Interferons
Proteins or glycoproteins produced in human or animal cells
in response to various stimuli including exposure to viruses.
They may also be produced through recombinant DNA tech-
nology. There are 3 major immunologically distinct types of
interferon: inlerferon alfa, interferon beta, and interferon
gamma.
Interferon Alfa
Interferon alfa may be derived from leucocytes or lympho-
blasts as well as through recombinant DNA technology. Sub-
species of the human alfa gene may produce interferon alfa
with protein variants or a mixture of proteins. The protein var-
iants may be designated by a number (as in interferon alfa-2)
which may be further qualified by a letter to indicate the ami-
no-acid sequences at positions 23 and 34. Interferon alfa-2a
has lysine at 23 and histidine at 34, interferon alfa-2b has ar-
ginine at 23 and histidine at 34. and interferon alfa-2c has ar-
ginine at both positions. In the case of a mixture of proteins
an alphanumeric designation is given (as in interferon alfa-
nl).
The name may be further elaborated on the label by approved
sets of initials in parentheses to indicate the method of pro-
duction: (rbe) indicates production from bacteria (Es-
cherechia coli) genetically modified by recombinant DNA
technology; (Ins) indicates production Iron] cultured lym-
phoblasts from the Namalwa cell line that have been simuulat-
ed by a Sendai virus: (bis) indicates production from
leucocytes from human blood that have been stimulated by a
Sendai virus.
Interferon Beta
NOTE. Interferon beta was previously known as fibroblast in-
terferon.
Interferon beta-la and Interferon beta-lb are both USAN.
Interferon beta may be derived from fibroblasts as well as
through recombinant DNA technology. Sub-species of the
human beta gene produce interferon beta with protein vari-
ants designated by a number (as in interferon beta-I). Inter-
feron beta-I is further qualified by a letter to indicate the
amino-acid sequences at positions I and 17, and to indicate
whether or not glycosylation is present. Interferon beta-la has
methionine at position I and cysteine at 17 and is glycosylat-
ed at position 80. Interferon beta-1 b has serine at position 17
and is not glycosylated.
The name may be further elaborated on the label by approved
sets of initials in parenthesis io indicate the method of produc
tion: (reh) indicates production from genetically engineered
Chinese hamster ovary cells: irbe) indicates production from
bacteria (Escherichia coli) genetically modified by recom-
binant DNA technology.
Interferon Gamma
NOTE. Interferon gamma was previously known as immune in-
terferon.
Interferon gamma-1 b is USAN and was previously known as
interferon gamma-2a.
Interferon gamma may be derived from immunologically
stimulated T-lymphocyies (hence its former name of immune
interferon ) as well as through recombinant DNA technology.
Similarly to interferon alfa. protein variants of interferon
gamma are designated by a number and further qualified by a
letter to indicate the amino-acid sequences at terminal posi-
tions I and 139. Interferon gamma-la has at position I hydro-
gen, cysteine, tyrosine and cysteine and at position 139
arginine, alanine, serine, glutamine and a hydroxyl group. In-
terferon gamma-1 b. formerly known as interferon gamma-2a.
has at position I hydrogen and methionine and at position 139
a hydroxyl group. Interferon gamma derived through recom
binant DNA technology is labelled (rbe).
Adverse Effects and Treatment
Most reports of the adverse effects of interferon
have involved interferon alfa. but limited clinical ex-
perience suggests that interferons beta and gamma
have similar adverse effects.
Interferons produce influenza-like symptoms with
fever, chills, headache, malaise, myalgia, and ar-
thralgia. 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, be
low).
Other adverse effects include nausea, vomiting, di
arrhoea. anorexia with weight loss, bone marrow de
pression. alopecia. rash. and taste alteration. There
may be signs of altered liver function and liver
necrosis has been reported. Renal failure and the ne
phrolic syndrome have occurred and there are rare
reports of interstitial nephritis. Severe hypersensi
tivity reactions including anaphylaxis and bronchos
pasm have occurred. Cardiovascular effects include
hypolension 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. ECG
abnormalities and neurological symptoms including ataxia, par-
aesthesia, somnolence, dizziness, confusion, and
rarely, convulsions and coma have been reported.
There may be severe fatigue, depression, anxiety,
depersonalisation or emotional lability. Visual dis-
turbances 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 reac-
tions including local necrosis,
Nasal administration may produce mucosal irrita-
tion and damage.
Effects on the blood. Restoration of bone-marrow function
following 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-mar-
row insufficiency and should not be given to marrow trans-
plant 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 fe-
ver 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 in-
creased in all patients; blood counts returned to normal
when
interferon therapy stopped. Interferon alfa produced a
decline
in CD4-positive T-lymphocytes resulting in opportunistic in-
fections 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 im-
mune thrombocytopenia. Haemorrhage occurred in a pa-
- tient with immune thrombocytopenic purpura treated with
interferon alfa and it was thought prudent to use
Interferons
with caution, if at all, in this condition. 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.
hypothyroidism and hyperthyroidism have been associated
with interferon alfa therapy. Recombinant interferon
gamma was reported not to affect thyroid function.
The development of type I diabetes has been associated with in-
terferon alfa therapy. Exacerbation of existing type 2 diabe-
tes has also been reported. Reversible hypopituitarism was
reported in I patient receiving interferon alfa.
Effects on the eyes. In a study of 43 patients with chronic
hepatitis receiving interferon alfa, retinopathy
developed in 11 non-diabetic patients and 3 diabetic
patients after about 8 to 10 weeks of therapy. None of
the patients had retinopathy prior to treatment, and it
was reversible in the non-diabetic patients on cessation
of therapy. Visual acuity remained unchanged.
Subconjunctival haemorrhage occurred in 3 of the
non-diabetic patients. This and other reports of
interferon-associated retinopathy have recently been
reviewed.
Pain in one eyeball leading to exophthalmos and complete
visual loss was reported in one patient receiving
interferon alfa; despite withdrawal of interferon and
instigation of antibiotic and corticosteroid treatment, the
eyeball subsequently ruptured necessitating ophthalmectomy.
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 comple-
tion of interferon therapy the hair regrowth returned to its
normal colour.
Reversible mild to moderate alopecia has been reported by
the manufacturers.
Effects on hearing. Sensorineural hearing loss was reported
in 18 of 49 patients and tinnitus in 14 of 49 patients receiv-
ing interferons. The effects were more common in those
receiving interferon beta than in those receiving interferon
alfa, and resolved in all patients on discontinuation of
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 contrast-
ed with the absence of adverse effect on kidney transplants
reported by Hirsch et 0[.2 who gave lower doses of
interferon alfa for the prophylaxis of cytomegalovirus
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. The manufacturers have noted rare
reports of interstitial nephritis.
Effects on lipids. Reversible hypertriglyceridemia
has been associated with interferon alfa treatment for
chronic hepatitis C. Gemfibrozil reduced the
hypertriglyceridaemia but lipid concentrations did not return to
base-line values and interferon treatment had to be withdrawn.
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. Neu-
rological 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 a week included abnormal EEC patterns in all 10 pa-
tients, 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 inter-
feron alfa was withdrawn and all patients tolerated its reintro-
duction at a lower dose. Reversible EEG abnormalities were
observed in a further 11 patients given interferon alfa in doses
of 100 million units per nr body-surface daily for 7 days by
continuous intravenous infusion. in 3 patients given 5 to 10
million units per nr three times per week by subcutaneous
injection, and in another patient given 4 million units per nr
daily for 6 weeks. Other adverse neurological effects report-
ed with interferon alfa include neuropsychiatric changes
neuralgic amyotrophy and polyradiculopathy. seizures
spastic diplegia (in infants), and severe neuropathy. Some of
these effects were observed with doses as low as 1.5 million
units' or 3 million units daily.
Depression associated with interferon therapy was success-
fully treated with fluoxetine in one patient thus allowing in-
terferon therapy to be continued.
Psychiatric disturbances leading to suicidal behaviour oc-
curred in 3 patients receiving interferon: they had no history
of psychiatric disorder.
Effects on the oral mucosa. Painful oral ulcers occurred
during interferon alfa treatment for chronic hepatitis in one
patient and necessitated withdrawal of interferon. Oropharyn-
geal lichen planus was associated with interferon alfa in an-
other patient.
Effects on skeletal muscle. Myalgia is one of the influen-
za-like symptoms frequently associated with interferons. Fa-
tal rhabdomyolysis and multiple organ failure was reported in
a patient receiving high doses of interferon alfa.
Effects on the skin. Exacerbation or development of pso-
riasis was reported in patients given recombinant interferon
alfa. However, no exacerbation was seen in 7 patients given
interferon gamma.) Exacerbation of lichen planus has also
been reported4 during interferon alfa treatment (see also Ef-
fects on the Oral Mucosa. above). 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 necrotizing cutaneous lesions were re-
ported at injection sites in a patient receiving recombinant in-
terferon beta-1b: the lesions healed when interferon alfa-n3
was substituted. However, cutaneous necrosis has also been
associated with interferon alfa. Fatal paraneoplastic pemphi-
gus developed in a patient receiving interferon alfa-2a.
Shock. Fatal non-cardiogenic shock occurred following 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, above).
Precautions
Interferons should be used with caution or avoided
altogether in patients with depression or psychiatric
disorders, epilepsy, severe renal or hepatic impair-
ment, cardiac disorders, myelosuppression. thyroid
or pulmonary disease, diabetes mellitus, coagula-
tion disorders, or a history of these conditions.
Blood counts should be monitored, particularly in
patients at high risk of myelosuppression (for exam-
pie those with haematological malignancies). He-
patic and renal function should be monitored during
treatment with interferons. The manufacturers of in-
terferon alfa recommended that patients should re-
ceive adequate fluids to maintain hydration. Patients
with psoriasis have been reported to experience ex-
acerbations during interferon alfa therapy. Interfer-
ons may affect the ability to drive or operate
machinery.
Antibodies may develop to exogenous interferon
that reduce its activity.
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 di-
abetes mellitus, autoimmune hepatitis, multiple sclero-
sis, rheumatoid arthritis, and systemic lupus
erythematosus.
Interactions
Interactions involving interferons have not been ful-
ly evaluated, but it is known that they can inhibit he-
patic oxidative metabolism and thus caution should
be exercised during concomitant administration of
drugs metabolised in this way. For example, inter-
feron alfa has been reported to enhance the effect of
theophylline. Drugs likely to exacerbate the effects
of interferons, such as those with myelosuppressive
activity, should also be used with caution.
Interferon alfa has been reported to cause increased toxicity,
accumulation, and increased plasma concentrations of vi-
darabine.' It has also been found to inhibit theophylline me-
tabolism, thus increasing plasma concentrations, and to
exhibit synergistic cytotoxicity with zidovudine in AIDS-as-
sociated Kaposi's sarcoma and in vitro. Interferon-induced
fever has been reported to lead to an increase in the cytotox-
icity of melphalan. An increased anticoagulant effect, to-
gether with increased serum-warfarin concentrations, has
been reported when interferon alfa therapy is introduccd.
Three patients experienced increases in liver enzyme values
when given paracetamole I g two or three limes a day on three
days a 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 ef-
fect of interferon alfa in healthy subjects. Severe granulocy-
topenia has been reported in three patients with mixed
cryoglobulinaemia treated with interferon alfa-2a who also
received ACE inhibitors. The effect was considered to be due
to synergistic haematological toxicity. However, in a further
report two patients developed only mild granulocytopenia
that was reversible despite continued therapy, while a third
patient retained a normal granulocyte count.
Antiviral Action
Interferons are produced by vinis-infected cells and
confer protection on uninfected cells of the same
species. They affect many cell functions demon-
strating, in addition to their antiviral activity, anti-
proliferative and immunoregulatory properties;
interferon gamma in particular is a potent macro-
phage-stimulating factor. These activities are con-
sidered to be interrelated. Following 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 in-
fections with hepatitis B virus, hepatitis C virus,
herpes simplex viruses, varicella-zoster virus, cy-
tomegalovirus, rhinoviruses, and papillomaviruses.
Pharmacokinetics
Interferons are not absorbed from the gastro-intesti-
nal tract. More than 80% of a subcutaneous or intra-
muscular dose of interferon alfa is absorbed:
interferon beta and interferon gamma are less well
absorbed by these routes. Following intramuscular
injection interferon alfa produced by recombinant
techniques and from cultured leucocytes produce
similar plasma concentrations, usually reaching a
peak within 4 to 8 hours. Half-lives of up to 16 hours
have been reported. Intravenous administration pro-
duces more rapid distribution and elimination. Inter-
feron alfa does not readily cross the blood-brain
barrier. Negligible amounts of interferons are ex-
creted in the urine.
Uses and Administration
The interferons have a range of activities. In addi-
tion to their action against viruses they are active
against malignant neoplasms and have an imnni-
nomodulating effect. There are several interferons
available: interferon alfa-2a (rbe), interferon alfa-2b
(rbe), alfa-nl (Ins), and alfa-n3 (bis); interferon
beta-la and interferon beta-lb; and interferon gam-
ma-lb (rbe).
Alfa interferons are used in chronic hepatitis B and
C (alfa-2a, alfa-2b, and alfa-nl); in several mali
gnant neoplasms including AIDS-related Kaposi's
sarcoma (alfa-2a and alfa-2b). hairy-cell leukaemia
(alfa-2a, alfa-2b. and alfa-nl). chronic myeloid leu-
kaemia. (alfa-2a, alfa-2b, and alfa-nl), follicular
lymphoma (alfa-2a and alfa-2b), cutaneous T-cell
lymphoma (alfa-2a). carcinoid tumours (alfa-2b),
melanoma (alfa-2b), myeloma (alfa-2b), and renal
cell carcinoma (alfa-2a); and in condylomata acumi-
nata (alfa-2b and alfa-n3). Beta interferons are used
in multiple sclerosis. Interferon gamma-1b is used as an adjunct
to antibacterial therapy in chronic granulomatous disease.
ADMINISTRATION AND DOSAGE. Dosage regimens are
as follows.
Chronic active hepatitis B. Interferon alfa-2a is give
in a dose of 2.5 to 5 million units per m2 body-surface
three times a week by subcutaneous injection for 4-6 mths
months. Interferon alfa-2b is given in doses of 5 to 10
million units three times a week for 4 to 6 months, or 5
million units daily for 4 months by subcutaneous or in-
tramuscular injection. Interferon alfa-nl is given either
in doses of 10 to 15 million units (to a maximum of 7.5
million units per nr) three times a week for 12 weeks, or
5 to 10 million units (to a maximum of 5 million units per
m2) three times a week for up to 6 months by subcutane-
ous or intramuscular injection.
Chronic hepatitis C. Interferon alfa-2a is given either in
an initial dose of 3 to 6 million units three times a week
for 6 months followed by 3 million units three times a
week for an additional 6 months, or in a dose of 3 million
units three times a week for 12 months, by subcutaneous
or intramuscular injection. Interferon alfa-2b is given in
a dose of 3 million units three times a week for 12 to 18
months, or for up (o 24 months, by subcutaneous or in-
tramuscular injection, interferon alfa-nl is given in a
dose of 3 or 5 million units three times a week for 48
weeks by subcutaneous or intramuscular injection.
AIDS-related Kaposi's sarcoma. Interferon alfa-2a is
usually given in an escalating dose of 3 million units dai-
ly for 3 days, 9 million units daily for 3 days. 18 million
units daily for 3 days, and 36 million units daily, if toler-
ated, 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 a week. Inter
feron alfa-2b is given in a dose of either 10 to 20 million
units daily by subcutaneous injection or 30 million units
per m2 three times a week by subcutaneous or intramus
cular 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 a week by subcutaneous
or intramuscular injection, interferon alfa-2b is given in
a dose of 2 million units per nr three times a week by
subcutaneous or intramuscular injection. Interferon alfa
nl 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 a week
thereafter. Alternative doses of 2 million units per m2 or
0.2 million units per m2 of interferon alfa-nl have also
been tried.
Chronic myeloid leukaemia. interferon alfa-2a is given
by subcutaneous or intramuscular injection in an escalat
ing dose of 3 million units daily for 3 days, 6 million
units daily for 3 days. and 9 million units daily to com
plete 12 weeks of treatment. Patients showing a response
should continue on 9 million units daily (or a minimum
of 9 million units 3 times a week) until a complete hae
matological response is achieved or for a maximum of 18
months. Treatment may continue in patients who achieve
a complete haematological response in order to achieve a
cytogenetic response, Interferon alfa-2b is given in a
dose of 4 to 5 million units per mZ daily by subcutaneous
injection, increasing to the maximum tolerated dose to
maintain remission (usually 4 to 10 million units per m2
daily), Interferon alfa-nl is given 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.
Follicular lymphoma. Interferon alfa-2a is given
adjunct to chemotherapy in a dose of 6 million units per
m2 daily by subcutaneous or intramuscular injection on
days 22 to 26 of a 28-day chemotherapy cycle. lnterferon
alfa-2b is given as an adjunct to chemotherapy in a dose
of 5 million units three times a week by subcutaneous
injection for 18 months.
Cutaneous T-cell lymphoma : Interferon alfa-2a is given in an
escalating dose of 3 million units daily for 3
days, 9 million units daily for 3 days, and 18 million units
daily to complete 12 weeks of treatment, by subcutane-
ous or intramuscular injection. The maximum tolerated
dose (but not exceeding 18 million units) is then given
three times a week for a minimum of 12 months.
Carcinoid tumours. Interferon alfa-lb is given in a dose
of 3 to 9 million units (usually 5 million units) three
times a week by subcutaneous injection. In advanced dis-
ease, 5 million units may be given daily.
Multiple myeloma. Interferon alfa-lb is given as main-
tenance treatment following chemotherapy induction at a
dose of 3 million units per m2 three times a week by sub-
cutaneous injection.
Melanoma. Interferon alfa-2b is given in an initial dose
of 20 million units per m2 daily on 5 days each week for
4 weeks by intravenous infusion over 20 minutes, and
then for maintenance 10 million units per m2 three times a week
by subcutaneous injection for 48 weeks.
Renal cell carcinoma. Interferon alfa-2a is given in an
escalating dose of 3 million units three times a week for
one week. then 9 million units three times a week for one
week, then 18 million units three times a week there after
for 3 to 12 months, by subcutaneous or intramuscular in-
jection.
Condylomata accuminata. Interferon alfa-lb is given in
a dose of I million units injected into each lesion three
times a week for three 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 addition-
al lesions may run sequentially. Interferon alfa-n3 is giv-
en 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.
• Multiple sclerosis. Interferon beta-la is given in a dose
of 6 million units once a week by intramuscular injection
or 6 million units three times a week by subcutaneous
injection, depending on the preparation. Interferon beta
1b is given in a dose of 8 million units (250 ng) on alter
nate days by subcutaneous injection.
* Chronic granulomatous disease. Interferon gamma-1b
is used as an adjunct to antibacterial therapy in a dose o
50 ng per nr (1.5 million units per nr) three times a
week by subcutaneous injection. Patients with a body
surface area of less than 0.5 mZ should receive 1.5 mcg
per kg body-weight.
See below for further details of these as well as some
other uses of interferons.
Age-related macular degeneration. In age-related mac-
ular degeneration (senile macular degeneration), a common
cause of visual impairment in the elderly, there is a gradual
and progressive deterioration of central vision usually effect-
ing both eyes. Although some encouraging results have
been obtained with systemic interferon alfa-2a or alfa-2b for
the treatment of choroidal neovascularisation considered un-
suitable for laser therapy, adverse effects have been common
and often severe and there is doubt over long-term benefit.
Angiomatous disease. Encouraging responses were re-
ported in 4 of 5 children treated with interferon alfa-2a with a
variety of angiomatous diseases. Regression of haemangi-
oma size by more than 50% was achieved in 11 of 18 infants
and children who received interferon alfa-2a for I to 5
months.
Behçet’s syndrome. Behçet’s syndrome is usually man-
aged with corticosteroids . Among many other
drugs that have been tried, interferon alfa-2b was reported to
produce beneficial responses in 3 patients with refractory oc-
ular symptoms. Encouraging results have also been obtained
in other small studies of interferon alfa-2a.
Blood disorders. Interferon is an alternative to anagrelide
or hydroxyurea in the treatment of essential thrombocythae-
mia Recombinant interferon alfa has generally been
successful in essential thrombocythemia. It has been ad-
ministered by subcutaneous or intramuscular injection, usual-
ly with an induction course followed by maintenance therapy
at a lower dose. A reduction in platelet count greater than 50%
after 28 days of treatment was observed in some patients.
A complete response (platelet count less than 440 x 10' per
litre) was achieved and maintained for 12 months in 71% of
patients with myeloproliferative disorders and associated
thrombocytosis in one study. Thrombocytosis recurred on
stopping maintenance therapy, although remission was ob-
tained on re-introducing interferon. Resistance to interferon
was observed in 8 .patients with thrombocythaemia;2 in 6 pa-
tients the resistance was secondary. A number of patients
have withdrawn from treatment because of adverse effects.
Another thrombocytosis-associated myeloproliferative dis-
ease in which interferon alfa has been reported to be
beneficial is polycythaemia vera.
Paradoxically, interferon alfa has also been tried in patients
with HIV-associated thrombocytopenia (see HIV Infection
and AIDS, below).
Following case reports of interferon alfa producing improve-
ments in patients with idiopathic hypereosinophilic
syndrome who had not responded to corticosteroids and
hydroxyurea two small studies have shown beneficial re-
sponses to interferon alfa alone and in combination with hy-
droxyurea.
Chronic granulomatous disease. Interferon gamma is re-
ported to reduce the incidence of infections in patients with
chronic granulomatous disease.
Common cold Despite the early promise of intranasal
interferon alfa for prophylaxis, later studies found it to be of
no value for prophylaxis or treatment. Interferon beta was
also reported to provide ineffective prophylaxis.
Hepatitis. Interferon alfa is the main drug used in the treat-
ment of chronic viral hepatitis .
Two meta-analysesl2 have confirmed the value of interferon
alfa in chronic hepatitis B. Benefits appear to be greatest in
patients with high aminotransferase concentrations and with
a history of acute hepatitis. It has been reported that about
40% of patients with chronic hepatitis C respond to interferon
alfa. Response is generally rapid, without the transient rise in
serum alanine aminotransferase which is seen during treat-
ment of hepatitis B. and it is suggested that treatment should
be discontinued in patients who do not respond within 12 to
16 weeks.
While long-term remissions may be achieved following inter-
feron therapy for hepatitis B, prolonged therapy is required
and relapse is frequent: relapse of hepatitis C may occur in
half of responding patients on cessation of treatment, but
sustained responses have been reponed.9 In addition, it has
been noted that about 70% of those who relapse may respond
to further interferon treatment, and more sustained responses
may be achieved with prolonged courses of treatment.
There is also some evidence that interferon alfa may reduce
the incidence of hepatocellular carcinoma in chronic active
hepatitis C with cirrhosis. Interferon beta has also been tried
in hepatitis C. In addition interferon alfa and beta may
decrease the risk of chronic hepatitis C developing after acute
infections.
The use of interferon alfa or beta in combination with tribavi-
rin for hepatitis C is reported to improve response rates.
A recent study has indicated that interferon alfa can benefit
some patients with chronic hepatitis D.
Although antivirals are generally not required in uncompli-
cated acute hepatitis, improvements in liver function were re-
ported in 4 patients with fulminant hepatitis A treated with
interferon beta.
Herpes simplex infections. Although herpes simplex in-
fections are commonly treated with aciclovir ,
beneficial responses to interferon alfa, applied topically, have
been reported in genital herpes and, in combination with
trifluridine or brivudine, in herpes keratitis. Similarly there
are case reports of improvement in herpes labialis with inter-
feron alfa in combination with trifluridine in 3 patients resist-
ant to aciclovir, 2 of whom were also resistant to foscarnet.
Interferon beta has also been tried in a small number of pa-
tients for the treatment of labial and genital herpes. However
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.
HIV Infection and AIDS. The effects of interferons on the
progression of AIDS have been mixed. Combinations of in-
terferon alfa with antiretroviral reverse transcriptase inhibi-
tors have produced variable response with some
investigators reporting enhanced or synergistic antiretro-
viral effects, though often at doses associated with a high in-
cidence of adverse effects.
Interferons have been tried with some success in the manage-
ment of Kaposi's sarcoma and mycobacterial infections in pa-
tients with AIDS (see below).
Promising results have been reported with interferon alfa in
patients with HIV-associated thrombocytopenia, although
interferons have been reported to induce immune thrombocy-
topenia, and there has been a report of bleeding in a patient
with idiopathic thrombocytopenic purpura (see Effects on the
Blood under Adverse Effects, above).
Inflammatory bowel disease. Interferon alfa is one of
many drugs that have been tried in inflammatory bowel dis-
ease . One recent 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
disease2 who received interferon alfa, but in another study in
12 patients interferon alfa was of no benefit. Aminosali-
cylates and corticosteroids remain the mainstays of drug
treatment at present.
Juvenile osteopetrosis. Interferon gamma has been tried in
the treatment of juvenile osteopetrosis . A study in
14 patients found that interferon gamma-1 b increased bone
resorption. In 11 who received this treatment for 18 months
there was stabilisation or improvement in clinical condition
and a reduction in the frequency of serious infection.
Kaposi's sarcoma. Interferon alfa has been
used in AIDS-related Kaposi's and in patients
with the classical, nonepidemic form, There have been
several small studies of interferon alfa in patients with immu-
nodeficiency or AIDS-related Kaposi's sarcoma. Results
have been mixed. From a review of published studies. Krown
concluded that the best responses to interferon alfa were
achieved in asymptomatic patients with relatively high CD4+
T lymphocyte counts (200 cells per mcL or better) and no prior
opportunistic infections. However, the adverse effects which
occur at the doses required limit the tolerability of long-term
administration.
Interferons have also been tried in AIDS-related Kaposi's sar-
coma in combination with other drugs including antineoplas-
tics (with disappointing results) and zidovudine (complete or
partial tumour response and/or evidence of antiviral effects in
some patients). Low doses of interferons in combination
with zidovudine have been reported to be the favoured treat-
ment for AIDS-associated Kaposi's sarcoma,
Leishmaniasis. Interferon gamma has been tried both sys-
temically and locally as an adjunct to standard treatment of
leishmaniasis with encouraging results. In a re-
view of the use of interferon gamma in non-viral infections,
Munay concluded that interferon gamma was effective when
combined with antimony compounds for treatment failures in
visceral leishmaniasis and could enhance the response to ini-
tial therapy in untreated patients. For cutaneous infections,
intralesional interferon gamma has been shown to be effective
but less so than intralesional antimony compounds. Subcuta-
neous administration of interferon gamma with antimony giv-
en intravenously was no more effective than antimony alone
when administered as a short course over 10 days. However,
encouraging responses have been reported in patients who
have failed to respond to antimony compounds alone.
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. Kapo-
si's sarcoma (see above), and chronic myeloid leukaemia.
where interferon alfa may be regarded as the treatment of
choice. Alfa interferons may improve the duration of remis-
sion in multiple myeloma, but not necessarily surviv-
al. Combination therapy including interferons has also
been used in non-Hodgkin's lymphoma and renal cell car-
cinoma where response to interferon alfa in combination
with interleukin-2 has been promising, but toxicity high.
(Interferon alfa alone produces very modest benefit.) Bene-
ficial responses have also been reported in a number of
other
neoplasms including melanoma, carcinoid tumours (al-
though some authorities were sceptical about its value); my-
elodysplasia: cutaneous T cell lymphomas including mycosis
fungoides and in one reported case of meningioma. In-
terferons have been administered locally as an adjunct to sur
gery for superficial bladder tumours and intralesionally in
basal cell carcinoma and also for keloid scars. Com-
bination of interferon alfa with fluorouracil has been tried
in inoperable colorectal cancer but may not be more
beneficial
than fluorouracil alone, Interferon alfa in combination with
zidovudine has produced encouraging results in adult T-cell
leukaemia-lymphoma.
Multiple sclerosis. Multiple sclerosis (MS) is characterised
by patches of demyelination that can be scattered throughout
the white matter of the CNS, but are usually localised in the
brain stem, periventricular areas, the optic nerve, and the cer-
vical spinal cord. The cause is unknown but may have an im-
munological basis. Symptoms may vary according to the
areas affected but typically include weakness, paraesthesias,
vision loss. incoordination, and bladder dysfunction. Most
patients improve to some degree after the initial attack but the
cource and severity of the disease are unpredictable. In many
patients the disease follows a relapsing-remitting course in
which there are recurrent exacerbations followed by relatively
long periods of remission. In some patients the disease is de-
scribed as relapsing-progressive when there is little or no im-
provement after each exacerbation and disability slowly
increases. In a few patients the disease progresses rapidly
without remission and leads to early disability and death.
The evaluation of therapy for any disease such as MS that has
spontaneous remissions is difficult. Until recently there has
been little convincing evidence that any treatment affects the
outcome of the disease. Treatment has therefore largely
been symptomatic and aimed at the management of spastic-
ity. pain. fatigue, and bladder dysfunction. Baclofen, dantro-
lene and diazepam are the usual drugs given for spasticity.
There has also been a suggestion that the syn-
thetic cannabinoid nabilone may improve spasticity. Patients
with MS can suffer from a number of different types of pain,
including pain from spasticity, and therapy must be individu-
alised for each specific pain syndrome. Paraesthesia
and dysaesthesia. which can be common, may respond to tri-
cyclic antidepressants or antiepileptics. Amantadine may al-
leviate fatigue associated with MS. Treatment of bladder
dysfunction may include an alpha blocker such as phenoxy-
benzamine and appropriate parasympathomimetic or an-
limuscarinic therapy to control bladder contractions.
Fampridine has
been reported to produce improvement in walking, dexterity.
and vision, possibly as a result of its potassium-channel
blocking activity. 3,4-Diaminopyridine has also been re-
ported to produce beneficial symptomatic responses.
A wide range of drugs with immunological actions have been
tried in the treatment of MS itself with the aim of improving
recovery from acute attacks, preventing or decreasing the
number of relapses, and halting the progressive stage of the
disease.
Short-term courses of corticotrophin have long been used to
hasten recovery from acute exacerbations although there is no
effect on the degree of recovery nor on the overall course of
the disease; successive treatments may be less benefi-
cial. Oral corticosteroids such as prednisolone or pred-
nisone have been widely used to achieve the same effect, but
there is a trend towards the use of high-dose intravenous
methylprednisolone. Some recommend the use of
high-dose oral or intravenous methylprednisolone (the latter
followed by a tapering course of oral prednisone). Also, there
have been signs that corticosteroids given to patients with
acute optic neuritis might reduce the rate of development of
MS, but a recent study using methylprednisolone in patients
with chronic progressive disease found that initial improve-
ment was not sustained.
There is promise too with interferon therapy. Many early
studies using interferons were conducted before the immu-
noregulatory effects of interferons were understood, but they
did demonstrate that natural interferon beta could reduce ex-
acerbations by inhibiting interferon gamma which in itself ap-
peared to act as a disease activator. Natural interferon alfa
alone was found to produce little or no benefit. Subsequent
studies in patients with relapsing-remitting disease have used
recombinant interferon beta and patients treated with interfer-
on beta-lb have obtained a reduction in the rate and severity
of exacerbations: there was also evidence from magnetic
resonance imaging of reduced disease activity and burden.
Encouraging results have also been obtained in patients with
secondary progressive disease. Similar results in relapsing-
remitting disease have been obtained with interferon beta-
la. However, the effect of interferon beta on the progres-
sion of disability remains to be determined. Concern has been
expressed over the detection of neutralising antibodies
against interferon in up to 36% of patients. Guidelines for
the use of interferon beta in selected patients in specialist
centres have been proposed.
Results of a study of glatiramer have shown that it can
reduce the number of relapses and may produce some im-
provements in neurological disability. These benefits are pro-
duced in a different way from those gained with interferon
bela-lb leading to expectations of a study of treatment with
both drugs. Intermittent intravenous immunoglobulin might
also be able to reduce the frequency of exacerbations and
slow disease progression without producing troublesome ad-
verse effects.
Although some studies have shown modest benefits with im-
munosuppressants, the general conclusions of large control-
led studies have tended to be that any slight benefits of
existing therapies with immunosuppressants such as azathio-
prine, cyclophosphamide, or cyclosporin are outweighed by
the toxicity of the doses required to have an effect."" How-
ever, it has been pointed out that in terms of relapse reduction
azathioprine appeared to be as effective as newer treatments
such as interferon beta. A study with cladribine suggested
that it might provide some benefit at well-tolerated doses,
and low-dose methotrexate might also slow progression of
chronic disease and provide a relatively non-toxic treatment
option. 38 Benefit has been reported with roquinimex .
Other immunological approaches under evaluation include
the use of monoclonal antibodies such as CD4 antibodies, al-
tered peptide ligands from myelin basic protein, and T-cell
vaccination. Combined total lymphoid irradiation with low-
dose corticosteroid therapy has also been investigated and
may slow progression of disease.
A review of the relationship between dietary fat and MS con-
cluded that the role of lipids remained to be proven. Some
studies found a reduction of severity and duration of relapse
in patients taking linoleic acid supplements (as sunflower
oil)" while another reported benefit in patients who limited
their intake of dietary saturated fatty acids and supplemented
their diet with polyunsaturated fatty acids. Despite a lack of
firm evidence many patients with MS practice dietary modi-
fication and take supplements of omega-6 group polyunsatu-
rated acids, sunflower oil, evening primrose oil, fish oils, and
omega-3 fatty acids.
The use of hyperbaric oxygen therapy in MS has been a mat-
ter of debate for many years and continues to be controversial.
Some workers have reported benefit, especially in bladder
and bowel function or in cerebellar function. Others have
been unable to substantiate any useful long-term effects and
a review of the many therapeutic options available in MS con-
cluded that there was no convincing evidence that hyperbaric
oxygen therapy was successful.
Mycobacterial infections. Interferon gamma injected into
lesions of patients with leprosy was reported to stimulate an
immune response similar to that of a delayed hypersensitivity
reaction and to reduce the intralesional bacterial count.
Experience with interferons for opportunistic mycobacterial
Infection in patients with AIDS is limited. Interferon gamma
given in conjunction with antimycobacterials produced bene-
ficial responses in 3 patients with Mycobacterium avium com-
plex infections, but produced no response or only a transient
response in 3 others who received interferon gamma alone.
Beneficial responses have also been reported following treat-
ment with interferons alfa- and gamma as adjuncts to an-
timycobacterial therapy in HIV-negative patients with
mycobacterial infections which had not responded to conven-
tional therapy.
A study of 5 patients with multidrug-resisiant tuberculosis
suggested that inhaled interferon gamma may be a useful ad-
junct in patients not responding to conventional therapy
alone.
Skin disorders. Interferons have been tried in skin disorders
in which lgE levels are raised. Subcutaneous interferon gam-
ma improved eczema and reduced serum-lgE concentration
in one patient, but the condition gradually returned within a
week of stopping treatment. In two studies subcutaneous
interferon gamma given to patients with severe atopic derma-
titis and raised serum-lgE concentrations resulted in improve-
ment of the skin condition; lgE concentrations were reduced
in one study but remained high in the other.l Subcutaneous
interferon alfa, however, was unsuccessful in 2 patients with
very severe atopic dermatitis; serum-lgE concentrations and
severity of the skin condition remained unaffected. Interfer-
on alfa has been tried in subacute cutaneous lupus
erythematosus and discoid lupus erythematosus. Although
marked improvement generally occurred, the condition tend-
ed to recur within several weeks of stopping treatment. For
discussion of the conventional treatment of eczema, and of lupus
erythematosus.
There have been reports of the successful use of interferon
alfa to control the symptoms of urticaria associated with mas-
tocytosis.
Interferons have also been proposed for antifibrotic therapy in
the management of diffuse scleroderma. A multi-
centre study of interferon gamma in scleroderma found that
cutaneous symptoms might be improved but that treatment
was associated with an unacceptable incidence of adverse ef-
fects. Interferon gamma has also been tried in eosinophilic
pustular folliculitis.
Interferons have also been used for the treatment of warts (see
below).
Interferon alfa has improved symptoms such as pruritus in pa-
tients with polycythemia Vera. For reference to the use of
interferon alfa-2b in polycythaemia vera, see Blood Disor-
ders, above.
Varicella-zoster infection. Interferons alfa, beta and
gamma have been tried in varicella-zoster infections by a va-
riety of routes of administration although the standard treat-
ment is with aciclovir and related antivirals which
are preferred since they produce fewer adverse effects.
Warts. Various interferons by various routes have been tried
in the treatment of anogenital warts (condylomata accuminata).
lntralesional injection has been used to ensure rel-
atively high concentrations of interferon in the wart but the
occurrence of systemic adverse effects demonstrated that
there is absorption from this site. Eron and colleagues'
report-
ed complete responses in 36% of patients receiving intrale-
sional interferon alfa-2b compared with 17% receiving
placebo, and a corresponding overall reduction in the affected
area of 62.4% compared with 1.2%. However, follow-up was
not sufficiently long to comment on relapse rates. Reichman
and colleagues found similar responses using interferons
alfa-2b, alfa-n I. or beta in patients with refractory warts,
with
complete responses in 47% of patients receiving iniralesional
interferons compared with 22% of patients receiving placebo.
A study evaluating two different doses of intralesional inter-
feron beta given three times a week for three weeks reported
complete responses in 63% of lesions injected with
I million units compared with 38% of lesions injected with
33 000 units. Good responses have also been reported in pa-
tients with both refractory and recurrent warts treated with
intralesional interferon alfa-n3. Relapses were delayed and
fewer warts recurred in patients who had received interferon
rather than placebo. Intralesional interferon alfa-2b given in
combination with podophyllum was more effective that podo-
phyllum 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 podophyllo-
loXin.6.7 Theoretically, systemic administration should have
advantages in controlling subclinical infections and reducing
relapses. However, responses to subcutaneous interferon alfa'
have generally been disappointing although Panici and
colleagues obtained responses comparable with cauterisa-
tion and a reduction in relapse rates with either subcutaneous
or intramuscular interferon alfa-2b. 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
receiving cryotherapy with subcutaneous interferon alfa or
cryotherapy alone. A study comparing subcutaneous interfer-
on alfa. beta. and gamma in combination with cryotherapy
found no significant difference in response rate. although pa-
tients receiving interferon beta or gamma developed new
warts at a lower frequency.