Continuing Education Activity

Interferons are currently used clinically to treat viral infections such as hepatitis C, cancers including non-Hodgkin’s lymphoma, and autoimmune diseases such as multiple sclerosis. This activity outlines the different types of interferons, namely interferon alpha, beta, and gamma. It discusses the pharmacological properties of different interferons, their medical uses, methods of administration, potential adverse effects, and other properties. It also highlights the important role that providers play in terms of correctly administering and dosing interferon medication, regularly monitoring patients for adverse effects, and counseling patients on the importance of medication adherence.

Objectives:

• Describe the different forms of interferons and their medical indications.
• Review the potential adverse effects of interferons.
• Summarize the methods of administration of interferon therapy and the necessary monitoring of patients on this treatment.
• Explain the importance of collaboration amongst the interprofessional team to enhance care delivery by ensuring that patients receive education regarding the importance of medication adherence and undergo routine monitoring while taking interferon.

Indications

Interferons are currently used clinically to treat viral infections such as hepatitis C, cancers including non-Hodgkin’s lymphoma, and autoimmune diseases such as multiple sclerosis. Interferon lambda currently has no FDA-approved uses, but researchers use it in research models of autoimmune diseases, cancers, and viral infections. The various types of interferons include interferon-gamma 1b, interferon beta 1a, lyophilized, PEGylated interferon-alpha 2b, interferon 1b, interferon beta 1a, biogenic form, interferon-alpha 2b, PEGylated interferon-alpha 2a, PEGylated interferon-alpha 2b plus ribavirin, PEGylated interferon-alpha 2b, interferon beta 1a liquid form, PEGylated interferon-alpha 2a, and interferon-alpha 2a.[1]

Interferon-alpha 2a is FDA-approved to treat chronic hepatitis C and hairy cell leukemia in adults, and chronic phase, Philadelphia chromosome-positive chronic myelogenous leukemia (CML). It is also used to treat follicular non-Hodgkin lymphoma, advanced renal cell carcinoma, and stage 2 malignant melanoma. Interferon-alpha 2-b (brand name: Intron A) is FDA approved for adults with chronic hepatitis C, hairy cell leukemia, AIDS-related Kaposi sarcoma, hepatitis B, and as an adjuvant for those with malignant melanoma.10 It also has approval for follicular non-Hodgkin lymphoma in combination with anthracycline chemotherapy, as well as for intralesional treatment of condylomata acuminata.[2] Interferon-beta 1a and b are FDA approved for the treatment of multiple sclerosis.[3] IFN-y1b is FDA approved to treat chronic granulomatous disease and osteoporosis.[4] Interferon-alpha 2a is FDA approved for the treatment of chronic hepatitis C in those above the age of 5 and adults with CHC/HIV co-infection. Interferon-alpha 2a is also a treatment of adults with chronic hepatitis B infection.[5][6] Interferon-alpha 2a is used for the treatment of chronic hepatitis C in adults in combination with ribavirin.[7] Interferon-alpha 2b is FDA approved for the treatment of chronic hepatitis C in adults in combination with ribavirin.[8] Ropeginterferon alpha 2b is FDA approved to treat polycythemia vera, myelofibrosis, graft vs. host disease, and essential thrombocythemia.[9] Interferon lambda has been used in animal models of autoimmune disease, cancer, and viral infections but has only demonstrated experimentally to have therapeutic benefit among patients with chronic HCV infection.[10]

Mechanism of Action

Interferons (IFNs) are proteins that belong to the group of signaling molecules known as cytokines involved in the upregulation of the immune response. Interferons are particularly important in fighting viral infections but also play a vital role in tumor suppression, upregulation of MHC Class 1 and 2, signal transduction, and activation of immune cells, including natural killer cells and macrophages. Interferons can broadly be classified into three main subtypes, interferon-alpha, beta, and gamma, with interferon-alpha and beta belonging to the Type 1 interferon subclass and interferon-gamma belonging to the Type 2 subclass.[11] More recently, there has been the discovery of a third subclass of interferons, namely Type 3, which includes interferon lambda.[10] 

Interferons exhibit immune-modulatory effects by initiating signaling cascades that lead to the expression of gene products such as MHC class 1, B2 microglobulin, and others. Alpha and beta interferons bind to the IFNA receptor, which has two parts, IFNAR1 and IFNAR2. IFNAR1 has a low affinity for interferon on its own, but binding is enhanced when accompanied by IFNAR2. Phosphatases SHP-1 and 2 associate with IFNAR1 and exhibit negative feedback in the activation of JAK signaling. IFNAR2 has three variants, short, soluble, and long-form. The long-form leads to activation of the JAK-STAT pathway and antiviral response. When stimulated by interferon, protein complexes form and translocate to the nucleus and activate STATs. This, in turn, leads to the dimerization of IFNAR1 and IFNAR2, which triggers a phosphorylation cascade. First, the JAK kinase, Tyk 2, which is associated with IFNAR1, is immediately phosphorylated by JAK1, another JAK kinase bound to IFNAR2. Activation of Tyk2 then phosphorylates JAK1, leading to phosphorylation of IFNAR1 and 2. Next, STAT2 binds to IFNAR1 at specific phosphorylated residues. Afterward, STAT2 is phosphorylated by JAK kinases, creating a port for STAT1, which is also phosphorylated. After becoming phosphorylated, the STATS dissociate and bind to the interferon regulatory factor 9, which forms the major interferon transcription factor, ISGF-3. IGSF-3 then translocates to the nucleus and binds to ISRE, initiating transcription of interferon-inducible genes. For interferon-gamma, there are different DNA regulatory sequences called gamma-activated sequence elements, which are present in promoters of interferon-gamma stimulated genes.[12]

Interferons exhibit antiviral activity at many stages of the viral replication cycle, including entry, transcription, RNA stability, translation, maturation, and release. This action is under the mediation of the expression of antiviral genes. Interferons stimulate the expression of PKR through an ISRE and GAS in the promoter of the PKR gene. The kinase activity of the PKR gene, in turn, phosphorylates the translation initiation factor eIF2-a at Ser51. eIF2-a-GTP is necessary for the initiation of viral translation. PKR also plays roles in cell proliferation, tumor suppression, and signal transduction through the regulation of serine phosphorylation of STAT1 and the phosphorylation of IkB, which leads to the activation of NF-kB-dependent genes. Additionally, the 2-5 A oligosynthetase/RNAse L system is strongly induced by interferons. RNAse Ls are activated by double-stranded RNAs and degrade all single-stranded RNA, thereby inhibiting viral replication. The Mx proteins are a family of GTPases induced by interferons and assemble into oligomeric and interfere with transcription in negative-sense virus replication. An additional protein involved in inhibiting viral replication that is induced by interferons is the guanylate binding protein.[12]

In addition to the antiviral properties of interferons, they also exhibit antiproliferative properties. Researchers suspect that these antiproliferative properties of interferons are due to the actions of STAT1 and PKR, the induction of CDK inhibitors, and the decrease of cyclin D and cdc25A. Interferons are also known to act in conjunction with dsRNA, TNF, and LPS to promote apoptosis.[12]

Research has shown interferon beta to upregulate and downregulate many interferon-dependent gene transcripts (SOCS 1, C-C motif, CCL1, CCL7, CCL2, JAK2, ISG20, and CCL20 were upregulated, while CXCL6 and IL-8 were downregulated). Interferon beta has also been demonstrated to increase levels of IL-10, IL-23A, and IL-5 while decreasing lymphocyte counts, including T cells, CT cells, Th cells, B cells, and NK cells.[13]

Furthermore, interferons have significant immunomodulatory effects, with interferon-gamma being the predominant immunomodulatory interferon. Type 1 interferons act as antiviral cytokines. Alpha interferons activate NK cells, which in turn destroy viral and other targets; increase the proliferation of B cells, which secrete antibodies against pathogens; and enhance CD8 T cell response by upregulating the expression of MHC class 1 on surface cells. Type 1 interferons also upregulate IL-12Rb and increase the expression of MHC class II molecules.[12] 

Administration

Interferon-alpha

For chronic viral hepatitis treatment, administer 10 MIU of interferon-alpha is administered three times a week subcutaneously for 24 weeks in combination with ribavirin. For non-Hodgkin lymphoma, hairy cell leukemia, and multiple myeloma, 3 MIU of interferon-alpha is administered subcutaneously until tumor progression stops. In treating renal cell carcinoma, administer 10 MIU of interferon-alpha until the cessation of tumor progression. For chronic myeloid leukemia, 10 MIU of interferon-alpha is administered three to five times a week subcutaneously in combination with cytarabine until tumor progression stops. For melanoma treatment, give 3 to 10 MIU of interferon-alpha three times a week subcutaneously as adjuvant therapy. Interferon-alpha is also used to treat condylomata acuminata, Behcet disease, and Kaposi sarcoma with varying schedules.[14]

Interferon-beta

Interferon-beta 1a and 1b are used to treat multiple sclerosis. Interferon-beta 1b is administered subcutaneously in a 250 ug dose every other day. Interferon-beta 1a is administered intramuscularly once per week at a dose of 30 mcg and subcutaneously three times a week at a dose of 22 to 42 mcg.[3]

Interferon-gamma

Interferon-gamma is used to treat chronic granulomatous disease. It is administered subcutaneously three times per week into the deltoid or anterior thigh. The dosage is 50 JLg/m for those with a body surface area greater than 0.5 m. For those with a body surface area less than or equal to 0.5 m, the dosage calculation formula is 1.5 JLg/kg.[15] 

Adverse Effects

Interferon-alpha

Patients taking interferon-alpha may experience flu-like symptoms (fever, headache, nausea, chills, myalgia, etc.) for a few hours after administration as well as chronic fatigue, skin rashes, alopecia, and autoimmune reactions.[14] There are also reports of anorexia and erectile dysfunction.[16]

Interferon-beta

Patients on Interferon-beta therapy often experience flu-like symptoms within 2 to 8 hours of injection, lasting less than 24 hours. These symptoms may include fever, chills, muscle aches, headaches, and back pain.[3]

Interferon-gamma

The adverse effects of Interferon-gamma include fever, headache, fatigue, rash, chills, injection site erythema or tenderness, diarrhea, vomiting, nausea, weight loss, myalgia, inflammation/autoimmune reactions, anorexia, and arthralgia.[15]

Contraindications

Contradictions to interferon therapy include kidney dysfunction, cirrhosis, hepatitis, autoimmune disease, past treatment with immunosuppressive therapy, organ transplantation, uncontrolled thyroid disease, epilepsy, severe mental and neurological disorders, CNS disorders, organ transplantation, and psoriasis.[16] 

Monitoring

Interferon-alpha

Prior to starting interferon-alpha therapy, a complete blood count, creatinine, serum aspartate, and alanine aminotransferase, lactic dehydrogenase, electrolytes, triglycerides, creatine kinase, and blood sugar tests should be performed weekly during the first four weeks, monthly during months 1 through 3, and every 3 months thereafter. Thyroid hormone levels should also be checked every 3 months after month 3 of treatment.[16]

Interferon-beta

Patients on interferon-beta therapy should have liver function and blood count tests before starting therapy and every 6 months afterward. Furthermore, patients should be screened for the formation of neutralizing antibodies every 6 months for the first two years of treatment.[3]

Interferon-gamma

Patients taking interferon-gamma should be screened regularly for thrombopenia, leucopenia, the elevation of transaminases, and anti-interferon antibodies.[17]

Toxicity

Interferon-alpha

Depression, delirium, and cognitive impairments have occurred with interferon-alpha therapy. Patients taking interferon-alpha are at risk for decreased blood counts, cardiotoxicity, pulmonary toxicity, hepatotoxicity, endocrine dysfunction (most commonly manifesting as diabetes mellitus and thyroid dysfunction), renal toxicity manifesting as proteinuria, and gastrointestinal toxicity (which leads to nausea, vomiting, diarrhea, and altered taste). Patients taking interferon-alpha are also at risk for developing autoimmune disorders and neurological impairments, such as seizures.[14]

Interferon-beta

Interferon-beta increases the risk of bone marrow suppression, pancreatitis, acute liver failure, and injection site reactions, including infection and necrosis.[3]

Interferon-gamma

Interferon-gamma increases the risk of gastrointestinal toxicity, induction of autoimmunity, encephalopathy, acute renal failure, and graft versus host disease following bone marrow transplantation.[17]

Enhancing Healthcare Team Outcomes

Interferon therapy has been shown to have therapeutic value for various diseases, including autoimmune diseases, viral diseases, and various forms of cancer. Interferons have also demonstrated significant immunomodulatory effects, making them beneficial for treating immune-related conditions such as multiple sclerosis and chronic granulomatous disease. However, given the potential for hepatotoxicity, renal toxicity, myelosuppression, autoimmune reactions, and other adverse outcomes, it is imperative for health care professionals to routinely monitor their patients through blood work while administering this medication. It is also essential that all interprofessional healthcare team members collaborate to determine the correct dosage and form of interferon therapy, as well as any adjuvant therapies, given there is significant variability in adverse effects. Lastly, medication adherence can be an issue with interferon treatment.[18] Healthcare teams can address this issue by working as a cohesive unit to educate patients about the importance of medication adherence and providing regular reminders to patients.