Interferon Background Information

[The following was extracted from an article by Robert Brodell, MD, 1996, Natural Alfa Interferon for Condyloma Acuminata, Infect Urol, 9(4):106-110]
Alpha interferon acts by binding to specific alpha interferon membrane receptors and then altering cell metabolism. This membrane-bound interferon has antiviral, antiproliferative, antitumoral and immunomodulatory activity. In the case of erradication of genital warts with intralesional injections, the exact mechanism involved is not known. However, one hypothesis suggests that intralesional interferon injections help target the virus and stimulate a host-immune response.
[From an article by M. Avidano, MD and G. Singleton, MD, 1995, Adjuvant drug strategies in the treatment of recurrent respiratory papillomatosis, Otolaryngol Head Neck Surg ,112(2):197-202]
The exact mechanism by which interferon (IFN) exerts its effect is not well understood. It is believed that there is modulation of the host immune response with production of a protein kinase and endonuclease, which results in both the inhibition of viral protein synthesis and breakdown of viral RNA. Several other cellular genes are also modulated by IFN with varying effects, and these regulatory mechanisms remain to be discovered.

Adverse Reactions to Interferon:

The most common side effects are flu-like symptoms, especially low-grade fevers, mild lethargy, fatigue and headache. Occassionally patients may experience an elevated liver function which would require at least a temproary discontinuation of the therapy.

Clinical Studies Involving Interferon(IFN) and RRP

1. Healy et al., 1988; N Engl J Med
Study Design - Randomized multi-center trial involving 123 patients (< age 21 ) - 62 receiving surgery plus IFN and 61 receiving only surgery (control)
Interferon product - Human leukocyte(alpha-n3) interferon from New York Blood Center
Dosage protocol - 2 MU/M² daily for 1 week and then 3 times a week for 12 months.
Result summary - Statistically significant improvement was seen in the interferon group for 6 months, but this was not sustained and by 12 months there was no significant difference.

2. Leventhal et al., 1991; N Engl J Med
Study Design - Long term follow-up beyond 12 months of 60 patients (< age 35 ).
Interferon product - Lymphoblastoid (alpha-n1) interferon (Wellferon).
Dosage protocol - 5 MU/M² daily for 28 days, then every other day for 6 months. Thereafter, either 4 MU/M² every other day or 2 MU/M² daily
Result summary - There were 22 "complete" remissions, 25 partial remissions and 13 who had no response. The median duration of the complete remissions was 550 days (with 15 still in remission at last follow-up).

3. Avidano and Singleton, 1995; Otolaryngol Head Neck Surg
Study Design - Long-term follow-up 34 patients.
Interferon product - Recombinant (alpha-2a) interferon (Roferon).
Dosage protocol - 5 MU/M² daily for 28 days, then every other day for 6 months. Thereafter, either 4 MU/M² every other day or 2 MU/M² daily
Result summary - There were 16 "complete" responses, 12 partial responses. Somewhat higher response rate in juvenile onset, versus adult onset.

4. Deunas et al., 1997; J Laryngol Otol
Study Design - One to five year treatment and follow-up program involving 125 patients, 92 children and 33 adults.
Interferon product - Human leukocyte(alpha) interferon from Center for Bologic Research in Havana (product similar to Alferon) - 102 patients;
Recombinant interferon (alpha-2b) from Center for Genetic Engineering and Biotechnology of Havana (product similar to Intron-A) - 12 patients.
The remaining 11 patients received a combination treatment.
Dosage protocol - A 12 month period of progressively reucing dosages for both children and adults as follows: Children started with 0.1MU/kg 3 times/wk for 1 month, then .075MU/kg 3 times/wk for the next month, .050MU/kg 3 times/wk for the next month, .050MU/kg 2 times/wk for the fourth month, and .050MU/kg U/kg 1 time/wk for the next 8 months. Adults started with 6MU 3 times/wk for 1 month, then 3MU 3 times/wk for the next 3 months, and 3MU U 2 times/wk for the remaining 8 months of treatment. If a rrelapse occurs the higher dosing schedule begins again.
Result summary - Of the 92 children relapses occurred in 41 during the period of interferon treatment and 12 after the period. For the 33 adults 11 had relapses during interferon treatment and 5 after.

Table 1: Interferon Efficacy vs. brands from RRPF Database

Interferon efficacy for RRP and neutralizing antibodies
( Bill Stern, RRPF Website - February-March 1999)

It has been suggested that there might be a substantial difference in the effectiveness of two types of Interferon due to the formation of neutralizing antibodies. Specifically, evidence that a much higher percentage of patients (Leukemia and Hepatitis C) being treated with Roferon-A developed neutralizing antibodies than those being treated with Intron-A. Thus far we cannot see this impact in data reported to the RRPF. Of 42 patients indicating on their RRPF surveys that they are using or have used Interferon regularly 17 treatments with brands have been reported (see table 1 above). Furthermore, in a careful reading of the Leventhal et al. paper detailing the Johns Hopkins interferon study for RRP patients, it is evident that they were concerned about the possiblility that neutralizing antibodies might result in a loss of effectiveness, however, as the following excerpt from their paper states, the presence of neutralizing anti-bodies did not appear to have an impact:
"Neutralizing antibodies can develop in patients who receive recombinant or natural preparations of interferon alfa. In patients with hairy-cell leukemia and chronic myelogenous leukemia there is some suggestion that the formation of antibody to recombinant interferon alfa is associated with an abrogation of response. In the extensively studied population with juvenile-onset respiratory papillomatosis described herein, 21 percent of the patients had neutralizing antibodies to interferon. There was no correlation, however, between the development of neutralizing antibodies and diminsihed clinical response."

[The following comments are from an expert on Interferon and HPV, Dr. William Bonnez.]

I agree that overall it appears that interferon alpha-2a (Roferon-A) has to
have a higher propensity to induce neutralizing antibodies than interferon
alpha-2b (Intron-A). Some work done by Roche suggests that the storage
temperature contributes to the antigenicity of Roferon-A; keeping the
preparation refrigerated being best. It should be noted that any of the
interferons, alpha, beta, or gamma, can induce the formation of neutralizing
antibodies. By and large this antigenicity phenomenon is not well
understood. For example, interferons alpha-2a and alpha-2b differ only by
one amino-acid, something that does not seem to provide a sufficient
explanation.
 These neutralizing antibodies appear to have an adverse effect on in
vivo interferon activity. Several reports have indicated that the presence
of interferon neutralizing antibodies was associated with treatment failure
(e.g., multiple sclerosis and interferon beta, hepatitis C and interferon
alpha,...) and that the administration of a different interferon, typically
a natural interferon alpha, could overcome treatment resistance (this has
been shown in the case of hepatitis C). Natural interferons alpha are
constituted by several species of interferon molecules. Antibodies directed
to one species, e.g. alpha-2, do not seem to cross-react with another
species, e.g. alpha-1. This is why presumably natural alpha interferon
retain most of its efficacy.
 As you know, the clinical trials of interferon for the treatment of
RRP were done using either interferon alpha-n1 (Wellferon) or alpha-n3
(Alferon N), two natural interferons. I have been involved in the only
three studies that have looked comparatively at the efficacy of different
interferons, either intralesionally of systemically administered, for the
treatment of genital warts (Reichman RC, Oakes D, Bonnez W, et al. Treatment
of condyloma acuminatum with three different interferons administered
 intralesionally: A double-blind, placebo-controlled trial. Ann Int Med
1988;108:675-9.; Reichman RC, Oakes D, Bonnez W, et al. Treatment of
condyloma acuminatum with three different alpha interferon preparations
administered parenterally: A double-blind, placebo-controlled trial. J
Infect Dis 1990;162:1270-6; Reichman RC, Oakes D, Bonnez W, et al. Treatment
of condyloma acuminatum with three different alpha interferon preparations
administered parenterally: A double-blind, placebo-controlled trial. J
Infect Dis 1990;162:1270-6; Bonnez W, Oakes D, Bailey-Farchione A, et al. A
randomized, double-blind, placebo-controlled trial of systemically
administered alpha-, beta-, or gamma-interferon in combination with
cryotherapy for the treatment of condyloma acuminatum. J Infect Dis
1995;171:1081-9). We did not observe any differences in efficacy, or lack
thereof, among interferon preparations. Obviously, lack of observable
differences does not mean that no differences exist, only that given the
size of the trials they could not be detected.
 Consequently, short of appropriate data and this point needs to be
emphasized, I think it is reasonable to expect that any interferon
preparation might be efficacious in the treatment of RRP. However, if in a
given patient one observes there is lack of clinical efficacy, I think it
would be then appropriate to try a different interferon preparation,
preferably moving from a recombinant interferon to a natural interferon. I
cannot make strong recommendations in favor of Intron-A versus Roferon-A
because the data are only inferential, but obviously everything being
equal, as a starting choice Intron-A might be preferred. Please note that if
the clinical trials were to be done, Roferon-A could turn out to be a more
potent interferon than Intron-A for the treatment of RRP, in spite of
neutralizing antibodies. We simply do not know.

William Bonnez, M.D.
Infectious Diseases Unit
University of Rochester Medical Center

As Dr. William Bonnez indicated above, the best way to evaluate the relative efficacy of any treatment
including various brands of interferon is to collect appropriate clinical data, ideally via double-blinded trials.
Furthermore, a search of literature for information on neutralizing antibodies and Interferon use , 
indicates that the extent to which these antibodies form in a patient may be a function of a number of factors 
including the type of disease being treated, the route of administration and the dosage. In addition, 
several studies (Itri et al., 1987; Steis et al., 1990) have indicated that the long-term effectiveness of 
Interferon therapy was not likely to be compromised by neutralizing antibodies. In this regard, 
the RRPF would like to once again state that not only is it counterproductive to
condemn those dedicated RRP practitioners who might have prescribed Roferon-A instead of Intron-A,
but it could be erroneous as well. As a matter of fact, I recently received an e-mail from an RRP patient
who has been treated with Interferon for more than 18 years, the following is an excerpt from that e-mail
indicating a greater effectiveness from Roferon-A than from Intron-A:

"... So I guess all I can say is that after many years of use of Roceron-A I did overcome the flu feelings.
Didn't feel a thing with Intron-A and couldn't see it was working at all. With Roferon-A I had a lot more
flu-feeling than in years. But that's hard to determine if it was because I've been more or less starting over
with interferon or not. At least Roferon-A was working better than Intron-A when it came to taking care of
the papilloma growth."

As a follow-up, the RRPF has learned that the Roferon product that has been used after 1996 is not  the same product 
that was being implicated in the past as having a greater tendency to form neutralizing antibodies.

The RRPF is not in a position to conduct a double-blinded clinical trial, but has been collecting data
regarding adjunct treatments and encourages RRP patients who have or are using Interferon to indicate
the brand(s) that have been used, as you complete updated patient survey forms.  It is our hope that 
a clinical study evaluating the relative efficacy of a variety of interferon products for RRP will
eventually take place.

It would seem that if one's situation dictates interferon as the therapy of choice and a particular brand is
ineffective or has become ineffective it would make sense to switch brands. To quote from Dr. Bonnez's
response below, "... if in a given patient one observes there is lack of clinical efficacy, I think it would be
then appropriate to try a different interferon preparation, preferably moving from a recombinant interferon
to a natural interferon."  In this regard, perhaps Alferon, which has been used in clinical trials and is FDA 
approved for treating genital HPV may be a promising interferon therapy. In clinical trials by 
Interferon Sciences (the manufacturer of Alferon), it was shown that effecitve  elimination of genital warts 
could be achieved at less than 1/4 the dosage as that required with Intron A, and  with less adverse 
side effects (Interferon Sciences, unpublished study). A very similar interferon to Alferon was used in the 
Cuban national RRP study, with good efficacy being reported.

Frequently Asked Questions:

Q: Is it time to stop using Interferon and how should this be done?
My daughter has been on Interferon for 6 months and it is showing no real signs of controlling her RRP. Her surgeries are still frequent. I would like to stop the Interferon today but my main concern is it could have a rebound effect and flare up worse than ever before. What should we do?

A: I have seen a wide response profile to interferon. Some respond and others don't. I still feel that everyone deserves several prolonged courses of the drug. (Jerome Thompson, MD, Dept. of Otolaryngology, University of Tennessee)

A: We did an interferon study many years ago, where we adjusted the dose to the individual patient. There were small (110 lb) women who needed a higher dose than a large man, even though we were suppossed to be correcting for body size. You might talk to your doctor about increasing the dose for a limited period (several weeks) to see if there is improvement. Removing interferon does result in return of the disease as it was before therapy in many patients who respond to interferon. I'm not sure whether it will get worse in someone who is not obviously responding. (Bettie Steinberg, PhD., Dept. of Otolaryngology, Long Island Jewish Medical Center)

A: I am not an expert on Interferon . However, based on literature that I have read and discussions with other RRP patients/parents, it seems that Interferon usually has an impact within 6 months of starting it and often sooner. I am assuming that your physician is following a protocol that has proven efficacy based on published results (e.g., the protocol that Kashima and others at Johns Hopkins recommends is written up in Leventhal et al., 1991). If indeed this is the case, and if she were my daughter, I would get her off Interferon - but I would do it gradually in consultation with an expert, so as to minimize any possibility of a "rebound" effect. (Bill Stern, RRP Foundation)

Q: Have there been any documented changes in the Inteferon side-effects during puberty?

A: I have not heard of a particular problem with puberty. (Jerome Thompson, MD, Dept. of Otolaryngology, University of Tennessee)

References:

Avidano MA; Singleton GT

Otolaryngol Head Neck Surg 1995 Feb;112(2):197-202

Adjuvant drug strategies in the treatment of recurrent respiratory papillomatosis.

Department of Otolaryngology-Head and Neck Surgery, University of Florida College of Medicine, Gainesville.

The purpose of this study was to evaluate adjuvant drug therapies
combined with standard laser excision in the treatment of
recurrent respiratory papillomatosis. Previous studies have
presented conflicting data on the efficacy of various treatments,
including interferon and isotretinoin. A retrospective study of
34 patients with moderate to severe papillomatosis who underwent
both laser surgery and adjuvant therapy was therefore performed.
All patients were treated with interferon. Five interferon
failures received isotretinoin, and three with recalcitrant
disease received methotrexate. Interferon produced a complete
response in 16 patients and partial response in 12 patients.
Juvenile-onset disease had a slightly higher response to
interferon than adult-onset disease. isotretinoin produced no
response in all five patients. Methotrexate demonstrated a marked
improvement in both severity of disease and treatment interval in
all three patients. Serious side effects were limited to one
interferon patient with febrile seizures, which resolved with
discontinuation of therapy. We conclude that adjuvant therapy
including interferon and methotrexate is clearly of benefit in
the treatment of patients with respiratory papillomatosis. A
detailed approach to surgery combined with an interferon dosing
regimen is presented. Further study of methotrexate appears
warranted.


Backe J; Roos T; Kaesemann H; Martius J; Ott M

Gynakol Geburtshilfliche Rundsch 1995;35(2):79-84 

[Local therapy and adjuvant interferon therapy in genital
papilloma virus infections]

Universitatsfrauenklinik Wurzburg, Deutschland.

OBJECTIVE: Is it possible to reduce the recurrence rates of
HPV-positive genital tract lesions by systemic interferon alfa-2a
in addition to local therapy? METHODS: Thirty-three of 63
patients with first manifestation of papillomavirus infection or
monolocal manifestation were treated by local therapy. The other
30 patients with recurrent or multiorgan infections received 3
courses with 12 x 10(6) IU interferon alfa-2a subcutaneously.
RESULTS: For the remaining 47 patients (16 were lost to
follow-up) we found a significantly lower recurrence rate of 21%
(5 of 24) in the group of interferon-treated patients compared to
52% (12 of 23) of patients treated without interferon.
CONCLUSIONS: The systemic treatment of HPV-positive genital tract
lesions with interferon alfa-2a in addition to CO2 laser surgery
or cone biopsy seems to reduce the recurrence rates of
HPV-positive lesions.

Billard C

Bull Cancer (Paris) 1993 Sep;80(9):741-56

[Interferons, a class of cytokines with a large therapeutic activity range]

Unite 365 INSERM, Institut Curie, Paris, France.

Initially discovered as antiviral agents, the interferons (IFNs)
proved to be a class of cytokines with multifunctional
properties, including inhibition of cell growth and modulation of
immune functions. A number of clinical trials were thus carried
out in cancer and viral diseases, and IFN-alpha therapy was shown
to have a wide range of indications in hematology and
dermatology: B-cell malignancies (hairy cell leukemia,
non-Hodgkin's lymphoma, multiple myeloma), myeloproliferations
(chronic myeloid leukemia, thrombocytosis), cutaneous T lymphoma,
basal-cell carcinoma, cutaneous squamous cell carcinoma, Kaposi's
sarcoma. IFN therapy also showed efficacy in viral tumors
(condyloma acuminatum and laryngeal papillomatosis) and chronic
hepatitis B and C. The antitumoral action of IFN-alpha mainly
involves its capacity to inhibit cell proliferation, partly via
antagonistic effects on growth factors. The elucidation of
IFN-alpha signalling pathway(s) leading to gene activation, a
better understanding of the interactions between IFN-alpha and
cytokine network, and the development of combination therapy with
other biological treatments or chemotherapy should greatly
improve the clinical use of IFNs.

Brodell R

Infect Urol 1996; 9(4):106-110

Natural Alfa Interferon for Condyloma Acuminata

Northeastern Ohio Universities College of Medicine, Case Western Reserve University School of Medicine

Intralesional interferon alfa-n3 has been approved by the Food and Drug
Administration for the treatment of persistent or recurring external genital warts.
Injections are easy to perform and well tolerated. Before treatment with alfa interferon,
it is important to assess the extent and duration of the disease, previously failed
treatments, potential side effects, the impact of treatments on patients' daily lives,
and patients' motivation to eliminate the disease.

Cantell K

Ann Med 1995 Feb;27(1):23-8

Development of antiviral therapy with alpha interferons: promises, false hopes and accomplishments.

National Public Health Institute, Helsinki, Finland.

This overview describes the development of interferon therapy in
four different types of viral diseases. (1) Upper respiratory
infections: despite extensive efforts interferons have not found
a place in the treatment of these very common diseases. (2)
Herpes keratitis: alpha interferons are highly active in
combination therapy, but have gained only very limited clinical
use. (3) Papillomavirus infections: alpha interferons have been
approved for the treatment of papillomavirus infections of skin
and mucous membranes and are in fairly wide clinical use. (4)
Chronic hepatitis B, C and D: alpha interferons have become the
treatment of choice and are used very extensively worldwide. The
four examples illustrate both the clinical potentials and the
limitations of alpha interferons and give some guidelines for
future work. The overall conclusion is that chronic viral
diseases lend themselves to interferon therapy more readily than
acute viral infections. The general trend is toward the use of
interferons in combination therapy.

Deunas L, Alcantud V, Alvarez F, Arteaga J, Benitez A, Bopuza M, Carniege L, Cartaya B, Comas C, Cotayo R, Escobar H, Fernandez H, Fernandez M, Fernandez R, Garcia M, Iznaga N, la O F, Marquez J, Nordet D, Perez J, Quintero J, Redonavich A, Robeleco M, Rodriguez H, Strander H

J Laryngol Otol 1997 Feb;111(2):134-40

Use of interferon-alpha in laryngeal papillomatosis: eight years of the Cuban national programme.

Otorhinolaryngology Services of Hospitals throughout Cuba, Ministry of Public Health, Havana, Cuba.

Laryngeal papillomatosis is one of the first diseases where interferon (IFN) was found to be effective. In
1983, a programme for the treatment of all such cases started in Cuba. Up to December 1991, 125 patients
(92 children, 33 adults) have been treated: 102 with leucocyte IFN-alpha, 12 with recombinant
IFN-alpha-2b, and 11 have received both preparations. Case management consisted of surgical removal of
the lesions followed by an IFN schedule starting with 10(5) IU/kg of weight in children or 6 x 10(6) IU in
adults, i.m. daily. The dose was progressively reduced, as long as no relapses occurred. At the end of the
one-year schedule the doses were reduced to 5 x 10(4) IU/kg in children or 3 x 10(6) IU in adults, weekly.
If there was a relapse, it was removed surgically and the patient returned to a higher dose level. Most
cases (89; 71 per cent) have not relapsed after the treatment; 60 of them have been followed for more than
three years. In those with relapses, the frequency of recurrence decreased in all but four patients. The
treatment seemed to be more effective if initiated less than three months after the disease onset. The
tracheostomy could be removed in five out of seven patients who needed it before the IFN treatment and
was necessary in only three new cases during IFN treatment. In two of these, decannulation was possible
later on. In a total of 14 patients relapses persisted after several cycles of IFN treatment. They were
considered resistant to such treatment. No severe side effects were reported. The most frequent ones
were fever, drowsiness, increased bronchial secretion, chills and headache. The establishment of this
programme has maintained the disease under control in Cuba. 

Finter NB; Chapman S; Dowd P; Johnston JM; Manna V; Sarantis N; Sheron N; Scott G; Phua S; Tatum PB

Drugs 1991 Nov;42(5):749-65

The use of interferon-alpha in virus infections.

Wellcome Research Laboratories, Beckenham, Kent, England.

The interferons (IFN) act too slowly to arrest acute viral
infections, but interferon-alpha (IFN alpha) preparations have
proved useful in some chronic infections and will clearly be used
increasingly in these in the future. In the preparations derived
from human leucocytes or cultured B lymphoblastoid cells, which
are in routine clinical use, mixtures of a number of distinct
subtypes of human IFN alpha have been identified. There are also
3 slightly different versions of the same single subtype, IFN
alpha-2, made by recombinant DNA procedures in bacteria. IFN
alpha preparations are injected intramuscularly or
subcutaneously. Dose-related side effects are common but usually
tolerable, but prolonged treatment may cause increasing fatigue
and depression. Some patients form neutralising antibodies which
block the effects of the IFN; these appear to be relatively more
common after recombinant IFN alpha-2 than after IFN derived from
human cells. Given intranasally, IFN alpha can prevent a
subsequent experimental rhinovirus infection, or the spread of
natural colds within a family. Repeated administration
progressively damages the nasal mucosa, so that long term
prophylaxis is not possible. IFN alpha has proved useful in
patients with papillomavirus warts of the larynx, ano-genital
region (condyloma acuminata) and skin (common warts). Treatment
regimens remain to be optimised and are likely to include surgery
or other treatments. IFN alpha and zidovudine (azidothymidine)
synergistically inhibit the growth of HIV in vitro, and
combination are on trial in patients with early AIDS. Very large
doses of IFN alpha are effective against Kaposi's sarcoma in some
AIDS patients. In chronic hepatitis B, continuing virus
replication may lead to cirrhosis or primary liver cancer.
Earlier clinical trials with IFN alpha gave inconclusive results,
but recent large studies have confirmed that 25 to 40% of
patients obtain benefit; this probably results from both the
antiviral and the immunomodulatory effects of IFN alpha. In
patients with chronic hepatitis C, the biochemical markers
usually improve rapidly during IFN alpha administration, but
relapse if treatment is stopped after only a few months; to
increase the chances of sustained cure, the treatment period is
now being prolonged.

Finter NB

Biotherapy 1994;7(3-4):151-9

Cytokines in the treatment of virus infections.

The interferon (IFN) system consists of both the formation of the
various IFN proteins, and the diverse cellular responses which
these induce: these result from the intracellular changes which
follow their binding to a specific cell surface receptor. There
is only a single human gamma, omega and beta IFN; in contrast,
there are 13 closely related chemical species (subtypes) of
human alpha IFN, which are nevertheless chemically and
biologically distinct. IFN preparations made from mass cultured
human cells or by using recombinant DNA techniques are now
readily available for clinical use. IFN have a major role in the
defence of the body against virus infections. In acute virus
infections, preformed exogenous IFN cannot be given soon enough
to be of value. However, IFN-alpha and IFN-beta have proved of
considerable value in some chronic virus infections, particularly
chronic virus hepatitis and chronic papillomavirus infections.
The doses routinely used are associated with both acute and
chronic toxic side effects. Also, some patients form specific
neutralising antibodies against the particular IFN preparation
injected, which may abrogate all the benefits of the treatment.
Nevertheless, IFN are now established as agents for use in
routine medical practice.

Gall SA

Am J Obstet Gynecol 1995 Apr;172(4 Pt 2):1354-9

Human papillomavirus infection and therapy with interferon.

Department of Obstetrics and Gynecology, University of Louisville School of Medicine, KY 40202, USA.

The studies summarized have shown that therapy of condylomata
acuminata with interferon is effective. The route of
administration does not appear to influence the results; the
intralesional, intramuscular, and subcutaneous routes were
effective. Additional research is required to determine whether
the natural interferon or recombinant product is superior. The
appropriate administration schedule may also not have been
attained.

Gangemi JD; Pirisi L; Angell M; Kreider JW

Antiviral Res 1994 Jul;24(2-3):175-90

HPV replication in experimental models: effects of interferon.

Greenville Hospital System/Clemson University, SC 29634.

Preclinical evaluation of the effectiveness of interferon (IFN)
therapy on human papillomaviruses (HPV) has been hampered by the inability 
to propagate these viruses in cell culture.
Nonetheless, interferon is used extensively in the treatment of
HPV infections. Alpha interferons in particular have found a
place in the treatment of anogenital disease, plantar warts, and
laryngeal papillomas. While their is significant clinical
evidence to suggest that interferon is useful in therapy of
disease, the cellular mechanism(s) (i.e., antiviral,
antiproliferative, immunomodulatory) by which IFN is able to
control HPV-induced pathology is not well understood. This review
focuses on experimental animal and cell culture models which are
currently being used to help identify the antiviral,
antiproliferative and immunomodulatory effects of IFN on HPV
infection.


Healy GB, Gelber RD, Trowbridge AL, Grundfast KM, Ruben RJ, Price KN

N Engl J Med 1988 Aug 18;319(7):401-7 

Treatment of recurrent respiratory papillomatosis with human leukocyte interferon. Results of a multicenter randomized clinical trial.

Department of Otolaryngology, Children's Hospital, Boston, MA 02115. 

Recurrent respiratory papillomatosis is a relentless disease of viral origin in which squamous papillomas
frequently obstruct the respiratory tract of children and young adults. No therapy has been proved to be
curative for this process. Recent reports have suggested that interferon may cure or dramatically control
airway papillomatosis. We evaluated the efficacy of human leukocyte interferon in the treatment of
respiratory papillomatosis. One hundred twenty-three patients were randomly assigned to receive
treatment with either surgery plus interferon or surgery alone. Interferon (2 X 10(6) IU per square meter of
body-surface area) was given daily for one week, then three times per week for one year; treatment was
followed by a year of observation, without the drug. Both study groups underwent serial endoscopy to
remove papillomas and to document the efficacy of treatment during the two years of study. During the
first six months, the growth rate of papillomas in the interferon group was significantly lower than in the
control group (P = 0.0007). This difference diminished during the second six months and was no longer
statistically significant (P = 0.68). Our data do not show that interferon is either curative or of substantial
value as an adjunctive agent in the long-term management of recurrent respiratory papillomatosis. The
initial benefit of interferon is not sustained. 


Herberhold C; Walther EK

Combined laser surgery and adjuvant intralesional interferon

Adv Otorhinolaryngol 1995;49:166-9 

Injection in patients with laryngotracheal papillomatosis.

Department of Otorhinolaryngology, University of Bonn, Germany.

[No Abstract Available]


Kol'tsov VD; Onufrieva EK; Chireshkin DG; Malinovskaia VV; Ershov FI

Vestn Otorinolaringol 1995 Sep-Oct;(5):24-6 

[Antibodies to alpha-2A interferon in children with juvenile respiratory papillomatosis]

Follow-up of 36 JRP children and 12 controls (as shown by
solid-phase enzyme immunoassay) has revealed that antibodies to
IFN-alpha 2a with titers 1:20 to 1:1280 were present in 73.7% (14
of 19) of patients after interferon therapy and in 5.8% (1 of 17)
of those who have not received interferon. None of the controls
had the antibodies. Among the patients who have received only
recombinant IFN-alpha 2a 88.8% carried the antibodies. In
leukocytic interferon-treated group this number made up 20%. The
primary results evidence that there is no negative effect of IFN
antibodies on the treatment results in the doses and schemes
used. Positive results of IFN in JRP were not reported either.

Leventhal BG, Kashima HK, Mounts P, Thurmond L, Chapman S, Buckley S, Wold D

N Engl J Med 1991 Aug 29;325(9):613-7

Long-term response of recurrent respiratory papillomatosis to treatment with lymphoblastoid interferon alfa-N1. Papilloma Study Group.

Department of Oncology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD.

BACKGROUND. We earlier reported that patients with recurrent respiratory papillomatosis responded to
six months of treatment with lymphoblastoid interferon alfa-n1. Because another study of patients treated
for one year with leukocyte interferon alfa-n3 found that the growth rate of papillomas was slowed in the
first six months but returned to base line during months 7 through 12 despite persistent interferon
treatment, we now report the long-term results in our original study patients who were followed for a
median of four years after the original one-year crossover study. METHODS. After the patients in our
study had completed the first study year, their physicians could continue or recommence treatment with
lymphoblastoid interferon alfa-n1 in a dose of either 2 MU per square meter of body-surface area per day
or 4 MU per square meter every other day. The extent of disease was measured by endoscopy when
clinically indicated. RESULTS. Data on late-follow-up were obtained for 60 of the 66 patients. There were
22 complete remissions and 25 partial remissions; 13 patients had no response. The median duration of the
complete remissions was 550 days, and 15 patients continued to be in complete remission. The median
duration of partial remissions was 400 days and seven patients were still in partial remission. Thirteen of 28
patients responded to a second course of interferon after an interruption in treatment of at least one month.
The rate of response in the 11 of 53 patients who had neutralizing antibody to interferon was the same as in
the patients without the antibody. CONCLUSIONS. Patients with severe recurrent respiratory
papillomatosis may have a sustained or repeated response to treatment with lymphoblastoid interferon
alfa-n1. We recommend that patients with recurrent respiratory papillomatosis who require surgery every
two to three months be given a six-month trial of interferon alfa-n1. 

Lopez Ocejo O; Perea SE; Reyes A; Vigoa L; Lopez Saura P

J Interferon Res 1993 Oct;13(5):369-75

Partial phenotypic reversion of HeLa cells by long-term interferon-alpha treatment.

Centro de Investigaciones Biologicas, La Habana, Cuba.

Human papillomaviruses (HPV) are associated with malignant
cervical neoplasia. Several HPV-related diseases have been shown
to be sensitive to interferon (IFN) treatment. HeLa cells contain
and express the HPV type 18 genome and were used as a model for
the evaluation of the viral expression regulation and the effect
on the malignant phenotype during IFN treatment. Cells were
treated continuously with 200 IU/ml IFN-alpha 2b or natural
leukocyte INF-alpha for six passages (42 days). Some IFN-induced
changes were observed: decrease of HPV-18 mRNA expression,
changes of cell morphology, and reduction of clonogenicity in
soft agar. Tumorigenicity in nude mice was not modified. Other
targets of the IFN system were analyzed, and an increase of the
2',5'-oligoadenylate synthetase mRNA level and a down-regulation
of type I IFN receptor were found. These results demonstrate that
long-term IFN-alpha treatment induces a partial phenotypic
reversion of HeLa cells to a more differentiated stage were
down-regulation of HPV-18 expression could play a central role.
It therefore confirms that the IFN-alpha treatment may be
therapeutically useful in cervix cancer produced by HPV-18.

Thurmond LM, Brand CM, Leventhal BG, Finter NB, Johnston JM

J Lab Clin Med 1991 Sep;118(3):232-40

Antibodies in patients with recurrent respiratory papillomatosis treated with lymphoblastoid interferon.

Burroughs Wellcome Co., Research Triangle Park, NC 27709.

Serum specimens from 53 evaluable patients enrolled in a clinical trial of lymphoblastoid interferon in
recurrent respiratory papillomatosis were screened for the presence of interferon-binding antibodies by an
indirect enzyme immunoassay and evaluated for neutralizing antibody measured as the inhibition of
antiviral activity. Immunoglobulin G antibodies that specifically bound lymphoblastoid interferon were
detected in 66% (35 of 53) of patients; neutralizing antibody was detected in 11 of the 35 patients having
binding antibody (and in none of the patients who were negative for binding antibody). The incidence of
detectable neutralizing antibody in this study population was 20.8% (11 of 53), which is markedly higher
than in previous reports of lymphoblastoid interferon in patients with other diseases (i.e., less than 1%
incidence). The cumulative dose received at the time of detection of neutralizing antibody ranged from 163
to 385 MU per square meter of body surface. Neutralizing antibody was detectable at a median time of 120
days after initiation of interferon therapy, and binding antibody appeared earlier in those patients (median
59 days) than in patients in whom only binding antibody was produced (median 116 days). Despite the
tendency of binding antibody to appear either in patients in whom neutralizing antibody was eventually
formed, the detection of binding antibody was not necessarily predictive of the subsequent development of
neutralizing antibodies. Binding antibody persisted after neutralizing antibodies had become undetectable.  
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