype 1 infection. This genotype refers to the specific strain of the virus the patient has been infected with, of which several have evolved over time. Genotype 1 is the most common HCV strain followed by types 2 and 3, with a very small number affected by strains 4, 5, and 6. Boceprevir must be used in combination with ribavirin and pegylated interferon alfa-2a, which are other antiviral medications. Boceprevir is approved in patients with compensated liver disease, cirrhosis, and patients who have been unresponsive to other antiviral therapies.

Boceprevir is classified as a direct-acting antiviral that functions by inhibition of specific host cell functions, the major one being replication of HCV. This is accomplished by reversibly binding to nonstructural protein 3 (NS3) serine protease, a key enzyme required for the maturation of the virus. By adhering to the antiviral therapy along with modifications in lifestyle, patients are capable of leading a normal life. Patients should be aware that even while on boceprevir, they are still capable of transmitting the disease.

The gene of interest is interferon-lambda 3 (IFNL3). This gene codes for a cytokine, which is a small protein that is released in response to a viral infection. It signals to the rest of the immune system the location of the virus in order for it to be effectively attacked.

Some studies have found a strong relationship between variations in the IFNL3 gene and response to boceprevir combination therapy. A change in a single nucleotide on the gene, thymidine for cytosine, is associated with improved response to boceprevir used in combination with ribavirin and pegylated interferon alfa-2a. Despite potential for some therapeutic consideration of this genetic variation, no change in therapy is currently recommended. The studies on this variation had a small sample size and thus did not provide compelling evidence for any strong recommendation to be given. As more studies are conducted in the future, a recommendation for alternate treatment based on genotype might be proposed. It is still possible that some physicians may want to take genotype testing in consideration when deciding on a treatment plan for HCV.

Lucas is a 32-year-old male that has been recently diagnosed with chronic hepatitis C. He is being treated at a large academic medical center that routinely screens patients with hepatitis C for their virus genotype and variations in IFNL3. Michael is found to have a hepatitis C viral genotype 1a and have the IFNL3 (IL28B) CT genotype (unfavorable). The IFNL genotype is not noticed during the initial therapy decision. The decision has been made to treat his hepatitis C infection with boceprevir, Peg-Interferon alfa-2a and ribavirin therapy given a lack of access to the new direct-acting antivirals at the local pharmacy.

During rounds, the pharmacy resident in the medical team notices this genotype in the patient's chart and sees that the patient has the unfavorable genotype for IFNL. The pharmacy resident explains how there is approximately a 60% chance of sustained virological response (SVR) after 48 weeks of treatment with this current therapy recommendation. The resident then recommends to start ledipasvir 90 mg/sofosbuvir 400 mg orally once daily for 12 weeks which has a much better chance for SVR. The medical team accepts this recommendation and finds a mail order pharmacy that can get the medication to the patient.

If the original recommendation of using boceprevir, Peg-Interferon alfa-2a and ribavirin was used, then there might be a higher chance of treatment failure.

IFNL3 genetic testing does not completely rule out the risks of taking boceprevir based therapies, nor will it guarantee that the patient will achieve SVR at the end of treatment. IFNL3 testing is a way personalize the treatment of patients and maximize the effectiveness while decreasing costs of treatment and potential harm to the patient.

The links below provide access to important articles and information relative to boceprevir. The links are to external websites and will be checked regularly for consistency.

• Boceprevir Prescribing Information
• Boceprevir Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: Boceprevir

IFNL3 [Internet]: U.S. National Library of Medicine; c2016 [cited 2016 March 8]. Available from: https://ghr.nlm.nih.gov/gene/IFNL3.

Klevens RM, Hu DJ, Jiles R, et al. Evolving epidemiology of Hepatitis C Virus in the United States. Clin Infect Dis. 2012;55(Suppl 1):S3-S9.

Muir J, Gong, L, Johnson SG, Lee MT, Williams MS, Klein TE, Nelson DR. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for IFNL3 (IL28B) genotype and PEG interferon-α-based regimens. Clin Pharmacol and Ther. 2014;95:141–6.

Victrelis (boceprevir) [package insert on the Internet]. Bethesda (MD): U.S. National Library of Medicine; [updated 2017 Jan 30; cited 2017 April 12]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ae879ebe-b620-4829-b6f8-74b58da1c771.