Small increased ability to replicate in large quantities in

Contents
FELINE INFECTIOUS monocytes and macrophages. There are two major
forms of FIP: effusive (wet) form and non-effusive

PERITONITIS (FIP)—
(dry) form. The effusive form is characterized
by rapid onset and widespread vasculitis with

NOW A TREATABLE
fibrinous-granulomatous serositis, with protein-
rich effusions in the thoracic or abdominal

DISEASE
cavities. The non-effusive form is typified by
pyogranulomatous lesions found within multiple
body organs. The median life expectancy ranges
Jane Yu from days to weeks in the effusive form, and weeks

Control & Therapy Series – Issue 302 March 2021

Merran Govendir to months in the non-effusive form. Once disease
commences, few cats are reported to survive.
Sally J Coggins
Jacqueline M. Norris In reviewing previous FIP treatments, the major
Sydney School of Veterinary Science, challenge lies in the lack of well-controlled clinical
trials and the use of some treatments that are
The University of Sydney
mostly based on in vitro studies. In addition, some
[email protected] older literature describes potential treatment
C&T No. success in cases without a confirmed diagnosis of
FIP. Furthermore, despite recent breakthroughs
in treatment of FIP using a nucleoside analogue
Clinical bottom line (GS-441524) and protease inhibitor (GC 376), these
Recent advances in anti-viral therapy are showing products are not registered for veterinary use and
that effective treatment for FIP is no longer are not commercially available. Even with recent
a desperate hope, but a reality. The search access to remdesivir (which is metabolised into
for reliable and efficacious treatment for cats GS-441524), the high cost for these newer antiviral
suffering from FIP has eluded our profession agents mean that some treatments may remain
since it was first documented in the 1960s. Many cost prohibitive for many clients.
treatment approaches have been explored and
have, until recently, been ineffective. In 2018, Treatment Approaches for FIP
the feline medicine world took note as published Eliminating feline coronavirus from our global
studies on the nucleoside analogue GS-441524 population of domestic and wild cats has not
(Murphy et al. 2018; Pedersen et al, 2019) and been possible to date. Similarly, the development
protease inhibitor GC 376 (Pedersen et al, 2018) of successful vaccinations has been unrewarding
showed disease inhibition and remission states although the recent global pandemic in humans
in cats with confirmed FIP. Currently, these caused by SARS CoV2 has provided a framework for
products are not legally available for cats with FIP; new approaches to coronavirus vaccination. When
however, other potential antiviral drugs, namely faced with an infection that we cannot currently
Est. 1965
another nucleoside analogue Remdesivir and eradicate, effective treatment is our current focus.
the antimalarial drug mefloquine are currently
registered in Australia with the Therapeutic Good When considering treatment approaches to FIP,
Administration (TGA). Remdesivir has shown great there are three major elements to consider:
|

firstly, the virus endogenously mutates and

Centre for Veterinary Education

promise in the field, with an increasing number

of treatment successes cured within Australia acquires an increased capacity to replicate within
(now >100 cases). Both drugs are now the focus of macrophages/monocytes; secondly, there is an
prospective treatment trials through the Sydney ineffective host immune response and failure
School of Veterinary Science. These studies aim to clear the virus from infected macrophages;
to further investigate the short- and long-term and thirdly, the immune-mediated inflammatory
outcomes of both remdesivir and mefloquine as cascade that ensues in response to activated
FIP therapeutics in formal in vivo clinical trials and macrophages results in the pathology seen with
are actively recruiting new cases of confirmed FIP FIP.
Australia wide.
The three main targets for therapeutic intervention
Introduction therefore have aimed to:
Feline infectious peritonitis (FIP) is a fatal immune-
mediated disease in cats caused by virulent
pathotypes of feline coronavirus (FCoV) known as 1 Directly inhibit the viral replication using
targeted antiviral drugs (e.g. nucleoside
analogues and protease inhibitors);
Page 3

feline infectious peritonitis virus (FIPV). FIPV has an

 2 Improve the efficacy of the hosts immune was also determined. This drug was then tested in

Contents
response with immunomodulators used to experimentally infected FIP cats and led to the rapid
stimulate the patient’s immune system non- reversal of clinical signs and remission in all 10 cats,
specifically (e.g. interferons and polyprenyl without apparent signs of toxicity. In the following
immunostimulants); and year, Pedersen et al, 2019 reported the use of GS-
441524 in cats with naturally occurring FIP. In this

3 Dampen the immune-mediated response

with immunosuppressive drugs, to attempt to
ameliorate the clinical signs (e.g. corticosteroids
study, 26 cats completed the 12-week course of
treatment with 18 out of 26 cats going into remission
after the first round of treatment. Eight cats
and cyclosporin). relapsed, and five of the eight cats were treated at a
Authors’ views are not necessarily those of the CVE

higher dosage (from 2.0 to 4.0mg/kg q24 h). These

five cats then went into remission. Three of the eight
cats were treated at the same dosage, however
relapsed. One cat was euthanized while the other
two relapsed cats were treated a third time at higher
dosage. Overall, the study produced 25 long-term
survivors. However, a higher dosage of GS-441524
was required to treat cats with neurological FIP
(Dickinson et al, 2020).

The following describes the pros and cons of the

immunomodulators, immunosuppressive drugs and
antiviral drugs.

Antiviral therapeutics Although GS-441524 has shown to be successful in

Antiviral treatments aim to target cellular treatment of FIP, it is not currently registered for
mechanisms to inhibit viral replication or a specific veterinary use and is not approved by the Australian
aspect of virus activity related to infection. Pesticides and Veterinary Medicines Authority
(APVMA). It has been available on the ‘black market’;
GS-441524 and Remdesivir (GS-5734) however, all Veterinary Practitioners Boards in
Control & Therapy Series – Issue 303 June 2021

Nucleoside analogues GS-441524 (not currently Australia have warned that clients and veterinarians
legal or commercially available in Australia) and its involved in the unlawful importation of unregistered
prodrug Remdesivir (GS-5734, legal and accessible veterinary chemicals may be subject to significant
via BOVA Compounding Pharmacy), were developed financial, civil or criminal penalties. Despite this,
to treat human viral infections such as Middle East some owners have accessed black market channels
respiratory syndrome virus and Ebola virus, for which via Facebook groups and inject their animals
they have subsequently been found to be ineffective. unsupervised at home.
Fortunately for the veterinary world, these drugs are
now showing efficacy against FIPV. One of the rare positives to come out of the
COVID-19 global pandemic is the chain of events
Nucleoside analogues mimic endogenous that has resulted in Remdesivir (GS-5734) now being
nucleosides and become incorporated into viral DNA registered in Australia by the TGA. Off-label use of
and RNA, thus inhibiting viral replication. For GS- this drug is now available to veterinarians via BOVA
441524, its active metabolite acts as a competitor Compounding Pharmacy. Anecdotal reports of its
of the natural nucleoside triphosphates in viral use have been very positive in cats with naturally
RNA synthesis by inhibiting RNA-dependent RNA occurring FIP, with increasing numbers of Australian
polymerase-mediated transcription (Murphy et cats responding incredibly well, even those with wet
al, 2018). Murphy et al, 2018 reported effective FIP. Dose rate starts at 10mg/kg/day SC or IV for the
inhibition of FIPV in vitro using GS-441524. In this first 3 days with close monitoring and hospitalization
Page 4

study, the pharmacokinetics of GS-441524 in cats recommended. Then 6mg/kg/day SC for 12 weeks.
In neurological cases, keeping the dose at 10mg/kg Itraconazole has demonstrated antiviral activity

Contents
is advised. Discussions are occurring to determine against FCoV (Takano et al, 2019). A case report
if these drugs are suitable and feasible for oral describing the use of itraconazole (Kameshima
administration (Xie et al, 2021 in submission). et al, 2020) showed initial reduction in pleural
effusion when treated with prednisolone, but with
subsequent neurological manifestations and was
Our research group is currently conducting eventually euthanized due to status epilepticus
a clinical trial to investigate the safety and after 38 days of treatment. A case series (Doki et
efficacy of Remdesivir in FIP-confirmed al, 2020) describing itraconazole use in three cats
cats. Close clinical and pathological with experimental induced FIP resulted in two of
monitoring (including the role of acute the three cats showing improvement in clinical signs,

Control & Therapy Series – Issue 302 March 2021

phase proteins in predicting clinical increase in lymphocyte count, and a decrease in
outcomes) is available. For further details, alpha-1-acid glycoprotein after treatment. Further
please contact - investigation of this drug is needed to determine its
Jacqui Norris long-term efficacy in naturally occurring FIP.
[email protected] or
Sally Coggins Dunowska et al, (2021) found dose dependent
[email protected] inhibition of FIPV in vitro using doxycycline 24 hours
post infection supporting the notion of future clinical
trials in this registered antimicrobial. Furthermore,
GC 376 there were also other agents that had shown to
The coronavirus 3C-like protease processes viral have in vitro antiviral activity towards FCoV, such as
polyproteins into functional proteins. As this is cholesterol transport inhibitor U18666A, a vacuolar
an essential step for virus replication, inhibition ATPase blocker (diphyllin) and its nanoformulation,
of 3C-like protease is an attractive target for a circular triple helix forming oligonucleotide RNA
therapeutic intervention. In Kim et al 2016, there was and concurrent use of Galanthus nivalis agglutinin
a reduction in viral titre and recovery in experimental and nelfinavir. There are currently no in vivo studies
infected FIP cats after GC 376 treatment. A field trial reported with these compounds.
(Pedersen et al, 2018) reported inhibition of disease
development and remission after the course of GC Mefloquine
376 treatment with seven out of 20 cats surviving As mefloquine is a human antimalarial prophylactic
after the treatment course. A minimum course and treatment, it is registered by TGA, is
of 12 weeks was recommended in this study. Side commercially available in Australia and is easy to
effects of this product were pain and subcutaneous access. The pharmacokinetic profile, plasma protein
inflammation at injection site, retention of deciduous binding and hepatic metabolism of mefloquine in
teeth and delayed development of adult teeth. This cats have been investigated (Izes et al, 2020, Izes
drug remains experimental and is not registered for et al, 2020, Yu et al, 2020). In Yu et al 2020, when
veterinary use, nor approved by the TGA. mefloquine was given at 10-12.5mg/kg orally twice

Other antiviral compounds Est. 1965

Other compounds have been trialed for their

antiviral activity against FIPV. McDonagh et al
|

2014 reported inhibition of FIPV replication by

Centre for Veterinary Education

three compounds: chloroquine, mefloquine and

hexamethylene amiloride inhibit viral load of FIPV.
Although chloroquine inhibits FIPV replication
in vitro, this drug had poor antiviral efficacy in
experimentally induced FIP cats, together with
its side effect of causing increase in alanine
aminotransferase (ALT) in cats which could
suggest hepatocellular injury (Takano et al, 2013),
suggesting that this drug is a less than an ideal
candidate for FIP treatment. A closely related drug weekly, a plasma concentration exceeding the
hydroxychloroquine (Takano et al, 2020) when tested dose required to inhibit FIPV in vitro was reached.
in vitro showed increased antiviral activity against Side effects of the drug included vomiting when
FIPV infection when used with recombinant feline given without food. Mefloquine could be used as a
interferon-omega. Hexamethylene amiloride is yet to potential treatment for cats with FIP. It is early days
be further investigated and mefloquine is described yet, but some local cats have responded to oral
Page 5

in more detail below. mefloquine medication.

 Product to stop faecal FCoV shedding Polyprenyl immunostimulant is a plant extract that

Contents
Besides FIP treatment, it is worth mentioning a enhances T-lymphocytes to promote cell-mediated
product that has been reported to stop faecal FCoV immunity. There has been some reported success in
shedding. Mutian®X is a synthetic adenosine analogue the treatment of non-effusive FIP with this product.
described by Addie et al 2020 to stop faecal FCoV Polyprenyl immunostimulant was initially reported in
shedding in chronically infected cats. Its potential Legendre & Bartges, 2009 and long-term survivals
use in treatment of FIP is being investigated. This were seen in three cats with dry form of FIP using
medication is not currently registered for use in this product. A field trial (Legendre et al, 2017) with
Australia. 60 cats also showed promising results, with eight
cats surviving longer than 200 days and four cats
Authors’ views are not necessarily those of the CVE

surviving more than 300 days. Authors of this study

Our research group is currently conducting did not believe that this product was efficacious for
a clinical trial to investigate the efficacy of severe or effusive form of FIP.
mefloquine with or without feline omega
interferon (Virbagen®) in FIP-confirmed Another example of an immunomodulator is anti-
cats. For further details, please contact- feline TNF-alpha monoclonal antibody. Doki et al,
Jacqui Norris 2016 reported a slightly prolonged survival time in
[email protected] or two out of three cats using this product compared
Sally Coggins to a controlled group (65 days compared to 25-
[email protected] 27 days in controlled group). Propionibacterium
acnes, a gram-positive bacterium, has been used
as an immunomodulator; however, its use has been
ineffective (Weiss et al, 1990).
FIP is now generally considered as a potentially
treatable disease, but there are some caveats. Immunosuppressive drugs
Although a nucleoside analogue (GS-441524) and Glucocorticoids are the most common type of
protease inhibitor (GC 376) have been successful immunosuppressive drugs used for FIP treatment. As
in treating cats with FIP, these products are not FIP is an immune mediated disease caused by FIPV,
registered for veterinary use. Whilst pending the the use of a glucocorticoid as an immunosuppressive
regulatory approval of these agents globally and drug dampens the immune response and reduces
through our APVMA, other commercially available the clinical signs of infected cats. Despite
agents, such as remdesivir and/or mefloquine, need the popularity of its use over many decades,
to be investigated more thoroughly through in vivo glucocorticoids remain a palliative treatment options
studies to assess their true potential as FIP antivirals. that improve the patients’ clinical signs and quality of
life temporarily, but are not curative for infected cats
Immunomodulators as the viral replication continues unabated.
Interferons and polyprenyl immunostimulant are
common types of immunomodulators in some Other immunosuppressive drugs including cytokine
countries. Interferons have been used for immune inhibitors (pentoxifylline and propentofylline) (Fischer
Control & Therapy Series – Issue 303 June 2021

response modification with limited success in FIP. et al, 2011), cyclophosphamide (Bocskei & Bilkei
There are two types of interferons that have been 1995), cyclosporin A, chlorambucil (Addie et al, 2009,
used on FIP cases to date: human interferon- Bilkei 1988) and thromboxane synthesis inhibitor
alpha and feline interferon-omega. Subcutaneous (Ozagrel hydrochloride) (Watari et al, 1998) and all
injections of human interferon-alpha had little have been reported as potential FIP treatments.
effect in an experiment trial of FIP (Bolcskei & Bilkei, Fischer et al, 2011 investigated propentofylline in FIP
1995). Feline interferon-omega is licensed in some infected cats. However, as glucocorticoids were co-
European countries, as well as Australia and Japan. administered with propentofylline in this study, it is
This product was initially reported in an uncontrolled difficult to determine the efficacy of propentofylline
trial with glucocorticoids (Ishida et al, 2004). The as a single therapeutic agent. Similarly, Bocskei
study yielded promising results with 67% of cats & Bilkei 1995 used cyclophosphamide with
achieving complete or partial remission; however, prednisolone and ampicillin, whereby 76 out of 151
some cats did not have a confirmed diagnosis of FIP. cats were regarded as ‘healthy’ at the end of the
Ritz and colleagues (Ritz et al, 2007) showed that study; however, not all cats had confirmed diagnosis
there was no significant difference in survival and of FIP. The use of chlorambucil was mainly based on
quality of life in cats treated with feline interferon- anecdotal evidence (Addie et al, 2009). Watari et
omega versus a placebo group. However, the al, 1998 explored a thromboxane synthesis inhibitor
efficacy of interferon in this study was difficult to (Ozagrel hydrochloride) and showed beneficial effect
assess because all cats in this study were treated in two cats; however, FIP was not confirmed in these
Page 6

with glucocorticoids and antibiotics concurrently. cats.

Cyclosporin A has been reported to inhibit FCoV 2019, 21, 271–281

Contents
replication in vitro (Pfefferle et al, 2011, Tanaka et 8. Bolcskei A, Bilkei G. Langzeitstudie iiber behandelte FIP-
al, 2012, Tanaka et al, 2013). Cyclosporin A was used verdachtige katzen. Tierarztliche Umschau. 1995;50:721-728.
to treat a cat with FIP (Tanaka et al, 2015) with a 9. Ritz S, Egberink H, Hartmann K. Effect of feline interferon‐
reduction in pleural effusion and viral load seen omega on the survival time and quality of life of cats with feline
initially but subsequent death due to respiratory infectious peritonitis. Journal of Veterinary Internal Medicine.
failure from relapsed pleural effusion on day 264. 2007;21(6):1193-1197.
Hence, the efficacy of cyclosporin A in vivo remains 10. Ishida T, Shibanai A, Tanaka S, et al. Use of recombinant feline
questionable. interferon and glucocorticoid in the treatment of feline infectious
peritonitis. Journal of Feline Medicine and Surgery. 2004;6(2):107-
109.

Control & Therapy Series – Issue 302 March 2021

Two clinical trials for naturally occurring 11. Legendre AM, Bartges JW. Effect of Polyprenyl Immunostimulant
FIP infected cats have commenced at the on the survival times of three cats with the dry form of feline
Sydney School of Veterinary Science at infectious peritonitis. Journal of Feline Medicine and Surgery.
The University of Sydney and are recruiting 2009;11(8):624-626.
Australia-wide; one looking at mefloquine, 12. Legendre AM, Kuritz T, Galyon G, et al. Polyprenyl
with and without interferon, the other immunostimulant treatment of cats with presumptive non-
looking at Remdesivir. effusive feline infectious peritonitis in a field study. Frontiers
in Veterinary Science. 2017;4(Article 7):7. doi: https://doi.
Contact Us org/10.3389/fvets.2017.00007.
If you have a suspected or confirmed case 13. Doki T, Takano T, Kawagoe K, et al. Therapeutic effect of anti-
of FIP and are interested in participating in feline TNF-alpha monoclonal antibody for feline infectious
our clinical trials, please do not hesitate to peritonitis. Research in Veterinary Science. 2016;104:17-23. doi:
contact us at 10.1016/j.rvsc.2015.11.005.
[email protected] or 14. Weiss RC, Cox N, Oostrom-Ram T. Effect of interferon or
[email protected]. Propionibacterium acnes on the course of experimentally
induced feline infectious peritonitis in specific-pathogen-free and
Please also contact us if you would just random-source cats. Am J Vet Res. 1990; 51(5):726–733
like any advice on a case you suspect has 15. Fischer Y, Ritz S, Weber K, et al. Randomized, placebo controlled
FIP and we are happy to help you with the study of the effect of propentofylline on survival time and
case. quality of life of cats with feline infectious peritonitis. Journal of
Veterinary Internal Medicine. 2011;25(6):1270-1276.
16. Bilkei G. Beitrag zur Therapie der FIP. Tierärztl Umschau.
1988;43:192-196.
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Contents
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