Veterinary Quarterly

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Current status on treatment options for feline
infectious peritonitis and SARS-CoV-2 positive cats
Aaron M. Izes , Jane Yu , Jacqueline M. Norris & Merran Govendir
To cite this article: Aaron M. Izes , Jane Yu , Jacqueline M. Norris & Merran Govendir (2020)
Current status on treatment options for feline infectious peritonitis and SARS-CoV-2 positive cats,
Veterinary Quarterly, 40:1, 322-330, DOI: 10.1080/01652176.2020.1845917
To link to this article: https://doi.org/10.1080/01652176.2020.1845917© 2020 The Author(s). Published by Informa
UK Limited, trading as Taylor & Francis
Group.
Published online: 13 Nov 2020.

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VETERINARY QUARTERLY
2020, VOL. 40, NO. 1, 322–330
https://doi.org/10.1080/01652176.2020.1845917

REVIEW

Current status on treatment options for feline infectious peritonitis and
SARS-CoV-2 positive cats
Aaron M. Izes, Jane Yu, Jacqueline M. Norris and Merran Govendir
Sydney School of Veterinary Science, The University of Sydney, Sydney, NSW, Australia
ABSTRACTARTICLE HISTORY

Feline infectious peritonitis (FIP) is a viral-induced, immune-mediated disease of cats causedby virulent biotypes of feline coronaviruses (FCoV), known as the feline infectious peritonitis
virus (FIPV). Historically, three major pharmacological approaches have been employed totreat FIP: (1) immunomodulators to stimulate the patient’s immune system non-specificallyto reduce the clinical effects of the virus through a robust immune response, (2) immunosuppressive agents to dampen clinical signs temporarily, and (3) re-purposed human antiviraldrugs, all of which have been unsuccessful to date in providing reliable efficacious treatment
options for FIPV. Recently, antiviral studies investigating the broad-spectrum coronavirus protease inhibitor, GC376, and the adenosine nucleoside analogue GS-441524, have resulted inincreased survival rates and clinical cure in many patients. However, prescriber access tothese antiviral therapies is currently problematic as they have not yet obtained registrationfor veterinary use. Consequently, FIP remains challenging to treat. The purpose of this review
is to provide an update on the current status of therapeutics for FIP. Additionally, due tointerest in coronaviruses resulting from the current human pandemic, this review provides
information on domesticated cats identified as SARS-CoV-2 positive.

Received 9 July 2020
Accepted 30 October 2020

1. Introduction
Feline infectious peritonitis (FIP) is a viral-induced,
immune-mediated disease with high fatality rates,
affecting domesticated cats and some wild felids globally (Addie et al. 2009; Drechsler et al. 2011;
Pedersen 2014a). The disease is caused by virulent
biotypes of feline coronaviruses (FCoV), known as
the feline infectious peritonitis virus (FIPV) (Addie
et al. 2009; Drechsler et al. 2011; Pedersen 2014a).
FIPV arises through unidentified genetic alterationsin FCoV leading to an enhanced capacity to replicate
within the monocytes and macrophages (Addie et al.
2009; Pedersen 2009). While FIP can affect cats ofany age, its incidence is greatest amongst cats lessthan three years of age, particularly, those aged
between four and sixteen months (Addie et al. 2009;
Pedersen 2009). The true prevalence of FIP is notknown. While some authors cite that approximately
12%, or one out of nine FCoV-infected cats, will progress to clinical signs of FIP (Addie et al. 2009;
Pedersen 2014b), this figure has been extrapolated
from veterinary hospital studies, rather than thedomesticated feline population at large, and is notcongruent with field estimates of the number ofcases seen relative to the population. Other studies
CONTACT Merran Govendir
2006, Australia.

merran.govendir@sydney.edu.au

KEYWORDS

Cat; feline; feline infectious
peritonitis; FIP; feline
infectious peritonitis virus;
therapeutics; treatment;
SARS-CoV-2

provide a lower prevalence of FIP. In a case–control
study spanning a ten-year period from 1986 to 1995,
out of 397,182 accessions presented to North
American veterinary medical teaching hospitals,
approximately 0.55% of new feline and 0.36% of
total feline accessions were cats with FIP (Rohrbach
et al. 2001). These FIP patients were significantly
more likely to be purebred, young and sexuallyintact males (Rohrbach et al. 2001; PesteanuSomogyi et al. 2006). In a study investigating feline
accessions at the North Carolina State University
College of Veterinary Medicine over a sixteen-year
period from 1986 to 2002, of the 11,535 cats ofknown breed that were examined, the prevalence ofsuspected or confirmed FIP in the mixed breed cat
population was 0.35% versus 1.3% in the purebred
cat population (Pesteanu-Somogyi et al. 2006). For
some of these studies, the diagnosis of FIP was
made on the basis of clinical examination alone andwithout confirmatory diagnostic tests (Rohrbach
et al. 2001; Pesteanu-Somogyi et al. 2006). In an
Australian study, young cats were significantly overrepresented amongst FIP cases (Worthing et al.
2012). Domestic crossbred, Persian and Himalayancats were significantly under-represented comparedto the Australian cat population, while several breeds

Sydney School of Veterinary Science, The University of Sydney, Sydney, NSW

ß 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

VETERINARY QUARTERLY

were over-represented, including the British
Shorthair, Devon Rex and Abyssinian breeds. A significantly higher proportion of males had FIP(Worthing et al. 2012).
FIP is categorised by its clinical presentation as
either a wet (effusive) or dry (non-effusive) form
(Addie et al. 2009; Pedersen 2009, 2014a). The wet
form is characterised by immune-mediated, fibrinous-granulomatous serositis, often with protein-richeffusions in the thoracic or abdominal cavities(Addie et al. 2009; Pedersen 2009, 2014a). In contrast, the dry form is typified by pyogranulomatous
lesions found in multiple body organs and aroundblood vessels (Addie et al. 2009; Pedersen
2009, 2014a).
FIP-associated mortality is extremely high once
clinical signs appear (Pedersen 2014b). As noted by
Pedersen (2014b, p.133), ‘the onset of overt disease isa signal that the cat’s battle with the virus has beenlost.’ Even though some cats can live with FIP forweeks, months or sometimes, years (Pedersen
2014b), survival times generally vary from days toweeks for effusive FIP and weeks to months for noneffusive FIP (Fischer et al. 2011; Tsai et al. 2011;
Hugo and Heading 2015). Providing a definitiveante-mortem diagnosis of FIP is challenging, particularly as current diagnostic tests cannot differentiate
between FCoV and FIPV (Fischer et al. 2011;
Pedersen 2014b). Furthermore, as a confirmed diagnosis relies on positive immunostaining of FCoV antigen by cytology or histopathology, invasive
diagnostic tests to collect tissue biopsies might benecessary in sick cats, making confirmation of thediagnosis more challenging at times (Tasker 2018).
The reader is directed to recent reviews on moredetailed information on the diagnosis of FIP(Drechsler et al. 2011; Pedersen 2014b; Tasker 2018;
Kennedy 2020). In reviewing treatment options for
FIP, numerous older studies describing potential
treatments are mostly based on cases without a confirmed diagnosis of FIP and hampered by the lack ofwell-controlled clinical trials (Hartmann and Ritz
2008). Likewise, the use of other reported treatment
options is currently only supported by in vitro studies rather than through in vivo clinical studies(Choong et al. 2014; Doki et al. 2016; Hu et al. 2017;
Takano et al. 2017). Despite recent antiviral studies
with GC376 and GS-441524 showing great promise
against FIPV in naturally and experimentally infectedcats (Murphy et al. 2018; Pedersen et al. 2018, 2019),
these agents have not yet obtained registration for
veterinary use (Wogan 2019a, 2019b). Consequently,
no effective treatments against FIP are currently
legally
available
toveterinary
clinicians(Pedersen 2019a).

323

2. Sars-CoV-2
There is currently great interest in the potential forsevere acute respiratory syndrome coronavirus 2 (SARSCoV-2) to infect animals, including reports of domesticated and zoo-housed wild cats testing positive for thisvirus (Hosie et al. 2020; United States Department ofAgriculture 2020; Wang et al. 2020). The coronaviruses
are single strand RNA viruses (Lundstrom 2020) classified
within four genera based on genotypic and serologicalcharacterisation (Alphacoronavirus, Betacoronavirus,
Gammacoronavirus and Deltacoronavirus; Woo et al.
2012). Whereas FCoV is an Alphacoronavirus (Felten andHartmann 2019), SARS-CoV-2, which causes COVID-19, isa Betacoronavirus (Chakraborty and Maity 2020; Lai et al.
2020). Coronaviruses have both a high frequency ofrecombination and inherently high mutation rates whichallow them to adapt rapidly with a heightened potential
to infect new hosts (Woo et al. 2006). Viral recombinationis mediated in part by the proofreading activity of thensp14 exoribonuclease, which previously has beenshown to hinder the development of nucleoside-based
coronavirus treatments (Agostini et al. 2018).
Domesticated cats that have tested positive for
SARS-CoV-2 have been associated with SARS-CoV-2
positive owners or suspected SARS-CoV-2 positive
owners (Halfmann et al. 2020; Newman 2020). A
small number of SARS-CoV-2 positive domesticatedcats have demonstrated upper or lower respiratory
signs (Sailleau et al. 2020), whereas others have had
no overt clinical signs (Newman 2020; Sailleau et al.
2020; Sit 2020; Sit et al. 2020). In limited experimental studies in which large viral inocula are used, it
has been reported that cats can transmit SARS-CoV-2
to other cats housed in the same facility via the airborne route (Shi et al. 2020). Another study reported
that inoculation and exposure to SARS-CoV-2 leads
to nasal shedding in cats and that cats without clinical signs are capable of direct transmission to othercats (Halfmann et al. 2020). Currently, there is no evidence that cats can transmit SARS-CoV-2 to humans(Hosie et al. 2020).
Although there are some antivirals described
below that have demonstrated activity against FCoV,
it is tempting to extrapolate that they may also
reduce shedding of SARS-CoV-2 in rare instances offeline infection. However, to the best of the authors’knowledge, there are no published in vivo studies toverify their SARS-COV-2 antiviral activity in the cat.

3. FIP therapeutics
In practice, three major approaches, used either individually or in combination, have been employed totreat FIP (Pedersen 2014b). The first approach seeks
to modulate the patient’s immune system non-specifically in order to reduce the clinical effects of the324

A. M. IZES ET AL.

virus through a robust immune response (Pedersen
2014b). The second approach relies on the use of
immunosuppressive drugs to dampen the inflammatory response that is central to the pathology in thisdisease (Hartmann and Ritz 2008; Addie et al. 2009;
Pedersen 2014b), whereas the third approach centreson the use of antiviral agents to inhibit viral replication (Murphy et al. 2018; Pedersen et al. 2018, 2019).
Although each of these major approaches can beused simultaneously, each will be addressed in turn.

3.1. Non-specific immunostimulants
Non-specific immunostimulants have been used astreatments for FIP for many years, often due tounsubstantiated anecdotal reports claiming that such
regimens either can improve survival times or serveas an outright cure for FIP (Pedersen 2014b). The
over-arching aim of this approach is to encourage
the patient to produce an immune response strong
enough to reduce the viral load sufficiently to
reduce clinical effects of the infection. However, it issomewhat paradoxical that the use of immunostimulants is often paired with immunosuppressive agents,
given that some of these drugs may work at crosspurposes to one another (Pedersen 2014b). Examplesof non-specific immunostimulants administered as
FIP treatments include staphylococcal A protein(Pedersen 2014b), Propionibacterium acnes (an immunomodulatory compound derived from gram positive bacteria) (Weiss et al. 1990), lymphocyte T-cell
immunomodulators (such as omega [x] interferon)(Pedersen 2014b) and plant extracts such as polyprenyl immunostimulant (PI) (Legendre and Bartges
2009; Legendre et al. 2017). All of these agents havebeen unsuccessful or have had limited success as FIP
treatments. For example, with respect to the biologic
plant extract PI, the use of this agent was originallysuggested by Legendre and Bartges (2009), after
three cats with the dry form of FIP were reportedly
cured after long-term treatment with PI. However,these researches conceded that the treatment had
no effect on cats with more severe FIP (Legendre
and Bartges 2009). A later field study of PI in 60 cats
showed improved survival times with four of thesecats surviving over 300 days with an improved quality of life (Legendre et al. 2017). The study also
showed that survival times with PI were significantly
longer in cats that were not treated with corticosteroids concurrently (Legendre et al. 2017).

3.2. Immunosuppressive agentsThe use of immunosuppressive agents to dampen
the inflammatory response to FIPV stands as something of a therapeutic placeholder. That is, a lack ofaccess to safe and effective alternatives can leaveveterinary clinicians with very few options otherthan to rely on immunosuppressive therapies to control the clinical signs of FIP (Hartmann and Ritz 2008;
Addie et al. 2009; Pedersen 2014a). Examples of
immunosuppressive agents as FIP treatments include
glucocorticoids (e.g. prednisolone, dexamethasone)(Disque et al. 1968; Addie et al. 2009), cytokine
inhibitors (e.g. pentoxifylline and propentofylline)(Fischer et al. 2011) and alkylating agents (e.g. cyclophosphamide and chlorambucil) (Bilkei 1988; Addie
et al. 2009). Although glucocorticoid administration
reduces clinical signs in cats with FIP, there is no evidence that they are curative for infected cats (Addie
et al. 2009). Claims that agents such as glucocorticoids are effective against FIP have been disprovedby placebo-controlled, double blinded studies by
Ritz et al. (2007) and Fischer et al. (2011). In thesestudies, investigating the effects of feline interferonx (Ritz et al. 2007) and propentofylline (Fischer et al.
2011) on the survival time and quality of life of FIPaffected cats, all cats (including those in a placebogroup) received dexamethasone and/or prednisolone. The respective authors reported that there wasno significant difference in survival times between
those FIP-affected cats that received either feline
interferon x (Ritz et al. 2007) or propentofylline(Fischer et al. 2011) (median survival time of ninedays for feline interferon x and eight days for propentofylline) and those in the control group administered glucocorticoids only (median survival time ofeight days in both studies). Given the co-administration of dexamethasone and/or prednisolone in bothof these studies, it is difficult to determine theeffects of feline interferon x or propentofylline as asingle therapeutic agent. Feline interferon x has
been shown to inhibit FCoV replication in vitro(Mochizuki et al. 1994). An uncontrolled trial withfeline interferon x and glucocorticoids yielded a
promising result with 67% of cats achieving complete or partial remission, but FIP was not confirmedin these cases (Ishida et al. 2004). When recombinanthuman leukocyte alpha interferon or feline fibroblastic beta interferon were used alone, neither reduced
the mortality in treated cats compared to controls(Weiss and Toivio-Kinnucan 1988; Bolcskei and Bilkei
1995; Ritz et al. 2007). However, when a high doseof alpha interferon was used in combination with
Propionibacterium acnes, the mean survival time wasprolonged, but only by three weeks (Weiss et al.
1990). Overall, although interferons are frequently
used in cats with FIP, their efficacy is questionable.
Likewise, the use of cyclophosphamide also has
been investigated in cats with FIP in combination
with prednisolone and ampicillin (Bilkei 1988).
Seventy-six of 151 cats were regarded as ‘healthy’VETERINARY QUARTERLY

after therapy. However, cats included in this study
had no confirmed diagnosis of FIP. Another study
investigating the use of cyclophosphamide in addition to prednisolone and ampicillin in suspected FIP
cases reported that 29–80% of cats died in three
years (Bolcskei and Bilkei 1995). Again, FIP was notconfirmed in these cats. Ozagrel hydrochloride (athromboxane synthesis inhibitor) has also been used
as an immunosuppressive agent against FIP (Watari
et al. 1998). Although it was shown to have a beneficial effect in two cats, FIP was not confirmed ineither of these patients (Watari et al. 1998).

3.3. Specific FIP therapeutics
The third approach to the treatment of FIP involves
the administration of antiviral agents to target either
the cellular mechanisms that viruses co-opt for replication, or alternatively, a specific aspect of virus
activity related to infection and/or replication(Hartmann and Ritz 2008; Addie et al. 2009;
Pedersen 2014a). Antiviral drugs that inhibit FCoVhave been identified but many have not been successfully trialled in infected patients (Weiss et al.
1993; Hartmann and Ritz 2008; Addie et al. 2009;
McDonagh et al. 2014; Pedersen 2014b). However, a
new therapeutic breakthrough using the nucleosideanalog GS-441524 as a direct acting antiviral drug
for FIP has been reported (Murphy et al. 2018;
Pedersen 2019a, 2019b; Dickinson et al. 2020). GS441524, the active metabolite of remdesivir, is an
RNA-chain terminator of viral RNA dependent RNA
polymerase (Murphy et al. 2018; Pedersen et al.
2019) and has been found to strongly inhibit FIPV
both in tissue culture and experimental cat infection
studies as well as in cases of naturally occurring FIP(Murphy et al. 2018; Pedersen et al. 2019). Utilising
an in vitro approach, Murphy et al. (2018) determined that GS-441524 was non-toxic in Crandell
Rees feline kidney (CRFK) cells at 100 mM concentrations whilst still being able to inhibit FIPV replicationin both cultured CRFK cells and naturally infected
feline peritoneal macrophages at 1.0 mM concentrations. In a companion in vivo study in cats experimentally infected with FIPV (serotype I FIPV m3c-2
strain), GS-441524 was administered once a day(5.0 mg/kg BW or 2.0 mg/kg BW as a subcutaneous
injection [SC]) for two weeks once the disease course
became established (Murphy et al. 2018). Requiring
at least two weeks of treatment, this regimen led toa rap id reversal of clinical signs and a return to normality in all subjects. No toxicity was noted. Buildingon this work, Pedersen et al. (2019) investigated thein vivo therapeutic effects of GS-441524 on naturally
occurring FIP, including both the wet and dry formsof the disease. In this study, 31 cats (26 with effusive

325

FIP and five with non-effusive FIP) were recruitedand administered a dosage of 2.0 mg/kg BW SC once
daily for at least 12 weeks. The dosage was increased
to 4.0 mg/kg BW SC once daily when indicated bydeteriorating clinical signs. Four cats were euthanised or died within the first five days of the experiment as a result of the severity of their infection. A
fifth cat was euthanised after 26 days due to a lackof treatment response. The remaining 26 cats successfully completed the twelve-week (or longer) trial.
Eighteen of the cats remained healthy after one
course of treatment whereas the remaining eightsuffered relapses within 3 to 84 days. Three of theeight relapsing cats were treated again at the same
dosage whilst five cats had the dosage increased
from 2.0 to 4.0 mg/kg BW. The five cats treated withthe higher dose remained healthy. Of the remaining
three cats treated at the original lower dose, two ofthem relapsed a second time and required a third
treatment with the higher dose. These two catsremained healthy after the second dose. The third
cat relapsed after a second round of the lower dose
and was euthanised due to the severity of its neurological disease. Ultimately, the study produced 25
long time survivors. Injection site reactions were themost common side effect (Pedersen et al. 2019).
Based on these findings, the authors concluded that
GS-441524 is a safe and effective treatment for FIP
when administered at a dosage of 4.0 mg/kg BW SC
once a day for at least 12 weeks (Pedersen et al.
2019). A higher dosage of 5.0 to 10.0 mg/kg BW SC
once a day for 12 weeks has been recommended forneurological FIP cases as determined by the treatment of four clinical cases (Dickinson et al. 2020).
Given the consistency of its reported efficacy, a burgeoning global black-market for GS-441524 hasarisen since it has not been formally approved forcommercial use anywhere (Pedersen 2019b).
Interestingly, GS-441524 has also displayed in vitro
antiviral activity against SARS-CoV (Cho et al. 2012).
Likewise, remdesivir (GS-5734), a prodrug of theparent adenosine nucleoside analog, GS-441524(Amirian and Levy 2020), has been granted emergency use authorisation by the U.S. Food and Drug
Administration (F.D.A.) to treat suspected or laboratory-confirmed COVID-19 in adults and children hospitalised with a severe infection. This emergency
authorisation was based on a randomised, doubleblinded, placebo-controlled trial conducted by the
National Institute of Allergy and Infectious Diseases(NIAID) (NCT04280705) and a sponsored openlabelled trial that evaluated different durations ofremdesivir (NCT04292899). Another randomised,double-blinded, placebo-controlled, multicentre trial
conducted in China also showed that the use ofremdesivir in adult patients with COVID-19 was326

A. M. IZES ET AL.

associated with a reduction in time to clinicalimprovement when treated early, although statistically significant clinical benefits were not observed(Wang et al. 2020). Clinical trials of remdesivir andmany other antivirals are currently underway inmany countries for the treatment of COVID-19(Amirian and Levy 2020).
Whilst not related to the direct treatment of FIP, a
medication proposed for reducing FCoV may be alikely precursor to FIP prevention. An antiviral prodR X, a synthetic adenosine anauct called MutianVlogue, whose exact nature is a ‘commercial secret’,has been shown to stop faecal feline coronavirus
shedding in chronically infected cats when administered orally at 4.0 mg/kg BW, once daily for fourdays (Addie et al. 2020). Addie et al. (2020) suggested that a combination of probiotics and interferon may have reduced feline coronavirus shedding
in two cats in the same study. Feline interferon x
has been shown to reduce viral excretion of feline
coronavirus in retrovirus infected cats (Gilet al. 2013).

3.4. Other antiviral compounds
Other candidate compounds have also been trialled
for their antiviral activity against FIPV. For example,
the antiviral ribavirin was tested in vivo in cats
experimentally infected with FIPV and found to possess marginal antiviral activity against FIPV and toxicity to cats (Weiss et al. 1993]. Cyclosporin A, acyclophilin inhibitor, has been shown to inhibit replication of feline coronavirus in vitro although themechanism of its inhibitory effects is unknown(Pfefferle et al. 2011; Tanaka et al. 2012, 2013).
Cyclosporin was administered to one cat with effusive FIP and a reduction in pleural fluid and viralload was observed after treatment. The cat died of
respiratory failure on day 264 but the cause of death
was not determined (Tanaka et al. 2015). Likewise,
two compounds, galanthus nivalis agglutinin (GNA)
and nelfinavir (a protease inhibitor) when used in
combination were able to inhibit FCoV replicationin vitro (Hsieh et al. 2010). Yet, ultimately, neither ofthese compounds was found effective when tested
under conditions simulating FIPV-infection. Similarly,
based on promising findings concerning 3 C-like protease inhibitors efficacy against FCoV (Kim et al.
2013, 2015, 2016), a field trial of GC376 was undertaken with 20 cats with various forms of FIP, excluding those with neurological signs (Pedersen et al.
2018). Cats were administered a dosage of 15.0 mg/
kg BW, SC, twice a day for a minimum of 12 weeks.
Whilst results were encouraging (with seven catsachieving a mean disease remission of 11.2 months),side effects developed, including transient pain upon

injection, subcutaneous fibrosis, alopecia and abnormal development of permanent teeth in cats treated
before 16–18 weeks of age (Pedersen et al. 2018).
Other protease inhibitors have been shown to target
the 3 C-like protein of coronaviruses (Rathnayake
et al. 2020; Theerawatanasirikul et al. 2020).
The antifungal itraconazole has demonstrated
in vitro anti-FIPV activity at low drug concentrations(2.5 mM) (Takano et al. 2019). A recent in vivo study
investigated the effects of a combination of itraconazole (50 mg/animal per os, once a day) and an antihuman TNF-alpha monoclonal antibody (10 mg/animal) for the treatment of three cats experimentally
infected with FIPV (Doki et al. 2020). Although twoof the three cats showed improvement from FIPVrelated clinical signs, an increase in the peripheral
blood lymphocyte count and a decrease in alpha-1acid glycoprotein were identified after treatment
began. The third cat was euthanised due to its failure to respond to treatment. The authors concluded
that this combination of drugs may be useful until
more effective anti-FIPV agents become available.
Itraconazole, in combination with prednisolone, havebeen used to treat effusive FIP in a three-month-old
male Scottish Fold kitten, leading to a reduction inpleural effusion (Kameshima et al. 2020). However,this cat showed neurological manifestations and waseuthanised due to status epilepticus after 38 days oftreatment (Kameshima et al. 2020). Moreover, otheragents have also been shown to have in vitro antiviral activity against FCoV, including an anti-feline
TNF-alpha monoclonal antibody (Doki et al. 2016);
U18666A (a cholesterol transport inhibitor) (Takano
et al. 2017; Doki et al. 2020); diphyllin (a vacuolar
ATPase blocker) and its nanoformulation (Hu et al.
2017) and a circular triple helix forming oligonucleotide RNA (Choong et al. 2014). However, no in vivo
studies have been reported using these compounds.
The human antimalarial drug chloroquine also
inhibits FIPV replication in vitro (Takano et al. 2013;
McDonagh et al. 2014). Chloroquine has long been
known to possess both anti-inflammatory andin vitro antiviral properties against a diverse range ofviruses (Takano et al. 2013). Yet, despite its goodin vitro efficacy, chloroquine displayed poor antiviralefficacy against in vivo experimentally induced FIP
infection (Takano et al. 2013). In their study, Takano
et al. (2013) found that chloroquine treatment was
associated with an improvement in clinical scores
and a slightly increased, but not statistically significant, survival time of cats infected with the highly
virulent FCoV FIPV1146. Additionally, increased activity levels of alanine aminotransferase in the chloroquine-treated groups indicated a potential problem
with hepatic damage. The dosage of 10 mg/kg BW
twice weekly SC was extrapolated from humanVETERINARY QUARTERLY

dosing protocols and not based on any known pharmacokinetic studies in cats. Recently, hydroxychloroquine’s antiviral activity against FIPV has also beenstudied in vitro. When used with recombinant feline
IFN-x, hydroxychloroquine showed increased antiviral activity against FIPV infection (Takano et al.
2020). Hydroxychloroquine has also been investigated in clinical trials for COVID-19 treatment in people (Lundstrom 2020). However, this drug has
resulted in controversial results, leading to the current conclusion that its clinical efficacy in patientswith COVID-19 has not been verified to date
(Lundstrom 2020).
McDonagh et al. (2014) screened 19 candidate
compounds used in the treatment of other coronavirus infections for their cell toxicity and effectiveness at inhibiting FIPV replication in infected CRFK
cells. In this in vitro study, a resazurin-based cytopathic effect (CPE) inhibition screening test wasdeveloped to investigate antiviral efficacy against
two strains of FCoV: FECV 1683 and FIPV 1146. Other
assays, including plaque reduction, virus yield reduction and viricidal suspension were used to evaluate
the antiviral effects of the candidate compounds.
Ultimately, the study identified three compounds(chloroquine, mefloquine and hexamethylene amiloride) that substantially reduced the viral load of FIPVin infected CRFK cells without cytotoxic effects at
10 mM concentrations. Moreover, preliminary experiments suggested that the antiviral mechanisms of all
three compounds acted at an early stage of viral
replication.
Given the potential impact of these results for thetreatment of FIP, further investigation of these compounds is warranted (McDonagh et al. 2014). Bothchloroquine and mefloquine are commercially available pharmaceutical agents registered for use inpeople. Each has an extensive body of supporting literature regarding their pharmacokinetics and safety
in non-feline species and some information is now
available on mefloquine’s pharmacokinetic profile incats (Izes 2019; Izes et al. 2020a, 2019, 2020b; Yu
et al. 2020). Considerably less is known about hexamethylene amiloride, particularly with respect to its
safety (McDonagh et al. 2014). As Takano et al.
(2013) previously discounted the in vivo efficacy ofchloroquine as an antiviral agent for FIP, clinical trialsof mefloquine to treat infected cats could be considered. Recent in vitro pharmacokinetic studies haveindicated that mefloquine undergoes phase I hepatic
metabolism, but not phase II glucuronidative metabolism, when catalysed by feline hepatic microsomes
and therefore is not likely to have delayed elimination in cats (Izes et al. 2020a). Mefloquine’s pharmacokinetic profile in cats has been investigated in
anticipation of undertaking clinical trials to inhibit

327

feline coronavirus and feline calicivirus in those catsclinically affected by these viral infections (Yu et al.
2020). Further research on the clinical efficacy of
mefloquine in FIP-confirmed cats is underway.
With respect to all these antiviral agents, it isimportant to note that a combination of therapeutics
may be required to be administered to patients toinhibit monotherapy selection of viral resistance.

4. Conclusion
Despite the absence of their commercial availability,
antivirals such as GS-441524 and GC376, have beenshown to be efficacious treatment options against
FIP. Whilst pending the regulatory approval of theseagents, other commercially available agents, such as
mefloquine and itraconazole, need to be investigated more thoroughly through in vivo studies toascertain their true potential as FIPV antivirals.
Moreover, whilst to date, the current SARS-CoV-2
pandemic has had little reported impact on veterinary medicine, a global One Health approach dictatesthat a vigilant watch is kept on therapeutic advancesin the fight against coronaviruses as the information
may ultimately be useful across species.

Acknowledgements
This is a component of a larger project investigating thepharmacokinetic properties of mefloquine in cats.

Authors’ contributions
AMI wrote the initial draft and all authors have contributed, edited and approved the final manuscript.

Disclosure statement
One of the authors (MG) is the Associate Editor of theVeterinary Quarterly but has had no role in the peer
review of this manuscript.

Funding
This project was financially supported by the Winn Feline
Foundation, the Australian Companion Animal HealthFoundation and the Feline Health Research Fund.

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