peginterferon has same properties as interferon alfa
Interferon Alfa
Adverse Effects and Treatment
Most reports of the adverse effects of interferons have involved interferon alfa, but limited clinical experience suggests that interferons beta and gamma have similar adverse effects.
Interferons produce 'flu-like' symptoms with fever, chills, fatigue, headache, malaise, myalgia, and arthralgia. These symptoms tend to be dose-related, are most likely to occur at the start of treatment, and mostly respond to paracetamol (but for a possible interaction with paracetamol, see Interactions).
Other adverse effects include nausea, vomiting, diarrhoea, anorexia with weight loss, bone marrow depression, alopecia, rash, taste alteration and, rarely, epistaxis, cough, and pharyngitis. There may be signs of altered liver function and hepatitis has been reported. Renal failure and the nephrotic syndrome have occurred. Severe hypersensitivity reactions including anaphylaxis and bronchospasm have been reported rarely. Cardiovascular effects include hypotension or hypertension, arrhythmias, oedema, myocardial infarction, and stroke. High doses may cause electrolyte disturbances including decreased calcium concentrations. Hyperglycaemia and thyroid dysfunction have been reported as have pulmonary oedema and pneumonitis. EEG abnormalities and neurological symptoms including ataxia, paraesthesia, somnolence, dizziness, confusion, and rarely, convulsions and coma have been reported. Depression, anxiety, depersonalisation, or emotional lability may be severe. Visual disturbances and, rarely, ischaemic retinopathy may occur. Menstrual irregularities have been reported, particularly with interferon beta.
Subcutaneous injection may produce a reaction at the injection site. The reaction is reported frequently with interferon beta, which can produce severe reactions including local necrosis.
Nasal administration may produce mucosal irritation and damage.
Auto-immune disorders.
For exacerbation or development of auto-immune disorders in patients receiving interferon, see under Precautions .
Effects on the blood.
Restoration of bone-marrow function after marrow transplantation was delayed in 3 patients given a human interferon alfa preparation. Laboratory results showed an inhibition of granulocyte colony growth by human leucocyte interferon alfa. It was considered that interferon alfa was contra-indicated in patients with severe bone-marrow insufficiency and should not be given to marrow transplant patients before the graft was fully functional. However, in another 5 patients recombinant interferon alfa did not affect bone marrow transplants, although 3 patients experienced fever and chills, 4 experienced more than a 60% reduction in absolute peripheral granulocyte counts, and 4 had a 37 to 80% reduction in absolute platelet counts. Lymphocytes were increased in all patients; blood counts returned to normal when interferon therapy stopped. Interferon alfa produced a decline in CD4+ T-lymphocytes resulting in opportunistic infections in 2 HIV-positive patients being treated for chronic hepatitis C.
Other haematological effects reported to be associated with interferon alfa include immune haemolytic anaemia and immune thrombocytopenia. Haemorrhage occurred in a patient with immune thrombocytopenic purpura treated with interferon alfa, and it was thought prudent to use interferons with caution, if at all, in this condition. Bleeding associated with induction of factor VIII inhibitor has been reported in a patient receiving interferon alfa to enhance hydroxycarbamide therapy for chronic myeloid leukaemia. Thrombosis associated with interferon alfa has also been reported.
Effects on the cardiovascular system.
There have been reports of cardiomyopathy and of Raynaud's syndrome associated with interferon alfa therapy.
Effects on the endocrine system.
Both hypothyroidism and hyperthyroidism have been associated with interferon alfa therapy. Recombinant interferon gamma was reported not to affect thyroid function. The development of type 1 diabetes has been associated with interferon alfa therapy. Exacerbation of existing type 2 diabetes has also been reported. Reversible hypopituitarism has been reported in patients receiving interferon alfa.
Effects on the eyes.
Reports of interferon-associated retinopathy have been reviewed.
In a study of 43 patients with chronic hepatitis given interferon alfa, retinopathy developed in 11 of 37 non-diabetic patients and in 3 of 6 diabetic patients after about 8 to 10 weeks of therapy. None of the patients had had retinopathy before treatment; the condition was reversible in the non-diabetic patients on stopping therapy. Visual acuity remained unchanged. Subconjunctival haemorrhage occurred in a further 3 of the non-diabetic patients. Severe irreversible loss of vision has been reported in a non-diabetic patient given interferon alfa.
Pain in one eyeball leading to exophthalmos and complete visual loss has been reported in a patient given interferon alfa; despite withdrawal of interferon and instigation of antibacterial and corticosteroid treatment, the eyeball subsequently ruptured necessitating ophthalmectomy.
Effects on the gastrointestinal tract.
There have been reports of the onset of coeliac disease during treatment of hepatitis C with interferon alfa, in some cases used with ribavirin. Symptoms generally resolved after interferon was stopped and a gluten-free diet started.
Effects on the hair.
A report of marked greying of the hair in a patient beginning after 5 months of treatment with interferon alfa for metastatic malignant melanoma; on completion of interferon therapy the hair regrowth returned to its normal colour. Marked straightening of scalp and body hair has been reported in 2 patients after combined treatment with interferon alfa-2b or peginterferon alfa-2b and ribavirin for chronic hepatitis C. In the first patient, there was also diffuse thinning of scalp hair, change in hair texture, increased greying of the hair, and eyebrow lengthening; the original curly hair began to regrow 6 months after stopping treatment, but the hair abnormalities recurred on rechallenge despite switching from interferon alfa-2b to peginterferon alfa-2b. In the second patient, treatment with peginterferon alfa-2b and ribavirin was associated with straightening of scalp hair, eyebrow hair, and pubic hair. Lengthening and thickening of eyelashes has also been reported with interferon alfa therapy.
Effects on hearing.
Sensorineural hearing loss was reported in 18 of 49 patients and tinnitus in 14 of 49 patients given interferons. The effects were more common in those given interferon beta than in those given interferon alfa, and resolved in all patients on stopping therapy.
Effects on the kidneys.
In a double-blind parallel-group study all of 8 renal transplant patients given, in addition to routine immunosuppression, high doses of recombinant interferon alfa (36 million units intramuscularly three times a week for 6 weeks followed by twice weekly for a further 6 weeks) had early rejection episodes which were corticosteroid-resistant; 3 also had transient nephrotic syndrome. All of 8 control patients, given human albumin and saline solution, also had early rejection episodes but only one was corticosteroid-resistant. These adverse effects on the transplant contrasted with the absence of adverse effects on kidney transplants reported by other workers who gave lower doses of leucocyte interferon alfa for the prophylaxis of CMV infections. There have been a number of other reports of nephrotic syndrome associated with interferon alfa; in one patient this was secondary to membranoproliferative glomerulonephritis. Nephrotic syndrome has also occurred after use of interferon beta.
Effects on lipids.
Reversible hypertriglyceridaemia has been associated with interferon alfa treatment for chronic hepatitis C. Gemfibrozil reduced the hypertriglyceridaemia but lipid concentrations did not return to baseline values and interferon treatment had to be withdrawn. Reversible hypertriglyceridaemia has also occurred in patients given interferon alfa for malignant melanoma.
Effects on the liver.
Therapy with interferon alfa has been associated with cases of fatal liver failure, sometimes in association with chronic hepatitis B and/or C infection.
Effects on the nervous system and mental state.
Neurological effects, reported in 10 women with advanced breast cancer treated for up to 12 weeks with recombinant interferon alfa in doses of 20 million units daily or 50 million units three times weekly, included abnormal EEG patterns in all 10 patients, profound lethargy and somnolence in 6, confusion and dysphasia in 5, paraesthesia in 2, and an upper motor-neurone lesion of the legs in one. These effects resolved when interferon alfa was withdrawn and all patients tolerated its reintroduction at a lower dose. Reversible EEG abnormalities were observed in a further 11 patients given interferon alfa in doses of 100 million units/m2 daily for 7 days by continuous intravenous infusion, in 3 patients given 5 to 10 million units/m2 three times weekly by subcutaneous injection, and in another patient given 4 million units/m2 daily for 6 weeks. Other adverse neurological effects reported with interferon alfa include delusions and hallucinations, neuropsychiatric changes, neuralgic amyotrophy and polyradiculopathy, seizures, spastic diplegia (in infants), and severe neuropathy. Mania attributed to interferon-induced hypothyroidism has been described. Some of these effects were observed with doses as low as 1.5 million units or 3 million units daily.
Psychiatric effects including depression and suicidal ideation have been associated with interferon alfa. Preliminary findings suggest that patients who develop depression may have higher pretreatment depression scores in psychometric tests, although a prospective study of 50 patients receiving interferon alfa found that patients with pre-existing mood or anxiety disorders were no more likely than controls to interrupt therapy. SSRIs have been used successfully to both treat patients with interferon-associated depression, thus allowing therapy to be continued, and to prevent its occurrence via pretreatment.
Effects on the oral mucosa.
Painful oral ulcers, necessitating withdrawal of interferon alfa therapy, have occurred in a patient treated for chronic hepatitis. Oropharyngeal lichen planus was associated with interferon alfa in another patient.
Effects on the respiratory system.
Treatment with interferon alfa resulted in severe exacerbation of mild asthma in 2 patients with hepatitis C.
Effects on skeletal muscle.
Myalgia is one of the 'flu-like' symptoms frequently associated with interferons. Rhabdomyolysis has occurred and in one case proved fatal when associated with multiple organ failure in a patient receiving high-dose interferon alfa.
Effects on the skin.
Exacerbation or development of psoriasis was reported in patients given recombinant interferon alfa. However, no such effect was seen in 7 patients given interferon gamma. Exacerbation of lichen planus has also been reported during interferon alfa treatment (see also Effects on the Oral Mucosa). Cutaneous vascular lesions with punctate telangiectasias were noted in 18 of 44 patients treated with interferon alfa-2a; lesions did not appear at the injection site. Severe necrotising cutaneous lesions were reported at injection sites in a patient receiving recombinant interferon beta-1b; the lesions healed when interferon alfa-n3 was substituted. However, cutaneous necrosis has also been associated with interferon alfa and peginterferon alfa. Fatal paraneoplastic pemphigus developed in a patient receiving interferon alfa-2a. Cutaneous sarcoidosis has also been reported. Hyperpigmentation of the skin and tongue has been described in 2 dark-skinned patients during treatment with interferon alfa and ribavirin.
Shock.
Fatal non-cardiogenic shock occurred after the third dose of interferon alfa-2b in a patient with malignant melanoma. There were similarities to a fatal reaction reported in another patient with malignant melanoma (see under Effects on Skeletal Muscle).
PRECAUTION
Interferons should be used with caution or avoided altogether in patients with depression or psychiatric disorders, epilepsy or other CNS diseases, renal or hepatic impairment, cardiac disorders, myelosuppression, poorly controlled thyroid dysfunction, pulmonary disease, diabetes mellitus, auto-immune diseases, coagulation disorders, or a history of these conditions. Patients with psoriasis or sarcoidosis have been reported to experience exacerbations during interferon alfa therapy.
Blood counts should be monitored, particularly in patients at high risk of myelosuppression (for example those with haematological malignancies). Assessment of cardiac function is advised before treatment is started. Patients receiving interferons who have visual disturbances should receive an eye examination. A baseline ocular examination is recommended before treatment, and periodic eye examinations should be performed throughout treatment in patients predisposed to retinopathy, such as those with diabetes mellitus or hypertension. Hepatic and renal function should be monitored during treatment with interferons. Interferon alfa should be discontinued in patients with chronic hepatitis who develop liver decompensation. Patients should receive adequate fluids to maintain hydration during treatment with interferon alfa.
Interferons may affect the ability to drive or operate machinery.
Antibodies may develop to exogenous interferon that reduce its activity.
Asthma.
For a report of severe exacerbation of asthma in patients receiving interferon alfa, see Effects on the Respiratory System.
Auto-immune disorders.
A number of disorders thought to have an auto-immune component have developed or been exacerbated during therapy with interferon alfa, including diabetes mellitus, auto-immune hepatitis, multiple sclerosis, rheumatoid arthritis, SLE, and thyroid disease.
For mention of a possible association between interferons and the occurrence of coeliac disease, see Effects on the Gastrointestinal Tract under Adverse Effects.
Breast feeding.
The American Academy of Pediatrics states that there have been no reports of any clinical effect on the infant associated with the use of interferon alfa by breast-feeding mothers, and that therefore it may be considered to be usually compatible with breast feeding. It has been suggested that interferons are too large in molecular weight to transfer into breast milk in clinically relevant amounts.
Psychiatric disorders.
For comment on the incidence of adverse effects in patients with pre-existing mood or anxiety disorders, see Effects on the Nervous System and Mental State.
Interactions
Interactions involving interferons have not been fully evaluated, but it is known that they can inhibit hepatic oxidative metabolism via cytochrome P450 enzymes and thus caution should be exercised during use with drugs metabolised in this way. Drugs likely to exacerbate the effects of interferons, such as those with myelosuppressant activity, should also be used with caution.
ACE inhibitors.
For a report of possible synergistic haematological toxicity in patients receiving interferon alfa and ACE inhibitors.
Anticoagulants.
For reference to potentiation of acenocoumarol or warfarin necessitating dosage reduction in patients also receiving interferon alfa.
Antineoplastics.
The manufacturer of interferon alfa-n1 has reported occasional cases of severe cytopenia with or without bone marrow aplasia in patients with chronic myeloid leukaemia who received interferon alfa-n1 immediately after busulfan. Caution has been advised if busulfan or hydroxycarbamide are reintroduced with interferon alfa-n1. Severe myelosuppression has been reported in patients receiving interferon alfa-n1 with relatively high doses of vinblastine.
For reduction in the area under the plasma concentration-time curve for melphalan in patients receiving interferon alfa.
Antivirals.
The manufacturer of interferon alfa-n1 has reported progressive renal failure in patients receiving interferon alfa-n1 and high doses of aciclovir.
For a report of synergistic bone-marrow toxicity with interferon alfa and zidovudine.
Paracetamol.
Three patients experienced increases in liver enzyme values when given paracetamol 1 g two or three times daily on three days each week to coincide with the days of administration of interferon alfa; vinblastine was also given every third week. Paracetamol has also been found to enhance the antiviral effect of interferon alfa in healthy subjects.
Theophylline.
For reference to reduced clearance of theophylline in patients receiving interferon alfa.
Antiviral Action
Interferons are produced by virus-infected cells and confer protection on uninfected cells of the same species. They affect many cell functions and have, in addition to their antiviral activity, antiproliferative and immunoregulatory properties; interferon gamma in particular is a potent macrophage-stimulating factor. These activities are considered to be interrelated. After binding of interferons to a specific cell-surface protein, several enzyme systems appear to be activated to block viral and possibly cellular RNA development.
Studies have shown interferons to have benefit in infections with hepatitis B virus, hepatitis C virus, herpes simplex viruses, varicella-zoster virus, CMV, rhinoviruses, and papillomaviruses.
Pharmacokinetics
Interferons are not absorbed from the gastrointestinal tract. More than 80% of a subcutaneous or intramuscular dose of interferon alfa is absorbed. After intramuscular injection, interferon alfa produced by recombinant techniques or from cultured leucocytes produce similar plasma concentrations, usually reaching a peak within 4 to 8 hours. Half-lives of about 3 to 8 hours have been reported. Intravenous administration produces more rapid distribution and elimination with a half-life of 2 to 3 hours. Interferon alfa does not readily cross the blood-brain barrier. Interferon alfa undergoes renal catabolism and negligible amounts of interferons are excreted in the urine.
Pegylation reduces the rate of absorption and excretion of interferon.
Uses and Administration
The interferons have a range of activities. In addition to their action against viruses they are active against malignant neoplasms and have an immunomodulating effect. Several alfa interferons are available: interferon alfa-2a (rbe), interferon alfa-2b (rbe), alfa-n1 (lns), alfa-n3 (bls), alfacon-1 (rbe), and the pegylated interferons peginterferon alfa-2a (rbe) and peginterferon alfa-2b (rbe).
Alfa interferons are used in chronic hepatitis B (alfa-2a and its pegylated form alfa-2b, and alfa-n1) and chronic hepatitis C (alfa-2a and its pegylated form, alfa-2b and its pegylated form, alfa-n1, and alfacon-1); in several malignant neoplasms including AIDS-related Kaposi's sarcoma (alfa-2a and alfa-2b), hairy-cell leukaemia (alfa-2a, alfa-2b, and alfa-n1), chronic myeloid leukaemia (alfa-2a, alfa-2b, and alfa-n1), follicular lymphoma (alfa-2a and alfa-2b), cutaneous T-cell lymphoma (alfa-2a), carcinoid tumours (alfa-2b), melanoma (alfa-2a and alfa-2b), myeloma (alfa-2b), and renal cell carcinoma (alfa-2a); and in condylomata acuminata (alfa-2b and alfa-n3).
administration and dosage. Dosage regimens for alfa interferons are as follows:
Chronic active hepatitis B. Interferon alfa-2a is given in a dose of 2.5 to 5 million units/m2 three times weekly by subcutaneous injection for 4 to 6 months. Peginterferon alfa-2a is given in a dose of 180 micrograms once weekly subcutaneously for 48 weeks. Interferon alfa-2b is given in a dose of 5 to 10 million units three times weekly for 4 to 6 months, or 5 million units daily for 16 weeks, by subcutaneous or intramuscular injection. Interferon alfa-n1 is given either in doses of 10 to 15 million units (to a maximum of 7.5 million units/m2) three times weekly for 12 weeks, or 5 to 10 million units (to a maximum of 5 million units/m2) three times weekly for up to 6 months, by subcutaneous or intramuscular injection. An initial escalating dosing schedule, usually over 5 days, may improve tolerance.
Chronic hepatitis C. Interferon alfa-2a is given in a dose of 3 to 4.5 million units three times weekly by subcutaneous or intramuscular injection for 6 months when it is used with ribavirin. In patients unable to tolerate ribavirin, interferon alfa-2a monotherapy is given either in an initial dose of 3 to 6 million units three times weekly for 6 months followed by 3 million units three times weekly for an additional 6 months, or in a dose of 3 million units three times weekly for 12 months, by subcutaneous or intramuscular injection. Peginterferon alfa-2a is given in a dose of 180 micrograms once weekly subcutaneously, with ribavirin or as monotherapy, for up to 48 weeks. Interferon alfa-2b is given in a dose of 3 million units three times weekly for 6 to 12 months with ribavirin or, when given as monotherapy, for 12 to 18 months, or for up to 24 months, by subcutaneous or intramuscular injection. Peginterferon alfa-2b is given subcutaneously in a dose of 1.5 micrograms/kg once weekly for 6 to 12 months with ribavirin, or in a dose of 0.5 or 1 microgram/kg once weekly for 6 to 12 months when given as monotherapy. Interferon alfa-n1 is given in a dose of 3 or 5 million units three times weekly for 48 weeks by subcutaneous or intramuscular injection. Interferon alfacon-1 is given in a dose of 9 micrograms three times weekly by subcutaneous injection for 24 weeks followed by 15 micrograms three times weekly for up to 48 weeks if necessary.
AIDS-related Kaposi's sarcoma. Interferon alfa-2a is usually given in an escalating dose of 3 million units daily for 3 days, 9 million units daily for 3 days, 18 million units daily for 3 days, and 36 million units daily, if tolerated, on days 10 to 84, by subcutaneous or intramuscular injection; thereafter the maximum tolerated dose (up to 36 million units) may be given three times weekly. Interferon alfa-2b is given in a dose of 30 million units/m2 three times weekly, by subcutaneous or intramuscular injection.
Hairy-cell leukaemia. Interferon alfa-2a is given in an initial dose of 3 million units daily for 16 to 24 weeks, then the same dose three times weekly, by subcutaneous or intramuscular injection. Treatment has continued for up to 20 months. Interferon alfa-2b is given in a dose of 2 million units/m2 three times weekly by subcutaneous or intramuscular injection for up to 6 months or more. Interferon alfa-n1 is given in an initial dose of 3 million units daily by subcutaneous or intramuscular injection, commonly for 12 to 16 weeks, then the same dose three times weekly thereafter. Alternative doses of 2 million units/m2 or 0.2 million units/m2 of interferon alfa-n1 have also been tried. Treatment may continue for 6 months or more.
Chronic myeloid leukaemia. Interferon alfa-2a is given by subcutaneous or intramuscular injection in an escalating dose of 3 million units daily for 3 days, 6 million units daily for 3 days, and 9 million units daily thereafter. Patients showing a response after 12 weeks should continue treatment until a complete haematological response is achieved or for a maximum of 18 months; those who achieve a complete haematological response should continue on 9 million units daily (or a minimum of 9 million units three times weekly) in order to achieve a cytogenetic response. Interferon alfa-2b is given in a dose of 4 to 5 million units/m2 daily by subcutaneous injection, continuing at the maximum tolerated dose to maintain remission (usually 4 to 5 million units/m2 daily). Interferon alfa-n1 is given, once the white blood cell count has been controlled by cytotoxic chemotherapy, in a dose of 3 million units daily for three weeks by subcutaneous injection. The dose is then adjusted to maintain a suitable leucocyte count (typically about 20 million units/week). Doses of 3 or 6 million units (occasionally 9 million units) daily have been used to achieve initial control of the white blood cell count.
Follicular lymphoma. Interferon alfa-2a is given as an adjunct to chemotherapy in a dose of 6 million units/m2 daily by subcutaneous or intramuscular injection on days 22 to 26 of each 28-day chemotherapy cycle. Interferon alfa-2b is given as an adjunct to chemotherapy in a dose of 5 million units three times weekly by subcutaneous injection for 18 months.
Cutaneous T-cell lymphoma. Interferon alfa-2a is given by subcutaneous or intramuscular injection in an escalating dose of 3 million units daily for 3 days, then 9 million units daily for 3 days, and then 18 million units daily to complete 12 weeks of treatment. The maximum tolerated dose (up to 18 million units) is then given three times weekly for a minimum of 12 months in responding patients.
Carcinoid tumours. Interferon alfa-2b is given in a dose of 3 to 9 million units (usually 5 million units) three times weekly by subcutaneous injection. In advanced disease, 5 million units may be given daily.
Melanoma. Interferon alfa-2a is given in a dose of 3 million units three times weekly by subcutaneous or intramuscular injection for 18 months. Treatment should start no later than 6 weeks after surgery. Interferon alfa-2b is given in an initial dose of 20 million units/m2 daily on 5 days each week for 4 weeks by intravenous infusion over 20 minutes, and then for maintenance 10 million units/m2 three times weekly by subcutaneous injection for 48 weeks.
Multiple myeloma. Interferon alfa-2b is given as maintenance treatment following chemotherapy induction at a dose of 3 million units/m2 three times weekly by subcutaneous injection.
Renal cell carcinoma. Interferon alfa-2a is given as an adjunct to cytotoxic chemotherapy in an escalating dose of 3 million units three times weekly for one week, then 9 million units three times weekly for one week, then 18 million units three times weekly thereafter for 3 to 12 months, by subcutaneous or intramuscular injection.
Condylomata acuminata. Interferon alfa-2b is given in a dose of 1 million units injected into each lesion three times weekly for 3 weeks, and repeated after 12 to 16 weeks if necessary. No more than 5 lesions should be treated in each treatment course, but courses for additional lesions may run sequentially. Interferon alfa-n3 is given in a dose of 0.25 million units per lesion twice weekly for up to 8 weeks, to a maximum of 2.5 million units in each session.
See below for further details of these as well as some other uses of alfa interferons.
Age-related macular degeneration.
In age-related macular degeneration (senile macular degeneration), a common cause of visual impairment in the elderly, there is a gradual and progressive deterioration of central vision usually affecting both eyes . Although some encouraging results have been obtained with systemic interferon alfa-2a or alfa-2b for the treatment of choroidal neovascularisation considered unsuitable for laser therapy, adverse effects have been common and often severe and a randomised study in 481 patients showed no benefit after treatment for one year.
Angiomatous disease.
Encouraging responses were reported in 4 of 5 children treated with interferon alfa-2a for various angiomatous diseases. Regression of haemangioma size by more than 50% was achieved in 11 of 18 infants and children given interferon alfa-2a for 1 to 5 months, and in 11 of 19 children treated for at least 4 months. Interferon alfa-2b has also been found to cause regression of haemangioma in 27 of 38 children treated for at least 6 months. In addition, there have been reports of the successful use of interferon alfa-2b to treat infantile giant cell angioblastoma and pelvic metastases of adult haemangioendothelioma of the liver.
Behçet's syndrome.
Behçet's syndrome is usually managed with corticosteroids. Among many other drugs that have been tried, interferon alfa-2b was reported to produce beneficial responses in 3 patients with refractory ocular symptoms. Encouraging results have also been obtained with interferon alfa-2a.
Blood disorders.
Interferon alfa may be used in the management of the myeloproliferative disorders primary (essential) thrombocythaemia and polycythaemia vera.A study in patients with a variety of chronic myeloproliferative disorders suggested that interferon alfa-2b could also be useful in the management of myeloid metaplasia.
Paradoxically, interferon alfa has also been used with some success in patients with thrombocytopenia associated with hepatitis C and with HIV infection (see also HIV Infection and AIDS).
In addition to case reports of interferon alfa producing improvements in patients with idiopathic hypereosinophilic syndrome who had not responded to corticosteroids or hydroxycarbamide, studies have also show n beneficial responses to interferon alfa used alone or with corticosteroids or hydroxycarbamide.
See also under Malignant Neoplasms.
Churg-Strauss syndrome.
For a report that interferon alfa may be beneficial in Churg-Strauss syndrome .
Hepatitis.
Interferon alfa (including peginterferon alfa) is one of the main drugs used in the treatment of viral hepatitis B and C and chronic hepatitis B and C co-infection with HIV and has been the subject of several general reviews.
Interferon alfa was the first drug approved for the management of chronic hepatitis B. A meta-analysis found that a significantly higher percentage of patients with chronic hepatitis B who were HBeAg-positive, and treated with interferon alfa for 3 to 6 months, became HbeAg-negative compared with the untreated control group. Results from various studies have demonstrated the increased effectiveness of peginterferon alfa, compared with lamivudine, in both HBeAg-positive and HBeAg-negative patients with chronic hepatitis B , when given peginterferon alfa once weekly for 48 weeks. However, the addition of lamivudine to peginterferon alfa did not significantly enhance efficacy. Interferon alfa can produce benefit in some patients co-infected with chronic hepatitis B and D However, these co-infected patients are less responsive to interferon therapy than patients infected with hepatitis B virus alone. A study with high-dose interferon alfa (9 million units) given 3 times a week for 48 weeks reported normalisation of ALT and inhibition of hepatitis D viral replication in 50% of the patients. However, relapse was common after treatment was stopped, although biochemical responses persisted for up to 4 years.
The first available treatment for chronic hepatitis C was interferon alfa-2b, and this was followed by interferon alfa-2a, given subcutaneously 3 times a week. A meta-analysis of studies involving interferon treatment of hepatitis C suggested that treatment with interferon alfa 3 million units three times weekly for at least 12 months had the best risk-benefit ratio for patients with chronic hepatitis C. Studies with once-weekly peginterferon alfa showed it to be more effective than interferon alfa given three times weekly in patients with chronic hepatitis C, including those with cirrhosis or extensive fibrosis. Combination therapy with interferon alfa and ribavirin for the treatment of chronic hepatitis C is more effective than either drug alone with sustained responses having been recorded, and is now generally considered to be the treatment of first choice. A meta-analysis and a systematic review of randomised studies have concluded that combination therapy is also more effective for chronic hepatitis C in patients who had failed to respond to interferon alone or to any other previous treatment. Studies suggest that combination therapy with peginterferon alfa and ribavirin may be more effective and better tolerated than interferon alfa plus ribavirin. One study with peginterferon alfa-2b or interferon alfa-2b and ribavirin showed a sustained virological response (SVR) of around 42% in patients with genotype 1, compared with about 80% in patients with genotypes 2 and 3. A review of the use of peginterferon alfa with ribavirin has also concluded that this combination is superior to interferon alfa plus ribavirin or to peginterferon alfa alone. The British Society for Gastroenterology and the American Association for the Study of Liver Diseases (AASLD) recommend peginterferon alfa with ribavirin as the first choice of treatment for chronic hepatitis C.
Evidence of improved long-term outcomes following treatment is accumulating. Long-term follow-up of patients with chronic hepatitis B or C has demonstrated a lower incidence of hepatocellular carcinoma in patients who had received interferons than in untreated patients.
For the management of HIV and hepatitis B co-infected patients who do not require HIV treatment, the British HIV Association guidelines recommend interferon alfa for 4 to 6 months for non-cirrhotic HBeAg-positive patients, but also point out the probable superiority of peginterferon alfa. Treatment of HIV and hepatitis C co-infected patients has been associated with a high rate of intolerance and a low rate of response. While combination therapy for hepatitis C is not as effective in co-infected patients as in those with hepatitis C alone, studies have shown sustained virological responses with peginterferon alfa and ribavirin treatment in co-infected patients. Two studies reported an SVR rate of 27% for patients given peginterferon alfa plus ribavirin as opposed to 12 to 20% in those treated with interferon alfa plus ribavirin. The APRICOT study group reported an SVR rate of 40% for patients treated with peginterferon alfa plus ribavirin, compared with 20% for those given peginterferon alfa monotherapy and 12% for those given interferon alfa plus ribavirin. A much reduced rate of SVR to peginterferon alfa plus ribavirin therapy was found, however, in co-infected patients with hepatitis C virus genotype 1 (29%) compared with hepatitis C virus of genotypes 2 and 3 (62%) and further study is required to develop strategies for treating infection with genotype 1. The British HIV Association guidelines for the treatment and management of HIV and hepatitis C co-infection now favour combination therapy with peginterferon alfa and ribavirin for 48 weeks in patients with moderate liver disease and well controlled HIV disease. The use of non-pegylated interferon is no longer recommended. For further discussion on the management of chronic hepatitis B and C patients co-infected with HIV.
Although antivirals are generally not required in acute hepatitis, treatment of acute hepatitis C with interferon alfa has been shown to produce more rapid resolution of viraemia and may decrease the risk of chronic hepatitis developing. Studies with peginterferon alfa-2b, in a small number of patients with acute hepatitis C, have shown similar efficacy. The AASLD recommends that either interferon or peginterferon alfa given for a period of at least 6 months should be considered for the treatment of acute hepatitis C.
Herpes simplex infections.
Although herpes simplex infections are commonly treated with aciclovir , beneficial responses to interferon alfa, used topically or subcutaneously, have been reported in genital herpes and, used with trifluridine or brivudine, in herpes keratitis. A systematic review of interventions for herpes simplex epithelial keratitis found that interferon monotherapy had a slightly beneficial effect on dendritic epithelial keratitis, but no more than that of other antivirals and concluded that the use of an antiviral nucleoside with interferon seemed to speed healing.
Similarly, there are case reports of improvement in herpes labialis with topical interferon alfa with trifluridine in 3 patients resistant to aciclovir, 2 of whom were also resistant to foscarnet. In a comparative study intramuscular interferon alfa was not superior to topical aciclovir either in treating first-episode genital herpes or in altering the frequency of recurrences. Topical application of interferon beta has also been tried in a small number of patients for the treatment of labial and genital herpes and in one study, it did reduce the rate of recurrence of genital herpes.
HIV infection and AIDS.
The effects of interferons on the progression of AIDS have been mixed. Combinations of interferon alfa with antiretroviral reverse transcriptase inhibitors have produced variable responses, with some investigators reporting enhanced or synergistic antiretroviral effects, though often at doses associated with a high incidence of adverse effects.
Interferons have been tried with some success in the management of Kaposi's sarcoma and mycobacterial infections in patients with AIDS .
Benefit has been reported with interferon alfa in patients with HIV-associated thrombocytopenia, although interferons have been reported to induce immune thrombocytopenia, and there has been a report of bleeding in a patient with idiopathic thrombocytopenic purpura (see Effects on the Blood under Adverse Effects).
Progressive Multifocal Leukoencephalopathy.
Beneficial responses were reported in patients with HIV-associated progressive multifocal leucoencephalopathy after treatment with interferon alfa. However, in a retrospective analysis of the relative value of HAART and interferon alfa in the treatment of progressive multifocal leucoencephalopathy, prolonged survival associated with interferon alfa was found to be not independent of the effects of HAART and it was concluded that interferon alfa provided no additional benefit.
Inflammatory bowel disease.
Interferon alfa is one of many drugs that have been tried in inflammatory bowel disease A study found that clinical remission was achieved in 26 of 28 patients with ulcerative colitis after 6 to 12 months of treatment with interferon alfa-2a. Partial remission was reported in 2 of 5 patients with Crohn's disease given interferon alfa, but in another study in 12 patients interferon alfa was of no benefit. Interferon beta has also been found to be of benefit for the treatment of ulcerative colitis unresponsive to corticosteroids.
Kaposi's sarcoma.
Interferon alfa has been used in AIDS-related Kaposi's sarcoma and in patients with the classical, nonepidemic form. There have been several small studies of interferon alfa in patients with immunodeficiency- or AIDS-related Kaposi's sarcoma. Results have been mixed. A review concluded that the best responses to interferon alfa were achieved in asymptomatic patients with relatively high CD4+ T lymphocyte counts (200 cells/microlitre or better) and no prior opportunistic infections. However, the adverse effects which occur at the doses required limit the tolerability of long-term use.
Interferons have also been tried in AIDS-related Kaposi's sarcoma with other drugs, including antineoplastics (with disappointing results) and zidovudine (complete or partial tumour response and/or evidence of antiviral effects in some patients). Low doses of interferons given with nucleoside reverse transcriptase inhibitors have been used for AIDS-associated Kaposi's sarcoma; efficacy and toxicity of these combinations have been reported to be dose-related.
Malignant neoplasms.
Many reports have been published on the effects of interferons on various neoplasms; most have involved interferon alfa.
Interferons have become established in the treatment of a few malignant disorders, notably hairy-cell leukaemia Kaposi's sarcoma , and chronic myeloid leukaemia . Alfa interferons may improve the duration of remission in multiple myeloma, but not necessarily survival. Combination therapy including interferons has also been used in indolent low-grade non-Hodgkin's lymphoma and interferon alfa has been used alone to maintain remission. In renal cell carcinoma response to interferon alfa used with interleukin-2 has been promising, but toxicity high; interferon alfa alone produces very modest benefit. Beneficial responses have also been reported in a number of other neoplasms including melanoma ; carcinoid tumours myelodysplasia; cutaneous T cell lymphomas including mycosis fungoides ; and in meningioma. Interferons have been given locally as an adjunct to surgery for superficial bladder tumours and intralesionally in basal cell carcinoma and also for keloid scars. Use of interferon alfa with fluorouracil has been tried in inoperable colorectal cancer but does not appear to be more beneficial than fluorouracil alone. Interferon alfa given with zidovudine has produced encouraging results in adult T-cell leukaemia-lymphoma.
Mycobacterial infections.
For the use of interferon alfa in mycobacterial infections, see Interferon Gamma.
Skin disorders.
For the use of interferon alfa in skin disorders associated with raised IgE concentrations, see Interferon Gamma.
Warts.
Various interferons have been tried by various routes in the treatment of anogenital warts (condylomata acuminata).
Intralesional injection has been used to ensure relatively high concentrations of interferon in the wart but the occurrence of systemic adverse effects shows that there is absorption from this site. Complete responses were reported in 36% of patients given intralesional interferon alfa-2b compared with 17% given placebo, and a corresponding overall reduction in the affected area of 62.4% compared with 1.2% respectively. However, follow-up was not sufficiently long to comment on relapse rates. Another study found similar responses using interferons alfa-2b, alfa-n1, or beta in patients with refractory warts, with complete responses in 47% of patients given intralesional interferons compared with 22% of patients given placebo. A study evaluating two different doses of intralesional interferon beta given three times weekly for 3 weeks reported complete responses in 63% of lesions injected with 1 million units compared with 38% of lesions injected with 33 000 units. Good responses have also been reported in patients with both refractory and recurrent warts given intralesional interferon alfa-n3. Relapses were delayed and fewer warts recurred in patients who had received interferon rather than placebo. Intralesional interferon alfa-2b used with podophyllum was more effective that podophyllum alone, although about 66% of patients in each group subsequently relapsed.
Topical application of interferon alfa has also been reported to be more effective than podophyllotoxin. Interferon beta has also been applied topically after surgical removal of warts.
Theoretically, systemic use should have advantages in controlling subclinical infections and reducing relapses. However, responses to subcutaneous interferon alfa have generally been disappointing although responses comparable with cauterisation and a reduction in relapse rates with either subcutaneous or intramuscular interferon alfa-2b have been obtained. Information on the use of systemic interferons as an adjunct to conventional therapy is scarce but a study in 97 patients with recurrent warts found no difference in either response or relapse rates in patients given cryotherapy with subcutaneous interferon alfa or cryotherapy alone. A study comparing subcutaneous interferon alfa, beta, and gamma used with cryotherapy found no significant difference in response rate, although patients given interferon beta or gamma developed new warts at a lower frequency.