What is Interferon
And how does it work?
Last edited on January 29, 2005
WHAT IS INTERFERON AND HOW DOES IT WORK?
WHY IS DAILY DOSING BETTER?
INTERFERON-ALPHA2 DILUTION INSTRUCTIONS
INTRODUCTION
#1) NEVER give with food. Inteferon breaks down in the stomach with stomach acid. Always squirt it directly into the mouth where it is absorbed in the mouth and throat lining.
#2) ALWAYS keep refridgerated. It's useless if it hits room temperature. Keep unused dilutions frozen until needed. It's unknown how long Interferon stays effective in the fridge. Keep unused dilutions frozen until needed.
#3) It's USELESS to do on/off dosing. It MUST be given every 24 hours to maintain consistent levels in the bloodstream. (See excerpts below regarding peaks and valleys). It must be kept in the blood at all times. On/Off protocols are worthless because it progresses forward in times of no intervention.
There are no studies on low dose IFN in veterinary practise that I'm aware
of.
Feline immunodeficiency virus lacks sensitivity to the antiviral activity of feline IFN-gamma.
The antiviral activity of recombinant feline interferon-gamma (rFeIFN-gamma) against feline immunodeficiency virus (FIV) was investigated. A persistently FIV(Bang)-infected feline T cell line (FeT-J/Bang) was treated with either rFeIFN-omega, rFeIFN-gamma, or recombinant human IFN-alpha2 (rHuIFN-alpha2), and the culture fluids were tested for antiviral activity by reverse transcriptase (RT) assay. FeT-J/Bang cell cultures treated with rFeIFN-omega showed dose-dependent inhibition of RT activity. In contrast, rFeIFN-gamma treatment had no antiviral effect on FIV replication but instead caused a statistically significant enhancement on day 9 of culture. Antiviral activity of rFeIFN-gamma was also tested on feline peripheral blood mononuclear cells (PBMC). PBMC cultures were inoculated with FIV(Bang) and simultaneously treated with either rFeIFN-omega, rFeIFN-gamma, or rHuIFN-alpha2. FeIFN-gamma had no effect on FIV replication, unlike the rFeIFN-omega and rHuIFN-alpha2, which had strong anti-FIV effects. In another study, rFeIFN-gamma treatment was initiated 3 days before FIV(Bang) infection, the day of FIV(Bang) infection, or 3 days post-FIV(Bang) infection and then tested for antiviral activity. The time of initiating rFeIFN-gamma treatment had no effect on the antiviral activity. Hence, these results suggest that unlike rHuIFN-alpha2 and rFeIFN-omega, rFeIFN-gamma has no inhibitory effect on FIV replication in PBMC but causes a slight enhancement in a feline T cell line.
PMID: 11798461 [PubMed - indexed for MEDLINE]
"unlike rHuIFN-alpha2 and rFeIFN-omega, rFeIFN-gamma has no inhibitory effect on FIV replication" of course is suggesting that these two Interferons have a significant effect on the replication of the FIV virus. Dr. Janet Yamamoto is a reknowned feline virologist with a specialty in Feline Leukemia
It is relatively new, and being used "off-label" which means no studies
were done for FDA approval in animals. The use of Interferon for feline viruses was experimental and the results that vets who use it are seeing are being shared and tried by others. Most of the medications used in veterinary practise are "off-label" human medications that have FDA approvals based on human trials and you will not find specific studies done on cats or dogs unless the drug was specifically developed for, and tested in animals for FDA approval.
Interferon is Interferon. It acts the same way in cats as it does in humans. The recent understanding that low doses can be as effective as the higher, more toxic doses and a better understanding of diluting and freezing the Interferon to extend its shelf life has meant great strides in it's use in veterinary medicine. The purpose of low dose Interferon in cats is to mimic the same levels that are naturally produced in response to a viral attack.
Many people ask what is the connection between human viral treatments and
feline, and why should I care? The connection is this. Viruses all work the
same way. They may be species specific, but their biochemical mechanisms are
the same. Just as we use human Amoxycillin to treat bacterial infections in
both humans and cats, so too can human anti-virals work to help reduce viral
loads in cats. Interferon works the same way against the Hepatitis C virus
in humans.
If you read the La Roche link you will see that the primary functions of
Interferon are: anti-viral, anti-proliferative and immunomodulatory. It
"interferes" with the virus replication. By keeping the level of the virus
down in the host's system it allows the cat's own weakened immune system to
help suppress symptoms. The lower dose in veterinary practise is not
designed
to eradicate the virus as it is with Hepatitis C. Cats chronically infected
with FIV or Herpes will always have the virus, so the high dosage therapy is
of really no use. The idea is to either replace or supplement the levels of natural Interferon the cat is either not producing or not producing enough of. Interferons are natural virus killers. There are definitely some immune boosting benefits to Interferon but it's primary function is to keep the viral load in the system down.
We also supplement Boots and Sammy with 250 mgms of L-lysine which is an
amino acid that boosts the immune system. The combination of the Interferon
(prohibits viral replication) and L-lysine (boosts the immune system) is a
double whammy which in our experience has had incredible results.
When I first began talking about Interferon 5 years ago, no one had heard of
it. Vets told their clients it was toxic, didn't work, hadn't had much
positive response in human cancer treatments, had side effects, warned
against developing an immunity to it. In fact there are some theories that the reason some patients became immune to Interferon is because they interrupted the medication with breaks. Much like stopping antibiotic treatment before the full course, it allows the viruses to mutate defenses against the medication.
My recommendation is that if you have questions or want to broach the subject
of daily dosing with your vet, arm yourself with information and other's
experiences. And if your vet isn't willing to work with you on this, or
understand the logic of the human trials and results, then seek a second
opinion.
This page is arranged in 3 sections: What is Interferon and how does it work?
WHAT IS INTERFERON AND HOW DOES IT WORK?:
What does Interferon Do?
A Note on Feline Interferon Omega: Feline Interferon Omega is currently being tested in Europe. It is not available as yet in the United States, however it is being investigated by the FDA. Feline IFN-O promises to be more effective and easier to use in treating feline viral diseases, but until FDA approval Interferon-Alpha daily dosing remains our best option.
WHY IS DAILY DOSING BETTER?
Three Times Weekly Is A Terribly Poor Way to Dose Interferon....
This is a great article and also discusses the development of longer
acting pegylated interferons to better manage the peak and valley
effects of the current generation of Interferons:
“PEAKS AND VALLEYS - Because interferon has a half-life in serum of only
about 7 -10 hours. This means it peaks in the body at about 12 hours and
is then rapidly metabolized and excreted. At 24 hours after injection it
is barely measurable. By 36 hours it is not detectable with current
measurements. During this peak the is a rapid, dramatic drop in viral
load. As the levels of interferons quickly drop to negligible levels at
about 24 hours viral loads start rapidly climbing again. By 48 or
especially 72 hours much of the gain in viral reduction has been lost.
In other words, viral loads in the body fluctuate directly and rapidly
along with levels of interferon in serum, and when plotted on a graph
look like a sine wave, or a roller coaster. This graph, along with a
description of this phenomena, can be viewed on many websites and texts
on the subject, including the http://www.roche-hepc.com/ page. These
peaks and valleys have been followed for days in human subjects, and are
invariably similar in those who respond to IFN.
As interferon levels go up viral loads go down immediately. Then as IFN
levels drop, viral loads increase again rapidly. In the period from 24
to 48 hours viral loads peak to erase most of the gains made. In
standard TIW dosing the increase in viral loads is even more pronounced
during the 72 hour break once each week.”
"While interferons have been used for a decade against hepatitis C, the
most effective standard doses and frequencies have not been
established," says Hough. "Studies over the past six or seven years show
that the three times weekly dosage is not as effective as daily dosing,
yet we still cause patients to fail interferon therapy by ignoring the
kinetics of the hep C virus. Three times weekly is a poor way to
prescribe interferons because their short half-life of 7 to 10 hours
gives the virus a chance to rebound between injections. In my opinion,
we could double or triple sustained response rates from interferon
monotherapy [IFN alone] if we used high-dose, daily induction
strategies.
Daily Dosing: 1999 Symposium - "Twenty-four hours after subcutaneous interferon administration, exogenous interferon is not detectable and viremia starts to increase. Daily interferon administration could induce a better virological response than interferon administered three times a week."
Additional Medical Research on Daily Dosing vs On/Off
You might be interested in the following articles regarding daily
interferon dosing in the treatment of Hepatitis C. All of them are
recent. Granted these articles are for human studies, but I believe
they are the forerunners of future veterinary practise. Although the
concept of high dosing, combination therapies and the various types of
Interferon discussed are not really relevant to the low dose IFN
treatment of FIV+ cats, I believe the concepts of viral rebound, the
half life of Interferon and dose scheduling to maintain a steady state
of IFN within the body are very relevant. I also found the discussion
of the next generation of Pegasyus Interferons to be very interesting.
These Interferons will be longer acting and will mean longer intervals
between dosing to maintain steady state.
TIW refers to the standard Three Times Weekly protocol determined by the
FDA for Hepatitis C treatments.
(PRINCIPLES OF INTERFERON INDUCTION THERAPY, AMERICAN JOURNAL OF
MEDICINE, DEC 1999)
“Induction therapy uses higher than usual doses of interferon, given on
a daily, rather than three times per week basis, for a defined period.
The goal is to minimize fluctuations in interferon levels, preventing
viral rebound in periods when drug levels are low.”
CLINCIAL IMPLICATIONS OF HEPATITIS C VIRAL KINETICS, 1999
“Antiviral treatment of patients with chronic hepatitis C can perturb
the steady-state of virus production and clearance. From serial
measurements of changes in viremia, kinetic information on the dynamics
of hepatitis C virus (HCV) replication can be obtained. After a delay of
about 9 h Due to interferon-a pharmacokinetics, the decline of viremia
in patients treated interferon-alpha is characterized by a concave
shape. In the first phase (day 1) a rapiddose-dependent decline in viral
load is observed. The second phase viral decline (> or =day shows a much
slower decline with no or less pronounced differences between the
applied interferon-alpha schedules. While a first phase decline can be
observed in almost all patients treated with interferon-alpha,
non-responders typically reveal no further decline of viremia during the
second phase. Kinetic analysis showed that combination therapy with
interferon-alpha ribavirin has no direct synergistic antiviral effect in
the initial 4 weeks of treatment of HCV-infected patients with 6 MU
IFNalpha three times per week. Calculations revealed a minimum virus
production and clearance per day in patients with chronic hepatitis C
ofapproximately 10(10)-10(12) virions per day and an in vivo half-life
of the virus in the order of a few hours. The high turnover rates of HCV
explain the rapid generation of viral diversity and the opportunity for
viral escape from the host immune surveillance and antiviral therapy.
The implications derived from HCV kinetics comprise the consideration of
more aggressive dosing regimens (especially daily doses), the
possibility to optimize therapy individually not only according to
pretreatment parameters but also according to the initial decline of
viral load and the perception that eradication of the virus will rely on
the half-life of infected cells.”
“Daily therapy IFN-alpha produced the most significant inhibition of
tumor growth, tumor vascularization, and down-regulation of basic
fibroblast growth factor and matrix metalloprotease-9 mRNA and protein
expression. Changing dose and schedule of IFN-alpha administration had
minimal effects on the expression of vascular endothelial growth factor
or interleukin 8. The daily s.c.administrations of 5,000 or 10,000 units
IFN-alpha-2a produced maximal inhibition of bFGF
and MMP-9 expression (mRNA and protein), maximal reduction in tumor
vessel density, and maximal reduction in serum levels of bFGF. Daily
administration of higher doses of IFN-alpha failed to produce
significant antiangiogenic effects. These data suggest that the
antiangiogenic activity of IFN-alpha is dependent on frequent
administration of optimal biological dose and not maximal tolerated
dose.”
ENHANCING THE RESPONSE TO INTERFERON-ALPHA, JUNE 1999
“To ameliorate response rates in antiviral IFN-therapy a profound
understanding of viral dynamics, as well as immunological conditions
associated with viral persistence, seems to be essential…A kinetic model
of HCV infection based on principles established in studying HIV-1
infection was presented which is predictive for the outcome of IFN-alpha
treatment. It involves different rates of velocity and compares the
rates of acute clearance after different dosages of IFN-alpha
application. Using the hypothesis to fit the changes in serum HCV RNA
measured in a set of patients, it was found that 5 mIU daily dosing on
average blocks 81% of HCV production/release, whereas 10 or 15 mIU
blocks about 95% of HCV -production/release.
This novel therapeutic strategy shows promise for patients with HCV infection, one that 1) relies on daily, or "induction," interferon dosing instead of the standard three-times-weekly regimen, and 2) uses the antiviral drug ribavirin to help keep the virus from making a comeback once it has been largely eliminated. Daily dosing is thought to increase the effectiveness of interferons,
one function of which is to modulate the body’ s immune responses.
DAILY LYMPHOBLASTOID INTERFERON SUCCESSFUL IN GENOTYPE-1B PATIENTS
“The findings from this study support a daily dosing schedule for the
treatment of patients with chronic HCV
(Hepatitis C Virus) infection. They provide corroborative evidence that
HCV can have a very fast replication cycle, necessitating a dosing
schedule that keeps a relatively constant level
of interferon in the blood to keep the virus in
check.”
“Previous viral kinetic and dynamic data indicated that better dosing
schedules are needed, and present sustained response rates certainly
reinforce this need. The aim of this study was to document the effect of
varying doses and regimens of interferon alfacon-1 on genotype 1
kinetics during the first 48 hours after interferon administration….Once
or twice a day regimens of IFN administration produced better viral
suppression than TIW dosing. Lead researcher Rajender Reddy, M.D. of the
University of Miami School of Medicine said this finding held true
whether the total daily dose was 15 or 9 mcg. "In fact, the 9 mcg daily
regimen also had comparable viral suppression as 15 mcg daily and 7.5
mcg twice a day," he noted. "This was evident at 24 and 48 hours. And
then when we looked at rebound, the rebound was seen more often in the
three times a week regimen rather than the daily or twice daily
regimen."
While TIW dosing was definitely inferior in this study, Dr. Reddy found
that dosing more frequently than QD provided no advantage.
"Interestingly, the 7.5 mcg twice a day did not have any advantage over
the daily regimen. So, really there is no need to go to twice a day
regimenhe said. "What is not part of this study but has been looked at
as part of other studies, is thatthe twice a day regimen is not as well
tolerated as daily regimen. So, once a day is adequate as an induction
regimen."
To achieve effective viral suppression, Dr. Reddy said, "I'd conclude
that if you're going to go an induction regimen, you need to go with a
protocol of daily interferon. You really don't need togo to twice a day
interferon. As to whether this translates into more effective long-term
sustained response rates needs to be seen."
DAILY HIGH-DOSE INFERGEN TREATMENT CLEARS HEPATITIS C VIRUS BETTER
THAN STANDARD DOSING
“Induction dosing with 15 mcg of interferon alfacon-1 once a day
appeared to be best at reducing viral levels, according to the interim
results of this study. "I think this well tolerated regimen," Dr.
Pockros said. "I think the key take home lesson here is that patients
can handle the daily dosing. It's a reasonable approach to treatment."
HEPATITIS C AND LIVER TRANSPLANTATION
DAILY LYMPHOBLASTOID INTERFERON SUCCESSFUL IN GENOTYPE-1B PATIENTS
"The findings from this study support a daily dosing schedule for the treatment of patients with chronic HCV infection. They provide corroborative evidence that HCV can have a very fast replication cycle, necessitating a dosing schedule that keeps a relatively constant level of interferon in the blood to keep the virus in check."
INTERFERON DILUTION INSTRUCTIONS:
These instructions were provided by several members on the FIV egroup list. Please NOTE: These are laymen instructions and are not intended to replace veterinary advice. There are for informational purposes only. Please review these directions with your vet at the time he gives you the prescription before giving any home diluted medication to your cat.
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
For all who are interested, here are the posts regarding Interferon
dilutions. NOTE: this dilution recipe is for INTRON A at a concentration of
3 million units (MU) per 0.5 ML. If you use a different concentration of
Interferon (there are several available), this recipe is NOT valid.
-The following is the recipe I used. My scrip was for Intron A, at a
concentration of 3 million units per .5 ml.
It was a small vial ...a single use dose for a human, I guess. I took it to
the vet (I was careful to keep it refrigerated and then transport it in a
cooler.) He made the different solutions in 12 cc large syringes. These are
frozen in my fridge. Make sure to leave some air in the syringes or they may
crack when frozen. The last dilution, solution D is the one I use each day
and is kept cold in the fridge. Each day I use a small tuberculin syringe to
measure out 0.3 ml from the larger syringe. The small syringe has no point
on the end and I just inject enought of the interferon. I put it into a
small dish...it's a tiny amount... and add one teaspoon of unsalted tuna
juice and Jubi laps it up. (Much easier than squirting it into his mouth!)
The solution D lasts a month for me since I use it every day. The next time
I have to make the D dilution I will make enough monthly syringes to last
the rest of the year and freeze them, so I won't have to defrost the C
syringe over and over.
Oh, the drugstore I went to had to order it...I had to call around the area
to find a pharmacy. Your best choice is an ethical pharmacy...one that only
sells drugs...not a big chain store. I used Arrow Pharmacy. It took about 2
days to get the vial. You will only use a tiny fraction of the original
vial. Although it may keep indefinitely, I will start over again in 1 year
(unless we have a power outage and it spoils in the freezer!) I ended up
donating the unused vial to the vet.
I know it sounds confusing, but it is really step by step logical! Let me
know how you're doing!
PS -- Solution A is 100,000 units/ml; B is 10,000 units/ml; C is 1000
units/ml; and D is 100 units/ml. So when all the D is used up, C is thawed
and one ml. of C is mixed with 9 ml. of saline to make more D. When
eventually all of C is used up, B is thawed and one ml of B is mixed with 9
ml. of saline to make more C. And so on...
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Good morning to you. I finally got around to ordering interferon for
Sunny-it should arrive Wed. I signed the release from responsibility my
vet insisted on and am really hoping this will be the magic cure for him.
Can you explain to me, in simple turns, the reasons for the 7 days on 7
days off protocol? I think that's the dosage I will start him on and see
how he does with it. By the way, my vet recommended a pharmacy that
others you know might be interested in. It's called Island Pharmacy
Service, located in Wisconsin. They deal exclusively with animal dosages
of drugs and will dilute various human drugs down to the proper strength
for critters so you don't have to mess around with trying to do it
yourself. For a 3 month supply of interferon I only had to pay $30 plus
$6 s&h, which is a heck of a lot cheaper than what I was finding anywhere
else. It's mixed to a 30 unit/ml solution so I will give 1 ml/day. Their
number is 1-800-328-7060. They were very nice about the whole thing.
Thanks again for all your help...I really found your website helpful and
informative!
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
I get 1 single dose (for humans) syringe which contains 3 million
units of interferon as Roferon (that is how the prescription reads). You
will need (initially) 200 10 cc containers that close tightly, 2 1000 ml
bags of saline and needles. I use 10 cc aquilots as containers, others
have used 12 cc syringes (with caps, without needles). Inject the entire
syringe (3 million units) into 1000 ml sterile saline for injection.
Agitate to mix. Draw 10 ccs. into each of your 100 containers, and
freeze all but one, marking them as containing 3,000 units. Inject this
10 ccs into the new bag of saline, mix and put 10 ccs each into your
next 100 containers. Mark the containers with the dilution (30 units per
ml), and freeze all but 2 (2 weeks worth). Refrigerate these for use. I
give 1 cc daily directly into the mouth, aimed at the tonsils. Others
use different protocols, and I'm sure will offer advice. I'm not sure
that this will help in every case, but I have a cat who should have died
months ago (undiagnosed probable auto immune condition) and is still
hanging in there! As my Vet so succinctly puts it..."can't hurt, might
help"
TIPS ON USING INTERFERON: Medline abstract of Interferon study for FIV done by Dr. Janet Yamamoto:
Tanabe T, Yamamoto JK.
Department of Pathobiology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA.
Why Is Daily Dosing Better - Extensive medical research links explaining viral load, peaks and valleys, Interferon half life and why daily dosing is better,
At Home Interferon Dilution Instructions - listed at the bottom of the page.
Interferon Alpha-2a - Protocol and dilution information from Island Pharmacy
About Alpha Interferons - Most forms of alpha interferon only stay in the body for one day
Interferon-Alpha - from La Roche Pharmaceuticals. Clinical pharmacology section explains elimination half-life of between 3.7 and 8.1 hours (pdf format requires Acrobat Reader)
Low Dose Interferon Alpha - Another article on what Interferon does
Discovery & Development of Interferon
How The Immune System Works - Dr. Margaret Muns, DVM
What's Up With Interferon?
Half Life IFN-A vs Pegylated Interferon
How Does Interferon Work in Your Body? - National Aids Treatment Advocacy Project
Interferon: Reducing Viral Load - National Aids Treatment Advocacy Project
Interferon Therapy for Feline Viruses - From the Cat Clinic
Feline Interferon Omega: Published Studies - European Case studies (articles are in English)
Daily Dosing Consensus
Interferon Therapy & Feline Herpes Virus Skin Conditions - This is a big file that loads in Acrobat Reader and takes several minutes to load. Contains photos. Excerpts from this study published in Veterinary Dermatology, 1999 include "One cat in this study with dermatitis...was negative for feline
herpesvirus with polymerase chain reaction testing. This cat had been treated with oral alpha interferon prior to PCR sample collection and it is possible that the treatment reduced the amount of virus to below levels detectable with PCR..."
New England Journal of Medicine Hepatitis C Study, 2001 - "Conclusions :Treatment of acute hepatitis C with interferon alfa-2b prevents chronic infection."
Frequency of Dosing - Hepatitis C - "Five times a week dosing of consensus interferon is twice as effective as the same dose administered three times a week for 48 weeks"
Daily Dosing More Effective
1996 Study - Viral Dynamics Supporting Rationale for Daily Dosing
Interferon Half Life - Section on Induction Therapy asserts half life of IFN is 7-8 hours. Daily Dosing section discusses 1996 study of daily dosing and viral dynamics supporting rationale of daily dosing
Efficacy of Escalating to Daily Interferon
1997 Conference Report on Daily Dosing in HepC Patients - "Overall, daily IFN dosing resulted in better viral suppression compared with TIW [Three Times Weekly] dosing...These preliminary results demonstrate that daily dosing produces an earlier and more pronounced decrease in viral load compared with TIW dosing"
Liver Education Articles, Cedar Sinai Hospital - "As the kinetics of viral clearance associated with interferon therapy is better defined, the concept of daily dosing (as compared to thrice weekly dosing) is generating considerable interest"
1998
“Standard dose interferon therapy for hepatitis C has shown limited
efficacy post-transplant. Liver transplant patients take
immunosuppressive medications, have high hepatitis C virus levels, and
frequently have of genotype 1 infection, all of which are associated
with low response rates.
Interferon alone, dosed at 3 million units three time weekly, leads
transient reduction in hepatitis C virus level, but sustained responses
are rare…We have recently found that daily interferon, even when given
in low doses, can reduce inflammation and stabilize liver scarring in
transplant patients. Long-term, low dose, daily interferon maintenance
therapy may prove to be a means to control liver damage in transplant
recipients with progressive hepatitis C.
[Home]