Interferons
Number: 0404
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Note: Requires Precertification:
Precertification of interferon beta-1a (Avonex) is required of all Aetna participating providers and members in applicable plan designs. For Medicare Part B plans, call (866) 503-0857, or fax (844) 268-7263.
Interferon alfa-2b (Intron A)
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Criteria for Initial Approval
Aetna considers interferon alfa-2b (Intron A) medically necessary for the following indications:
- Malignant melanoma; or
- Adult T-cell leukemia/lymphoma (ATLL) when the requested medication is used in combination with zidovudine; or
- Mycosis fungoides (MF)/Sezary syndrome (SS); or
- Hairy cell leukemia; or
- Follicular lymphoma (clinically aggressive); or
- Renal cell carcinoma (RCC) when the requested medication will be used in combination with bevacizumab; or
- Condylomata acuminata; or
- AIDS-related Kaposi sarcoma; or
- Chronic myeloid leukemia (CML); or
- Giant cell tumor of the bone; or
- Chronic hepatitis C virus infection; or
- Chronic hepatitis B (including hepatitis D virus co-infection) virus infection; or
- Ocular surface neoplasia (conjunctival and corneal neoplasm).
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
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Continuation of Therapy
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Chronic Hepatitis C
Aetna considers continuation of interferon alfa-2b (Intron A) therapy (up to a total of 96 weeks) medically necessary for chronic hepatitis C when the member is receiving clinical benefit and there is no evidence of an unacceptable toxicity while on the current regimen.
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Chronic Hepatitis B
Aetna considers continuation of interferon alfa-2b (Intron A) therapy (up to a total of 24 weeks) medically necessary for chronic hepatitis B when the member is receiving clinical benefit and there is no evidence of unacceptable toxicity while on the current regimen.
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All Other Indications
Aetna considers continuation of interferon alfa-2b (Intron A) therapy medically necessary for an indication listed in Section I, other than chronic hepatitis C and chronic hepatitis B, when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.
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Interferon alfa-n3 (Alferon N)
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Criteria for Initial Approval
Aetna considers interferon alfa-n3 (Alferon N) medically necessary for intralesional treatment of refractory or recurring external condylomata acuminata (venereal/genital warts).
Aetna considers all other indications as experimental and investigational.
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Continuation of Therapy
Aetna considers continuation of interferon alfa-n3 (Alferon N) therapy medically necessary in members requesting reauthorization for an indication listed in Section I, when the member is receiving clinical benefit or there is no evidence of unacceptable toxicity.
Interferon beta Avonex (interferon beta-1a)
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Criteria for Initial Approval
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Relapsing forms of multiple sclerosis
Aetna considers interferon beta Avonex (interferon beta-1a) medically necessary for the treatment of members who have been diagnosed with a relapsing form of multiple sclerosis (MS) (including relapsing-remitting and secondary progressive disease for those who continue to experience relapse).
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Clinically isolated syndrome
Aetna considers interferon beta Avonex (interferon beta-1a) medically necessary for the treatment of members with clinically isolated syndrome (CIS) of multiple sclerosis.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
For Betaseron (interferon beta-1b) and Extavia (interferon beta-1b), see Specialty Pharmacy Clinical Policy Bulletin Betaseron-Extavia 1840-A SGM.
For Rebif (interferon beta-1a), see Specialty Pharmacy Clinical Policy Bulletin Rebif 1839-A SGM.
For Plegridy (peginterferon beta-1a) refer to the pharmacy benefit plan.
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Continuation of Therapy
Aetna considers continuation of interferon beta Avonex (interferon beta-1a) therapy medically necessary for an indication listed in Section I for members who are experiencing disease stability or improvement while receiving interferon beta Avonex (interferon beta-1a).
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Prescriber Specialties
This medication must be prescribed by or in consultation with a neurologist.
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Related Policies
Interferon gamma-1b (Actimmune)
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Criteria for Initial Approval
Aetna considers interferon gamma-1b (Actimmune) medically necessary for the following indications:
- Chronic granulomatous disease - to reduce the frequency and severity of infections associated with chronic granulomatous disease; or
- Mycosis fungoides and Sezary syndrome; or
- Severe, malignant osteopetrosis - to delay time to disease progression in members with severe, malignant osteopetrosis.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
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Continuation of Therapy
Aetna considers continuation of interferon gamma-1b (Actimmune) therapy medically necessary for members for an indication listed in Section I, who are experiencing benefit from therapy as evidenced by disease stability or disease improvement.
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Prescriber Specialties
This medication must be prescribed by or in consultation with one of the following:
- Chronic granulomatous disease (CGD): immunologist or prescriber who specializes in the management of CGD;
- Severe, malignant osteopetrosis (SMO): endocrinologist;
- Mycosis fungoides/Sezary syndrome: hematologist or oncologist.
Peginterferon alfa-2a (Pegasys)
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Criteria for Initial Approval
Aetna considers peginterferon alfa-2a (Pegasys) therapy medically necessary for the following indications:
- Adult T-cell leukemia / lymphoma; or
- Chronic hepatitis B virus (HBV) infection (including HDV coinfection) for treatment up to a total of 48 weeks (Note: treatment of chronic hepatitis B with peginterferon alfa-2a for more than 48 weeks is considered experimental and investigational); or
- Chronic hepatitis C virus (HCV) infection; or
- Chronic myeloid leukemia in pregnancy; or
- Erdheim-Chester disease; or
- Hairy cell leukemia; or
- Mycosis fungoides/Sezary syndrome; or
- Myeloproliferative neoplasm, including essential thrombocythemia, polycythemia vera, and symptomatic lower-risk myelofibrosis; or
- Primary cutaneous CD30+ T-cell lymphoproliferative disorders, or
- Systemic mastocytosis.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
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Continuation of Therapy
Aetna considers continuation of peginterferon alfa-2a (Pegasys) therapy medically necessary for the following indications when criteria met:
- Myeloproliferative neoplasm for members experiencing benefit from therapy as evidenced by improvement in symptoms and/or disease markers (e.g., morphological response, reduction or stabilization in spleen size, improvement of thrombocytosis/leucocytosis, etc.); or
- Systemic mastocytosis for members experiencing benefit from therapy as evidenced by improvement in symptoms and/or disease markers (e.g., reduction in serum and urine metabolites of mast cell activation, improvement in cutaneous lesions, skeletal disease, bone marrow mast cell burden, etc.); or
- For all other medically necessary indications, in Section I, not previously listed when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.
Ropeginterferon alfa-2b-njft (Besremi)
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Criteria for Initial Approval
Polycythemia Vera
Aetna considers ropeginterferon alfa-2b-njft (Besremi) medically necessary for treatment of adults with polycythemia vera.
Aetna considers all other indications as experimental and investigational.
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Continuation of Therapy
Aetna considers continuation of ropeginterferon alfa-2b-njft (Besremi) therapy medically necessary if the member is experiencing benefit from therapy as evidenced by improvement in symptoms and/or disease markers (e.g., morphological response, reduction or stabilization in spleen size, improvement of thrombocytosis/leukocytosis, etc.).
Dosage and Administration
Interferon gamma-1b (Actimmune)
Interferon gamma-1b (Actimmune) is available as 100 mcg (2 million International Units) of Interferon gamma-1b in 0.5 mL solution in a single use vial for subcutaneous injection.
The recommended dosage of Actimmune administered subcutaneously, for the treatment of patients with chronic granulomatous disease (CGD) and severe, malignant osteopetrosis (SMO) is shown in Table 1 below:
|
Body Surface Area (m2) |
Dose (mcg/m2) |
Dose (International Units/m2)Footnote3*** |
Frequency |
|---|---|---|---|
| Greater than 0.5 m2 | 50 mcg/m2 | 1 million International Units/m2 |
Three times weekly |
| Equal to or less than 0.5 m2 | 1.5 mcg/kg/dose | ---------- | Three times weekly (for example, Monday, Wednesday and Friday) |
Footnote3*** Note that the above activity is expressed in International Units (1 million International Units/50 mcg). This is equivalent to what was previously expressed as units (1.5 million units/50 mcg).
Source: Horizon Therapeutics, 2021
Interferon alfa-2b (Intron A)
Interferon alfa-2b (Intron A) is available as:
- Powder for injection: 10, 18 and 50 million IU/vial
- Solution for injection in vials: 18 and 25 million IU multidose vial
Chronic Hepatitis B
- Adult: The recommended dose is 30‐35 million IU per week administered subcutaneously or intramuscularly, either as 5 million IU daily or as 10 million IU three times a week for 16 weeks.
- Pediatric: The recommended dose is 3 million IU/m2 administered three times a week for the first week of therapy followed by dose escalation to 6 million IU/m2 three times a week (maximum of 10 million IU TIW) administered subcutaneously for a total duration of 16 to 24 weeks.
Chronic Hepatitis C
- The recommended dose is 3 million IU three times a week administered subcutaneously or intramuscularly.
- In persons tolerating therapy with normalization of ALT at 16 weeks of treatment, Intron A therapy should be extended to 18 to 24 months (72 to 96 weeks) at 3 million IU three times a week to improve the sustained response rate. Persons who do not normalize their ALTs or have persistently high levels of HCV RNA after 16 weeks of therapy rarely achieve a sustained response with extension of treatment. Consideration should be given to discontinuing these individuals from therapy.
Hairy cell leukemia
The recommended dose is 2 million IU/m2 administered intramuscularly or subcutaneously 3 times a week for up to 6 months. Persons with platelet counts of less than 50,000/mm3 should not be administered Intron A intramuscularly, but instead by subcutaneous administration.
Malignant melanoma
The adjuvant treatment is given in two phases, induction and maintenance:
- Induction dose is 20 million IU/m2 as an intravenous infusion, over 20 minutes, 5 consecutive days per week, for 4 weeks.
- Maintenance dose is 10 million IU/m2 as a subcutaneous injection 3 times per week for 48 weeks.
Follicular lymphoma
The recommended dose is 5 million IU subcutaneously 3 times per week for up to 18 months in conjunction with anthracycline-containing chemotherapy regimen and following completion of the chemotherapy regimen.
Condylomata accuminata
The recommended dose is one million IU per lesion in a maximum of 5 lesions in a single course. The lesions should be injected three times weekly on alternate days for 3 weeks. An additional course may be administered at 12 to 16 weeks.
AIDS-related Kaposi's sarcoma
The recommended dose is 30 million IU/m2/dose administered subcutaneously or intramuscularly three times a week until disease progression or maximal response has been achieved after 16 weeks of treatment.Source: Merck, 2021
Interferon Beta Avonex (interferon beta-1a)
Interferon beta-1a (Avonex)
Avonex is for intramuscular use only and is available as follows:
- Injection: 30 micrograms per 0.5 mL solution in single-dose prefilled syringe
- Injection: 30 micrograms per 0.5 mL solution in single-dose prefilled autoinjector.
The recommended dose is 30 micrograms once a week.
Source: Biogen, 2021
Peginterferon alfa-2a (Pegasys)
Peginterferon alfa-2a (Pegasys) is available as 180 mcg/mL in a vial and as 180 mcg/0.5 mL in a prefilled syringe administered by subcutaneous injection.
- In adults with chronic hepatitis C (CHC), Pegasys is dosed as 180 mcg per week and the duration of treatment depends on indication, genotype, and whether it is administered with other HCV antiviral drugs.
- In adults with chronic hepatitis B (CHB), Pegasys is dosed as 180 mcg per week for 48 weeks.
- In pediatric persons with CHC, Pegasys is dosed as 180 mcg/1.73 m2 x BSA per week, in combination with ribavirin, and the duration of treatment depends on genotype.
- In pediatric persons with CHB, Pegasys is dosed as 180 mcg/1.73 m2 x BSA per week for 48 weeks
Please see full prescribing information for dosage modification.
Source: Genentech, 2020
Note: Pegasys ProClick and Interferon alfa-2a (Roferon A) have been discontinued.
Peginterferon alfa-2b (PegIntron)
Note: PegIntron Redipen and PegIntron 80 mcg, 120 mcg, and 150 mcg vials have been discontinued in the U.S. PegIntron 50 mcg vials will be disconinued; however, will remain available in limited quantities; based on current demand, Merck anticipates product should continue to be available through May 2021.
Pegintron (pegintergeron alfa-2b) is available for injection as 50 mcg per 0.5 mL, 80 mcg per 0.5 mL, 120 mcg per 0.5 mL, 150 mcg per 0.5 mL in single-dose vial (with 5 mL diluent) and single-dose pre-filled pens.
- For adults, the recommended dose of Pegintron is 1.5 mcg/kg/week. The volume of Pegintron to be injected depends on the strength of Pegintron and person’s body weight. Pegintron is used in combination with other products including ribavirin and HCV direct acting antivirals. For further information on dosing and administration, refer to the prescribing information.
- For pediatrics, the recommended dose of Pegintron is 60 mcg/m2 /week subcutaneously for pediatric persons aged 3 to 17 years. Those who reach their 18th birthday while receiving Pegintron/ribavirin should remain on the pediatric dosing regimen. The treatment duration for persons with genotype 1 is 48 weeks. Persons with genotype 2 and 3 should be treated for 24 weeks.
Ropeginterferon alfa-2b-njft (Besremi)
Ropeginterferon alfa-2b-njft is availalble as Besremi 500 mcg/mL solution in a single-dose prefilled syringe.for subcutaneous injection.
Polycythemia vera:
The recommended dosing is as follows:
- Starting dose: 100 mcg by subcutaneous injection every 2 weeks (50 mcg if receiving hydroxyurea)
- Increase dose by 50 mcg every 2 weeks (up to a maximum of 500 mcg) until hematological parameters are stabilized.
Source: PharmaEssentia, 2021
Experimental and Investigational
Interferon alfa-2b (Intron A)
Aetna considers interferon alfa-2b (Intron A) experimental and investigational for the treatment of the following (not an all-inclusive list) because its effectiveness for indications other than the ones listed above has not been established:
- Acute hepatitis B
- Age-related macular degeneration
- AIDS-related complex
- AIDS in combination with AZT
- Basal cell carcinoma
- Behçet's uveitis
- Bladder (urothelial) cancer
- Breast cancer
- Cervical cancer
- Chickenpox
- Cholangiocarcinoma
- Chronic delta hepatitis
- Colorectal cancer
- Cutaneous squamous cell carcinoma
- Cutaneous warts
- Cytomegalovirus (CMV)
- Familial Mediterranean fever
- Gardner syndrome
- Hemangioma
- Hepatocellular carcinoma
- Hepatitis D
- Hereditary hemorrhagic telangiectasia
- Herpes keratoconjunctivitis
- Islet cell tumors
- Kasabach-Merritt syndrome
- Keloids
- Leptomeningeal metastases
- Menigioma
- Mesothelioma
- Multiple myeloma
- Multiple sclerosis
- Neuroendocrine tumors of the gastrointestinal tract, lung, and thymus (Carcinoid tumors)
- Ocular herpes simplex (interferon alfa eye drops)
- Osteosarcoma
- Ovarian cancer
- Pancreatic cancer
- Pelvic fibromatosis
- Peyronie's disease
- Plexiform neurofibroma
- Primary cutaneous anaplastic large cell lymphoma with multifocal lesions
- Primitive neuroectodermal tumor (PNET)
- Prostate cancer
- Retinal vasculitis
- Rhinoviruses
- Sjogren's syndrome-associated dry eye
- Solitary plasmacytoma
- Sudden hearing loss
- Systemic light-chain amyloidosis
- Systemic lupus erythematosus
- Vaccinia
- Varicella zoster virus (VZV)
- Vulvar vestibulitis
- Waldenstrom's macroglobulinemia.
Interferon beta [Avonex (interferon beta-1a), Rebif (interferon beta-1a), Betaseron (interferon beta-1b), and Extavia (interferon beta-1b)]
Aetna considers use of interferon beta [Avonex (interferon beta-1a), Rebif (interferon beta-1a), Betaseron (interferon beta-1b), and Extavia (interferon beta-1b)] in combination with other treatments for multiple sclerosis (excluding Ampyra and Nuedexta) experimental and investigational because there is a lack of reliable evidence that interferon beta in combination with other disease modifying treatment is more effective than interferon beta alone.
Aetna considers interferon beta [Avonex (interferon beta-1a), Rebif (interferon beta-1a), Betaseron (interferon beta-1b), and Extavia (interferon beta-1b)] experimental and investigational for the treatment of the following (not an all-inclusive list) because its effectiveness for indications other than the ones listed above has not been established:
- Anogenital warts
- Chronic inflammatory demyelinating polyradiculoneuropathy
- Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS)
- Guillain Barre syndrome
- Pancreatic cancer
- Systemic lupus erythematosus.
Aetna considers testing for neutralizing antibodies to interferon beta [Avonex (interferon beta-1a), Rebif (interferon beta-1a), Betaseron (interferon beta-1b), and Extavia (interferon beta-1b)] experimental and investigational. See CPB 0264 - Multiple Sclerosis.
Because interferon beta is administered subcutaneously [Rebif (interferon beta-1a), Betaseron (interferon beta-1b), and Extavia (interferon beta-1b)] or intramuscularly [Avonex (interferon beta-1a)], it is appropriate for administration by the member in the home setting.
The Biojector 2000 (Bioject, Inc.) is a needle-free injection system that uses CO2 as the power source and disposable needle-free syringes to deliver medication in a fraction of a second through a tiny orifice. Biojector 2000 is considered a medically necessary acceptable alternative to conventional needle and syringes for members with exacerbating-remitting MS who cannot safely use needles for self-injection due to tremors and decreased coordination.
Interferon gamma-1b (Actimmune)
Aetna considers interferon gamma-1b (Actimmune) experimental and investigational for the treatment of the following (not an all-inclusive list) because its effectiveness for indications other than the ones listed above has not been established:
- Atopic dermatitis
- Anogenital warts
- Brain tumors
- Evaluation of salivary and serum interferon-gamma levels in individuals with oral lichen planus
- Idiopathic pulmonary fibrosis
- Juvenile dermatomyositis
- Juvenile idiopathic arthritis
- Macrophage activation syndrome
- Malignant neoplasm of peritoneum
- Pancreatic cancer
- Pulmonary tuberculosis
- Systemic lupus erythematosus
- Waldenstrom's macroglobulinemia.
Peginterferon alfa-2a (Pegasys)
Aetna considers peginterferon alfa-2a (Pegasys) experimental and investigational for the treatment of the following (not an all-inclusive list) because its effectiveness for indications other than the ones listed above has not been established:
- Chronic myelogenous leukemia
- Desmoid tumor
- Eosinophilia/hyper-eosinophilic syndrome
- Human papilloma virus
- Osteosarcoma
- Plexiform neurofibroma
- Progressive multi-focal leukoencephalopathy
- Squamous cell carcinoma
- Systemic lupus erythematosus
- Warts.
Peginterferon beta-1a (Plegridy)
Aetna considers use of peginterferon beta-1a (Plegridy) in combination with other treatments for multiple sclerosis (excluding Ampyra and Nuedexta) experimental and investigational because there is a lack of reliable evidence that interferon beta in combination with other disease modifying treatment is more effective than peginterferon beta-1a (Plegridy) alone.
Aetna considers peginterferon beta-1a (Plegridy) experimental and investigational for the treatment of the following (not an all-inclusive list) because its effectiveness for indications other than the ones listed above has not been established:
- Anogenital warts
- Chronic inflammatory demyelinating polyradiculoneuropathy
- Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS)
- Guillain Barre syndrome
- Pancreatic cancer
- Systemic lupus erythematosus.
Aetna considers testing for neutralizing antibodies to peginterferon beta-1a (Plegridy) experimental and investigational. See CPB 0264 - Multiple Sclerosis.
Because peginterferon beta-1a (Plegridy) is administered subcutaneously or intramuscularly, it is appropriate for administration by the member in the home setting.
The Biojector 2000 (Bioject, Inc.) is a needle-free injection system that uses CO2 as the power source and disposable needle-free syringes to deliver medication in a fraction of a second through a tiny orifice. Biojector 2000 is considered a medically necessary acceptable alternative to conventional needle and syringes for members with exacerbating-remitting MS who can not safely use needles for self-injection due to tremors and decreased coordination.
Background
Interferons are biological response modifiers that are indicated in the treatment of numerous malignant and infectious disease conditions. Interferons are proteins secreted in response to viral infection through binding at specific membrane receptors on the cell surface. Binding results in induction of certain enzymes, suppression of cell proliferation, enhancement of the phagocytic activity of macrophages, augmentation of specific cytotoxicity of lymphocytes for target cells, and inhibition of virus replication in virus‐infected cells.
Interferons bind to specific cell surface receptors and initiate a sequence of intracellular events that lead to the transcription of interferon‐stimulated genes. The three major groups of interferons (alfa, beta, and gamma) have partially overlapping biological activities that include immunoregulation such as increased resistance to microbial pathogens and inhibition of cell proliferation. Type 1 interferons (alfa and beta) bind to the alfa/beta receptor. Interferon‐gamma binds to a different cell surface receptor and is classified as Type 2 interferon. Specific effects of interferon‐gamma include the enhancement of oxidative metabolism of macrophages, antibody dependent cellular cytotoxicity (ADCC), activation of natural killer (C+NK) cells, and the expression of Fc receptors and major histocompatibility antigens.
Interferon alfa products (Roferon; Intron-A; Alferon; Infergen) have been granted orphan-drug status by the Food and Drug Administration (FDA) for several types of malignancies and viral infections and have unlabeled uses for several others. Although the efficacy of all alfa interferons (e.g., interferon alfa 2a, alfa 2b, alfa-n3, and alfacon-1) for various indications appear to be similar, differences in relative efficacy for a particular indication may exist. Interferon alfa should be used with caution in patients with pre-existing psychiatric conditions or a history of severe psychiatric disorders. According to the product labeling, depression, confusion, and other alterations of mental status have been observed in some patients and suicidal ideation and attempted suicide have been observed rarely.
In 1986, the FDA approved interferon alfa-2a (Roferon A) for the treatment of hairy cell leukemia; however, it was later discontinued in the United States in 2007 due to a business decision.
Boceprevir (Victrelis)
Boceprevir capsules (Victrelis, Merck) is a protease inhibitor that has been FDA approved to treat adults with chronic hepatitis C genotype 1 with compensated liver disease, and who either have not been previously treated with interferon therapy for their hepatitis C or who have failed such treatment. Boceprevir is approved for use in combination with peginterferon alfa and ribavirin. The safety and effectiveness of boceprevir was evaluated in 2 phase 3 clinical trials with 1,500 adult patients. In both trials, 2/3 of patients receiving boceprevir in combination with pegylated interferon and ribavirin experienced a significantly increased sustained virologic response (i.e., the hepatitis C virus was no longer detected in the blood 24 weeks after stopping treatment), compared to pegylated interferon and ribavirin alone. Boceprevir is taken 3 times a day with food. The most commonly reported side effects in patients receiving boceprevir in combination with pegylated interferon and ribavirin include fatigue, anemia, nausea, headache and dysgeusia. According to the FDA-approved labeling, 800 mg of boceprevir is administered orally 3 times daily in combination with peginterferon alfa and ribavirin. Duration of therapy is determined by Response-Guided Therapy (RGT) guidelines based upon the patient's HCV-RNA levels at treatment weeks 8, 12 and 24.
Consensus interferon - Interferon alfacon-1 (Infergen)
Note: Infergen (interferon alfacon-1) was discontinued in September 2013. Consensus interferon (interferon alfacon-1; Infergen) is a non-naturally occurring recombinant type 1 alfa interferon. It has been approved by the FDA for use in the treatment of chronic hepatitis C in person 18 years of age or older with compensated liver disease who have anti-hepatitic C virus serum antibodies and/or the presence of hepatitis C virus RNA. Although there are studies comparing standard alfa interferon to consensus interferon, and limited evidence regarding the use of consensus interferon in persons with hepatitis C who fail to respond to standard alfa interferon therapy, current guidelines indicate pegylated interferons as the treatment of choice for persons with hepatitis C, including those who fail to respond to standard alfa interferon therapy. There are insufficient published studies comparing consensus interferon to pegylated interferons in persons with hepatitis C who have failed standard interferon therapy.
An open-label multicenter controlled clinical trial evaluated the effectiveness of consensus interferon plus ribavirin in persons with hepatitis C who were non-responsive to previous pegylated interferon and ribavirin. This study, the DIRECT (Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy) trial compared the effectiveness of ribavirin plus 2 different doses of consensus interferon versus no treatment in subjects with hepatitis C who were nonresponsive to pegylated interferon and ribavirin therapy (Bacon et al, 2006; Bacon et al, 2009; Three Rivers Pharmaceuticals, 2010). This study compared 2 doses of consensus interferon (9 mcg or 15 mcg) administered daily plus ribavirin (1,000 mg or 1,200 mg weight-based dosed) administered daily for 48 weeks to subjects who were non-responders to previous pegylated interferon plus ribavirin therapy. Prior non-response was defined as a less than 2 log decline in viral load while undergoing at least 12 weeks of previous pegylated interferon/ribavirin therapy with greater than or equal to 80 % adherence or a detectable viral load at end-of-treatment after completing at least 24 weeks of therapy. Ninety-five percent of study subjects were infected with genotype 1. Approximately 80 % of subjects were null responders (less than 2 log drop in viral load during their previous pegylated interferon/ribavirin therapy). In study IRHC-001, 515 subjects were randomized to consensus interferon 9 mcg plus ribavirin, consensus interferon 15 mcg plus ribavirin, or no treatment. In study IRHC-002, 144 subjects in the no treatment arm of IRHC-001 were re-randomized to either consensus interferon 9 mcg plus ribavirin or consensus interferon 15 mcg plus ribavirin. Subjects were treated for up to 48 weeks. The primary endpoint was sustained virologic response, defined as undetectable HCV RNA 24 weeks after the end of treatment. None of the subjects in the no-treatment arm of IRHC-001 achieved a sustained virologic response. The overall rate of sustained virologic response in subjects treated with consensus interferon 9 mcg plus ribavirin was 5 %, and 9 % for subjects treated with consensus interferon 15 mcg plus ribavirin. Persons with genotype 1 had less benefit from retreatment. The sustained virologic response rates for persons infected with genotype 1 was 4 % for persons assigned to consensus interferon 9 mcg and 6 % for persons assigned to consensus interferon 15 mcg. The sustained virologic response rates for other genotypes was 21 % for consensus interferon 9 mcg and 67 % for consensus interferon 15 mcg. Persons with high viral load were less likely to benefit from re-treatment. The sustained virologic response rate for persons with HCV RNA less than 850,000 IU/ml was 13 % and 14 % for persons assigned to 9 mcg and 15 mcg of consensus interferon, respectively. The sustained virologic response rate for persons with HCV RNA greater than or equal to 850,000 IU/ml was 2 % and 6 % for persons assigned to 9 mcg and 15 mcg of consensus interferon, respectively.
The recommended dose of consensus interferon for monotherapy is 9 mcg 3 times weekly for 24 weeks (as initial treatment) or 15 mcg 3 times weekly for up to 48 weeks (as retreatment). The recommended dose of combination treatment is 15 mcg consensus interferon daily with 1,000 mg or 1,200 mg ribavirin (for body weight less than 75 kg and greater than or equal to 75 kg) daily for up to 48 weeks (as re-treatment). According to the product labeling, persons who fail to achieve at least a 2 log drop at 12 weeks or undetectable HCV-RNA at week 24 are highly unlikely to achieve a sustained virologic response and discontinuation of therapy should be considered.
Interferon alfa-2b (Intron A)
U.S. Food and Drug Administration (FDA)-Approved Indications for Intron A
- Malignant melanoma
- Condylomata acuminata
- Hairy cell leukemia
- AIDS-related Kaposi sarcoma
- Chronic hepatitis B virus infection
- Chronic hepatitis C virus infection
- Follicular non-Hodgkin’s lymphoma
Compendial Uses for Intron A
- Adult T-cell leukemia/lymphoma (ATLL)
- Mycosis fungoides (MF)/Sezary syndrome (SS)
- Renal carcinoma
- Chronic myeloid leukemia (CML)
- Giant cell tumor of the bone
- Ocular surface neoplasia (conjunctival and corneal neoplasm)
Interferon alfa‐2b is available as Intron A (Merck & Co., Inc.) is a recombinant alfa interferon (IFN).
Intron A is indicated for the initial treatment of clinically aggressive follicular Non-Hodgkin’s Lymphoma in conjunction with anthracycline-containing combination chemotherapy in patients 18 years of age or older. Efficacy of Intron A therapy in patients with low-grade, low-tumor burden follicular Non-Hodgkin’s Lymphoma has not been demonstrated. The safety and efficacy of Intron A (Interferon alfa-2b, recombinant) in conjunction with CHVP, a combination chemotherapy regimen, was evaluated as initial treatment in patients with clinically aggressive, large tumor burden, Stage III/IV follicular Non-Hodgkin’s Lymphoma. Large tumor burden was defined by the presence of any one of the following: a nodal or extranodal tumor mass with a diameter of greater than 7 cm; involvement of at least three nodal sites (each with a diameter of greater than 3 cm); systemic symptoms; splenomegaly; serous effusion, orbital or epidural involvement; ureteral compression; or leukemia.
In a randomized, controlled trial, 130 patients received CHVP therapy and 135 patients received CHVP therapy plus Intron A therapy at 5 million IU subcutaneously three times weekly for the duration of 18 months. CHVP chemotherapy consisted of cyclophosphamide 600 mg/m2, doxorubicin 25 mg/m2, and teniposide (VM-26) 60 mg/m2, administered intravenously on Day 1 and prednisone at a daily dose of 40 mg/m2 given orally on Days 1 to 5. Treatment consisted of six CHVP cycles administered monthly, followed by an additional six cycles administered every 2 months for 1 year. Patients in both treatment groups received a total of 12 CHVP cycles over 18 months. The group receiving the combination of Intron A therapy plus CHVP had a significantly longer progression-free survival (2.9 years versus 1.5 years, P=0.0001, Log Rank test). After a median follow-up of 6.1 years, the median survival for patients treated with CHVP alone was 5.5 years while median survival for patients treated with CHVP plus Intron A therapy had not been reached (P=0.004, Log Rank test). In three additional published, randomized, controlled studies of the addition of interferon alpha to anthracycline-containing combination chemotherapy regimens, the addition of interferon alpha was associated with significantly prolonged progression-free survival. Differences in overall survival were not consistently observed.
The guidelines cite a phase III study by Yao et al (2017) which assessed the progression-free survival (PFS) of bevacizumab or interferon alfa-2b (IFN-α-2b) added to octreotide among patients with advanced NETs. The Southwest Oncology Group (SWOG) S0518 study was conducted in a US cooperative group system and enrolled patients with advanced grades 1 and 2 NETs with progressive disease or other poor prognostic features. Patients were randomly assigned to treatment with octreotide LAR 20 mg every 21 days with either bevacizumab 15 mg/kg every 21 days or 5 million units of IFN-α-2b three times per week. The primary end point was centrally assessed PFS. This trial is registered with ClinicalTrials.gov as NCT00569127. A total of 427 patients was enrolled, of whom 214 were allocated to bevacizumab and 213 to IFN-α-2b. The median PFS by central review was 16.6 months (95% CI, 12.9 to 19.6 months) in the bevacizumab arm and was 15.4 months (95% CI, 9.6 to 18.6 months) in the IFN arm (hazard ratio [HR], 0.93; 95% CI, 0.73 to 1.18; P = .55). By site review, the median PFS times were 15.4 months (95% CI, 12.6 to 17.2 months) for bevacizumab and 10.6 months (95% CI, 8.5 to 14.4 months) for interferon (HR, 0.90; 95% CI, 0.72 to 1.12; P = .33). Time to treatment failure was longer with bevacizumab than with IFN (HR, 0.72; 95% CI, 0.58 to 0.89; P = .003). Confirmed radiologic response rates were 12% (95% CI, 8% to 18%) for bevacizumab and 4% (95% CI, 2% to 8%) for IFN. Common adverse events with bevacizumab and octreotide included hypertension (32%), proteinuria (9%), and fatigue (7%); with IFN and octreotide, they included fatigue (27%), neutropenia (12%), and nausea (6%). The authors concluded that no significant differences in PFS were observed between the bevacizumab and IFN arms, which suggests that these agents have similar antitumor activity among patients with advanced NETs.
Extensive study of alfa interferons in combination with 5‐fluorouracil (5‐FU) for the treatment of colorectal cancer has shown no benefit over 5‐FU therapy alone. In 1986, the FDA approved interferon alfa‐2b for the treatment of hairy cell leukemia. An extended release formulation of interferon alfa‐2b (PEG‐Intron) has been approved by the FDA. Current AASLD/IDSA recommendations do not recommend use of interferon products for chronic hepatitis C. Peginterferon and ribavirin, typically in combination with a direct-acting antiviral, remain in use for certain genotypes, particularly in resource-limited settings where newer interferon-free regimens are not accessible (AASLD/IDSA 2018).
Alfa interferons, including Intron A, may cause or aggravate fatal or life‐threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders.
Safety and efficacy in pediatric members < 3 years of age have not been established other than for chronic hepatitis B or hepatitis C.
In an interventional, comparative case series, Lane and colleagues (2009) examined if interferon (IFN)-alfa-2a treatment after radiation or enucleation reduces death rates in patients with uveal melanoma. Patients were identified through the ocular oncology clinic of the Massachusetts Eye and Ear Infirmary. Subjects eligible for the study were at increased risk of metastasis because of the presence of at least 1 of the following characteristics:- age greater than or equal to 65 years,
- largest tumor diameter (LTD) greater than or equal to 15 mm,
- ciliary body involvement of the tumor, or (iv) extra-scleral tumor extension.
A total of 121 patients with choroidal or ciliary body melanoma began a 2-year course of therapy (3 million international units [MIU] IFN-alfa-2a subcutaneously 3 times per week), initiated within 3 years of primary therapy. All patients underwent regular monitoring for drug toxicity. To evaluate IFN-alfa-2a efficacy, these researchers selected a series of historical controls frequency-matched (2:1) to IFN-alfa-2a-treated patients on age (+/- 5 years), LTD (+/- 3 mm), gender, and survival time between primary therapy and initiation of IFN therapy. Survival status was ascertained for all patients. Main outcome measures were melanoma-related mortality, metastasis, IFN-related toxicities. A total of 55 patients (45 %) completed therapy; the median dose for IFN-alfa-2a-treated patients was 792 MIU (85 % of the theoretic dose). The median follow-up time in the IFN-alfa-2a-treated group was approximately 9 years. Treatment and control groups were similar with respect to age (p = 0.78), LTD (p = 0.38), and gender (p = 1.0). Of 363 patients, 108 developed metastasis under observation; 42 of these were IFN-alfa-2a-treated patients. Cumulative 5-year melanoma-related death rates were 17 % in the radiation or enucleation-only group, 15 % in those who completed the entire IFN-alfa-2a course, and 35 % in those who discontinued IFN-alfa-2a therapy. In multi-variate Cox regression, IFN-alfa-2a had no significant influence on melanoma-related mortality (rate ratio = 1.02, 95 % confidence interval [CI]: 0.68 to 1.5, p = 0.91) or all-cause mortality (rate ratio = 0.84, 95 % CI: 0.58 to 1.2, p = 0.34). The authors concluded that interferon-alfa-2a has no material influence on survival in patients with choroidal melanoma.
In a Cochrane review, Shepherd and colleagues (2017) examined the effects of intravesically administered Bacillus Calmette-Guerin (BCG) plus IFN-α compared with BCG alone for treating non-muscle-invasive bladder cancer (NMIBC). These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2016), Medline (OvidSP) (1946 to 2016), Embase (OvidSP) (1974 to 2016), http://ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) as well as reference lists of retrieved articles and hand-searched abstract proceedings of relevant conferences for the past 3 years. They applied no language restrictions and the date of last search of all databases was August 25, 2016. These researchers included RCTs and pseudo-randomized trials assessing intravesically administered BCG plus IFN-α versus BCG alone in adults of either gender with histologically confirmed Ta and T1 superficial bladder cancer, with or without carcinoma in-situ, treated with trans-urethral resection (TUR). Two review authors independently assessed study eligibility, extracted data, and assessed the risk of bias of included studies. They used Review Manager 5 for data synthesis and employed the random-effects model for meta-analyses. For pre-specified outcomes, where these researchers were unable to derive time-to-event information (e.g., time-to-recurrence), they assessed dichotomous outcomes (e.g., recurrence) instead. These researchers assessed the quality of the evidence for the main comparisons using the GRADE approach. They included 5 RCTs involving a total of 1,231 participants with NMIBC in this review. Due to poor reporting, the risk of bias in the included studies was often unclear. They assessed the studies under 2 main comparisons: intravesical BCG plus IFN-α versus intravesical BCG alone (4 RCTs), and intravesical BCG alternating with IFN-α versus intravesical BCG alone (1 RCT). Intravesical BCG plus IFN-α versus intravesical BCG alone (4 RCTs): These investigators observed no clear difference between BCG plus IFN-α and BCG alone for recurrence (average RR 0.76, 95 % CI: 0.44 to 1.32; 4 RCTs; 925 participants; very low-quality evidence) or progression (average RR 0.26, 95 % CI: 0.04 to 1.87; 2 RCTs; 219 participants; low-quality evidence). The included RCTs did not report on the other primary outcome of this review, discontinuation of therapy due to adverse events (AEs). Regarding secondary outcomes, these researchers observed no clear difference for disease-specific mortality (RR 0.38, 95 % CI: 0.05 to 3.05; 1 RCT; 99 participants; very low-quality evidence); 2 RCTs reporting contradictory findings for AEs could not be pooled due to variation in definitions. There were no data from the included RCTs on time-to-death or disease-specific quality of life (QOL). Intravesical BCG alternating with IFN-α versus intravesical BCG alone (1 RCT): These researchers observed shorter time-to-recurrence for participants in the BCG alternating with IFN-α group compared with the BCG alone group (hazard ratio (HR) 2.86, 95 % CI: 1.98 to 4.13; 1 RCT; 205 participants; low-quality evidence), but no clear differences in time-to-progression (HR 2.39, 95 % CI: 0.92 to 6.21; 1 RCT; 205 participants; low-quality evidence) and discontinuation of therapy due to AEs (RR 2.97, 95 % CI: 0.31 to 28.09; 1 RCT; 205 participants; low-quality evidence). Regarding secondary outcomes, there were no clear differences between the BCG alternating with IFN-α and BCG alone groups for disease-specific mortality (HR 2.74, 95 % CI: 0.73 to 10.28; 1 RCT; 205 participants; low-quality evidence), time-to-death (overall survival [OS]) (HR 1.00, 95 % CI: 0.68 to 1.47; 1 RCT; 205 participants; low-quality evidence), or systemic or local AEs (RR 1.65, 95 % CI: 0.41 to 6.73; 1 RCT; 205 participants; low-quality evidence). There were no data on disease-specific QOL. The authors concluded that they found low- to very low-quality evidence suggesting no clear differences in recurrence or progression with BCG plus IFN-α compared with BCG alone for people with NMIBC; there was no information to determine the effect on discontinuation of therapy due to AEs. Low-quality evidence suggested BCG alternating with IFN-α compared with BCG alone may increase time-to-recurrence, however low-quality evidence also suggested no clear differences for time-to-progression or discontinuation of therapy due to AEs. They stated that additional high-quality, adequately powered trials using standardized instillation regimens and doses of both BCG and IFN-α, reporting outcomes in subgroups stratified by patient and tumor characteristics, and on long-term outcomes related not only to recurrence but also to progression, discontinuation due to AEs, and mortality may help to clarify the ideal treatment strategy and provide a more definitive result.
Steinberg and associates (2017) noted that conflicting reports exist regarding disparate outcomes among BCG strains. These researchers examined if a difference in recurrence-free survival (RFS) existed between TICE BCG and Connaught BCG strains used with IFN for the treatment of NMBIC. A post-hoc analysis of the phase-II BCG/IFN clinical trial, was conducted from May 1999 to February 2001. A total of 901 patients had sufficient records for analysis. Enrollment criteria were liberal and included primary and recurrent NMIBC, patients with and without carcinoma in-situ, and patients with prior BCG failure. At the beginning, 3 to 8 weeks after TUR or biopsy, patients received induction with 6 weekly intravesical treatments of BCG (TICE or Connaught) with 50 million units of IFN. Surveillance for recurrence began 4 to 6 weeks after induction and quarterly thereafter for 2 years. If no recurrence was identified, patients received maintenance therapy. Separate models were created for BCG naive and failure patients. Multi-variable analysis was performed using Cox proportional hazards regression. A total of 609 patients received TICE BCG and 292 received Connaught BCG with similar baseline characteristics; BCG strain was not associated with worse RFS in both the multi-variable BCG naïve model (p = 0.28) and BCG failure model (p = 0.53). Duration of disease, tumor focality, tumor size, and BCG failure interval (in the BCG failure model) were associated with worse RFS. The authors concluded that no significant difference in RFS was observed among patients treated with TICE BCG or Connaught BCG in combination with IFN.
In a clinical statement by the American Academy of Ophthalmology, the authors conclude that while topical preparations of interferon α2B exhibit antiviral activity against HSV epithelial keratitis, the clinical use of topical interferon remains experimental, is limited by the availability of sufficiently concentrated interferon in the U.S. market, and is not FDA approved. A Cochrane evidence review of treatments for herpes simplex eye disease (Wilhelmus, 2007) found that the combination of interferon-alfa eye drops and either trifluridine or acyclovir resulted in faster healing of dendritic keratitis than treatment with trifluridine or acyclovir alone; 90 % of eyes healed within 1 week with combined interferon-antiviral therapy However, according to an updated Cochrane review by the same author (Wilhelmus 2015), the combination of an antiviral with either interferon or debridement had inconsistent effects on expediting healing and improving outcome compared to topical antiviral monotherapy. The addition of interferon to a nucleoside antiviral agent and the combination of debridement with antiviral treatment need to be further assessed to substantiate any possible advantage in healing. According to UpToDate, the addition of topical interferons to antiviral therapy enhances the speed of healing, but these agents are not commercially available for this use. Interferon as monotherapy was not better than other antiviral agents.
In a review by Ivancic et al, the authors state that interferon (IFN) therapy is one of the first systemic adjuvant treatments used to manage recurrent respiratory papillomatosis (RRP). Interferons are proteins released from leukocytes in response to a variety of stimuli, including viral infection, to upregulate antigen production and activate immune cells. The clinical efficacy of IFN therapy in the treatment of RRP is controversial. One group reported that 117 of 160 (73.1%) of patients treated with adjuvant IFN‐alpha‐2b had complete or partial response measured by extent of recurrence. Conversely, another group showed that initial growth rate reduction of papillomas from IFN‐alpha treatment in the first six months post‐treatment was not durable and became insignificant in the second six months post‐treatment. Unmodified recombinant IFN‐alpha is no longer on the market and has been replaced by pegylated‐IFN‐alpha‐2a (peg‐IFN‐alpha‐2a). One study treated 11 AO‐RRP patients with peg‐IFN‐alpha‐2a in combination with granulocyte monocyte–colony‐stimulating factor (GM‐CSF) and found that 11/11 (100%) showed no relapse at 12 months' follow‐up. Side effects for IFN therapy include neurologic disorders, mental disturbances, thrombocytopenia, leukopenia, hair loss, and fever. Despite some positive evidence for adjuvant IFN therapy, it is rarely used due to the emergence of intralesional adjuvants, such as cidofovir and bevacizumab, which have fewer local and systemic side effects.
Interferon alfa-n3 (Alferon N)
U.S. Food and Drug Administration (FDA)-Approved Indications for Alferon N
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Alferon N (interferon alfa‐n3) is indicated for the intralesional treatment of refractory or recurring external condylomata acuminata in patients 18 years of age or older.
Interferon alfa-n3 is available as Alferon N and is a formulation of purified, natural, human interferon (IFN) alfa proteins derived from human leukocytes.
Interferon alfa‐n3 acts similarly to native interferon alfa. Endogenous alfainterferons (IFNs) are secreted by leukocytes (e.g., macrophages, B lymphocytes, and non‐B non‐T lymphocytes) in response to viral infection or various synthetic and biological inducers. All alfa‐IFNs share common biologic activities generated by the binding of interferon to the cell‐surface receptor. Although the exact mechanism of action is not fully understood, interferon binding to the cell surface receptor is followed by activation of tyrosine kinases, which leads to the production of several IFN‐stimulated enzymes such as 2'‐5'‐oligoadenylate synthetase (2'‐5'‐OAS) and beta2‐microglobulin. These and possibly other IFN‐stimulated enzymes are thought to be responsible for the pleiotropic biologic effects of alfa‐IFNs, which include antiviral, antiproliferative and immunomodulatory effects, cellular differentiation, regulation of cell surface major histocompatibility antigen expression (HLA class I), and cytokine induction.
Genital warts usually begin to disappear after several weeks of treatment with Alferon N. Treatment should continue for a maximum of 8 weeks. In clinical trials with Alferon N, many patients who had partial resolution of warts during treatment experienced further resolution of their warts after cessation of treatment. Of the patients who had complete resolution of warts due to treatment, half the patients had complete resolution of warts by the end of the treatment and half had complete resolution of warts during the 3 months after cessation of treatment.
Alferon N is contraindicated in patients with known hypersensitivity to human interferon proteins or any component of the product, anaphylactic hypersensitivity to mouse immunoglobulin, egg protein, or neomycin.
Because of the fever and other "flu‐like" symptoms associated with Alferon N, it should be used cautiously in patients with debilitating medical conditions such as cardiovascular disease (e.g., unstable angina, uncontrolled congestive heart failure, and arrhythmias), severe pulmonary disease (e.g., chronic obstructive pulmonary disease), or diabetes mellitus with ketoacidosis.
Alferon N should be used cautiously in patients with coagulation disorders (e.g., thrombophlebitis, pulmonary embolism and hemophilia), severe myelosuppression, or seizure disorders.
Acute, serious hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have not been observed in patients receiving Alferon N. However, if such reactions develop, drug administration should be discontinued immediately and appropriate medical therapy should be instituted.
As of June 2021, according to the manufacturer, AIM ImmunoTech Inc., the commercial status for Alferon N injection is stated as "Sales anticipated to resume upon successful pre-approval inspection and supplemental approval by FDA per the website, https://aimimmuno.com/products/.
Interferon beta Avonex (interferon beta-1a)
U.S. Food and Drug Administration (FDA)-Approved Indications for Avonex
- Avonex is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
The American Academy of Neurology (AAN) has concluded that, on the basis of several consistent Class I studies, interferon-beta has been demonstrated to reduce the attack rate (whether measured clinically or by MRI) in patients with multiple sclerosis (MS) or with clinically isolated syndromes who are at high-risk for developing MS (Type A recommendation). The AAN has stated that treatment of MS with interferon beta produces a beneficial effect on MRI measures of disease severity such as T2 disease burden and probably also slows sustained disability progression (Type B recommendation).
There currently are two types of interferon beta (recombinant) commercially available in the United States, interferon beta-1a and interferon beta-1b. Important differences in beneficial effects (clinical, MRI measures of response) between these different types of interferon beta in the management of multiple sclerosis have not been reported and the existence of such differences is as yet unknown (Luzzio, 2013). Clinical interpretation of head-to-head comparative studies involving various interferon beta preparations is limited by methodologic problems (e.g., short duration, open-label studies, nonstandardized dosages and/or routes of administration). In addition, the comparative efficacy of interferon beta preparations and other disease-modifying agents (e.g., glatiramer acetate, mitoxantrone) has not been evaluated in well-designed, controlled studies (Luzzio, 2013).
The efficacy of interferon beta-1a (Avonex, Rebif) and interferon beta-1b (Betaseron, Extavia) appear similar for reducing the frequency and severity of exacerbations in relapsing, remitting MS. A randomized clinical study comparing Avonex to Rebif in 677 patients with primary relapsing/remitting MS found a statistically significant difference in favor of Rebif in the proportion of patients who were relapse free at 24 weeks. The investigators found that 75 % of patients treated with Rebif were relapse-free, compared to 63 % of patients treated with Avonex. However, the design of the study did not support any conclusion regarding effects on accumulation of disability.
However, the effectiveness of interferon beta in slowing disease progression and lessening accumulation of disability in secondary progressive MS is still being studied. Furthermore, the FDA has not approved interferon beta for the additional indication of chronic progressive MS.
The Therapeutics and Technology Assessment Subcommittee of the AAN (Goodinc et al, 2007) evaluated the clinical and radiological impact of developing neutralizing antibodies (NAbs) to interferon beta (IFN-beta) while on this therapy for MS. On the basis of Class II and III evidence, it is concluded that treatment of patients with MS with IFN-beta is associated with the production of NAbs (Level A). NAbs in the serum are probably associated with a reduction in the radiographical and clinical effectiveness of IFN-beta treatment (Level B). In addition, the rate of NAb production is probably less with IFN-beta-1a treatment than with IFN-beta-1b treatment, although the magnitude and persistence of this difference is difficult to determine (Level B). Finally, it is probable that there is a difference in sero-prevalence due to variability in the dose of IFN-beta injected or in the frequency or route of its administration (Level B). Regardless of the explanation, it seems clear that IFN-beta-1a (as it is currently formulated for IM injection) is less immunogenic than the current IFN-beta preparations (either IFN-beta-1a or IFN-beta-1b) given multiple times per week subcutaneously (Level A). However, because NAbs disappear in some patients even with continued IFN-beta treatment (especially in patients with low titers), the persistence of this difference is difficult to determine (Level B). Although the finding of sustained high-titer NAbs (greater than 100 to 200 NU/ml) is associated with a reduction in the therapeutic effects of IFN-beta on radiographical and clinical measures of MS disease activity, there is insufficient information on the utilization of NAb testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, or which cutoff titer to apply.
Hughes et al (2010) carried out a dose-ranging efficacy study of IFN-beta-1a in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Adults with intravenous immunoglobulin (IVIG)-dependent CIDP (n = 67) were enrolled in this 32-week double-blind trial and randomized to intramuscular (IM) IFN-beta-1a. Patients received 30 microg once-weekly plus placebo (n = 12), IM IFN-beta-1a 60 microg once-weekly plus placebo (n = 11), IM IFN-beta-1a 30 microg twice-weekly (n = 11), IM IFN-beta-1a 60 microg twice-weekly (n = 11), or placebo twice-weekly (n = 22). Participants were maintained on IVIG through week 16, when IVIG was discontinued. Patients who worsened were re-started on IVIG. The primary outcome was total IVIG dose (g/kg) administered from week 16 to 32. There was no difference in total IVIG dose administered after week 16 for patients treated with IFN-beta-1a (1.20 g/kg) compared with placebo (1.34 g/kg; p = 0.75). However, exploratory analyses suggested IFN-beta-1a significantly reduced total dose of IVIG compared with placebo for participants who required either high-dose IVIG (greater than 0.95 g/kg per month) or had greater weakness at baseline (Medical Research Council sum score less than 51). Adverse events included flu-like symptoms, headache, and fatigue in the IFN-beta-1a groups. The authors concluded that IFN-beta-1a therapy did not provide significant benefit over IVIG therapy alone for patients with CIDP. However, IFN-beta-1a might be beneficial for patients with more severe disability or those needing high doses of IVIG. This study was designed to provide Class I evidence for the safety and efficacy of IM IFN-beta-1a in the treatment of CIDP but has been subsequently classified as Class II due to a greater than 20 % patient drop-out rate. Thus, this randomized controlled trial (RCT) provided Class II evidence of no effect on primary and secondary endpoints of 4 dosage regimens of IM IFN-beta-1a added to IVIG in persons with CIDP.
Interferon gamma-1b (Actimmune)
U.S. Food and Drug Administration (FDA)-Approved Indications for Actimmune
- Actimmune is indicated for reducing the frequency and severity of serious infections associated with chronic granulomatous disease (CGD).
- Actimmune is indicated for delaying time to disease progression in patients with severe, malignant osteopetrosis (SMO).
Compendial Uses for Actimmune
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Mycosis fungoides/Sezary syndrome
Interferon gamma-1b is available as Actimmune (Horizon Therapeutics USA, Inc.) and is a synthesized version of interferon gamma, a naturally occurring protein believed to stimulate the immune system.
FDA-approved indications for interferon gamma (Actimmune) includes treatment of chronic granulomatous disease and delaying time to disease progression in patients with severe, malignant osteopetrosis.
Chronic Granulomatous Disease (CGD) is an inherited disorder of the leukocyte function caused by defects in the enzyme complex responsible for phagocyte superoxide generation. Gamma interferon enhances phagocytic function, resulting in an increase in superoxide anion production by granulocytes and monocytes. Gamma interferon also enhances the oxygen‐independent antimicrobial activity of monocytes from patients with classic X‐linked CGD.
Severe Malignant Osteopetrosis is an inherited disorder characterized by an osteoclast defect, leading to bone overgrowth, and by deficient phagocyte oxidative metabolisms. Gamma interferon enhances superoxide production by phagocytes in situ and enhances osteoclast function in vitro.
Contraindications to interferon gamma‐1b therapy include patients who develop or have known hypersensitivity to interferon gamma, E. coli derived products, or any component of the product. Patients undergoing interferon gamma‐1b treatment should be monitored for changes in pre‐existing cardiac conditions (ischemia, congestive heart failure or arrhythmia), neurologic disorders (seizure disorders or compromised central nervous system function), bone marrow toxicity, hepatic toxicity and hypersensitivity reactions, and renal toxicity.
In addition to those tests normally required for monitoring patients with chronic granulomatous disease and osteopetrosis; hematologic tests (including complete blood count, differential and platelets counts), blood chemistries (renal and hepatic function tests), and urinalysis are recommended for all patients on interferon gamma ‐1b therapy prior to the beginning and at three month interval during treatment. In patients less than one year of age, hepatic function test should be measured monthly.
Patients undergoing interferon gamma‐1b treatment should not be vaccinated with a live vaccine due to increased risk of infection.
Interferon gamma was not better than placebo in improving progression‐free survival, pulmonary function, or the quality of life in patients with idiopathic pulmonary fibrosis (Raghu et al, 2004). Idiopathic pulmonary fibrosis (IPF) is a condition that has a poor prognosis, with a median survival of 4 to 5 years. Preliminary data from a phase III trial of interferon (IFN) gamma-1b injection for the treatment of IPF failed to show a significant difference between IFN gamma-1b-treated patients and control group patients in progression free survival time, the primary endpoint of the study. The double-blind, placebo-controlled trial at 58 U.S. and European centers randomized 300 patients to receive either placebo or 200 mcg of IFN gamma-1b injected subcutaneously 3 times a week. However, there was non-significant 10 % difference in progression-free survival time in favor of IFN gamma-1b treated patients, where progression free survival time is defined as either a decrease in forced vital capacity of greater than 10 %, or an increase in A-a gradient of 5 mmHg, or death. There was also a positive trend in increased survival in IFN gamma-1b treated patients versus the control group; this survival benefit was statistically significant in IFN gamma-1b-treated patients with mild-to-moderate disease. The overall mortality in the IFN gamma-1b-treated patients was 9.9 % versus 16.7 % in the control population. Of the 254 patients with mild-to-moderate disease, mortality was 4.8 % in the IFN gamma-1b-treated patients and 16.4 % in the control group. Trends were also observed later in the course of the study in favor of IFN gamma-1b in terms of improved breathing and reduced need for supplemental oxygen. All remaining phase III trial patients in the active and control groups are being transitioned into an open-label clinical trial in which all patients receive IFN gamma-1b to track longer-term outcomes with IFN gamma-1b for a minimum of 1 year.
In a randomized prospective multi-center clinical trial, Antoniou et al (2006) examined the clinical effects of IFNgamma-1b administered subcutaneously thrice weekly versus colchicine for 2 years. This study had no pre-specified end-points. Fifty consecutive IPF patients were randomized. Patients with mild-to-moderate IPF were eligible for the study if they had histologically proven IPF, or, in the absence of surgical biopsy, fulfilled the European Respiratory Society/American Thoracic Society criteria. In the intent-to-treat population, 5 out of 32 (15.6 %) IFN gamma-1b patients and 7 out of 18 (38.8 %) colchicine patients died after a median follow-up period of 25 months. Patients treated with IFN gamma-1b showed a better outcome after 2 years of therapy, and fewer symptoms, as assessed using the St George's Respiratory Questionnaire, after 12 months of therapy. Also, the IFN gamma-1b group exhibited a higher forced vital capacity (percentage of the predicted value) after 24 months of treatment. No significant differences were detected in resting arterial oxygen tension, total lung capacity (% pred), transfer factor of the lung for carbon monoxide (% pred) and high-resolution computed tomographic scoring between the 2 treatment groups. These data suggest that long-term treatment with IFN gamma-1b may improve survival and outcome in patients with mild-to-moderate IPF. The authors stated that further studies are needed to verify these results. Additionally, the effect of IFN gamma-1b on progressive cases needs to be evaluated.
Walter et al (2006) noted that the clinical course of IPF is variable; however, the long-term survival in IPF is poor. Prednisone has been the mainstay of therapy since its release for clinical use in 1948. Recently, prednisone combined with azathioprine or cyclophosphamide has been used. A number of other drug combinations have been tried with prednisone (e.g., methotrexate, colchicine, penicillamine, or cyclosporine) but have failed or are not well-tolerated by the patient. Few high quality, prospective, controlled clinical trials have been performed. Thus, there is no good evidence to support the routine use of any specific therapy in the management of IPF. Additional large clinical trials are needed to confirm the potential usefulness of the newer agents (e.g., IFN gamma-1b, pirfenidone, N-acetylcysteine, coumadin, bosentan, or etanercept).
It should be noted that in March 2007, InterMune abandoned efforts to develop Actimmune (IFN gamma-1b) as a treatment for IPF because results from a late-stage clinical trial showed the drug did not prolong lives. The phase 3 INSPIRE clinical trial evaluating Actimmune (IFN gamma-1b) in IPF patients with mild-to-moderate impairment in lung function was discontinued based upon the recommendation of the study’s independent data monitoring committee (DMC). In a planned interim analysis that included a total of 115 deaths, the DMC found the overall survival result crossed a pre-defined stopping boundary for lack of benefit of Actimmune relative to placebo. Among the 826 randomized patients, there was not a statistically significant difference between treatment groups in overall mortality (14.5 % in the Actimmune group as compared to 12.7 % in the placebo group). Based on a preliminary review of the interim safety data, the adverse events associated with Actimmune appear generally consistent with prior clinical experience, including constitutional symptoms, neutropenia and possibly pneumonia.
In a multi-center, randomized, placebo-controlled study, King et al (2009) evaluated if treatment with IFN gamma-1b improved survival compared with placebo in patients with IPF and mild-to-moderate impairment of pulmonary function. A total of 826 patients with IPF were enrolled from 81 centers in 7 European countries, the USA, and Canada. Patients were randomly assigned (double-blind) in a 2:1 ratio to receive 200 microg IFN gamma-1b (n = 551) or equivalent placebo (n = 275) subcutaneously, 3 times per week. Eligible patients were aged 40 to 79 years, had been diagnosed in the past 48 months, had a forced vital capacity of 55 to 90 % of the predicted value, and a hemoglobin-corrected carbon monoxide diffusing capacity of 35 to 90 % of the predicted value. The primary endpoint was overall survival time from randomization measured at the second interim analysis, when the proportion of deaths had reached 75 % of those expected by the study conclusion. At the second interim analysis, the hazard ratio for mortality in patients on IFN gamma-1b showed absence of minimum benefit compared with placebo (1.15, 95 % CI: 0.77 to 1.71, p = 0.497), and indicated that the study should be stopped. After a median duration of 64 weeks (IQR 41 to 84) on treatment, 80 (15 %) patients on IFN gamma-1b and 35 (13 %) on placebo had died. Almost all patients reported at least 1 adverse event, and more patients on IFN gamma-1b group had constitutional signs and symptoms (influenza-like illness, fatigue, fever, and chills) than did those on placebo. Occurrence of serious adverse events (e.g., pneumonia, respiratory failure) was similar for both treatment groups. Treatment adherence was good and few patients discontinued treatment prematurely in either group. The authors concluded that they cannot recommend treatment with IFN gamma-1b since the drug did not improve survival for patients with IPF, which refutes previous findings from subgroup analyses of survival in studies of patients with mild-to-moderate physiological impairment of pulmonary function.
Mozaffari and colleagues (2019) noted that cytokines have regulatory and leading roles in the immuno-pathogenesis of oral lichen planus (OLP). These researchers presented the findings of a meta-analysis that evaluated salivary and serum interferon-gamma (IFN-γ) levels in patients with OLP compared with those in controls and the correlation of this cytokine with the progression of OLP. A total of 4 databases – PubMed, Web of Science, Scopus, and Cochrane Library-were searched, from their start dates to November 2017, for reports in all languages on the effect of OLP on salivary and serum IFN-γ. A total of 11 studies were included and analyzed in this meta-analysis. The pooled mean difference (MD) values were estimated to be 3.60 pg/ml (p = 0.23) and -0.02 pg/ml (p = 1.00) for serum and salivary levels of IFN-γ, respectively, in the patients with OLP compared with controls. The pooled MD values were -2.52 pg/ml (p = 0.03) and -2.01 pg/ml (p = 0.20) for serum and salivary IFN-γ levels in the erosive type, respectively, compared with the non-erosive type. The authors concluded that according to the results of meta-analysis, there was no statistically significant differences in IFN-gamma levels between the OLP group and the control group both in salivary and serum levels and also between erosive and non-erosive types of OLP at the salivary level; thus, this cytokine was not considered to have an important role in the pathogenesis or severity of OLP.
In a systematic review and meta-analysis, Westfechtel and colleagues (2018) examined the available evidence from RCTs on the efficacy of adjuvant systemic IFN after ablative treatment for ano-genital warts (AGWs). These researchers carried out a literature search in Cochrane Central Register of Controlled Trials, Embase and Medline. Available data were classified according to the interferon type and dosage. Pooled effect estimates were calculated for pre-defined outcomes. The Cochrane Collaboration's risk of bias tool was used to assess the included trials and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to evaluate the confidence in the effect estimates. A total of 12 trials were identified that met the inclusion criteria and assessed immunocompetent patients with external AGW. Compared with placebo, adjuvant alpha-, beta- and gamma-IFN were generally not significantly superior in terms of complete clearance over the short-, intermediate- or long-term, nor with regard to intermediate- or long-term recurrence. However, the low-dose subgroup of adjuvant alpha-IFN was significantly superior compared with placebo regarding intermediate-term complete clearance and recurrence. Further data were available for the comparison of different dosages of alpha- and beta-IFN and for comparisons of the 3 IFN types. No significant differences were seen in these comparisons regarding efficacy. Data on quality of life (QOL) were not available. The authors concluded that the GRADE quality of the evidence ranged from “very low” to “high”. The significantly higher efficacy of low-dose alpha-IFN compared with placebo was based on a single trial, and the confidence in the effect estimates rated as “low”. Overall, the authors found no reliable evidence favoring the systemic use of IFN after ablative treatment of AGW.
Wong and colleagues (2012) stated dermatomyositis (DM) is an autoimmune disease that affects mainly the skin, muscle, and lung. The pathogenesis of skin inflammation in DM is not well-understood. These researchers analyzed genome-wide expression data in DM skin and compared them to those from healthy controls. They observed a robust up-regulation of IFN-inducible genes in DM skin, as well as several other gene modules pertaining to inflammation, complement activation, and epidermal activation and differentiation. The IFN-inducible genes within the DM signature were present not only in DM and lupus, but also cutaneous herpes simplex-2 infection and to a lesser degree, psoriasis. This IFN signature was absent or weakly present in atopic dermatitis, allergic contact dermatitis, acne vulgaris, systemic sclerosis, and localized scleroderma/morphea. These investigators observed that the IFN signature in DM skin appeared to be more closely related to type I than type II IFN based on in-vitro IFN stimulation expression signatures. However, quantitation of IFN mRNAs in DM skin showed that the majority of known type I IFNs, as well as IFN g, were over-expressed in DM skin. In addition, both IFN-beta and IFN-gamma (but not other type I IFN) transcript levels were highly correlated with the degree of the in-vivo IFN transcriptional response in DM skin. The authors concluded that as in the blood and muscle, DM skin was characterized by an overwhelming presence of an IFN signature, although it was difficult to conclusively define this response as type I or type II. Understanding the significance of the IFN signature in this wide array of inflammatory diseases would be furthered by identification of the nature of the cells that both produce and respond to IFN, as well as which IFN subtype is biologically active in each diseased tissue.
Enders and colleagues (2017) noted that in 2012, a European initiative called Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched to optimize and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile dermatomyositis (JDM) is a rare disease within the group of pediatric rheumatic diseases (PRDs) and could lead to significant morbidity. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. Consequently, treatment regimens differ throughout Europe. These investigators provided recommendations for diagnosis and treatment of JDM. Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was constituted, consisting of 19 experienced pediatric rheumatologists and 2 experts in pediatric exercise physiology and physical therapy, mainly from Europe. Recommendations derived from a validated systematic literature review were evaluated by an online survey and subsequently discussed at 2 consensus meetings using nominal group technique. Recommendations were accepted if greater than 80 % agreement was reached. In total, 7 overarching principles, 33 recommendations on diagnosis and 19 recommendations on therapy were accepted with greater than 80 % agreement among experts. Topics covered included assessment of skin, muscle and major organ involvement and suggested treatment pathways. The authors concluded that the SHARE initiative aimed to identify best practices for treatment of patients suffering from PRD. Within this remit, recommendations for the diagnosis and treatment of JDM have been formulated by an evidence-informed consensus process to produce a standard of care for patients with JDM throughout Europe. The expert group proposed recommendations for treatment of newly diagnosed patients and resistant disease. Treatment of refractory patients with or without calcinosis is still a challenge. Treatments used for refractory disease include IVIG, cyclophosphamide, cyclosporine A (CsA), azathioprine, mycophenolate mofetil (MMF), hydroxychloroquine, tacrolimus, rituximab, infliximab and autologous stem cell transplantation. No head-to-head or superiority trial has been carried out. Interferon is not mentioned as a therapeutic option.
Peginterferon alfa-2a (Pegasys)
U.S. Food and Drug Administration (FDA)-Approved Indications for Pegasys
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Chronic Hepatitis C
Pegasys, as part of a combination regimen with other hepatitis C virus (HCV) antiviral drugs, is indicated for the treatment of adults with chronic hepatitis C (CHC) with compensated liver disease. Pegasys in combination with ribavirin is indicated for treatment of pediatric patients 5 years of age and older with CHC and compensated liver disease. Pegasys monotherapy is only indicated for the treatment of patients with CHC with compensated liver disease if there are contraindications or significant intolerance to other HCV antiviral drugs.
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Chronic Hepatitis B
Pegasys is indicated for the treatment of adult patients with HBeAg-positive and HBeAg-negative chronic hepatitis B infection who have compensated liver disease and evidence of viral replication and liver inflammation. Pegasys is indicated for the treatment of HBeAG-positive CHB in non-cirrhotic pediatric patients 3 years of age and older with evidence of viral replication and elevations in serum alanine aminotransferase (ALT).
Compendial Uses for Pegasys
- Adult T-cell leukemia/lymphoma
- Chronic myeloid leukemia
- Erdheim-Chester disease
- Hairy cell leukemia
- Mycosis fungoides/Sezary syndrome
- Myeloproliferative neoplasm (essential thrombocythemia, polycythemia vera, symptomatic lower-risk myelofibrosis)
- Primary cutaneous CD30+ T-cell lymphoproliferative disorders
- Systemic mastocytosis
Peginterferon alfa-2a is available as Pegasys (Genentech, Inc.) and is in the interferon alfa therapeutic class. Pegasys (peginterferon alfa‐2a) is a covalent conjugate of recombinant alfa‐2a interferon with a single branched bis‐monomethoxy polyethylene glycol (PEG) chain. Pegasys (peginterferon alfa‐2a) is indicated for the treatment of chronic hepatitis C and chronic hepatitis B. However, current AASLD/IDSA guidelines do not recommend the use of interferon products (Genentech, 2020).
Peginterferon alfa-2a (Pegasys) carries a boxed warning that it may cause or aggravate fatal or life‐threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders (Genentech, 2020).
Per the prescribing information, peginterferon alfa-2a (Pegasys) carries the following contraindications:
- Autoimmune hepatitis
- Hepatic decompensation in patients with cirrhosis
- Use in neonates/infants
- Known hypersensitivity reactions: urticaria, angioedema, bronchoconstriction and anaphylaxis to alpha interferons or any component of the product.
Additional contraindications for use with other HCV antiviral drugs include (Genentech, 2020):
- All contraindications also apply to Pegasys when used in combination with other HCV antiviral drugs
- Ribavirin is contraindicated in pregnant women and men whose female partners are pregnant.
Per the prescribing information, Pegasys carries the following warnings and precautions:
- Use with Ribavirin may cause birth defects and/or death of the exposed fetus
- Clinically significant adverse reactions or risks include the following:
- Neuropsychiatric reactions
- Cardiovascular disorders
- Bone marrow suppression
- Autoimmune and endocrine disorders (including thyroid disorders; hyperglycemia)
- Ophthalmologic disorder
- Cerebrovascular disorders
- Hepatic decompensation in cirrhotic patients. Exacerbation of hepatitis during hepatitis B treatment.
- Pulmonary disorders
- Infections (bacterial, viral, fungal)
- Colitis and pancreatitis
- Hypersensitivity and serious skin reactions including Stevens-Johnson syndrome
- Growth impairment with combination therapy in pediatric patients
- Peripheral neuropathy when used in combination with telbivudine.
The most common adverse reactions (incidence ≥40%) include fatigue/asthenia, pyrexia, myalgia, and headache in adult patients. Pediatric patients share a similar adverse reaction profile (Genentech, 2020).
Roche Pharmaceutical's Pegasys (pegylated interferon alfa-2a) has been approved by the FDA for the treatment of adults with chronic hepatitis C who have compensated liver disease and have not previously been treated with interferon alfa. Patients in whom efficacy was demonstrated included patients with compensated cirrhosis. Pegasys was granted approval based on the results of 3 phase III clinical trials that demonstrated it is an effective treatment for patients with chronic hepatitis C, including cirrhotic patients with compensated liver disease, versus treatment with Roferon-A (interferon alfa-2a). The sustained virological response rate in the patients treated with pegylated interferon alfa-2a was as high as 38 % in the overall population versus 19 % in the interferon alfa-2a group. The sustained virological response in patients with cirrhosis treated with pegylated interferon alfa-2a was as high as 30 % versus 8 % in the interferon alfa-2a group. Higher sustained virological response results were also found in patients with genotype 1, on pegylated interferon alfa-2a treatment (23 %) versus interferon alfa-2a (6 %), the most common type in the U.S. and most difficult to treat. Sustained virological response was defined as undetectable serum hepatitis C RNA levels post-treatment (on or after study week 68). Pegylated interferon alfa-2a is dosed at 180 µg as a subcutaneous injection once-weekly for a recommended duration of 48 weeks.
Peginterferon alfa-2a (Pegasys) has also been approved by the FDA for treatment of hepatitis C in HIV coinfected persons, whose HIV disease is clinically stable (e.g., anti-retroviral therapy not required or receiving stable antiretroviral therapy). In studies submitted to the FDA, 868 HCV/HIV coinfected patients were randomized to receive peginterferon alfa-2a plus placebo, peginterferon alfa-2a plus ribavirin, or interferon alfa-2a plus ribavirin (Roche, 2005). All subjects received 48 weeks of therapy, and sustained virologic response was assessed at 24-weeks of treatment free follow-up. All subjects included in the study had compensated liver disease, a CD4+ cell count greater than or equal to 200 cells/µL or CD4+ cell count greater than or equal to 100 cells/µL but less than 200 cells/µL and HIV-1 RNA less than 5,000 copies/ml, and stable status of HIV. Approximately 15 % of patients in the study had cirrhosis. Sustained virologic response was noted in 40 % of subjects treated with peginterferon alfa-2a plus ribavirin, 20 % of patients treated with peginterferon alfa-2a plus placebo (p < 0.0001), and 11 % of subjects treated with interferon alfa-2a plus ribavirin (p < 0.0001). Of patients who did not demonstrate either undetectable HCV RNA or at least a 2 log 10 reduction from baseline in HCV RNA titer by 12 weeks of peginterferon alfa-2a and ribavirin combination therapy, 2 % achieved a sustained virologic response.
There is inadequate evidence for the effectiveness of use of pegylated interferons as maintenance therapy. According to the FDA-approved labeling for pegylated interferons, there are no safety and efficacy data on treatment with pegylated interferons for more than one year.
Peginterferon alfa-2b (PegIntron)
PegIntron, peginterferon alfa-2b powder for injection, either alone or in combination with ribavirin (Rebetol), is an alternative to standard interferon alfa plus ribavirin for treatment of chronic hepatitis C. However, peginterferon regimens are no longer recommended in the HCV treatment guidelines (AASLD/IDSA 2018). PegIntron is a covalent conjugate of recombinant alfa interferon with monomethoxy polyethylene glycol (PEG). It offers an alternative to patients in whom combination therapy may be a contraindication or who are intolerant of this therapy. The drug is self-administered subcutaneously once-weekly by patients and, therefore, is more convenient to use than the standard interferon alfa, which is injected 3 times weekly. Studies of combination therapy with weekly PegIntron and daily ribavirin (Rebetol) reported that this combination was somewhat more effective than alfa interferon (Intron A) with Rebetol. Twenty-four weeks after treatment ended, 52 % of patients who received the PegIntron combination had undetectable HCV virus levels in the blood compared to 46 % for the Intron A combination. In patients with genotype 1 virus (a particularly difficult to treat variant of the HCV virus), the difference in sustained responses was 41 % compared to 33 %. PegIntron from Schering-Plough is the first pegylated interferon to have FDA approval in the United States.
PegIntron, as part of a combination regimen, is indicated for the treatment of Chronic Hepatitis C in patients with compensated liver disease. PegIntron in combination with Rebetol (ribavirin) and an approved Hepatitis C Virus (HCV) NS3/4A protease inhibitor is indicated in adult patients (18 years of age and older) with HCV genotype 1 infection. PegIntron in combination with Rebetol is indicated in patients with genotypes other than 1, pediatric patients (3‐17 years of age), or in patients with genotype 1 infection where use of an HCV NS3/4A protease inhibitor is not warranted based on tolerability, contraindications or other clinical factors.
PegIntron is contraindicated in: hepatic decompensation (Child‐Pugh class B or C) in cirrhotic members before or during treatment; hepatic decompensation (Child‐Pugh class B or C) in cirrhotic members co‐infected with HIV before or during treatment; autoimmune hepatitis; and kidney, liver, heart, or other solid‐organ transplant.
Use with Ribavirin may cause birth defects and death of the unborn child.
Alfa interferons, including PegIntron, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders.
The safety and efficacy in pediatric patients less than 3 years of age has not been established.
On September 24, 2015, the FDA announced the voluntary discontinuation of Merck's PegIntron (peginterferon alfa-2b). Merck discontinued the manufacturing and distribution of PegIntron effective February 1, 2016 (OptumRx, 2015). According to LexiComp (2020), PegIntron Redipen and PegIntron 80 mcg, 120 mcg, and 150 mcg vials have been discontinued in the U.S. for more than 1 year. PegIntron 50 mcg vials remain available in limited quantities; based on current demand, Merck anticipates product should continue to be available through May 2021.
Peginterferon alfa-2b (Sylatron)
Sylatron (peginterferon alfa‐2b) is a member of the interferon drug class. It is a covalent conjugate of recombinant alfa‐2b interferon with monomethoxy polyethylene glycol (PEG). Although the exact mechanism of Sylatron (peginterferon alfa‐2b) effects in melanoma is unknown, interferon‐stimulated genes modulate many biological effects including the inhibition of viral replication in infected cells, inhibition of cell proliferation and immunomodulation.
Sylatron (peginterferon alfa‐2b) is FDA-approved for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy (Merck, 2018).
Sylatron (peginterferon alfa‐2b) therapy is not recommended for persons with hepatic decompensation (Child‐Pugh score >6 [class B and C]).
The risk of serious depression, with suicidal ideation and completed suicides, and other serious neuropsychiatric disorders are increased with alfa interferons, including Sylatron (peginterferon alfa‐2b). Permanently discontinue Sylatron (peginterferon alfa‐2b) in patients with persistently severe or worsening signs or symptoms of depression, psychosis, or encephalopathy. These disorders may not resolve after stopping Sylatron (peginterferon alfa‐2b).
Sylatron (peginterferon alfa‐2b) should not be used in the following:
- Pediatric patients < 18 years of age because safety and efficacy have not been established.
- Women who are pregnant or lactating and have not been apprised of the potential hazard to the fetus.
- Patients with a history of anaphylaxis to peginterferon alfa‐2b or interferon alfa‐2.
Merck announced plans to discontinue Sylatron by December 2019 for business reasons. Per LexiComp (2020), Sylatron 600 mcg vials were discontinued on or near December 2018. Sylatron 200 mcg and 300 mcg vials were discontinued on or near December 2019.
Ropeginterferon alfa-2b-njft (Besremi)
U.S. Food and Drug Administration (FDA)-Approved Indications for Besremi
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Besremi is indicated for the treatment of adults with polycythemia vera.
Ropeginterferon alfa-2b-njft is available as Besremi (PharmaEssentia USA Corporation) and is an N-terminal monopegylated covalent conjugate of proline interferon alfa-2b. It is produced in Escherichia coli cells via recombinant DNA technology and contains a methoxy polyethylene glycol (mPEG) moiety. Ropeginterferon alfa-2b-njft, similar to other type I interferons, mediates cellular effects in polycythemia vera in bone marrow by binding to interferon alfa receptor (IFNAR), This binding then causes events downstream involving the activation of kinases, specifically Janus kinase (JAK1) and tyrosine kinase 2 (TYK2) and activator of transcription (STAT) proteins. The processes involved in the therapeutic effects of interferon alfa in polycythemia vera are not completely understood. (PharmEssentia, 2021).
Per the prescribing information, ropeginterferon alfa-2b-njft (Besemri) carries the following contraindications:
- Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation or suicide attempt
- Hypersensitivity to interferons or to any component of Besremi
- Hepatic impairment (Child-Pugh B or C)
- History or presence of active serious or untreated autoimmune disease
- Immunosuppressed transplant recipients.
Per the prescribing information, ropeginterferon alfa-2b-njft (Besremi) carries the following warnings and precautions:
- Black box warning of risk of serious disorders: Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders.
- Depression and suicide
- Endocrine toxicity
- Cardiovascular toxicity
- Decreased peripheral blood counts
- Hypersensitivity reactions
- Pancreatitis
- Colitis
- Pulmonary toxicity
- Ophthalmologic toxicity
- Hyperlipidemia
- Hepatotoxicity
- Renal toxicity
- Dental and periodontal toxicity
- Dermatologic toxicity
- Driving and operating machinery.
The most common adverse reactions noted in > 40% of patients included influenza-like illness, arthralgia, fatigue, pruritus, nasopharyngitis, and musculoskeletal pain (PharmEssentia, 2021)
On November 12, 2021, the U.S. Food and Drug Administration approved Besremi (ropeginterferon alfa-2b-njft) injection for the treatment of adults with polycythemia vera. Besremi received orphan drug designation for the treatment of polycythemia vera and the FDA approval was based on supporting data from the PEGINVERA study (FDA, 2021).
Gisslinger and colleagues (2015) assessed the efficacy and safety of ropeginterferon alfa-2b (Besremi) in the treatment of adult participants with polycythemia vera in the PEGINVERA study, a prospective, open-label, multicenter phase 1/2 dose escalation, single arm trial of 7.5 years duration. This study consisted of 51 adult participants with polycythemia vera. A primary objective was to determine the maximum tolerated dose of ropeginterferon alfa-2b in addition to efficacy and safety evaluation. Ropeginterferon alfa-2b was administered in the dose range of 50 to 540 µg without apparent dose-limiting toxicities and all drug-related adverse events were known to be related to interferon-α therapy. The study results included cumulative overall response rate as 90%, consisting of complete response in 47% and partial response in 43% of participants. Additionally, the best individual molecular response level showed a complete response in 21% of participants and partial response in 47% of participants. No correlation was observed between the dose level and response rate or response duration.
Telaprevir (Incivek)
Telaprevir tablets (Incivek, Vertex) are protease inhibitors that have received FDA approval to treat chronic hepatitis C genotype 1 infection in adults who have either not received interferon-based drug therapy for their infection or who have not responded adequately to prior therapies. Telaprevir is approved for use with peginterferon alfa and ribavirin. The safety and effectiveness of telaprevir was evaluated in 3 phase 3 clinical trials with about 2,250 adult patients who were previously untreated, or who had received prior therapy. In all studies patients also received the drug with standard of care. In previously untreated patients, 79 % of those receiving telaprevir experienced a sustained virologic response. The sustained virologic response for patients treated with telaprevir across all studies, and across all patient groups, was between 20 and 45 % higher than current standard of care. Studies indicate that treatment with telaprevir can be shortened from 48 weeks to 24 weeks in most patients; 60 % of previously untreated patients achieved an early response and received only 24 weeks of treatment (compared to the standard of care of 48 weeks). The sustained virologic response for these patients was 90 %. According to the FDA-approved labeling, 750 mg of telaprevir is taken 3 times a day (7 to 9 hours apart) with food (not low fat). The labeling states that telaprevir must be administered with both peginterferon alfa and ribavirin for all patients for 12 weeks, followed by a response-guided regimen of either 12 or 36 additional weeks of peginterferon alfa and ribavirin depending on viral response and prior response status. The most commonly reported side effects in patients receiving telaprevir in combination with peginterferon alfa and ribavirin include rash, low red blood cell count, nausea, fatigue, headache, diarrhea, pruritus, and anal or rectal irritation and pain. Rash can be serious and can require stopping telaprevir or all 3 drugs in the treatment regimen.
Commenting on the data from randomized trials of protease inhibitors in genotype 1 hepatitis C, Rosen (2011) stated that a reasonable initial regimen would be telaprevir with peginterferon and ribavirin for 12 weeks. If tests for HCV RNA were negative at weeks 4 through 12 (indicating an extended rapid virologic response), only 12 additional weeks of peginterferon and ribavirin would be recommended, whereas if an extended rapid virologic response were not achieved, peginterferon and ribavirin would be continued for an additional 36 weeks. If boceprevir were used, according to FDA guidelines, a 4-week lead-in phase of peginterferon and ribavirin would be followed by peginterferon and ribavirin and boceprevir for 24 weeks (a total of 28 weeks) if tests for HCV RNA were negative at weeks 8 through 24 of treatment. If the tests were positive between weeks 8 and 24 but negative at week 24, peginterferon and ribavirin and boceprevir would be continued for an additional 8 weeks, followed by an additional 12 weeks of peginterferon-ribavirin (a total of 48 weeks).
Behcet's Syndrome
In an open, non-randomized, uncontrolled, interventional, prospective study, Sobaci et al (2010) evaluated the intermediate-term safety and effectiveness of interferon alfa-2a (IFN-alfa2a) in patients with Behcet's uveitis (BU) refractory to corticosteroids and immunosuppressive agents. A total of 53 patients (106 eyes) with active, vision-threatening BU who failed to respond to conventional treatments were included in this study. In 53 patients, acute inflammation was suppressed with effective prednisolone dosage (1 to 2 mg/kg/day, tapered to 10 mg within 4 to 6 weeks). The patients were treated with IFN-alfa2a 4.5 MIU 3 times per week for the first 3 months followed by IFN-alfa2a 3 MIU 3 times per week for the next 3 months. Observation or other treatment methods were performed according to the decision tree developed for this study. Primary outcome measures were remission and complete response; secondary outcome measures were frequency of uveitis attacks, visual acuity (VA), and adverse effects. During 2 years of follow-up (median of 65 months, range of 12 to 130 months), compliance with the therapy was excellent. At the end of 1-year follow-up, treatment response was obtained in 45 of 53 patients (84.9 %). The mean attack rate of 3.6 +/- 1.1 per year (range of 2 to 8) decreased to 0.56 +/- 0.75 (range of 0 to 4) per year (p = 0.001). Visual acuity improved (greater than or equal to 0.2 logarithm of the minimum angle of resolution units from initial VA) in 30 eyes (28.3 %) and worsened in 12 eyes (11.3 %). Five patients (9.4 %) did not respond to the initial treatment, and 3 patients (5.6 %) developed severe adverse effects, including psoriasis, epileptic seizure, and extreme tiredness. Fifteen patients (28.3 %) were off treatment for all the medications and disease free for 28 +/- 13.1 months (range of 12 to 50 months). The authors concluded that these findings suggested that IFN-alfa2a may be a valuable treatment option in BU that is refractory to corticosteroids and conventional immunosuppressive agents. The possible role of IFN-alfa2a as a first-line agent in BU should be validated in RCTs against newly described biologic agents.
In a Cochrane review, Nava et al (2014) evaluated the benefit and harms of available treatments for neuro-Behcet's syndrome (NBS), including biologics, colchicine, corticosteroids, immunosuppressants and IFN-alfa. The authors concluded that there is no evidence to support or refute the benefit of biologics, colchicine, corticosteroids, immunosuppressants and IFN-alfa for the treatment of patients with NBS. They stated that well-designed multi-center RCTs are needed in order to inform and guide clinical practice.
Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS)
Rico and colleagues (2016) noted that chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described inflammatory disease of the CNS, distinguished by brainstem- and spinal cord-centered lesions with a characteristic contrast enhancement on MRI, a lymphocytic perivascular infiltrate on pathological examination, and a dramatic response to and dependence on steroids therapy. Since its initial description in 2010, different glucocorticoid-sparing agents, mostly immunosuppressant drugs, have been used to minimize the dosage, but these therapies also carry the risk of important secondary effects. These researchers presented the first reported case of CLIPPERS treated with IFN-beta-1a as add-on therapy. The case entailed a previously healthy 31-year old man presented with gait ataxia and dysarthria; MRI showed pons-centered hyper-intense patchy lesions on T2-weighted images. Additional tests ruled out other possible diagnoses and symptoms reversed with intravenous methylprednisolone. Over the years the patient presented with several episodes of deterioration each year, which were partly reversed with glucocorticoid therapy, but leaving him with growing sequelae. Four years after the initial event, treatment with IFN-beta-1a was initiated, achieving reduced frequency of the relapses to 1 every 4 years, which were no longer associated to increasing disability. This allowed reducing glucocorticoids to 30 mg of Deflazacort every other day. The authors concluded that IFN-beta-1a could be an alternative to corticosteroid-combined therapy in CLIPPERS and its more benign profile of secondary effects compared to immune-suppressants could make it an attractive choice. These preliminary findings need to be validated by well-designed studies.
Familial Mediterranean Fever (FMF)
In a double-blind, placebo-controlled trial, Tunca et al (2004) examined the effect of INF-alfa on acute attacks of familial Mediterranean fever (FMF). These investigators treated 34 acute abdominal attacks with IFN-alfa 5 MIU or placebo subcutaneously in the early phase of the attack. Leucocytes, thrombocytes, the erythrocyte sedimentation rate, fibrinogen, C-reactive protein (CRP), serum amyloid A protein (SAA), haptoglobin, transferrin, IL-1beta and TNF-alfa were measured at hours 0, 6, 12, 24 and 48. The median time to recovery in those treated with IFN-alfa and placebo was not significantly different, while the leukocytosis and high levels of fibrinogen were significantly more prolonged in placebo-treated patients; CRP and SAA were extremely elevated and peaked at 24 hours, remaining less marked in the patients treated with IFN-alfa, but the difference was not statistically significant. Observations regarding the other parameters were unremarkable. The authors concluded that although there were some clues indicating a depressed inflammatory response with IFN-alfa, they could not demonstrate a definitive effect of this agent in this double-blind trial. The drug may suppress the acute inflammation of FMF only if administered at the earliest phase.
Guillain Barre Syndrome
In a Cochrane review, Hughes et al (2011) reviewed systematically the evidence from RCTs for pharmacological agents other than plasma exchange, intravenous immunoglobulin and corticosteroids for the treatment of Guillain Barré syndrome. Only very low quality evidence was found for 4 different interventions. One RCT with 13 participants showed no significant difference in any outcome between IFN beta-1a and placebo. Another with 10 participants showed no significant difference in any outcome between brain-derived neurotrophic factor and placebo. A third with 37 participants showed no significant difference in any outcome between cerebrospinal fluid filtration and plasma exchange. In a fourth with 20 subjects, the risk ratio of improving by 1 or more disability grades after 8 weeks was significantly greater with the Chinese herbal medicine tripterygium polyglycoside than with corticosteroids (risk ratio 1.47; 95 % CI: 1.02 to 2.11). The authors concluded that the quality of the evidence was very low. Three small RCTs, of IFN beta-1a, brain-derived neurotrophic factor and cerebrospinal fluid filtration, showed no significant benefit or harm. A fourth small trial showed that the Chinese herbal medicine tripterygium polyglycoside hastened recovery significantly more than corticosteroids but this result needs confirmation. It was not possible to draw useful conclusions from the few observational studies.
Hepatitis B
Hepatitis B can cause both acute and chronic infection. Hepatitis B is one of the world’s most common infectious pathogens. HbeAG‐positive chronic hepatitis is characterized by high levels of viremia and persistently or intermittently increased ALT levels. If untreated, the majority of patients will maintain high HBV replication and active liver inflammation.
HbeAG‐negative chronic hepatitis is characterized by persistent HVB replication, lower viremia and progressive inflammation and fibrosis of the liver. A spontaneous remission of HbeAG‐negative hepatitis is rare and this type of hepatitis B is associated with poor response to therapy.
The goals of treating hepatitis B are to achieve sustained suppression of HBV replication and remission of liver disease. There are three key guidelines used for the treatment of hepatitis B. The European Association for the study of liver (EASL) recommends the use of IFNα as first line drug therapy. The American Association for the Study of Liver Diseases (AASLD) recommends lamivudine and adefovir as first line drug therapy. The Asia‐Pacific Association for Study of the Liver (APASL) another European guidelines, list lamivudine, adefovir, IFNα, and Peg IFNα, all as first line therapy drug therapy options.
The safety and effectiveness of peginterferon alfa-2a (Pegasys) for the treatment of chronic hepatitis B was assessed in 2 phase III controlled clinical trials in HBeAg positive and HBeAg negative patients with hepatitis B. In each study, patients were randomized to peginterferon alfa-2a 180 µg subcutaneously once-weekly, lamivudine 100 mg once-daily, or both peginterferon alfa-2a plus lamivudine. All patients received 48 weeks of their assigned therapy followed by 24 weeks of treatment-free follow-up. These 2 clinical trials demonstrated that 24 weeks after a defined 48 week period of therapy, more patients achieved a sustained response with peginterferon alfa-2a than with lamivudine (Epivir). These studies demonstrated that the addition of lamivudine to peginterferon alfa-2a did not improve response rates over peginterferon alfa-2a alone.
All patients included in these studies of peginterferon alfa-2a for chronic hepatitis B virus (HBV) infection were adults with compensated liver disease and evidence of HBV replication (serum HBV greater than 500,000 copies/ml for the study of HBeAg positive patients and serum HBV greater than 100,000 copies/ml for the study of HBeAg negative patients). All patients had serum alanine aminiotransferase (ALT) between 1 and 10 times the upper limit of normal and liver biopsy findings compatible with the diagnosis of chronic hepatitis.
In a study of HBeAg positive patients with chronic HBV infection, 32 % of 271 patients treated with peginterferon alfa-2a seroconverted by the end of follow-up versus 19 %sero-conversion among 272 patients treated with lamivudine. Subjects treated with peginterferon alfa-2a had a higher rate of DNA response (defined as less than 100,000 copies per ml) (32 %) by the end of follow-up than subjects treated with lamivudine (22 %). In a study of HBeAg negative patients with chronic HBV infection, 43 % of 177 patients treated with peginterferon alfa-2a exhibited a HBV DNA response (defined as less than 20,000 copies per mL) by the end of follow-up versus 29 % of 181 patients treated with lamivudine. Subjects treated with peginterferon alfa-2a had a higher rate of ALT normalization (59 %) by the end of follow-up than subjects treated with lamivudine (44 %). Conclusions regarding comparative efficacy of peginterferon alfa-2a and lamivudine treatment based upon the end of follow-up results are limited by the different mechanisms of action of the two compounds. Most treatment effects of lamivudine are unlikely to persist 24 weeks after therapy is withdrawn.
The effectiveness of repeat or maintenance pegylated interferon treatment of chronic HBV infection is unknown. According to guidelines from the American Gastroenterological Association (Dienstag and McHutchison, 2006), re-treatment is indicated for persons who have relapsed (with relapse defined as where HBV RNA is undetectable during and at the end of therapy but re-appears after completion of therapy) after having completed a course of less-effective therapy. For example, it may be appropriate to re-treat a person with pegylated interferon plus ribavirin who have relapsed after a course of standard interferon plus ribavirin. However, relapsers are likely to experience a response only to subsequently relapse again with a subsequent course of the same therapy (e.g., re-treatment of a person with pegylated interferon plus ribavirin who had relapsed following previous treatment with this same regimen).
Hepatitis C
Hepatitis C is an inflammation of the liver caused by the hepatitis C virus (HCV). Hepatitis C is one of the most common causes of chronic liver disease in the U.S. Hepatitis is a single stranded RNA virus. HCV is classified into six major genotypes, numbered 1 to 6. In the United States the most common genotypes are 1a and 1b. Hepatitis C is one of the top causes for liver transplantation. The goal of treating hepatitis C is to prevent complications associated with this infection, which is principally achieved by eradication of infection.
Although HCV has 6 genotypes labeled 1 through 6, there are also subtypes labeled with letters (e.g., 1a and 1b). People infected with HCV usually have a single, dominant genotype; however, it is possible to have more than one at the same time, called mixed infection (e.g., 1a and 2). All HCV genotypes cause the same amount of liver damage. However, people infected with genotype 1, particularly subtype 1b, may have a greater chance of developing cirrhosis. Genotypes 1b and 3 may increase the risk of liver cancer (AASLD and IDSA, 2017; TAG, 2017).
Clinical trials of pegylated interferon alfa-2a have shown that patients with HCV genotypes 1 and 4 can determine at 12 weeks if they are unlikely to attain an early virological response with pegylated interferon alfa-2a. According to an NIH Consensus Statement on Hepatitis C (1997; 2002), 12 weeks after beginning an initial course of therapy, patients who are unlikely to respond to that dosage and frequency can be identified by persistent elevation of serum ALT levels and presence of HCV RNA in the serum. In this situation, therapy should be discontinued because the likelihood of future response is extremely low. If HCV RNA is below the detection level of the assay or if there is at least a 2 log10 reduction in the HCV RNA titer from baseline, therapy should be continued for an additional 36 weeks. Non-responders should be encouraged to participate in clinical trials directed toward this difficult-to-treat group.
According to guidelines from the National Institute for Health and Clinical Excellence (NICE, 2004), people infected with HCV of genotype 1, 4, 5 or 6, should initially be treated for 12 weeks. Only people showing, at 12 weeks, a reduction in viral load to less than 1 % of its level at the start of treatment (at least a 2-log reduction) should continue treatment until 48 weeks. For people in whom viral load at 12 weeks exceeds 1 % of its level at the start of treatment, treatment should be discontinued. These guidelines note that people infected with more than one genotype that includes one or more of genotypes 1, 4, 5, or 6 should be treated as for genotype 1 (NICE, 2004; see also Hadziyannis et al, 2004; NIH, 2002). These guidelines are based upon the observation that the SVRs for patients infected with HCV genotype 1 are much lower than those for genotypes 2 and 3, whereas SVRs for genotypes 4, 5 and 6 appear to be between those of the more prevalent genotypes.
Guidelines from the American Association for the Study of Liver Diseases (Ghany et al, 2009) state that "for patients with genotype 1 infection who have delayed virus clearance (HCV RNA test becomes negative between weeks 12 and 24), consideration should be given to extending therapy to 72 weeks (Class IIa, Level B)." The strategy of extending therapy in naive subjects with delayed virological responses, defined as clearance of HCV RNA between weeks 12 and 24, was evaluated in two studies (Berg et al, 2006; Sanchez-Tapias et al, 2006). One study randomized subjects to either 48 or 72 weeks of treatment at week 12 if HCV RNA remained detectable (Pearlman et al, 2007), and the other was a post-hoc analysis of a study in which randomization of treatment duration occurred at baseline (Berg et al, 2006). The study populations were not homogeneous, differing in their baseline characteristics and the regimens utilized were different. Nevertheless, the results showed a trend toward a higher SVR rate by extending therapy from 48 to 72 weeks. The SVR rate increased from 18 % for 48 weeks treatment to 38 % for 72 weeks of treatment in one study (Pearlman et al, 2007) and 17 % to 29 % in the other study (Berg et al, 2006). The increased SVR was primarily due a lower relapse rate in the patients treated for 72 weeks. An additional study demonstrated that patients who failed to achieve an RVR (HCV RNA detectable at treatment week 4) also seemed to benefit from extending therapy from 48 to 72 weeks (Sanchez-Tapias et al, 2006). The SVR rates were significantly higher in patients who received treatment for 72 (45 %) compared to those treated for 48 weeks (32 %). It is clear that not all patients will benefit from extended therapy judging from the results of the trial in which randomization to 48 or 72 weeks of therapy occurred at baseline (Berg et al, 2006). No difference in SVR rates was observed between those treated for 48 compared to 72 weeks (53 % versus 54 %, respectively). Thus, prolonging therapy can be considered in patients who are slow to respond (clearance of HCV RNA between weeks 12 and 24) (Ghany et al, 2009). Further studies are needed to determine whether extended therapy would be beneficial to patients who fail to clear virus between weeks 4 and 12.
For persons with other HCV genotypes (i.e., genotypes 2 and 3), there is no proven benefit to extending therapy beyond 24 weeks (Hadziyannis et al, 2004; NIH, 2002; NICE, 2004).
Infection with hepatitis C virus (HCV) genotype 6 is common in patients from parts of China and Southeast Asia. There is limited evidence regarding the appropriate duration of therapy for persons with genotype 6. Fung et al (2008) evaluated the effectiveness of pegylated interferon plus ribavirin for the treatment of chronic infection with hepatitis C virus (HCV) genotype 6 compared to genotype 1. Forty-two patients chronically infected with HCV were treated with pegylated interferon combined with oral ribavirin for 48 weeks. The investigators found no difference between genotypes 1 and 6 in the rates of early virological response (76 % versus 81 %) and end-of-treatment response (71 % versus 81 %). Patients infected with genotype 6 had a higher SVR than did patients infected with genotype 1 (86 % versus 52 %). The overall adverse-effects profile was similar in both genotype groups. The investigators concluded that treatment with pegylated interferon and ribavirin for 48 weeks resulted in a significantly higher rate of SVR in patients infected with genotype 6 than in those infected with genotype 1. This suggests that the response of HCV genotype 6 to pegylated interferon is more similar to that for genotypes 2 and 3 than for genotypes 1 and 4. The investigators stated that further studies are required to determine whether lower dosages and 24 weeks of therapy may be sufficient for the treatment of genotype 6 infection. The findings of a higher SVR with interferon treatment in persons infected with genotype 6 versus genotype 1 was also found in an earlier study of standard interferon plus ribavirin (Yuen and Lai, 2006).
Nguyen et al (2004) reported on a retrospective study of 190 consecutive Asian-American patients who were diagnosed with HCV genotype 6 at a gastroenterology clinic in northern California between 2001 and 2004, 66 of whom were treatment-naïve and subsequently completed 24 weeks of interferon plus ribavirin or pegylated interferon plus ribavirin, or 48 weeks of pegylated interferon plus ribavirin therapy. These investigators found no statistical difference in SVR of 31 patients treated with 24 weeks of interferon plus ribavirin and in 23 patients treated with 24 weeks of pegylated interferon plus ribavirin (51.6 % versus 39 %, p = 0.363). The SVR in 12 patients treated with 48 weeks of pegylated interferon plus ribavirin was significantly higher than that in those treated for only 24 weeks (75 % versus 39 %, p = 0.044). The investigators concluded that treatment-eligible patients with HCV genotype 6 should be treated with a full course of 48 weeks as tolerated. The investigators noted that larger prospective studies of patients with HCV genotype 6 are needed to confirm the optimal treatment duration with pegylated interferon plus ribavirin.
Data are scarce on patients infected with hepatitis C virus of genotype 5, due to the low prevalence of this genotype around the world. Antaki et al (2008) reported on a retrospective study of treatment outcomes of 26 HCV genotype 5 patients who had completed a course of therapy and a 6-month follow-up. Treatment consisted of ribavirin plus standard or pegylated interferon. Patients were treated for 24 or 48 weeks. The investigators reported that an SVR was achieved in 54 % (47 % with standard interferon and 67 % with pegylated interferon, p = 0.43). A trend towards better results was observed for younger patients, low viremia and mild fibrosis. The investigators reported that SVR was similar for treatment course of 24 or 48 weeks. The investigators concluded that treatment of HCV genotype 5 with combination therapy resulted in SVR in 54 % of patients. The investigators stated that 24 weeks of treatment might be adequate, and that further research should evaluate the ideal duration of treatment.
The NIH Consensus Conference on Hepatitis C (2002) stated: “Failure to respond to optimal therapy with pegylated interferon and ribavirin presents a significant problem, particularly in the presence of advanced fibrosis or cirrhosis. Currently, several large-scale, multi-center U.S. trials are evaluating the role of maintenance therapy with pegylated interferon alone in preventing further progression of cirrhosis, clinical decompensation, or development of HCC. Until the results of these studies are available, the role of long-term, continuous therapy with pegylated interferon (or ribavirin or both) for non-responders should be considered experimental.”
Patients without initial responses to peginterferon and ribavirin did not benefit from long-term low-dose peginterferon therapy in the HALT-C trial.
The HALT-C trial found that patients without initial responses to peginterferon and ribavirin did not benefit from long-term low-dose peginterferon therapy (Di Bisceglie et al, 2008). In this multi-center study, 1,050 patients with chronic hepatitis C and advanced fibrosis who had not responded to previous treatment were randomized to receive maintenance therapy with weekly peginterferon alfa-2a or no therapy for 3.5 years. Patients were seen every 3 months and underwent liver biopsies at baseline and 1.5 and 3.5 years after randomization. The criteria for the primary outcome – progression of liver disease – varied according to whether patients had cirrhosis or noncirrhotic fibrosis at baseline. Maintenance therapy was associated with significant decreases in aminotransferase and hepatitis C virus RNA levels, but it did not influence the likelihood of disease progression, which was about 34 % in each group (hazard ratio, 1.01). Serious adverse events occurred in 39 % of peginterferon recipients versus 32 % of untreated patients (p = 0.07). Commenting on this study, Baddour (2008) said that long-term low-dose peginterferon does not reduce the rate of disease progression and may increase the risk for serious adverse events in patients with failure on initial regimens. "Based on these data, the continued use of peginterferon in this setting cannot be recommended."
The impact of interferon (IFN) treatment on the occurrence of complications related to HCV-related cirrhosis is controversial since the majority of studies are retrospective. In a randomized controlled trial, Fartoux et al (2007) compared the effectiveness of prolonged IFN alfa-2a treatment versus non-treatment on complication-free survival in patients with compensated HCV cirrhosis. A total of 102 patients (mean age of 60.5 +/- 9.5 years; male/female ratio, 0.82) with biopsy examination-proven HCV cirrhosis, Child-Pugh score A, who were hepato-cellular carcinoma (HCC) free, and had at least 1 risk factor of complications, were randomized to receive IFN or no therapy for 24 months. During the follow-up evaluation, the complication rate was 24.5 %: HCC occurred in 12 and decompensation unrelated to HCC occurred in 13 patients. The number of HCC patients was similar in both groups. The probability of complication-free survival was not significantly different between treated and untreated patients (98 % and 72.3 % versus 90 % and 70.7 % at 12 and 24 months, respectively, p = 0.59). The median time until complication occurrence was 17.1 months in the treated group versus 13.6 months in the untreated group (p = 0.2). The authors concluded that this randomized controlled trial showed that a 2-year course of IFN has little or no impact on complication-free survival in patients with high-risk compensated HCV cirrhosis.
A technology assessment of ribavirin and pegylated interferon in hepatitis C for the Wessex Institute for Health Research and Development (Shepherd et al, 2004) noted that cryoglobulinemia and vasculitis occurs in a minority of patients with hepatitis C, and these conditions are not likely to be the subject of clinical trials because of the relatively small number of patients affected. The report noted, however, that clinicians point out that in some patients with vasculitis due to viral/antibody complexes the vasculitis can resolve after long-term treatment. The report stated that appropriate treatment of such patients needs to be addressed.
HCV-related liver cirrhosis is the most common indication for liver transplantation in most transplant centers. However, recurrence of hepatitis C-infection after liver transplant in HCV positive patients is almost universal (Neumann and Neuhaus, 2004). Severity of graft hepatitis increases during the long term follow-up and up to 30 % of patients develop severe graft hepatitis and cirrhosis. This led to decreased patient and graft survival in HCV positive patients. Prophylactic or therapeutic regimens which alter the course of disease in HCV positive patients are not established yet. Anti-viral treatment with ribavirin in combination with pegylated interferon is being investigated to reduce the complications of HCV recurrence in the future (Triantos et al, 2005). Treatment of recurrent hepatitis C virus after liver transplantation with either interferon or interferon and ribavirin has yielded only limited success (Shiffman et al, 2003; Triantos et al, 2005). Regardless of this, treatment is instituted. Pegylated interferon is more effective than standard interferon for treatment of chronic hepatitis C virus infection in the non-transplantation setting when used either alone or with ribavirin. The effectiveness of peginterferon, both with and without ribavirin in the post-transplantation setting, is currently being explored.
Triantos et al (2005) reported on the results of a systematic evidence review of anti-viral therapy for HCV in liver transplant recipients. The authors concluded that anti-viral therapy for recurrent HCV infection and disease after liver transplantation has only been evaluated in 16 randomized studies (534 patients) and thus robust data to evaluate efficacy is scanty. However it is clear from both randomized and the 74 non-randomized (2,061 patients) that treatment is far less effective and with more side effects than for chronic HCV hepatitis pre-transplant. Moreover, the data concerning combinations of either interferon or pegylated interferon with ribavirin mainly reflect on treatment virologic response (OTVR) (maximum 36 %) or end of treatment virologic response (ETVR) (maximum 32 %) with very little data on sustained virologic response (SVR). Thus, the authors concluded, currently there is no easily applicable, nor reasonably effective, anti-viral therapy for HCV recurrence after liver transplantation, considering the frequency of side effects and need to reduce doses or to discontinue therapy. The most applicable strategy is to treat established disease with pegylated interferon and ribavirin but only future results of ongoing randomized studies will define the cost-effectiveness and applicability of this regimen. The authors noted that the number of patients who have already failed antiviral therapy pretransplant may well further limit the likelihood of sustained viral clearance. Most importantly data on stopping the progression of fibrosis or slowing it down significantly, are not available and unfortunately initial results are not promising.
Consensus guidelines from the from the International Liver Transplantation Society Expert Panel on Liver Transplantation and HCV (Wiesner et al, 2003) state that “[a]lthough no firm recommendations can be made based on data, there are enough anecdotal and single center reports that suggest that a patient with recurrent HCV disease who has grade II fibrosis or higher should be given a trial of combination therapy with interferon.” Regarding maintenance therapy in liver transplant recipients with recurrent HCV diseases, the Expert panel agreed that there were no data to recommend maintenance therapy as an approach. Regarding the role of preemptive therapy in liver transplant recipients prior to HCV recurrence, the Expert panel stated that preemptive therapy should be considered in patients who undergo retransplantation for rapidly progressive recurrent hepatitis C and HCV-negative transplant recipients who receive organs from HCV-positive donors because of great clinical need. The Expert panel noted, however, that “demonstration of efficacy is lacking at this time.”
Current AASLD/IDSA recommendations do not recommend use of interferon products for chronic hepatitis C. Peginterferon and ribavirin, typically in combination with a direct-acting antiviral, remain in use for certain genotypes, particularly in resource-limited settings where newer interferon-free regimens are not accessible (AASLD/IDSA 2018). The guidelines state direct-acting antiviral agents (DAAs) are generally simpler, better tolerated, of shorter duration, and more effective than interferon-based treatment.
Hepatocellular Carcinoma (HCC)
Recurrence is common following hepatic resection for HCC. Interferon possesses anti-angiogenic, anti-proliferative, anti-viral, and immunomodulatory effects; and may be an effective form of adjuvant therapy. Small randomized controlled clinical trials suggest a benefit from prolonged interferon therapy following resection of hepatocellular carcinoma in persons with hepatitis C (Shiratori et al, 2003; Nishiguchi et al, 2005; Mazzaferro et al, 2006).
Chen et al (2012) examined the clinical efficacy of adjuvant interferon alfa-2b (IFNα-2b) therapy on recurrence-free survival (RFS) of patients with post-operative viral hepatitis-related hepatocellular carcinoma (HCC). Patients with curative resection of viral hepatitis-related HCC were eligible, and were stratified by underlying viral etiology and randomly allocated to receive either 53 weeks of adjuvant IFNα-2b treatment or observation alone. The primary endpoint of this study was RFS. A total of 268 patients were enrolled with 133 in the IFNα-2b arm and 135 in the control arm. Eighty percent of them were hepatitis B surface antigen sero-positive. At a median follow-up of 63.8 months, 154 (57.5 %) patients had tumor recurrence and 84 (31.3 %) were deceased. The cumulative 5-year recurrence-free and overall survival rates of intent-to-treat cohort were 44.2 % and 73.9 %, respectively. The median RFS in the IFNα-2b and control arms were 42.2 (95 % confidence interval [CI]: 28.1 to 87.1) and 48.6 (95 % CI: 25.5 to infinity) months, respectively (p = 0.828, log-rank test). Adjuvant IFNα-2b treatment was associated with a significantly higher incidence of leucopenia and thrombocytopenia. Thirty-four (24.8 %) of treated patients required dose reduction, and 5 (3.8 %) of these patients subsequently withdrew from therapy because of excessive toxicity. Adjuvant IFNα-2b only temporarily suppressed viral replication during treatment period. The authors concluded that in this study, adjuvant IFNα-2b did not reduce the post-operative recurrence of viral hepatitis-related HCC. They stated that more potent anti-viral therapy deserves to be explored for this patient population.
Interferon is also being evaluated for use following resection of hepatocellular carcinoma in persons with hepatitis B. Lo et al (2007) performed a randomized controlled trial of adjuvant interferon therapy in patients with predominantly hepatitis B-related HCC to examine if the prognosis after hepatic resection could be improved. Patients with no residual disease after hepatic resection for HCC were randomly assigned with stratification by pathologic tumor-node-metastasis (pTNM) stage to receive no treatment (control group), interferon alfa-2b 10 MIU/m (IFN-I group) or 30 MIU/m (IFN-II group) thrice-weekly for 16 weeks. Enrollment to the IFN-II group was terminated because adverse effects resulted in treatment discontinuation in the first 6 patients. A total of 40 patients each had been enrolled into the control group and IFN-I group. The baseline clinical, laboratory, and tumor characteristics of both groups were comparable. The 1- and 5-year survival rates were 85 % and 61 %, respectively, for the control group and 97 % and 79 %, respectively, for the IFN-I group (p = 0.137). After adjusting for the confounding prognostic factors in a Cox model, the relative risk of death for interferon treatment was 0.42 (95 % CI: 0.17 to 1.05; p = 0.063). Exploratory subset analysis showed that adjuvant interferon had no survival benefit for pTNM stage I/II tumor (5-year survival 90 % in both groups; p = 0.917) but prevented early recurrence and improved the 5-year survival of patients with stage III/IVA tumor from 24 % to 68 % (p = 0.038). The authors concluded that in a group of patients with predominantly hepatitis B-related HCC, adjuvant interferon therapy showed a trend for survival benefit, primarily in those with pTNM stage III/IVA tumors. They stated that further larger RCTs stratified for stage are needed. An editorial that accompanied the afore-mentioned article stated that any new strategy to prevent HCC recurrence following resection must still be tested in randomized controlled studies, including a control group without treatment (Clavien, 2007).
Hypereosinophilic Syndrome (HES)
Hypereosinophilic syndromes (HES) constitute a rare and heterogeneous group of disorders, defined as persistent and marked blood eosinophilia (greater than 1.5 x 10(9)/L for more than 6 consecutive months) associated with evidence of eosinophil-induced organ damage, where other causes of hypereosinophilia such as allergic, parasitic, and malignant disorders have been excluded (Roufosse et al, 2007). Target-organ damage mediated by eosinophils is highly variable among patients, with involvement of skin, heart, lungs, and central and peripheral nervous systems in more than 50 % of cases. Other frequently observed complications include hepato- and/or splenomegaly, eosinophilic gastroenteritis, and coagulation disorders. Diagnosis of HES relies on observation of persistent and marked hypereosinophilia responsible for target-organ damage, and exclusion of underlying causes of hypereosinophilia, including allergic and parasitic disorders, solid and hematological malignancies, Churg-Strauss disease, and HTLV infection (Roufosse et al, 2007). Other second line options for corticosteroid-resistant cases include hydroxycarbamide and imatinib (Roufosse et al, 2007).
Idiopathic Sudden Sensorineural Hearing Loss (ISSHL)
Kanemaru et al (1997) employed IFN-alfa in the treatment of severe idiopathic sudden sensorineural hearing loss (ISSHL). A total of 42 patients were studied and had an average hearing ability of greater than or equal to 70 dB before treatment. These researchers also examined 2'-5' oligoadenylate synthetase (2,5A-S) activity, one of the parameters indicating anti-viral activity of IFN, to investigate the relationship between the suppression of viral proliferation and prognosis and explain the pathogenesis of ISSHL. Complete recovery was found in 27 patients (64.3 %) after IFN therapy. Increased 2,5A-S activity was observed on the 3rd day of IFN therapy in 24 of the 27 patients who completely recovered. No severe adverse events were reported after IFN therapy. The authors concluded that these findings suggested that IFN therapy may be effective and safe in the treatment of ISSHL and calls for further investigation.
The American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF)'s clinical practice guideline on "Sudden hearing loss" (Stachler et al, 2012) noted that "[t]he panel made a recommendation against clinicians routinely prescribing anti-virals, thrombolytics, vasodilators, vasoactive substances, or anti-oxidants to patients with ISSNHL .... In addition to the therapies discussed above, a host of other therapies have been used to treat SSNHL (i.e., vitamins, minerals, interferon, nitroglycerin, and other complementary and alternative medications). The evidence base for these therapies was insufficient to review in this guideline and no comment is made on their use".
Interferon Alfa-2b for the Treatment of Fibrolamellar Hepatocellular Carcinoma
Fakih et al (2014) noted that fibro-lamellar cancer (FLC) is a rare primary hepatic malignancy with no established standard systemic treatments. Case reports and subgroup analyses from larger liver cancer studies suggested possible activity for fluoropyrimidines, platinum agents, and interferon-α. However, randomized studies are lacking, and the merits of any particular regimen in FLC are still largely unsubstantiated. These investigators reported the outcome of a case of metastatic FLC with previous progressive disease on 5-FU plus interferon-α and FOLFOX regimens that was treated with bevacizumab and erlotinib. The patient derived a prompt palliative response with complete resolution of cancer-related pain 2 weeks after initiation of erlotinib. Computed tomography (CT) after 2 months of treatment showed disease regression in distant lymphadenopathy. Molecular testing failed to confirm any evidence of epidermal growth factor receptor (EGFR) mutation, whereas immunohistochemistry showed 2 to 3+ staining for EGFR expression. To the authors’ knowledge, this was the 1st case report of a clinical benefit for FLC in association with erlotinib and bevacizumab treatment. These researchers stated that FLC over-expressed EGFR in comparison to hepato-cellular cancer (HCC), suggesting that EGFR targeting may be an interesting therapeutic approach in this rare malignancy.
Okur et al (2014) stated that fibro-lamellar variant of HCC (FLHCC) does not have a favorable prognosis than conventional HCC, and there is no difference regarding the response to chemotherapy and the degree of surgical resectability. FLHCC commonly recurs after complete surgical resection, and there is a high rate of lymph node metastases. These investigators reported a 12-year old girl with metastatic FLHCC with multiple recurrences aggressively treated with surgery, chemotherapy, and anti-angiogenic agents. She was in complete remission (CR) after 4 years and 2 months after the diagnosis of metastatic FLHCC. The standard treatment of FLHCC is excision of the primary tumor and its metastases. Chemotherapy for FLHCC is controversial, and it has been suggested that cytoreductive chemotherapy was ineffective and adjuvant chemotherapy did not improve survival. This patient with multiple recurrences was successfully treated with surgery, 1st-line chemotherapy with cisplatin and doxorubicin, 2nd-line chemotherapy with 5-fluorouracil (5-FU)/interferon-α combination, and adjuvant anti-angiogenic agents like cyclophosphamide and thalidomide. As FLHCC patients have no underlying liver disease, they can tolerate higher doses of chemotherapy compared with conventional HCC patients. The authors supported the use of repeated aggressive surgery with adjuvant chemotherapy and anti-angiogenic therapy, which provided CR in this patient with metastatic and recurrent FLHCC.
A Medscape review on “Fibrolamellar carcinoma treatment & management” (Choti, 2020) noted that a phase-II clinical trial reported in 2003 examined the 21-day courses of systemic continuous 5-FU repeated monthly and thrice-weekly subcutaneous recombinant interferon α-2b in a mixed population of 43 patients with FLC or typical HCC. All of these patients were ineligible for surgical therapy due to extent of hepatic disease as determined by CT scan, but none had extra-hepatic disease. Of the 9 patients with FLC, 8 were radiologically assessed for response, which showed 1 complete response (CR), 4 partial responses (PR), and 1 minor response (MR). The median survival of the FLC patients was 23 months, compared with 15.5 months for typical HCC.
Furthermore, an UpToDate review on “Epidemiology, clinical manifestations, diagnosis, and treatment of fibrolamellar carcinoma” (Kalman and Abou-Alfa, 2020) states that “Case reports suggest some efficacy for platinum-based regimens, such as cisplatin, epirubicin, and fluorouracil (FU) combinations. In one series of 25 patients treated with FU and recombinant interferon alpha (IFNa) 2B, there was a 32 percent objective response rate, and two patients had complete response”.
Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome
Avau and Matthys (2015) noted that IFN-gamma (IFN-γ) affects immune responses in a complex fashion. Its immune-stimulatory actions (e.g., macrophage activation and induction of T helper 1-type responsiveness), are widely acknowledged, however, as documented by a large body of literature, IFN-γ has also the potential to temper inflammatory processes via other pathways. In autoimmune and auto-inflammatory disorders, IFN-γ can either play a disease-enforcing role or act as protective agent, depending on the nature of the disease. In animal models of any particular autoimmune disease, certain changes in the induction procedure can reverse the net outcome of introduction or ablation of IFN-γ. These investigators reviewed the role of endogenous IFN-γ in inflammatory disorders and related murine models, with a focus on systemic juvenile idiopathic arthritis (sJIA) and macrophage activation syndrome (MAS). In particular, these researchers discussed their recent findings in a mouse model of sJIA, in which endogenous IFN-γ acted as a regulatory agent, and compared with results from mouse models of MAS. Furthermore, the authors elaborated on the complexity in the activity of IFN-γ and the resulting difficulty of predicting its value or that of its antagonists as therapeutic option.
Ocular Surface Neoplasia
Lee and colleagues (2018) stated that the use of topical interferon alpha-2b is a well-established treatment for ocular surface squamous neoplasia. There have been numerous reports on its efficacy and high safety profile. Benign reactive lymphoid hyperplasia in ocular tissues has not been previously documented by histopathology after interferon treatment. This case report described a 55-year old man who had successful resolution of his ocular surface squamous neoplasia after topical treatment, but developed forniceal tissue deposits. The appearance of the lesions was unexpected and alerted the clinician to the possibility of further neoplastic extension. The authors noted that excisional biopsy of the lesions confirmed benign reactive lymphoid hyperplasia and resolved with no recurrence.
The American Academy of Ophthalmology’s webpage on “Ocular surface squamous neoplasia” (AAO, 2017) stated that “The use of topical chemotherapeutic agents, including interferon-α2b, mitomycin C, and 5- fluorouracil, has the advantage of treating the entire ocular surface and avoiding surgical complications such as positive margins, scarring, and limbal stem cell deficiency”.
Pancreatic Cancer
Schmidt and associates (2007) stated that data from a phase II clinical trial combining chemoradiotherapy with IFN-alfa (CapRI scheme) for adjuvant treatment of pancreatic carcinoma are very encouraging. Thus, a phase III trial comparing chemotherapy with the chemoradiotherapy with IFN-alfa scheme has been initiated in August 2004. Translational research with a focus on immunomodulation is performed in parallel to the study. Blood and serum samples were taken at various time points. Patients in arm A (chemo-radioimmunotherapy) receive a single low-dose interferon injection before therapy to investigate the direct effect of IFN-alfa. So far, samples from 44 patients have been investigated for surface molecule expression, cytokine levels, natural killer cell cytotoxicity, and antigen-specific Granzyme B release. Patients in arm A showed 1 day after IFN-alfa injection a significant increase in spontaneous cytotoxicity; this effect was fading after repeated injections. Furthermore, cells releasing Granzyme B after stimulation with CA 19.9 and MUC-1 protein increased under therapy. Five days after the first IFN-alfa injection, interleukin-12 and tumor necrosis factor-alfa serum levels peak. These researchers observed significant increases of monocytes, peripheral dendritic cells, CD40 cells, central and effector memory T cells, and CD8 cells, CD4 cells decreased during therapy. All these effects were only observed in arm A patients and none of them in arm B patients. The authors concluded that in a translational research project accompanying a challenging multi-modality treatment trial including IFN-alfa, they observed an immediate activation of antigen-presenting cells and natural killer cells followed later on by antigen-specific activation. It will be most interesting if the immunologic data will show a correlation with the clinical course of the patients.
In a feasibility study, Nitsche and colleagues (2008) noted that recent studies give rise to the hypothesis, that adjuvant chemo-radioimmunotherapy with 5-fluorouracil (5-FU), cisplatin and IFN-alfa might be a possible new treatment of pancreatic cancer in resected patients. These researchers reported the up-to-now experience at their institution. A total of 11 patients with histological diagnosis of localized carcinoma of the pancreas (n = 7) or peri-ampullary (n = 4) were prospectively analyzed. Four patients were deemed unresectable because of local invasion of adjacent organs (neoadjuvant setting) and 7 patients underwent curative resection (adjuvant setting). Eight patients were classified as T3 carcinomas and 3 T4 carcinomas. Six of the 11 (55 %) patients presented with positive lymph node involvement. One histological grade I, 6 grade II and 3 grade III were detected. External conformal irradiation to a total dose of 50.4 Gy with 1.8 Gy per day was delivered. All patients received a concomitant chemotherapy with continuous 5-FU 200 mg/m2 per day on 28 treatment days and intravenous bolus cisplatin 30 mg/m2 per week (day 2, 9, 16, 23, 30). A recombinant r-IFN-alfa was administered on 3 days weekly during week 1 to 5 of the radiotherapy course as subcutaneous injections with 3*3 Mio. I.U. weekly. The 4-year overall survival rate for all patients was 55 %. In the neoadjuvant group, 3 of 4 patients died due to progressive disease; in the adjuvant group, combined chemo-radioimmunotherapy lead to controlled disease in 5 of 7 patients. The overall toxicity was well-managed. The authors concluded that these findings strengthened the hypothesis of concomitant chemo-radioimmunotherapy with 5-FU, IFN-alfa and cisplatin as a possible new treatment of pancreatic cancer in resected patients.
Booy et al (2015) stated that pancreatic cancer is a highly aggressive malignancy with limited treatment options. To improve survival for patients with pancreatic cancer, research has focused on other treatment modalities like adding biological modulators such as type-I interferons (IFNs). Type I IFNs (i.e., IFN-alpha/IFN-beta [IFN-α/IFN-β]) have anti-proliferative, anti-viral as well as immunoregulatory activities. Furthermore, they are able to induce apoptosis, exert cell cycle blocking, and sensitize tumor cells for chemo- and radiotherapy. A few years ago, in-vitro, in-vivo, and several clinical trials have been described regarding adjuvant IFN-α therapy in the treatment of pancreatic cancer. Some studies reported a remarkable increase in the 2- and 5-year survival. Unfortunately, the only RCT did not show a significant increase in overall survival, although the increased median survival implicated that some patients in the experimental group benefited from the adjuvant IFN-α therapy. Furthermore, encouraging in-vitro and in-vivo data pointed to a possible role for adjuvant IFN therapy. However, up till now, the use of IFNs in the treatment of pancreatic cancer remains controversial.
An UpToDate review on “Adjuvant therapy for resected exocrine pancreatic cancer” (Ryan and Mamon, 2015) does not mention interferon as a therapeutic option.
Pelvic Fibromatosis
Arien et al (2015) stated that fibromatosis is a rare, non-invasive but aggressive tumor. The tumor displaces tissue by "pushing" the normal structures aside. Optimal treatment should be individualized. These researchers reported the case of a 35-year old woman who presented with a recurrent fibromatosis, which filled the vagina and extended into the pelvis. The classical surgical removal would have had a high morbidity. Therefore, it was decided, after shared decision-making, to opt for treatment with alfa IFN. The side effects of the therapy were tolerable, and a complete regression of the fibromatosis was achieved. At present, 13 years after the diagnosis and 7 years after discontinuation of the therapy, the patient is well with no signs of disease. The authors concluded that IFN may be considered as primary treatment for extensive pelvic fibromatosis. Moreover, they stated that more research is needed to elucidate its working mechanism.
Plexiform Neurofibromas
In a phase I clinical trial, Jakacki et al (2011) evaluated preliminary effectiveness and determined the recommended phase II dose (RP2D) for pegylated interferon-α-2b (PI) in patients with unresectable progressive or symptomatic plexiform neurofibromas (PN). Pegylated interferon-α-2b was administered weekly in cohorts of 3 to 6 patients during the dose-finding phase and continued for up to 2 years. A total of 12 patients were treated at the RP2D to further evaluate toxicity and activity. Thirty patients (median age of 9.3 years, range of 1.9 to 34.7 years) were enrolled in this study. No dose-limiting toxicity (DLT) was seen in patients treated at the 3 μg/kg dose level (DL) during the first 4 weeks. All 5 patients treated at the 4.5 μg/kg DL came off study or required dose reductions for behavioral toxicity or fatigue. Similar DLT on the 3 μg/kg DL became apparent over time. There was 1 DLT (myoclonus) in 12 patients enrolled at the 1.0 μg/kg DL. Eleven of 16 patients with pain showed improvement and 13 of 14 patients with a palpable mass had a decrease in size. Five of 17 patients (29 %) who underwent volumetric analysis had a 15 % to 22 % decrease in volume. Three of 4 patients with documented radiographical progression before enrollment showed stabilization or shrinkage. The authors concluded that the RP2D of PI for pediatric patients with PN is 1 μg/kg/wk. Clinical and radiographical improvement and cessation of growth can occur. The authors acknowledged the limitations of using subjective assessments to determine clinical response and more stringent, validated criteria have been incorporated into an ongoing phase II clinical study.
Primitive Neuroectodermal Tumor (PNET)
Primitive neuroectodermal tumor (PNET) is a neural crest tumor. It is a rare tumor, usually occurring in children and young adults under 25 years of age. After successful chemotherapy or radiotherapy, the 5-year survival rate is only 8 %. Primitive neuroectodermal tumor belongs to the Ewing family of tumors; ependymoblastoma is a synonym for PNET. Based on location in the body, PNET is classified into 2 types: peripheral PNET and central nervous system (CNS) PNET. It is also possible to add a third category, involving tumors of the autonomic nervous system, such as neuroblastoma. The peripheral PNET (pPNET) is now thought to be virtually identical to Ewing sarcoma. Primitive neuroectodermal tumor of the CNS are grossly divided into supra-tentorial PNET and infra-tentorial PNET, the latter being more common. An example of infra-tentorial PNET includes medulloblastoma, which occurs in the cerebellum. An example of supra-tentorial PNET includes pinealoblastoma, which occurs in the pineal region. The NCCN guidelines on Ewing sarcoma make no recommendation for use of interferon alfa. Furthermore, NCCN guidelines on CNS cancers only recommend interferon alfa for meningiomas, making no recommendation for use of interferon alfa for medulloblastoma or supratentorial PNET.
Pulmonary Tuberculosis
Gao et al (2011) evaluated the safety and effectiveness of adjunctive therapy using interferon-gamma (IFN-γ) for the treatment of pulmonary tuberculosis (TB). These investigators conducted a systematic review of controlled clinical trials that compared anti-TB drugs in combination with IFN-γ with the same anti-TB drugs alone for the treatment of pulmonary TB. A total of 9 trials were identified, with IFN-γ being aerosolized or administered subcutaneously in 1 trial, aerosolized only in 5 trials, and administered intramuscularly in 3 trials. The methodology quality of all trials was rated "C". Meta-analysis of the trials with aerosolized IFN-γ showed statistical benefits on sputum negative conversion and chest radiograph: the pooled relative risk (RR) for conversion was 1.97 (95 % CI: 1.20 to 3.24, p = 0.008) after 1 month of treatment, 1.74 (95 % CI: 1.30 to 2.34, p = 0.0002) after 2 months of treatment, 1.53 (95 % CI: 1.16 to 2.01, p = 0.003) after 3 months of treatment, 1.57 (95 % CI: 1.20 to 2.06, p = 0.001) after 6 months of treatment, and 1.55 (95 % CI: 1.17 to 2.05, p = 0.002) at the end of treatment; the pooled RR for the chest radiograph was 1.38 (95 % CI: 1.10 to 1.17, p = 0.006) at the end of treatment. For intramuscularly administered IFN-γ, meta-analysis of 3 trials showed its significant improvement on sputum negative conversion after 2 months of treatment. A RCT with aerosolized and subcutaneously administered IFN-γ reported significant reductions in the symptoms of fever, wheeze, and night sweats in the IFN-γ-treated groups compared with the control group after 1 month of treatment. No patients discontinued treatment because of adverse effects caused by IFN-γ. The authors concluded that adjuvant therapy using IFN-γ, especially by aerosol, might be beneficial to TB patients, but large RCTs are needed for further evaluation of its safety and effectiveness considering the quality of the trials analyzed.
Retinal Vasculitis
Rosenbaum et al (2016) noted that ophthalmologists and rheumatologists frequently have a miscommunication among themselves, and as a result differ in their opinion for patients consulting them with retinal vasculitis. These investigators sought to establish a common understanding of the term, retinal vasculitis, and reviewed recent studies on this diagnosis. The genetic basis of some rare forms of retinal vascular disease has recently been described. Identified genes include CAPN5, TREX1, and TNFAIP3; Behcet's disease is a systemic illness that is very commonly associated with occlusive retinal vasculitis; retinal imaging, including fluorescein angiography and other newer imaging modalities, has proven crucial to the identification and characterization of retinal vasculitis and its complications; although monoclonal antibodies to interleukin-17A or interleukin-1 beta failed in trials for Behcet's disease, antibodies to TNF-alfa, either infliximab or adalimumab, have demonstrated consistent benefit in managing this disease. These researchers stated that IFN treatment and B-cell depletion therapy via rituximab may be beneficial in certain types of retinal vasculitis. The authors concluded that retinal vasculitis is an important entity for rheumatologists to understand. Retinal vasculitis associated with Behcet's disease responds to monoclonal antibodies that neutralize TNF, but the many other forms of non-infectious retinal vasculitis may require alternate therapeutic management.
Sjogren Syndrome
Akpek et al (2011) reviewed treatment options for patients with dry eye secondary to Sjogren's syndrome (SS). A search strategy was developed to identify prospective, interventional studies of treatments for SS-associated dry eye from electronic databases. Eligible references were restricted to English-language articles published after 1975. These sources were augmented by hand searches of reference lists from accessed articles. Study selection, data extraction, and grading of evidence were completed independently by 4 or more review authors. The searches identified 3,559 references as of August 10, 2010. After duplicate review of the titles and abstracts, 245 full-text papers were assessed, 62 of which were relevant for inclusion in the review. The authors concluded that in the current literature on SS-associated dry eye, there is a paucity of rigorous clinical trials to support therapy recommendations. Nonetheless, the recommended treatments include topical lubricants, topical anti-inflammatory therapy, and tear-conserving strategies. The efficacy of oral secretagogues seems greater in the treatment of oral dryness than ocular dryness. Although oral hydroxychloroquine is commonly prescribed to patients with SS to alleviate fatigue and arthralgias, the literature lacks strong evidence for the efficacy of this treatment for dry eye. Intrferon-alfa was discussed in this review ; but it was not recommended as a therapeutic option.
Squamous Cell Carcinoma
Cranmer et al (2010) stated that cutaneous squamous cell carcinoma (SCC) is an already common disorder with a rapidly increasing incidence. Treatment of early disease depends primarily on surgery or destructive techniques. In contrast to the frequency of early SCC, unresectable or metastatic SCC is relatively rare, but potentially life-threatening without clearly proven therapeutic options. Few rigorous studies of the treatment of advanced SCC have been undertaken. In the past, various agents have been explored in a limited fashion, including chemotherapy (cisplatin, fluoropyrimidines, bleomycin, doxorubicin), 13-cis-retinoic acid, and interferon-α2a. Clinical activity has been suggested by these trials, but their small sizes, heterogeneous patient populations, and lack of randomization have hindered the use of their results in defining treatment paradigms. Only 1 rigorous randomized trial has focused on cutaneous SCC. Enrolling 66 patients, that trial randomized patients at high recurrence risk to either observation or post-operative interferon-α2a and 13-cis-retinoic acid. This treatment did not improve time to recurrence or prevent secondary cutaneous SCC from developing. Though not in the metastatic setting, this study casts doubt on the ability of this regimen to control metastatic disease. Recently, agents targeting the human epidermal growth factor receptor (erlotinib, gefitinib, cetuximab) have displayed preliminary evidence of activity in phase II clinical trials and case series reports. Expression of this receptor is frequent in cutaneous SCC and appears to be prognostically adverse. Only the conduct of rigorous trials, with well-defined endpoints, adequate patient numbers, and preferably randomization, can prove the clinical efficacy of this promising treatment approach and define better therapy for this vexing clinical problem.
Kim et al (2004) noted that intra-lesional interferon (IFN) alpha-2b has been shown to be a safe and effective mode of treatment for basal cell carcinoma and squamous cell carcinoma. Multiple studies published in the 1980s through the early 1990s have demonstrated the efficacy of intra-lesional interferon in the treatment of these malignancies. Unfortunately, this modality appears to be under-used. These investigators reminded dermatologists that in addition to cryotherapy, electro-desiccation, and surgical excision, intra-lesional IFN-alpha is an important part of the armamentarium in the treatment of non-melanoma skin cancers. In addition to a review of the literature, these researchers presented 8 cases in 7 patients successfully treated with intra-lesional IFN for basal cell carcinoma and squamous cell carcinoma. The authors concluded that its non-surgical approach and excellent cosmetic results made IFN alpha-2b an attractive option for patients and an important alternative when other treatment modalities are impractical or contraindicated. They stated that further, more extensive, controlled clinical trials are needed to confirm this assessment.
In a pilot study, Karp et al (2010) examined the effectiveness of pegylated interferon alpha 2b (PEGIFNalpha2b) for treatment of ocular surface squamous neoplasia (OSSN). A total of 3 patients with histologically proven OSSN were studied prospectively. Patients were given subconjunctival/perilesional injections of 1 ug/kg of PEGIFNalpha2b (PEG Intron, Schering-Plough, Kenilworth, NJ) until the tumor resolved. Patients were followed clinically and photographically for evidence of tumor resolution and recurrence. All patients had clinical resolution of the tumor. The mean time to resolution was 47 days. During the follow-up time after resolution of the lesion (mean of 41 months), 1 patient had disease recurrence 7 months after clinical resolution. This was successfully treated with 1 further injection. The authors concluded that PEGIFNalpha2b may be a viable medical alternative for the treatment of OSSN. They stated that more studies are needed to examine if PEGIFNalpha2b is as effective as recombinant interferon alpha 2b.
Systemic Lupus Erythematosus
Chasset and Arnaud (2018) noted that significant advances in the understanding of the molecular basis of innate immunity have led to the identification of IFNs, particularly IFN-α, as central mediators in the pathogenesis of systemic lupus erythematosus (SLE). Thus, targeting of IFNs and of their down-stream pathways has emerged as important developments for novel drug research in SLE. Based on this, several specific interferon blocking strategies using anti-IFN-α antibodies, anti-type I interferon receptor antibodies, Interferon-α-kinoid, or anti-IFN-γ antibodies have all been assessed in recent clinical trials. Alternative strategies targeting the plasmacytoid dendritic cells (pDCs), Toll-like receptors (TLRs)-7/9 or their down-stream pathways such as the myeloid differentiation primary-response protein 88 (MYD88), spleen tyrosine kinase (Syk), Janus-kinases (JAKs), interleukin-1 receptor-associated kinase 4 (IRAK4), or the tyrosine kinase 2 (TYK2) are also investigated actively in SLE, at more preliminary clinical development stages, except for JAK inhibitors that have reached phase_ II clinical trials. The authors concluded that in the near future, in-depth and personalized functional characterization of IFN pathways may provide further guidance for the selection of the most relevant therapeutic strategy in SLE, tailored at the patient-level.
Systemic Mastocytosis
Systemic mastocytosis (SM) describes forms of mastocytosis in which pathologic mast cells infiltrate multiple extracutaneous organs, most commonly the bone marrow and in some cases, the gastrointestinal tract, with or without skin involvement. SM presents with symptoms of mediator release, as well as signs and symptoms related to infiltration of various noncutaneous organs by mast cells. SM is further divided into four distinct disorders: indolent systemic mastocytosis (ISM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL). Patients with any form of SM may experience episodic symptoms of mast cell activation, including apparent allergic reactions triggered by a variety of exposures (eg, physical factors, alcohol, medications, emotional stress, and allergens). All patients should be equipped with epinephrine autoinjectors, because up to half of individuals with SM experience anaphylaxis.
Treatment focuses on preventing mast cell-mediator release and minimizing the resulting symptoms (eg, flushing, gastrointestinal symptoms, and neuropsychiatric symptoms). Treatment options include antihistamines, antileukotriene agents, cromolyn sodium, and other therapies for specific allergic conditions. Interferon-alfa has been used to treat SM for many years and is reserved for patients with slowly progressive symptomatic disease who are not candidates for other therapies (eg, older adults), given the slow time to response and frequent toxicities. IFN-alfa increases bone density and so may be particularly useful in patients with severe bone disease and multiple fractures. It is also an option for patients with organ involvement limited to the liver with ascites. Case series have described the use of IFN-alfa as a single agent or in combination with prednisone.
Appendix
| Measure | 1 point | 2 points | 3 points | units |
|---|---|---|---|---|
| Bilirubin | < 34.2 (< 2) | 34.2 to 51.3 (2 - 3) | > 51.3 (> 3) | μmol/l (mg/dl) |
| Albumin | > 3.5 | 2.8 - 3.5 | < 2.8 | g/dl |
| INR | < 1.7 | 1.7 - 2.3 | > 2.3 | no unit |
| Ascites | Absent | Slight | Moderate | no unit |
| Encephalopathy | None | Grade 1 to 2 | Grade 3 to 4 | no unit |
A total Child-Turcotte-Pugh score of 5 to 6 is considered Child-Pugh class A (well-compensated disease), 7 to 9 is class B (significant functional compromise), and 10 to 15 is class C (decompensated disease).
Source: Goldber E, Chopra S, 2021
| Grade | Criteria |
|---|---|
| Grade 1 | Trivial lack of awareness; euphoria or anxiety; shortened attention span; impairment of addition or subtraction; altered sleep rhythm |
| Grade 2 | Lethargy or apathy; disorientation for time or place; obvious personality change; inappropriate behavior; dyspraxia; asterixis |
| Grade 3 | Somnolence to semistupor; responsive to stimuli; confused; gross disorientation; bizarre behavior |
| Grade 4 | Coma |
Source: Ferenci P, 2022
The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist.
| Score | Description |
|---|---|
| 1.0 | No disability, minimal signs in one FS |
| 1.5 | No disability, minimal signs in more than one FS |
| 2.0 | Minimal disability in one FS |
| 2.5 | Mild disability in one FS or minimal disability in two FS |
| 3.0 | Moderate disability in one FS, or mild disability in three or four FS. No impairment to walking |
| 3.5 | Moderate disability in one FS and more than minimal disability in several others. No impairment to walking |
| 4.0 | Significant disability but self-sufficient and up and about some 12 hours a day. Able to walk without aid or rest for 500m |
| 4.5 | Significant disability but up and about much of the day, able to work a full day, may otherwise have some limitation of full activity or require minimal assistance. Able to walk without aid or rest for 300m |
| 5.0 | Disability severe enough to impair full daily activities and ability to work a full day without special provisions. Able to walk without aid or rest for 200m |
| 5.5 | Disability severe enough to preclude full daily activities. Able to walk without aid or rest for 100m |
| 6.0 | Requires a walking aid - cane, crutch, etc - to walk about 100m with or without resting |
| 6.5 | Requires two walking aids - pair of canes, crutches, etc - to walk about 20m without resting |
| 7.0 | Unable to walk beyond approximately 5m even with aid. Essentially restricted to wheelchair; though wheels self in standard wheelchair and transfers alone. Up and about in wheelchair some 12 hours a day |
| 7.5 | Unable to take more than a few steps. Restricted to wheelchair and may need aid in transferring. Can wheel self but cannot carry on in standard wheelchair for a full day and may require a motorized wheelchair |
| 8.0 | Essentially restricted to bed or chair or pushed in wheelchair. May be out of bed itself much of the day. Retains many self-care functions. Generally has effective use of arms |
| 8.5 | Essentially restricted to bed much of day. Has some effective use of arms retains some self care functions |
| 9.0 | Confined to bed. Can still communicate and eat |
| 9.5 | Confined to bed and totally dependent. Unable to communicate effectively or eat/swallow |
| 10.0 | Death due to MS |
Criteria for Clinically Definite or Laboratory Supported Definite MS
-
Clinically definite MS is defined as either:
- Two attacks and clinical evidence of 2 separate lesions; or
- Two attacks; clinical evidence of 1 lesion and para-clinical evidence of another, separate lesion
-
Laboratory-supported definite MS consists of demonstration of any of the following:
- Two attacks; either clinical or para-clinical evidence of 1 lesion; and cerebro-spinal fluid (CSF) OB/IgG; or
- One attack; clinical evidence of 2 separate lesions; and CSF OB/IgG; or
- One attack; clinical evidence of 1 lesion and para-clinical evidence of another separate lesion; and CSF OB/IgG
CSF OB/IgG is defined as either:
- IgG oligoclonal band (OB) in the CSF; or
- Increased CNS synthesis of IgG (IgG is higher in CSF than in serum, and is increased in the CSF in the presence of a normal concentration of total protein).
Limits: Oligoclonal bands must not be present in the member's serum and the serum IgG level must be normal.
Source: Olek, 2022
References
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