A new strain of coronavirus in FIP-infected cats breaks the pattern

Lisa Wogan
Original article: Novel coronavirus strain in FIP-infected cats defies pattern;
5.12.2023

A cat with Feline Infectious Peritonitis (FIP) in Cyprus shows several signs of the disease, including a swollen abdomen due to fluid build-up in the abdominal lining, unkempt fur and poor muscle condition.

The first signs of problems appeared at the end of last year (2022) in Cyprus, an island state in the eastern Mediterranean, known for its abundance of free-roaming cats. Some veterinarians there have begun to see an increase in cases of Feline Infectious Peritonitis (FIP), a fatal disease of cats.

The cats had a fever, were lethargic, losing weight and did not want to eat. Some had swollen abdomens, others had tumor-like lesions. Some were staggering, uncoordinated. Some had inflamed, cloudy or discolored eyes.

FIP usually occurs in cats as a rare reaction to infection with a common pathogen, feline enteric coronavirus (FECV). The virus is shed in the feces of infected cats, from where it can be spread to other cats. FECV is a subtype of feline coronavirus (FCoV), which is one of hundreds of known coronaviruses and does not infect humans. However, this virus is very common among stray cats and cats that live with several other cats. Cats infected with FECV are generally asymptomatic and remain healthy. However, sometimes the virus mutates and causes FIP.

In Cyprus, thousands of cats were diagnosed in the first months of this year. The disease spread rapidly, contradicting common ideas about how FIP develops.

"It's just not right," said Dr. Danielle Gunn-Moore when she discovered this summer that the number of diagnoses on the island had increased 40-fold compared to the previous year. Gunn-Moore is Professor of Feline Medicine at the Royal (Dick) School of Veterinary Studies at the University of Edinburgh.

So far unpublished work, which was published on the bioRxiv portal in November before being published in a peer-reviewed journal, offers preliminary answers to the question of why so many cats fell ill in Cyprus. Based on RNA sequencing of samples from dozens of cats with FIP, the authors of the paper argue that a strain of coronavirus that arose from separate feline and canine coronaviruses may have combined, linking the fecal excretion and infectivity of the common FECV virus with the virulence of the mutated FIP virus to one pathogen.

"In normal FIP, the FIP virus is rarely spread," said Gunn-Moore, the paper's author. "That's a huge difference in the case of a new epidemic. Everything says that it is directly portable.”

Veterinary researchers contacted by the VIN news service for comment on the paper called the evidence "interesting" and "highly suggestive" but not definitive. They say that more research is needed, which the authors say is in full swing.

Concerns are growing on the "cat island".

In short

  • Thousands of cats on the Mediterranean island of Cyprus have been diagnosed this year with feline infectious peritonitis, a fatal and usually rare feline disease.
  • The disease spread quickly among the many free-ranging cats on the island, upsetting the conventional wisdom about how FIP develops.
  • The authors of the new paper, which has not yet been peer-reviewed, say the outbreak was caused by a new strain of the pathogen that evolved from separate cat and dog coronaviruses, a recombination that increases its ability to spread.
  • Veterinarians in Cyprus are treating many sick cats with antivirals, some of which have been developed to treat humans with Covid-19.
  • A cat imported to the UK from Cyprus in August has been confirmed to be infected with the new strain.

dr. Demetris Epaminondas, vice-president of the Pancyprian Veterinary Association (PVA), first learned of the "worryingly increased number of FIP cases" last December from his wife, a clinical veterinarian. He soon began receiving similar messages from other doctors.

A possible increase in the deadly feline disease is causing particular concern in the area, sometimes called "cat island," where cats roam, stretch, hunt and sleep everywhere. Large colonies of cats, which are revered as saints, live in and near monasteries, where they are cared for by monks. Elsewhere, residents feed and care for neighborhood felines. The number of cats on the island is not officially estimated.

PVA sent a questionnaire to 150 veterinary clinics in Cyprus to try to find out what was going on. Twenty-four clinics reported a total of approximately 500 cases of FIP in the first three months of 2023, a tenfold increase over the first three months of the previous year. In April, the number of reports peaked at around 2,000 cases.

These numbers only include cats on about half the island, an area of more than 2,000 square miles. Cyprus has been divided since the 1970s: The area to the south and west is under the control of the Republic of Cyprus, which has a Greek Cypriot majority and is a member of the European Union. The area to the north is occupied by Turkish military forces and is not under the effective control of the Cypriot government. There have been no official FIP announcements from the north.

dr. Charalampos Attipa, a veterinary pathologist from Cyprus, noticed the increase in cases in January while reviewing test results for Vet Dia Gnosis Ltd., a veterinary diagnostic laboratory he helped found in 2021.

There is no single test that can diagnose every case of FIP. Therefore, the diagnosis is often made based on a summary of clues from the patient's history, physical examination, and various diagnostic tests, including PCR tests. PCR stands for polymerase chain reaction, a technique that allows users to rapidly amplify a small sample of genetic material for study.

In the diagnosis of FIP, small segments of the genetic material of the coronavirus are identified by PCR in a sample of fluid from the lining of the abdomen (peritoneum) or lungs (pleura) or from the spine, or from a biopsy of tumor-like lesions.

In 2021 and 2022, Vet Dia Gnosis recorded three and four positive PCR tests in cats with FIP in Cyprus. From January to August 2023, 165 positive FIP-related PCR tests were recorded.

"These are only cats whose owner paid for the PCR to be performed," said Attipa. "It is most likely the tip of the iceberg. But we don't really know the size of the glacier. That's the problem."

Attipa, who started at the University of Edinburgh in April, is the lead author of the preprint paper. He is also a key member of an international collaboration investigating the virology, epidemiology and therapy of the current epidemic.

At the beginning of the year, Attipa, Epaminondas and others focused on raising awareness among veterinarians and the public. The effort led to several missteps, including a report picked up by multiple news outlets that 300,000 cats had died from the disease. Epaminondas said the figure was an unofficial and inaccurate estimate by animal welfare organizations. Additionally, the PVA estimate of 8,000 infected cats by mid-July was incorrectly reported by the Associated Press as 8,000 dead. There is no official estimate of the number of dead.

The number of PCR-confirmed cases began to decline in April, but this may not be cause for celebration just yet.

"At first, people didn't know what the disease was, so they took the animals to the vet for a diagnosis," Epaminondas said. However, with increasing awareness, cat owners and carers have been aware of an increase in FIP and clinical signs such as a swollen abdomen present in one form of the disease. "Because they can find treatment on the black market, they don't want to spend money to properly diagnose the disease," he said.

In recent years, antiviral compounds have shown remarkable promise in reversing the course of FIP. However, these compounds are not approved for veterinary use in many countries. As a result, a black market for antiviral drugs, mostly made in China, is flourishing, fueled by desperate cat owners who treat their animals on their own. A 2021 study of cats given unlicensed antivirals in the US found a survival rate of 80 % and above.

The number of PCR tests increased again in August, which may be due to the Cypriot government approving the veterinary use of molnupiravir, an antiviral drug used to treat Covid-19 in humans. Cats must be PCR positive for their owners or caretakers to receive a prescription.

According to Epaminondas, caseload data for most of the second half of the year, based on clinic surveys, should be available soon.

dr. J. Scott Weese, an infectious disease veterinarian at the Ontario Veterinary College at the University of Guelph, said in an email to VIN News that the epidemiology of the outbreak is not well described, adding that it is "a common problem in field studies where the information is piecemeal and often unofficial".

According to Weese, the number of cases confirmed by PCR - 165 - is very small, especially for a country with a lot of feral cats. He also said that the rate of diagnosis based on questionnaires begs the question: Are more diagnoses due to a significant increase in the disease, a significant increase in testing, or both?

“There appears to be an increase in the incidence of FIP in Cyprus. It's hard to say by how much," he said. "When there is more discussion and awareness increases, there are also more diagnoses of an endemic disease that may have been there all along, but was just ignored. Often times these are combined situations where there is a real increase or a small local clustering, but the increased discussion and testing leads to an overestimation of the rate of change.”

He added: “I am not ruling out that this was a real epidemic or that this is a worrying new strain. We just don't know (or at least I don't). This work shows that we need to deal more with this issue."

Introducing FCoV-23

Basic information of FIP

If you find the specifics of feline infectious peritonitis difficult to understand, ask Dr. Brian Murphy for advice: It is. "FIP is probably the most complicated virus in veterinary medicine," said Murphy, a veterinary pathologist and FIP researcher at the University of California, Davis, School of Veterinary Medicine. Much of what science knows about FIP was pioneered by Murphy's mentor, Dr. Niels Pedersen, who is already retired.

FIP is caused by mutations in a ubiquitous and otherwise insignificant pathogen called feline enteric coronavirus. These mutations allow the virus to infect immune system cells called macrophages, which multiply and cause deadly inflammation. FIP is estimated to affect 1.3 % cats, most often kittens in catteries and shelters.

There are two forms of FIP: wet and dry. Cats may initially have one form and later develop another. In wet FIP, the fluid created as a result of inflammation accumulates most often in the abdomen, less often in other parts of the body. In dry FIP, the patient develops tumor-like lesions in the abdomen, chest, eyes, and/or brain. Early symptoms of FIP include fever, loss of appetite, weight loss, and depression. Cats with neurological FIP may develop lack of coordination, seizures, and dementia. Eye disease can cause inflammation, discoloration, or clouding of a cat's eyes, which impairs vision.

No test can diagnose every case of FIP with absolute sensitivity and specificity. Therefore, the diagnosis is often established based on a summary of clues from the patient's history, physical examination, and various diagnostic tests.

First identified in the 1950s, FIP was considered a death sentence for decades. However, in recent years, antivirals – including those used against the coronavirus that causes Covid-19 in humans, such as remdesivir, molnupiravir and Paxlovid – have been shown to reverse the course of FIP in cats. None of these antivirals are approved for veterinary use in the United States (except at universities that are researching these drugs in cats with FIP). These medicines are variously available for veterinary use in several European countries, including Cyprus, Finland, Norway, Sweden and the United Kingdom, as well as Australia and New Zealand.

In countries where the treatment is not approved by regulators, pet owners have resorted to buying unlicensed antivirals, mostly made in China, to treat sick cats themselves.

Understanding why the new strain behaves differently from what some researchers call "traditional FIP" requires a closer look at how FECV leads to FIP.

For reasons that are not fully understood, sometimes the FECV mutates inside the cat. These changes allow it to escape from intestinal cells and infect a key cell of the immune system, the macrophage. This macrophage-infecting virus is known as the FIP virus or FIPV. Now it can travel throughout the body and, in Gunn-Moore's words, "devastate the environment" and cause potentially fatal inflammation.

Once established, the FIPV coronavirus has two important characteristics: First, it is no longer an enteric virus, so it can only very rarely return to the gut to be excreted as FIPV in the feces. Second, FIPV has a gene sequence that is unique to a given cat.

FCoV-23, as the new strain has been named, appears to violate both of these schemes. Gunn-Moore said it thrives in the intestines of Cypriot cats. Furthermore, based on RNA sequencing from PCR samples, the virus in many cats had the same genetic sequence. The genetic sequencing was carried out by researchers at the Roslin Institute, an animal science research center at the University of Edinburgh.

Gunn-Moore had some early hypotheses about what might have caused the outbreak, but genetic analysis points to her main theory — that a pantropical canine coronavirus combined with a feline enteric coronavirus. Pantropic viruses can spread to different tissues in the body, a property that would allow FCoV-23 to enter other organs and nerves, as well as continue to multiply in the intestinal tract.

"I think a dog came to Cyprus and defecated on the floor. A cat that already had FECV then got dog feces on her feet, licked her paws, and got both viruses," she said. ” And this is what these viruses do, they recombine, they are party animals. They get together and go, 'Hey, do you want some of this? Shall I give you some?' "

Gunn-Moore added that further work is planned to confirm the case for their direct transmission.

"We are currently carrying out experiments to sequence the virus from feces, because we need to sequence the virus and prove that it is the same sequence as in the blood," she explained.

dr. Brian Murphy, a veterinary pathologist and FIP researcher at the University of California, Davis, School of Veterinary Medicine, said the recombinant feline and canine coronavirus described in the Cyprus paper had been identified before, including by a team at Washington State University's School of Veterinary Medicine. Medicine in the 1970s.

"This is a replication of that virus, but it's a highly virulent form of the virus," Murphy said based on the evidence so far. He welcomes the scientists' plans for further genetic analysis and suggests further investigation.

"Sequencing an enteric corona or a virus coming from the gut alone is conclusive, but it's not proof," he said. "It wouldn't be a bad experiment to take fecal material containing the virus from the gut, infect cats with it, and then, when they get sick, save those cats with antiviral treatment. That would be good evidence of transmission of a virulent form of the virus.”

Murphy admitted that this kind of test on companion animals is essentially banned in Europe and would likely be very controversial. "I think most people will probably disagree with me," he said. "However, I think it can be done ethically because we have high-quality, highly effective drugs."

Dr. Maria Lyraki, an internal medicine specialist in Athens, Greece, who coordinates treatment protocols with veterinarians in Cyprus and is an author of the paper, said Murphy is right that the experiment would be proof, although some of the infected cats may not get sick if they develop an adequate immune response.

"However, it is something that we would not be able to implement from an ethical point of view," she said.

Thousands of sick cats

If the Cypriot epidemic had occurred 10 years ago, countless cats would probably have died because until recently there was no known way to stop the disease.

Antivirals have changed this situation.

Two promising products are remdesivir, made by pharmaceutical company Gilead to treat Covid-19 in humans, and the related compound GS-441524. GS, as it's called for short, was shown to be effective in reversing FIP in cats in an infectious disease study at the University of California, Davis in 2018.

Gilead has not granted a license to develop GS-441524 as a veterinary medicinal product. Remdesivir is not approved as a veterinary medicine in the United States, Canada, and some European countries.

However, since August, Cypriot vets have been able to import compounded versions of GS and remdesivir, manufactured by Bova, a veterinary pharmaceutical company based in the UK and Australia, under a special permit, to based on instructions UK Veterinary Medicines Directorate.

GS and remdesivir "are the first-line drugs we use because we have the most literature on them," Lyraki said. "But they're really expensive... which is really challenging, especially for such a large number of stray cats."

According to Epaminondas, treating one cat with these drugs can cost from €3,000 to €7,000 ($3,250 to $7,580).

"We contacted people from all over the world who are treating cases of FIP," Lyraki said. "And the specialists advised us that they use molnupiravir. There is a published literature on this drug and we have a lot of anecdotal discussion among FIP specialists around the world that it is really effective.”

The government's decision to allow veterinary use of molnupivirus has made a huge difference.

"It actually works pretty well," Lyraki said. Initially, boxes of molnupiravir were donated to the PVA to fight the epidemic. They were available at an exceptionally low price of around €100 ($108) per cat, a significant saving. The actual price of the drug is much higher, but still significantly cheaper than GS.

However, the replacement of molnupivir will not last long. Merck Sharp and Dohme BV, which sells the antiviral under the name Lagevrio, will stop making it for Europe next year after the European Medicines Agency decided earlier this year not to support the registration of molnupiravir based on its finding that the antiviral's benefit in treating Covid in adults has not been proven.

"Now we are working on finding alternatives," said Lyraki.

Limitation of dissemination

A healthy free-roaming cat lies outside a bakery in Paphos, Cyprus. Stray cats are everywhere on the island - although no one knows how many there are. In response to the FIP outbreak, the Cyprus Veterinary Association, together with ThePetzApp, is launching an initiative to engage cat owners and carers in Cyprus to count the cats in their homes or in the stray cat colonies they care for.

In addition to the immediate situation in Cyprus, there are fears that the strain could spread to other countries or that it is already in other countries from which it has reached Cyprus, as yet unrecognized.

The new strain was confirmed in a cat imported to the UK from Cyprus in August. This cat has been quarantined and is responding to treatment.

Keeping the cats on the island under control can be a challenge. Cyprus is home to many cat rescue activities. Stray cats are regularly collected and taken to other parts of Europe where they are given a new home. According to Epaminondas, there are no regulations regarding the export of cats from Cyprus.

But vets like Lyraki urge rescue groups to be careful. "Our team of experts has issued a recommendation that cats be tested before traveling outside Cyprus and that only cats with negative FCoV antibodies be exported," said Dr. Lyraki. Once the cats arrive at their destination, they should be quarantined for three weeks and then retested for antibodies "until the outbreak is under control and the number of affected cats is significantly reduced."

Meanwhile, Greece, which has its own large stray cat population, has also seen an increase in FIP cases, according to Lyraki.

"We believe that it is only a matter of time before this outbreak spreads to Greece, because Greece and Cyprus are culturally, geopolitically very, very close. There is a lot of exchange and travel between them," she said. "So it's something we're actively monitoring."

A mysterious new type of stone in cats

Original article: Mysterious New Stone Type In Cats

Krátka správa o výskyte nezvyčajných močových kameňoch obsahujúcich GS441524.
Figure 1: Feline uroliths

Between January and April 2023, the Urolite Center in Minnesota received three shipments of atypical stones (Figure 1). All three samples were obtained from cats. All three cats were under 1 year old. Cats came from North and South America. In each case, the infrared spectrographic pattern of the stones was identical. Urinary stones usually contain large amounts of phosphorus, calcium and magnesium. In these cases, electron dispersion spectroscopy revealed a high proportion of nitrogen, carbon and oxygen.

Mystery solved. When asked about their medical history, all three cats were diagnosed with feline infectious peritonitis. All three were treated with either Remdesivir or its metabolite GS-441524. We requested samples of their antiviral drugs for analysis. The antiviral drugs were spectrographically identical (Figure 2). The stones were composed of GS-441524.

Figure 2: FT-IR spectroscopy of urinary stone of patient and reference sample GS-441524

After administration, GS-441524 is excreted primarily in the urine. Although GS-441524 is very soluble in organic solvents such as DMSO (10-59 mg/ml), it is poorly soluble in aqueous solutions such as water (0.0004 to 0.1 mg/ml). Its limited solubility makes GS-441524 a prime candidate for stone formation. Observation of urinary symptoms in cats receiving Remdesivir or GS-441524 is an indication to look for stones. Observation of atypical crystalluria or uroliths may be an indication to limit the dose of the drug (if possible) and increase water consumption to minimize stone formation.

Passhaei Y. Analytical methods for the determination of Remdesivir as a promising antiviral candidate drug for the COVID-19 pandemic. Drug Discoveries and Therapeutics. 2020;14:273-281

Wei D. et al. Potency and pharmacokinetics of GS-441524 derivatives against SARS-CoV-2. Bioorg Med Chem. 2021;46:116364

Unfair practices of some manufacturers of anti-FIP drugs

Analysis of anti-FIP drugs with detected Molnupiravir content

We have received information that several Chinese drug manufacturers, in an effort to reduce the production costs of drugs and their sales price as much as possible while maintaining the largest possible margin, have started to use Molnupiravir (EIDD-2801) as an active ingredient.

The information came from the global group FIP Warriors 5.0, which published several analyzes of drugs declaring GS441524 or GC376 as the active ingredient, but the results of the analyzes show that the drugs contain the already mentioned Molnupiravir. You can see one of the analyzes below. If someone would object that analytics are some means of competitive struggle, it is not so. There were several independent analyses, we also know about the analysis from Bulgaria, one analysis also took place in Slovakia, but the one published by the global FIP Warriors group is the most complex.

Medicines in the CR/SR with the declared content of GS441524 containing EIDD-2801

Figure 1: Suyi 20mg/ml - The manufacturer declares the content of GS441524, but it actually contains Molnupiravir.

This fact also affects our group. One of the drugs where the presence of EIDD-2801 was detected is the widely distributed Suyi brand. The fact that the medicine contains another active substance is not a problem for the person himself. The problem is that the manufacturer hid this fact and declared GS441524 as the active ingredient of their products. This fact should apply to "water" based injectable solutions, which do not sting when applied and whose pH is around 6.

Figure 2: The drug used in the "How we beat FIP" group, for which the manufacturer declares GS441524, but in fact also contains Molnupiravir.

It should be emphasized here that both EIDD2801 and GS441524 are very effective in the treatment of FIP. However, some specifics apply to their use. For example, they have different pharmacokinetics. The one with GS441524 allows application once every 24 hours, while Molnupiravir should be administered twice a day. Anyway, GS441524 is already a very well-proven drug with a minimum of side effects. EIDD-2801 has been used in the treatment of FIP for a shorter time and the official clinical trial is only ongoing, or has not yet been published. That is why other drug manufacturers have so far only recommended it for the treatment of relapses, or in case the cat does not respond to treatment with GS441524. In other words, the drug of first choice is still GS441524. On the other hand, precisely because of the policy of Gilead, which holds the patent for GS441524, hope has dawned for the official treatment of FIP with Molnupiravir, as it has been registered and approved for the treatment of Covid-19 in humans. As a result, a legally available drug (Lagevrio) also appeared in the Czech Republic, but its price was and still is very high and its availability for veterinary use is very complicated.

In an effort to ensure the cheapest possible medicines in order to save as many cats as possible, very cheap medicines also entered our market. The truth is that medication works. We also encountered versions of the solutions that really stung a lot, so it's quite possible that Suyi actually contained GS441524, but over time the manufacturer decided to arbitrarily change the active ingredient, but still declared that it supplied GS441524.

But Suyi is not the only drug containing EIDD-2801 available on our market, about which its manufacturer provided misleading information. In the "How we defeated FIP" group, the drugs from Figure 2 are used.

Why is information about the active substance important?

  • GS441524 and Molnupiravir have a slightly different mechanism of action. GS441524 acts as a terminator of the viral RNA chain, thereby preventing the virus from replicating. EIDD-2801 integrates into the virus's genome, where it causes an accumulation of virus mutations known as a viral error catastrophe, rendering the virus unable to replicate.
  • The pharmacokinetics of GS441524 allows application once a day, while EIDD-2801 in oral form should be applied twice a day according to current knowledge. Official information on the frequency of application of the injection form does not yet exist.
  • GS441524 has already been used for several years in the treatment of FIP, several clinical trials, while the use of EIDFD-2801 in clinical practice is relatively new.
  • The cytotoxicity of GS441424 is lower than that of EIDD-2801. However, it should be noted here that both substances are safe if the recommended dosage is not exceeded. However, if the dosage is significantly exceeded, side effects may appear in the form of significant neutropenia, drooping/dropped ears, etc.
  • GS441524 was originally created for injection use, later a tablet form was added. EIDD-2801 was initially intended only for oral use (tablets), while the injectable form was never the subject of a clinical trial. It is only assumed that EIDD and GS have similar bioavailability limits as GS. This means that approximately 50% of the active substance is used for the tablet.
  • There is a lack of information on the potential side effects of EIDD-2801 in the long term. Considering that the active substance - N4-hydroxycytidine - is a strong mutagen, it is not clear whether after a treatment lasting 12 weeks, which is much longer than the recommended period of 5 days in human medicine, the side effects cannot manifest/accumulate more significantly way.

What is the impact of using another active substance to treat FIP?

  • Pills
    In principle, there is no problem with tablets, provided that the content of Molnupiravir corresponds to the stated content of GS. The dosage remains the same, we only recommend dividing the dose calculated for GS into 2x a day. This means, for example, that if you administered 1 tablet of Suyi once a day, you will administer 1/2 tablet twice a day. Actually, even with GS, it is recommended, especially with higher dosages, to administer the medication twice a day.
  • Injection solutions
    With them, the situation is a bit more complicated, as the stated concentration of 20mg/ml differs considerably from the measured one (Suyi 40mg/ml, while the real measured concentration of the second solution "Cat rehabilitation nutrition supplement" is up to 70mg/ml). Due to the relatively unclear dosage of EIDD in injectable form and the significantly higher concentration, we recommend not to overdo the dosage. The manufacturer Suyi rejects the accusation regarding the change of the active ingredient.

Previous experience with the use of Suyi medicines

Given that the manufacturer still claims that Suyi products contain GS441524, the drug was used and dosed as GS441524, including application only once a day. After more than 9 months, we can declare that its therapeutic effect is indisputable, we register a large number of cured cases, the price of the treatment is favorable, so it would probably be a hasty decision to stop recommending this medicine. However, due to the manufacturer's attitude, we cannot really guarantee the active ingredient in Suyi products. Again, I emphasize that both GS441524 and EIDD-2801 are effective in treating FIP, so it cannot be said that the drug itself is a scam. Of course, it would be better if the manufacturer, instead of ignoring the analyses, simply and clearly declared the active substance according to reality. Until that happens, it is important that you share your experiences with this medicine. For example, in the form of reviews on the website, or directly in the FIP Warriors CZ/SK group.

We certainly do not want to cause panic with this warning. The truth is that the drop in the price of treatment has made it available even for cases where their owners would otherwise have decided on euthanasia. However, in light of the above findings, it is up to you which medication you decide to use. In any case, pay extra attention to checking/monitoring the cat's condition.

Medicines with directly declared EIDD-2801 content

If the manufacturer openly produces drugs containing EIDD-2801, this is of course a good and serious approach. You can find some medicines containing EIDD-2801 here:

https://www.fipwarriors.eu/kategoria-produktu/molnupiravir/

More information about molnupiravir and the treatment of FIP using it

Cyprus becomes 'island of dead cats' after feline coronavirus outbreak kills 300,000 cats

Many cats could die if virus spreading in Cyprus reaches Britain, experts warn

Original article: Cyprus becomes 'island of dead cats' after outbreak of feline coronavirus kills 300,000
Sarah Newey, GLOBAL HEALTH SECURITY CORRESPONDENT
11.7.2023

A new strain of feline coronavirus is ravaging the cat population in Cyprus
CREDIT: CHRISTINA ASSI/AFP via Getty Images

Experts have warned that Cyprus is at risk of becoming an "island of dead cats" after the outbreak of the feline coronavirus.

Stray and domestic cats have been killed since January by the Feline Infectious Peritonitis (FIP) virus, which is one of the strains of the coronavirus. Experts have warned that "a lot of cats" could die if the virus, which is circulating in Cyprus, reaches Britain.

The country, which is sometimes called the "island of cats", is home to the first evidence of animal domestication. However, there is growing concern over the threat posed by "feline Covid" - which does not infect humans but is usually fatal in felines if left untreated.

"Local vets are reporting an alarming increase in FIP cases, which started in January in the capital Nicosia and spread throughout the island within three to four months," said Dr Demetris Epaminondas, vice-president of the Pancyper Veterinary Association.

Veterinarian Kostis Larkou treats a sick cat at a clinic in Nicosia
CREDIT: CHRISTINA ASSI/AFP via Getty Images

In a recent blog post, he added that this was the first "outbreak of this magnitude" ever recorded, with previous cases of FIP generally confined to cat farms. Symptoms include fever, abdominal distension, loss of energy, and sometimes increased hostility. The virus usually affects kittens and young cats.

Professor Danièlle Gunn-Moore, an expert in feline medicine at the University of Edinburgh, told the Telegraph that an outbreak of this scale "has never been seen in history", with reports of dead cats lying on the streets and suspicions that a new one could be emerging. a more deadly strain of FIP. Tests are currently underway to confirm this fact.

She added that local authorities have set up an advisory team, launched a media information campaign and are working to change legislation so that drugs can be used to treat cats, but stressed that no feline should be allowed to leave the country without negative tests.

"There is already some evidence - albeit anecdotal - that the infection may have also appeared in Turkey, Lebanon and potentially Israel. If this virus reaches the UK it could cause the death of many of our cats. It would be heartbreaking. We have to take it seriously."

The country, which is sometimes called the "island of cats", has the oldest evidence of animal domestication
CREDIT: CHRISTINA ASSI/AFP via Getty Images

Cyprus is a cat-loving country, and its history has a long history with these furry animals – archaeologists have found evidence of their domestication dating back 9,500 years.

However, locals who feed stray cats on the island report that their regulars are increasingly disappearing as they succumb to the virus. Although only 107 cases have been officially reported, veterinarians and animal rights activists estimate that the true number is much higher.

"Since January, we have lost 300,000 cats [due to FIP]," Dinos Ayioamitis, head of Cats PAWS Cyprus and vice-president of Cyprus Voice for Animals, told Agence France Presse. The island's cat population is estimated at around one million.

He said part of the problem with counting cases is that with so many stray animals living in Cyprus, it is almost impossible to diagnose and document all cases of the disease.

Dr. Epaminondas said that "the only way to stop the disease is treatment," but even that proved difficult.

Experts want to start using the two treatments on cats, but bureaucratic hurdles and costs have prevented further progress.

These are the drugs remdesivir, which is used to treat Covid-19, and the closely related drug GS-441524. Although approved for use on animals in the UK and for import into Cyprus, they are expensive - from £2,500 to £6,000 for a 3-4kg cat.

Experts want to start using two treatments on cats
CREDIT: CHRISTINA ASSI/AFP via Getty Images

Another option is a cheaper antiviral used to treat Covid-19 in humans called molnupiravir. Dr Epaminondas estimates it would cost around £170 per animal - but the Veterinary Association's application for permission to treat the cats was rejected in May because the government said human medicines could not be imported for use in veterinary care.

Professor Gunn-Moore urged the Cypriot government to make the drugs GS-441524, remdesivir and molnupiravir available to all cats, but said the ultimate control tool would be a vaccine.

"It's a coronavirus, so based on the Covid epidemic, it could very well happen if pharmaceutical companies want to do it," she said.

With the government taking no action, some people are buying the drugs themselves - and Dr Epaminondas told Cyprus News in May that a black market for cheap, unlicensed drugs was "flourishing".

Among those looking for their own solutions is Vasiliki Mani, 38, a member of several animal welfare organizations who spent around £3,000 from her savings to treat two sick strays. She told AFP that if FIP is not stopped soon, Cyprus will become an "island of dead cats".

Local residents who feed stray animals report that their resident cats are increasingly disappearing as they succumb to the virus
CREDIT: CHRISTINA ASSI/AFP via Getty Images

What to do when your cat gets FIP?

A huge outbreak of Feline Infectious Peritonitis (FIP) has raised concerns in Cyprus, particularly with reports that a slightly different version of the virus may be circulating, but is not unique to the country and has previously been reported in the UK.

If your cat shows symptoms such as fever, abdominal distension, loss of energy and sometimes aggressive behavior, experts recommend that you take it to the vet immediately. Kittens and cats under two years of age are most at risk.

An antiviral drug used to treat Covid-19 called remdesivir is available in the UK, as well as a closely related drug called GS-441524, approved for use in cats with FIP.

Veterinarians say that the "gold standard" of treatment is the application of remdesivir in an infusion for three to four days, followed by injections of the drug for up to two weeks. The oral drug GS-441524 is then used to prevent relapse – the total duration of treatment is approximately 12 weeks.

Outbreak of feline infectious peritonitis in Cyprus

Article provided and translated with permission Danielle Gunn-Moore.
Original article: VetRecord, Volume192, Issue 11, 3/10 June 2023, Pages 449-450, published 6/2/2023.

Colleagues and the public are alerted to an outbreak of Feline Infectious Peritonitis (FIP) in Cyprus that broke out in the capital city of Nicosia in January 2023. An increasing number of cases have been reported in the districts of Larnaca, Limassol and Famagusta. Within 12 weeks, the number of PCR-confirmed FIP cases increased more than 20-fold compared to the previous year.

Biopsies of cavitary fluids, abdominal lymph nodes by fine needle aspiration or tissue biopsies of cats with clinical signs consistent with FIP were sent to Vet Dia Gnosis in Limassol. After cytological or histopathological examination, samples were subjected to automated extraction of total nucleic acid and RT-PCR for the detection of feline coronaviruses (FCoV) at Laboklin Bad Kissingen, Germany. 1

Three and four PCR-confirmed FIP cases were reported in 2021 and 2022, respectively, while 98 PCR-confirmed FIP cases were reported from January to April 2023.

Outbreaks of FIP have already been documented in the UK, USA and Taiwan, but only in breeding facilities and trapping centres. 2-4 This outbreak spread very quickly in different districts of the island, with local veterinarians reporting clinical cases even in cats living exclusively indoors. This is extremely alarming and suggests that there is a highly virulent strain of FCoV in Cyprus that can potentially be transmitted by mechanical vectors. We therefore recommend that cats be kept indoors.

Paphos district is geographically the farthest from Nicosia and has not yet seen an increase in cases.

To prevent the spread of this strain of FCoV outside the island, we encourage veterinarians to serologically test every cat before it travels outside Cyprus. No seropositive cat should travel outside of Cyprus until we have a better understanding of the current outbreak. Ideally, if the cat is allowed to travel, it should be kept indoors for 10 to 14 days and retested, as acutely infected cats are likely to seroconvert later. 5

The disease spread very quickly in different districts of Cyprus, indicating that a highly virulent strain of feline coronavirus is present on the island.

Introducing travel measures for cats traveling from Cyprus must be a priority for the UK. This is due to the high number of animals traveling between the two countries, which reflects the existing historical ties; parts of Cyprus are British Overseas Territories and there are significant numbers of British expatriates residing in Cyprus permanently or seasonally. In the past we have seen the introduction of other infectious agents into the UK via dogs traveling from Cyprus, for example Hepatozoon canis and Leishmania infantum. 6

We are currently analyzing FCoV before and during the outbreak, and we are implementing an epidemiological monitoring system. This will provide us with important information regarding this highly virulent strain and help us understand what is causing this epidemic and how we can control its impact on the cat population and the risk of spreading to other countries.

The high number of stray and free-ranging domestic cats in Cyprus is something that could potentially have played a key role in the outbreak, but there are other factors to consider, including the recent introduction of FIP treatment and the recent Covid-19 pandemic.

Charalampos Attipa, senior lecturer in veterinary clinical pathology Danielle Gunn-Moore, professor of feline medicine Stella Mazeri, EBVS European Specialist in veterinary public health Royal (Dick) School of Veterinary Studies and The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG email: charalampos.attipa@ed.ac.uk Demetris Epaminondas, vice president of the Pancyprian Veterinary Association Veterinary Services, Ministry of Agriculture, Natural Resources and Environment, Cyprus Maria Lyraki, EBVS European Specialist in small animal internal medicine Vets4Life Referral Hospital, Athens, Greece Alexandros Hardas, lecturer in veterinary anatomic pathology Department of Pathobiology and Population Sciences, Royal Veterinary College, Hatfield, Hertfordshire AL9 7TA Stavroula Loukaidou, veterinary surgeon Vet Dia Gnosis Ltd, Limassol, Cyprus Michaela Gentil, veterinary surgeon Laboklin GmbH and Co KG, Bad Kissingen, Germany

References

  1. Gut M, Leutenegger CM, Huder JB, et al. One-tube fluorogenic reverse transcription-polymerase chain reaction for the quantitation of feline coronaviruses. J Virol Methods 1999;77:37–46
  2. Wang YT, Su BL, Hsieh LE, et al. An outbreak of feline infectious peritonitis in a Taiwanese shelter: epidemiologic and molecular evidence for horizontal transmission of a novel type II feline coronavirus. Vet Res 2013;44:57
  3. Barker EN, Tasker S, Gruffydd-Jones TJ, et al. Phylogenetic analysis of feline coronavirus strains in an epizootic outbreak of feline infectious peritonitis. J Vet Intern Med 2013;27:445–50
  4. Healey EA, Andre NM, Miller AD, et al. Outbreak of feline infectious peritonitis (FIP) in shelter-housed cats: molecular analysis of the feline coronavirus S1/S2 cleavage site consistent with a 'circulating virulent-avirulent theory' of FIP pathogenesis. JFMS Open Rep 2022;8:20551169221074226
  5. Stoddart ME, Gaskell RM, Harbor DA, et al. Virus shedding and immune responses in cats inoculated with cell culture-adapted feline infectious peritonitis virus. Vet Microbiol 1988;16:145–58
  6. Attipa C, Maguire D, Solano-Gallego L, et al. Hepatozoon canis in three imported dogs: a new tick-borne disease reaching the United Kingdom. Vet Rec 2018;183:716

Antiviral drugs to treat enzootic feline coronavirus infection in kennels and why it might not be a good idea

Niels C. Pedersen, DVM PhD,
1.4.2023

Original article: Antiviral Drugs for Control of Enzootic Feline Coronavirus Infection in Pedigreed Catteries and why it may not be a good idea

When discussing feline coronavirus (FCoV) infection in a multicat setting, it is important to understand the correct terminology. The term FCoV is a collective term for two historically named viruses. A coronavirus was eventually identified as the causative agent of feline infectious peritonitis (FIP) in cats, which was named FIP virus or FIPV (Ward, 1970; Zooket al., 1968). Subsequently, FIPV was found to be a mutant form of FCoV that was present in cats infected with a widespread and minimally pathogenic enteric coronavirus and was named feline enteric coronavirus (FECV) (Pedersen et al., 1981). To avoid misunderstandings, this author prefers to refer to the form of FCoV that applies to the immediate discussion. Therefore, it is appropriate to use the term FIPV when discussing the form of FCoV found in a specific type of white blood cell (monocyte/macrophage) in the affected tissues and body fluids of cats with FIP. The term FECV is used to refer to the form of FCoV that causes chronic and intermittent infections of the epithelium in the lower intestine of healthy cats and is excreted in large quantities in the feces. Enzootic is the correct term for infections that occur in animal populations, while endemic is the corresponding term used for humans. Clinical "signs" are what veterinarians and pediatricians observe during physical examination or what owners/parents communicate to them, while symptoms are what patients describe to their doctors. Therefore, "epizootic" and "symptoms" are not strictly veterinary terms.

FECV, like many other microbial infections in cats, is maintained in the population as a chronic or recurrent asymptomatic infection. FECV is first shed in faeces from around 9–10 weeks of life, coinciding with the loss of maternal immunity (Pedersen et al., 2008). Infection occurs via the faecal-oral route and targets the intestinal epithelium, and primary signs of enteritis are mild or usually inconspicuous (Pedersen et al., 2008; Vogel et al., 2010). Subsequent faecal excretion occurs from the colon and usually ceases after several weeks or months (Herrewegh et al., 1997; Pedersen et al., 2008; Vogel et al., 2010) with the development of immunity. The resulting immunity is notoriously short-lived, and repeated infections are common throughout life (Pearson et al., 2016; Pedersen et al., 2008). A stronger immunity appears to develop over time and cats over 3 years of age have been shown to be less likely to become reinfected and become faecal shedders (Addie et al., 2003). Although the level of exposure to FECV is the primary risk factor for FIP in cat breeds (Foley et al., 1997), the health of the immune system at the time of emergence of mutant FIPV is a major determinant of the occurrence of FIP in any population or group of cats.1

FIP is caused by specific mutants that arise during FECV infection (Poland et al., 1996; Vennema et al., 1995).1 These FlP-causing mutants develop with some frequency in the organism, but fortunately most of them are eliminated by the healthy immune system (Poland et al., 1996).1 Given the relationship between FECV enzootic infection and FIP, it is logical to prevent FIP by minimizing FECV exposure. As “no vaccine can produce better immunity than natural infection” and given what is known about the weakness and short-term nature of natural immunity against FECV (Pearson et al., 2016; Pedersen et al., 2008), it is unlikely that it will succeed to develop effective vaccines against FECV.

Although enzootic FECV infection is not amenable to vaccination, thorough carrier testing and strict quarantine can eliminate FECV in a group of breeding research cats (Hickman et al., 1995). However, FECV is so ubiquitous in nature and easily spread by direct and indirect cat-to-cat contact and on human-borne fomites that the strictest quarantine facilities and procedures are required to prevent its spread. How strict must the quarantine be? Experience with testing and removal in conjunction with quarantine to eliminate and prevent FECV infection is limited to one report (Hickman et al., 1995). FECV was eliminated from a specific pathogen-free breed of cats at UC Davis by removing the virus shedders and rigorously tightening quarantine procedures for the remaining colony (Hickman et al., 1995). Nevertheless, FECV re-entered this colony for several years, despite all attempts to prevent its spread (Pedersen NC, UC Davis, unpublished, 2022). The only example of effective quarantine for FECV was described for cats in the Falkland Islands (Addie et al., 2012). These islands in the remote South Atlantic have fortunately remained free of FECV, probably due to their extreme isolation. Measures have been taken to prevent future inadvertent introduction of FECV to the islands (Addie et al., 2012). Based on this experience with feline and murine enteric coronaviruses, it is unlikely that FECV could be kept out of any group of domesticated cats with anything less than the strictest isolation and infection prevention practices.

An interesting approach to prevent or delay FECV infection in kittens in breeding centers has been referred to as "early weaning and isolation" (Addie et al. 19952). It was based on the finding that kittens born to FECV-exposed or infected mothers have maternal immunity to infection up to 9 weeks of age (Pedersen et al., 2008). Therefore, kittens weaned a few weeks before the loss of this immunity (4-6 weeks of age) are usually free of infection and, if removed from the mother and isolated from other cats, could theoretically be kept virus-free. This practice was initially popular, but the necessary facilities and quarantine procedures required to prevent later infection were difficult to maintain in kennels with larger numbers of breeding cats (> 5 cats, Hartmann et al., 2005; > 10 cats Addie et al., 19952). Therefore, elimination of FECV in kittens by early weaning and isolation has been doomed to failure in most common homes/kennels due to the largely unavoidable exposure to FECV that occurs in the breeding, rearing and exhibition of breeding cats.

Another problem with early weaning and isolation is the need to separate virus-free kittens from other cats in a large group. This problem could be avoided if all the cats could get rid of the infection at the same time. This can be achieved by serially testing faeces for FECV excretion over a period of time and culling all shedding cats. However, since a significant proportion of cats in farms involved in FECV enzootic disease shed FECV in their faeces (Foley et al., 1997; Herrewegh et al., 1997), culling cats can have a serious impact on the gene pool (Hickman et al., 1995). . This begs the question – can FECV be eliminated in all cats in a group at the same time? Interestingly, the relatively recent discovery of effective antivirals against FIP has also provided a possible method of eliminating all the spreaders of the virus at the same time (Pedersen et al., 2018, 2019). Early studies of such use of antivirals such as GS-441524, although of a rather preliminary nature, suggest that FECV can be eliminated from a closed population of cats with relatively short treatment (Addie et al., 2023).

Assuming that FECV can be eliminated as an enzootic virus from the feline population by using specific antivirals, what are the pitfalls of doing so? The first pitfalls are the cost of antivirals, the frequent testing of feces required to identify shedding animals, and the establishment and maintenance of adequate quarantine facilities and practices. Therefore, domestic facilities with poor barrier isolation practices are doomed to failure to maintain this group of cats FECV-free for extended periods of time. The second pitfall is related to the normal activities of breeding and exhibiting breeding cats. Breeding cats involves frequent interaction between the cats as well as humans in contact with the cats and with each other. It is also difficult to imagine that a breeder and avid show participant would give up all the joys of breeding and showing their cats by avoiding all such interactions. The final question is: "Now that the cats are free of FECV, what are you going to do with them?". What is the chance that they will remain without FECV for any length of time after leaving the controlled environment? They will have no immunity to FECV and will be very sensitive to the slightest exposure. The same will apply to the group of cats they come from. Finally, the continuous antiviral treatment required to maintain a group of cats free of FECV infection is likely to result in the development of drug resistance. We now know that resistance to GS-441524 can occur in cats treated for FIP, and UC Davis researchers1 and Cornell University3 agree that acquisition of drug resistance in enzootic FECV infections would outweigh any potential benefit of such treatment on FIP incidence. FIP is currently curable in more than 90 % cases4 and even if resistance to antivirals does develop, it is largely confined to the affected cat. It can be argued that HIV-1 infection in humans is currently prevented by antivirals without any reported concerns about drug resistance. Preventive treatment of HIV-1 however, it is not a monotherapy, but includes several drugs of different classes.3 This is not done to increase the effectiveness of treatment, but rather to prevent drug resistance. If the virus develops resistance to one drug in the drug mix, the other drugs will prevent it from replicating.

In conclusion, I would like to paraphrase: "Just because something can be done, should it be done?" The author believes that much larger and better designed studies, conducted over a long period of time, are needed before this practice can be seriously considered. The overall incidence of FIP in smaller and well-maintained farms with enzootic FECV infection is usually less than 1 %, and currently more than 90 % cases of FIP that might arise can be cured.4 A practical way to reduce the incidence of FIP is to keep the number of breeding cats and kittens low, to keep more older cats, to not breed individuals and bloodlines that have given rise to cases of FIP, and to minimize the stress of frequent introductions of new cats and changes in placement or relocated.1 In smaller farms, isolation and early weaning can also be useful.

References

  • Addie DD, Bellini F, Covell-Ritchie J, Crowe B, Curran S, Fosbery M, Hills S, Johnson E, Johnson C, Lloyd S, Jarrett O. 2023. Stopping Feline Coronavirus Shedding Prevents Feline Infectious Peritonitis. Viruses. 15(4), 818.
  • Addie DD, McDonald M, Audhuy S, Burr P, Hollins J, Kovacic R, Lutz H, Luxton Z, Mazar S, Meli ML, 2012. Quarantine protects Falkland Islands (Malvinas) cats from feline coronavirus infection. J Feline Med Surg, 14, 171-176.
  • Addie DD, Schaap IA, Nicolson L, Jarrett O, 2003. Persistence and transmission of natural type I feline coronavirus infection. Journal of General Virology 84, 2735-2744.
  • Addie, D.; Jarrett, O. Control of feline coronavirus infections in breeding catteries by serotesting, isolation, and early weaning. 1995. Feline Pract. 23, 92-95.
  • Foley JE, Poland A, Carlson J, Pedersen NC, 1997. Risk factors for feline infectious peritonitis among cats in multiple-cat environments with endemic feline enteric coronavirus. J Amer Vet Med Assoc. 210, 1313-1318.
  • Hartmann K, 2005. Feline infectious peritonitis Vet Clin North Am Small Anim Pract. 35(1), 3979.
  • Herrewegh AAPM, Mahler M, Hedrich HJ, Haagmans BL, Egberink HF, Horzinek MC, Rottier PJM, de Groot RJ, 1997. Persistence and evolution of feline coronavirus in a closed cat-breeding colony. Virology 234, 349-363.
  • Hickman MA, Morris JG, Rogers QR, Pedersen NC, 1995. Elimination of feline coronavirus infection from a large experimental specific pathogen-free cat breeding colony by serologic testing and isolation, Feline Practice 23, 96-102.
  • Pearson M, LaVoy A, Evans S, Vilander A, Webb C, Graham B, Musselman E, LeCureux J, VandeWoude S, Dean GA, 2019. Mucosal Immune Response to Feline Enteric Coronavirus Infection. Viruses 11, 906.
  • Pedersen NC, Theilen G, Keane MA, Fairbanks L, Mason T, Orser B, Che CH, Allison C, 1977. Studies of naturally transmitted feline leukemia virus infection. American Journal of Veterinary Research 38, 1523-1531.
  • Pedersen NC, Boyle JF, Floyd K, Fudge A, Barker J, 1981. An enteric coronavirus infection of cats and its relationship to feline infectious peritonitis. American Journal of Veterinary Research 42, 368-377.
  • Pedersen NC, Allen CE, Lyons LA, 2008. Pathogenesis of feline enteric coronavirus infection. Journal of Feline Medicine and Surgery 10, 529-541.
  • Pedersen NC, Liu H, Dodd KA, Pesavento PA, 2009. Significance of coronavirus mutants in feces and diseased tissues of cats suffering from feline infectious peritonitis. Viruses 1, 166-184.
  • Pedersen NC, Kim Y, Liu H, Galasiti Kankanamalage AC, Eckstrand C, Groutas WC, Bannasch M, Meadows JM, Chang KO, 2018. Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. Journal of Feline Medicine and Surgery 20, 378–392.
  • Pedersen NC, Kim Y, Liu H, Galasiti Kankanamalage AC, Eckstrand C, Groutas WC, Bannasch M, Meadows JM, Chang KO, 2018. Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. Journal of Feline Medicine and Surgery 20, 378–392.
  • Poland AM, Vennema H, Foley JE, Pedersen NC, 1996. Two related strains of feline infectious peritonitis virus isolated from immunocompromised cats infected with the feline enteric coronavirus. Journal of Clinical Microbiology 34, 3180–3184.
  • Vennema H, Poland A, Foley J, Pedersen NC, 1995. Feline infectious peritonitis viruses arise by mutation from endemic feline enteric coronaviruses. Virology 243, 150–157.
  • Vogel L, Van der Lubben M,, Te Lintelo EG, Bekker CPJ, Geerts T, Schuif LS, Grinwis GCM, Egberink HF, Rottier PJM, 2010. Pathogenic characteristics of persistent feline enteric coronavirus infection in cats. Veterinary Research 41, 71.
  • Ward JM, 1970. Morphogenesis of a virus in cats with experimental feline infectious peritonitis. Virology 41, 191-194.
  • Zook BC, King NW, Robinson RL, McCombs HL, 1968. Ultrastructural evidence for the viral etiology of feline infectious peritonitis. Veterinary Pathology 5, 91-95.
  1. Pedersen NC. History of Feline infectious Peritonitis 1963-2022 – First description to Successful Treatment. https://sockfip.org/wp-content/uploads/2022/04/Review-FIP-1963- 2022-final-version.pdf-4.29.22.pdf.
  2. Addie D. Prevention of feline coronavirus (FCoV) infection. https://www.catvirus.com/PreventionS1.htm.
  3. Cornell University blog. Fight FIP. Unraveling feline infectious peritonitis from the ground up. https://blogs.cornell.edu/fightfip/fip-antivirals/.
  4. FIP Treatment – Czechia / Slovakia. Basic data, 2023. https://docs.google.com/spreadsheets/d/e/2PACX-1vRAni FV fteWIW1HXsROLuJ7YY1- i Sf81BCmM9JT9LbCT2mcnwD1rL9IBsLCTB1U59CcnalOGiFqq/pubhtml?gid=1340189982&singl e=true

Antivirals and FIP treatment protocols

Although currently the most widely used active substance in the treatment of FIP is the nucleoside analog GS-441524, in fact there are already several agents with antiviral activity that can be successfully used in the treatment of FIP. In this article, I would like to introduce you to currently used antivirals, or recommendations for their use.

Due to the absence of clinical studies other than GS-441524 and GC-376, unless otherwise stated, the recommended duration of treatment for FIP is still 12 weeks. This does not mean that the treatment cannot be shorter for a specific individual, but at the same time there are also cases where the treatment must be extended. It should also be noted that the treatment should always be terminated only after the assessment of the cat's clinical condition and the results of the blood test.

GS-441524

Currently the most widely used antiviral drug for the treatment of FIP. Nucleoside analog GS-441524 has been the subject of several clinical studies. The first to prove its effectiveness in the treatment of FIP was Dr. Niels Pedersen and his team. You can find his pioneering clinical study here.
The subject of this clinical study was injection form active substance, but it didn't take long, and tablet forms of the drug also appeared on the market. The originally determined dosage was gradually increased over time along with the decreasing price of the treatment, and nowadays it is good to stick to the values listed below. In addition, GS-441524 is a very safe antiviral, and because of minimizing the risk of relapse, it is better overdose, such as underdosing.

Unfortunately, the patent holder of GS-445424, Gilead, never licensed it to another company (with the exception of Bova), and is not even trying to commercialize this substance. For this reason, practically all medicines containing GS-441524 come from the black market.

In the case of a severe condition, it is possible and even advisable to use at least the first 3 days of the so-called booster dosage at the dosage level for neurological FIP, even if the cat does not have neurological FIP. There are even opinions that it is good to use neurological dosage for the first 14 days even in non-neurological forms of FIP (Dr. Addie).

FIP typeGS-441524 - injection solutions
Wet FIP (abdominal effusion, without ocular and neurological symptoms)6 mg/kg once a day sc
Dry FIP (without effusion, or with effusion in the chest cavity without eye and neurological symptoms)8 mg/kg once daily SC
Ocular FIP (ocular symptoms - cloudy eye, blood in the eye chamber, etc.)10 mg/kg once daily SC
Neurological FIP (neurological symptoms, eg anisocoria or mydriasis)12 mg/kg once daily SC
Relapse of FIP (usually associated with neurological manifestations)15 mg/kg once daily SC

Arrival tablets got a little confused with the dosage during treatment, because some manufacturers started to list the so-called equivalent GS content so that the dosage used is "compatible" with injections, while other manufacturers state the real GS content. It is believed that the oral bioavailability of the drug is only about 50% compared to injections, so in practice it is necessary to count on twice the dosage of such tablets compared to injections, or simply use tablets with a known real GS content as tablets with a half-equivalent GS content. There is only one company licensed to use GS-441542 in tablet form in veterinary practice, and that is the British company Bova. Its GS 50 mg tablets are used for the legal treatment of FIP in Australia and the UK. Unfortunately, they are very expensive. It is necessary to take into account the price of 1 tablet approx. 1000 CZK. For this reason, similar to injectable solutions, tablets from the Chinese black market are mainly used for treatment.

Note that for neurological FIP, the recommendation is to split the dose twice a day. This is due to the presumed reduced absorption capacity of the drug in the digestive tract at an equivalent dosage higher than 10mg/kg.

FIP typeGS441524 - tablets with the specified real GS contentGS441524 - tablets with the stated equivalent GS content
Wet FIP (abdominal effusion, without ocular and neurological symptoms)10-12 mg/kg once a day6 mg/kg once a day
Dry FIP (without effusion, or with effusion in the chest cavity without eye and neurological symptoms)12-16 mg/kg once a day8 mg/kg once a day
Ocular FIP (ocular symptoms - cloudy eye, blood in the eye chamber, etc.)20 mg/kg once a day or 10 mg/kg twice a day10 mg/kg once a day or 5 mg/kg twice a day
Neurological FIP (neurological symptoms, eg anisocoria or mydriasis)12 mg/kg twice a day6 mg/kg twice a day
Relapse of FIP (usually associated with neurological manifestations)15 mg/kg twice a day7.5 mg/kg twice a day

As already mentioned, GS-441524 is a safe antiviral, but on the other hand, neutropenia is very often observed after treatment, which can last for a very long time (up to several months). In the case of long-term and very significant neutropenia, the application of filgrastim - a factor that stimulates the formation of hematopoietic cells - can be considered.

GC376

Protease inhibitor GC376 is actually a first generation anti-FIP drug. Its effectiveness has been proven in the treatment of wet and dry FIP, but due to the significantly reduced ability to penetrate through the blood-ocular and blood-brain barrier, it is not suitable for the treatment of ocular or neurological forms of FIP. Given that very shortly after pilot study GC376 was lost to Dr. Niels Pedersen with the nucleoside analog GS-441524, the importance of the protease inhibitor GC376 has declined significantly. However, it turns out that it can be, and probably will be in the future, an important component of the combined treatment of FIP, for example together with GS-441524, where the effect of both active substances is mutually potentiated, and as a result is much more pronounced than with each active substance alone .
Currently, the company is trying to launch GC376 on the market Anivive.

FIP typeGC376 - solution for injection
Wet FIP (abdominal effusion, without ocular and neurological symptoms)15 mg/kg 2x daily sc
Dry FIP (without effusion, or with effusion in the chest cavity without eye and neurological symptoms)15 mg/kg 2x daily sc
Ocular FIP (ocular symptoms - cloudy eye, blood in the eye chamber, etc.)it is not used
Neurological FIP (neurological symptoms, eg anisocoria or mydriasis)it is not used
Relapse of FIP (usually associated with neurological manifestations)it is not used

GC376 is a safe antiviral, but its most significant side effect is a delay in the development of permanent teeth in young cats.

Remdesivir

This is another drug from Gilead. In fact, it is the so-called prodrug of the above GS-441524. After the application of remdesivir, intracellular metabolism to GS-441524 occurs in the organism. Remdesivir was marketed by Gilead under the trade name Veklury and has played a significant role in the treatment of Covid-19 in humans. However, its use in veterinary practice is very questionable and impractical. Firstly, it lacks approval for veterinary use and secondly, it is very expensive. Application is also a weak point of the drug, as it is intended for intravenous administration. The concentration of Veklura after reconstitution is only 5mg/ml.

The company Bova managed to obtain a license for the use of remdesivir for veterinary use and produces a product with a concentration of 10 mg/ml, which can be used in the form of subcutaneous injections. Unfortunately, the price is very high, so it is not used much in common practice.
Remdesivir has approximately 2x the molecular weight of GS-441524, so the dosage of remdesivir must be approximately 2x higher than that of GS-441524.

FIP typeRemdesivir - solution for injection
Wet FIP (abdominal effusion, without ocular and neurological symptoms)10-12 mg/kg once a day iv/sc
Dry FIP (without effusion, or with effusion in the chest cavity without eye and neurological symptoms)10-12 mg/kg once a day iv/sc
Ocular FIP (ocular symptoms - cloudy eye, blood in the eye chamber, etc.)15 mg/kg once daily iv/sc
Neurological FIP (neurological symptoms, eg anisocoria or mydriasis)20 mg/kg once a day iv/sc
Relapse of FIP (usually associated with neurological manifestations)25 mg/kg once a day iv/sc

Molnupiravir

Antiviral with a long history primarily intended for the treatment of Covid-19 in humans. Molnupiravir (EIDD-2801) is incorporated into the genome of RNA viruses and causes random mutations resulting in the so-called virus bug disaster. The drug exists in the form tablets or capsules. Most legally manufactured drugs (e.g. Lagevrio) contain capsules containing 200 mg of the active substance, and re-encapsulation of the drug is necessary for use in the treatment of FIP. Of course, Chinese manufacturers also produce tablets intended for direct use in animals. Although molnupiravir is not strictly the drug of first choice in the treatment of FIP, it shows great potential in the treatment of FIP relapses, resistance to GS-441524, or can be an important part of FIP combination therapy.

FIP typeMolnupiravir
Wet FIP (abdominal effusion, without ocular and neurological symptoms)8 mg/kg twice a day
Dry FIP (without effusion, or with effusion in the chest cavity without eye and neurological symptoms)8-10 mg/kg twice a day
Ocular FIP (ocular symptoms - cloudy eye, blood in the eye chamber, etc.)10-12 mg/kg twice a day
Neurological FIP (neurological symptoms, eg anisocoria or mydriasis)12 mg/kg twice a day
Relapse of FIP (usually associated with neurological manifestations)15 mg/kg twice a day

With molnupiravir, as with GS-441524, neutropenia can often be observed after the end of treatment, especially at high dosages.

Mefloquine

Mefloquine is an interesting substance that has its primary application in the treatment of malaria in humans. It is not effective as a monotherapy in the treatment of FIP, but it is shown that it can play an important role in the adjunctive treatment of FIP, for example with GS-441524. It mainly makes it possible to reduce the price of FIP treatment or reduce the risk of relapse. The normal length of treatment using GS-441524 is about 12 weeks, but in principle it is possible to shorten this treatment to about 8 weeks and use mefloquine for the next 4 weeks. In Europe, mefloquine is available under the trade name Lariam. One tablet contains up to 250 mg of active substance. In practice, the drug is administered at a dose of 12.5 mg/kg twice a week, or 62.5 mg twice a week for one cat. This corresponds to 1/4 tablet of Lariam twice a week (for example, Monday and Thursday). Lariam must be given with food, otherwise there is a higher probability of the cat vomiting.

I strongly reiterate the fact that mefloquine is not intended for the treatment of FIP as a monotherapy, and should always follow as a supplement after the treatment of FIP with one of the above-mentioned antivirals, or in combination with them.

FIP typeMefloquine (Lariam)
Wet FIP (abdominal effusion, without ocular and neurological symptoms)62.5 mg per cat twice a week
Dry FIP (without effusion, or with effusion in the chest cavity without eye and neurological symptoms)62.5 mg per cat twice a week
Ocular FIP (ocular symptoms - cloudy eye, blood in the eye chamber, etc.)62.5 mg per cat twice a week
Neurological FIP (neurological symptoms, eg anisocoria or mydriasis)62.5 mg per cat twice a week
Relapse of FIP (usually associated with neurological manifestations)62.5 mg per cat twice a week

Other antivirals

It turns out that there is actually up to several dozen of potentially suitable antivirals applicable to the treatment of FIP. Unfortunately, no clinical studies have yet been conducted for many of them, which are important not only for the verification of effectiveness, but mainly for the determination of cytotoxicity. The goal, of course, is to cure the animal without causing poisoning or other health problems that would lead to the cat's death.

Combined therapies

The currently used FIP treatment usually takes the form of monotherapy, that is, the drug contains only one active substance. Unfortunately, this approach has the disadvantage that it is only a matter of time before resistance to the used antiviral begins to manifest itself. The way out of this situation is combined therapy, when 2 or more antivirals are used simultaneously for the treatment of FIP. It is not an entirely simple issue, as in some combinations the therapeutic effect is significantly strengthened, but there are also combinations where, on the contrary, the therapeutic effect is weakened. Currently, the most likely drug combinations are the pairs GS-441524 and Molnupiravir, or GS-441524 and GC376. Regarding the second named combination, it has already taken place in China study, the result of which is really encouraging. In addition to curing all cats, the treatment time was reduced from 12 weeks to 4 weeks. It turns out that a dosage of GS-441524 5mg/kg/24h and GC-376 20mg/kg/12h could be used to achieve a therapeutic effect. However, this combination therapy still needs further independent verification of efficacy.

FIV – Testing and treatment?

As the name suggests, this is not about FIP, but it's important to know. I registered the strange information that when treating FIP with molnupiravir, it was also possible to cure FIV. And that cats that were positive before treatment were negative for FIV after treatment. And that the tests were not quick tests, but tests from Laboklin...

Apparently, many of you have the misconception that if something comes from a lab, that automatically means there is a clear answer. But it is a huge mistake. Let's talk about the principle of FIV and FeLV testing. Rapid tests (snaptests) are antibody-based for FIV and antigenic for FeLV. And here is the basic stumbling block. Antibodies, even if there is some miraculous cure, do not disappear after treatment. Antibodies are proteins produced by the immune system and their purpose is to identify and neutralize foreign objects in the body. So the very negative result of the proilase test after the treatment, before which the test was positive, means only one thing - One of the two tests was false positive (or false negative) and therefore defective.

It is for this reason that it is strongly recommended, especially in the case of a positive FIV or FeLV test, to perform a confirmation test using another laboratory method.

And why did I say that the fact that something is done in the laboratory does not necessarily mean anything? Simply. If you have the FIV and FeLV test done by a laboratory and do not specify the method, it is very likely that the laboratory will do a SNAP test or an ELISA (EIA) test. You can tell by the price of the test, but also by what is on the report. The image below shows that this was a test FIV AK, but what does it mean? antibody test (AK=Antikörper). In parentheses is EIA, which stands for “enzyme-linked immunosorbent assay”. The abbreviation ELISA is also used. You should know that the gold standard of the confirmation test for FIV is the method test Western Blot... In that case, it would be mentioned in the report like this. Although the WB test is also an antibody test, it works on a completely different principle. For FeLV, the standard PCR is used as a confirmatory test. And something else. Why do you think you will test positive for FCoV antibody after treatment for FIP? Exactly for the reason I wrote about above. Antibodies remain in the body after treatment for FIP and this is completely natural. Even after you are cured of the much-maligned Covid, you will still have antibodies. Otherwise, it would be very bad for you. And ask yourself why FCOV antibodies would remain after treatment and FIV antibodies would disappear? Antibodies remain in the body for several months after treatment, and in some cases or for incurable diseases such as FIV, even for years.

In the picture you can see an FIV antibody test with a negative result, which led the cat's owner to the fantastic but unfortunately premature conclusion that the FIV was cured by treating the FIP.

For the sake of completeness, I am also attaching an FIV test using the Western Blot method for my cat, which unfortunately confirmed that it is FIV positive. And we even had a few snap tests done before (one even in the laboratory), some of which were negative and some were positive.

Please stop jumping to conclusions and tame the euphoria about the FIV cure. The result of two antibody tests with a conflicting result does not mean that a cure has occurred, but that one of the tests showed a faulty result.

In addition to the above information, you should also be aware that after vaccination based on the principle of an inactivated virus, it is no longer possible to use antibody tests for the diagnosis of the given disease, because the vaccination serves precisely to make the body create antibodies.

Antibody tests can come out positive even in the case of young kittens (under 20 weeks), when they can have maternal antibodies from breast milk and subsequently the tests can be negative.

Regarding PCR testing for FIV, I would add that you should read the article https://www.fivcats.com/FIV/fiv_testing.html, where the basic principles of FIV tests and their reliability are presented. You will learn, for example, that the error rate of negative PCR tests is really very high.

FIV treatment ???

The FIV virus is a retrovirus related to the virus that causes HIV (AIDS). The main problem is that the virus is "built-in" into the host's genome, and that is why such a disease is not curable. Of course, this does not mean that the life expectancy of an affected individual cannot be extended with the use of symptomatic therapy. If an FIV cat is affected by an infection, antivirals can help, if a bacterial infection appears, ATB is used... Thus, accompanying diseases and infections are dealt with, and with this treatment, the FIV disease itself is kept under control, but it is not cured. To be sure, I also asked those actually called about the possibility of FIV treatment with molnupiravir. Answers by Danielle-Gunn Moore - professor of feline medicine from the University of Edinburgh and Yunjeong Kim - professor at Kansas State University, who together with Dr. Pedersen is behind the discovery of the treatment of FIP using GS-441524, hopefully they will convince those who got "drunk" on the croissant and succumbed to the vision of treating FIV with molnupiravir.

Translation: “Retroviruses such as FIV or HIV (AIDS) are not treatable with antivirals because the viruses are embedded in the host's genome. If there is a good antiviral for FIV, it can help the cat stay symptom-free for a longer period of time (similar to HIV drugs in humans), but I don't think there is any evidence that molnupiravir is effective against FIV.”
Translation: "It was pointed out to me that molnupiravir, because it works on the replicating virus, will never cure FIV, just like the effectiveness of these HIV drugs, because the proviral non-replicating virus can never be their target. Even HIV always requires 3-4 drugs, occasionally 2 – just to keep it under control, so really no chance of a cure.”

Status of FIP treatment and prevention in 2022

Niels C. Pedersen, DVM PhD, November 28, 2022

Original article: Status of FIP treatment in 2022

I am pleased to announce that I have ended my advisory role at SOCKFIP and have officially become a member of the SOCKFIP Board of Directors. It reflects my transition from university to private life, but will not affect my commitment to FIP research. I hope that this more direct involvement will help SOCKFIP transition to a broader role in cat health issues beyond FIP. FIP research continues at the University of California, Davis, as well as at other institutions around the world. Research projects related to FIP at UC Davis are summarized in ” Best regards SOCK FIP” of 2022. SOCKFIP continues to provide financial assistance for such studies through public donations, and I will provide scientific knowledge whenever needed.      

I wish there was a licensed antiviral treatment for FIP in cats, but even the efforts of many individuals and groups have not been able to change the current reality. Therefore, it is questionable whether legal antivirals for FIP will reach the market in the next 2 to 5 years, even if the obstacles are removed immediately. Fortunately, restrictions on the general use of closely related human medicines for COVID-19 are being eased worldwide, allowing them to be prescribed by all doctors and used more widely in the field. Full human approval allows their use in animals, provided the drug needed is derived directly from the actual human product. This would allow drugs made for humans, such as remdesivir and molnupiravir (EIDD-2801), to be used legally in animals, albeit at the cost of human drugs. The goal should still be for drugs specifically licensed for animals and available at a veterinary rather than a medical price. 

More and more veterinarians are already helping owners with treatment. However, it still saddens me that some vets have not heard of effective treatments for FIP, believe that published treatment reports are bogus, or that obtaining drugs from unapproved markets is so scary that they can't even help with treatment once an owner buys it. I commend those veterinarians who accept the reality of treatment and work with owners and their cats with FIP.  

The most significant discovery after GS-441524 is the use of molnupiravir (EIDD-2801) (Merck) as a second effective treatment for FIP. Molnupiravir is also extremely effective in treating cats that have developed resistance to GS-441524, which are the most common cats that develop neurologic FIP during or after treatment with GS-441524. Reports of its use in cats are just beginning to emerge and are being posted on the SOCK FIP website. 

I believe that there are several areas of research that veterinary researchers should consider. One area concerns the safety and efficacy of EIDD-1931 (beta-d-N4-hydroxycytidine), which is the biologically active component of molnupiravir, just as GS-441524 is the active component of remdesivir. This orally administered drug has been the subject of research for almost half a century and should no longer be patent protected. Preliminary research at the University of California, Davis suggests that it may be even more effective and safer than molnupiravir. I also believe that the oral protease inhibitor (nirmatrelvir) component of Paxlovid (Pfizer) should be tested for non-ocular/non-neurological cases of FIP. Nirmatrelvir is broken down into a simple chemical modification of GC373, the active form of GC376. Paxlovid is widely available and can be easily prescribed by both pharmacists and doctors for general treatment of COVID-19. This should make it widely available for use by veterinarians. I also believe that further research should be pursued to find ways to limit FECV infection and to understand the factors that suppress the natural normal protective immunity against FECV mutants. At this point, it is clear that most healthy cats have strong natural and acquired immunity to FIP viruses. What is this immunity and how can this knowledge contribute to strengthening immunity against FIP?

Unlicensed molnupiravir is an effective rescue treatment after failure of unlicensed GS-441524 therapy in cats with suspected FIP

Meagan Roy 1, Nicole Jacque 2, Wendy Novicoff 3, Emma Li 1,Rosa Negash 1 , Samantha JM Evans 1 *

  1. Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
  2. Independent Researcher, San Jose, CA 95123, USA
  3. Departments of Orthopedic Surgery and Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA
  4. * Author to whom correspondence should be addressed.

Academic editors: Alessia Giordano and Stefania Lauzi
Pathogens 2022, 11(10), 1209; https://doi.org/10.3390/pathogens11101209
Received: 19/09/2022 / Revised: 9/10/2022 / Received: 19/10/2022 / Published: 20/10/2022
(This article is part of a special issue of Advances on Feline Coronavirus Infection)

Original article: Unlicensed Molnupiravir is an Effective Rescue Treatment Following Failure of Unlicensed GS-441524-like Therapy for Cats with Suspected Feline Infectious Peritonitis

Abstract

Feline infectious peritonitis (FIP) is a complex and historically fatal disease, although recent advances in antiviral therapy have revealed treatment options. A newer therapeutic option, unlicensed molnupiravir, is used as first-line therapy for suspected FIP and as salvage therapy for cats that have persistent or recurrent clinical signs of FIP after treatment with GS-441524 and/or GC376. Treatment protocols for 30 cats were documented based on owner-reported data. 26 cats treated with unlicensed molnupiravir as rescue therapy were treated with a mean starting dose of 12.8 mg/kg and a mean final dose of 14.7 mg/kg twice daily for a median period of 12 weeks (IQR = 10-15). A total of 24 of the 26 cats were still living without signs of disease at the time of writing this report. One cat was euthanized after treatment due to persistent seizures and the other cat underwent retreatment due to relapse of clinical signs. Few adverse effects have been reported, with the most prominent - drooping ears (1), broken whiskers (1) and severe leukopenia (1) - occurring at doses above 23 mg/kg twice daily. This study provides proof of principle for the use of molnupiravir in cats and supports the need for future studies to further evaluate molnupiravir as a potentially safe and effective therapy for FIP.

Keywords: FIP; coronavirus; antiviral drug; EIDD-2801; black market

1. Introduction

Feline infectious peritonitis (FIP) is a complex and historically fatal disease caused by mutation of the ubiquitous feline enteric coronavirus (FECV) [1]. Recent advances in feline and antiviral medicine have revealed potential treatment options for FIP. The 3C-like protease inhibitor GC376 was the first targeted antiviral therapy used against this disease [2]. GC376 was highly effective in improving clinical signs of FIP in 19 of 20 naturally infected cats, but showed limited ability to manage long-term disease [2]. Pedersen et al. continued to investigate the antiviral compound GS-441524, a nucleoside analog and active metabolite of remdesivir (GS-5734). GS-441524 demonstrated superior ability to treat and control disease in naturally infected cats compared to GC-376, with 25 of 31 cats disease-free at the time of writing [3].
Since these discoveries, cat owners worldwide have obtained these mostly unlicensed drugs to treat their FIP cats with remarkably high success rates [4]. Legal FIP treatment is in high demand in the United States due to ethical and legal concerns regarding the unlicensed drugs GC376 and GS-441524. In addition, some cats with FIP have exhausted all current treatment options due to disease relapse and/or treatment failure after GS-441524, GC376 and/or combination therapy. Therefore, an effective and legal treatment option for FIP is urgently needed.
In connection with the recent outbreak of SARS-CoV-2, a number of new antivirals have entered the market. Molnupiravir (EIDD-2801), manufactured by Merck, is currently available under an emergency use authorization (EUA) from the FDA for the treatment of COVID-19 in adults [5]. It is an oral prodrug of the nucleoside analog BD-N4-hydroxycytidine, which increases guanine to adenine and cytosine to uracil nucleotide transition mutations in coronaviruses [6]. This mechanism increases the rate of mutations above the accepted limit, which in turn inactivates the virus [7]. Molnupiravir has been found to be safe and well tolerated at doses up to 800 mg twice daily in patients with COVID-19 [8]. Some studies have reported significant reductions in hospitalizations and deaths in mild-to-moderate COVID-19 patients, although efficacy appears to be lacking in severe COVID-19 patients [7].

Because of molnupiravir's strong potential to treat other coronavirus infections, cat owners have begun using unlicensed molnupiravir (or its active metabolite EIDD-1931) purchased over the Internet to treat FIP. However, the use of molnupiravir for the treatment of FIP is currently not documented in any scientific literature. Unlicensed molnupiravir can be used as first-line therapy for suspected FIP, but also as rescue therapy to treat cats that have persistent or recurrent clinical signs of FIP after GS-441524 and/or GC376 therapy. The aim of this study is to document this use and provide proof of principle for molnupiravir as a potential treatment for FIP based on owner-reported data.

2. Materials and methods

The survey was conducted using the Qualtrics XM program (Qualtrics Version May-August 2022, Provo, UT, USA) under license from Ohio State University. The survey (Supplementary Data S1) was written in English and consisted of 94 multiple-choice and free-response questions asking about FIP diagnosis, clinical signs, initial therapy (used before molnupiravir), molnupiravir treatment, adverse events, duration of treatment, and remission time. The number of free-response questions was limited to limit recall bias. The survey also allowed owners to upload relevant documents (eg veterinary medical records and laboratory results). The survey was formatted using questions from previous studies to maintain consistency of language and style, as well as newly developed questions specific to the experience of molnupivir treatment. The logic of the survey dictated that some questions appeared only after a particular answer was selected, while others were skipped when a particular answer was selected. This conditional logic was used to reduce questionnaire completion bias and questionnaire fatigue. The survey took approximately 20-30 minutes to complete and could be saved and completed later if needed. This study was approved by the Ohio State University Institutional Review Board (Protocol No. 2021E0162).

The survey was distributed to participants individually by email and data were collected from June to August 2022. Participants were selected from a subset of owners seeking molnupiravir therapy for their cat with suspected FIP through popular FIP therapy and social media support groups. Inclusion criteria were surveys of cats suspected of having FIP based on veterinary diagnosis, failure to respond to initial therapy, or recurrence of clinical signs after completion of initial therapy other than molnupiravir (eg, GS-441524 or GC376) and completion of 8–10 weeks of oral molnupiravir therapy (or those who subsequently died or were euthanized during therapy). This study also included a small group of cats that received molnupiravir for 8-10 weeks as initial and sole therapy, which will be referred to as first-line therapy in the rest of this paper, when FIP is suspected. Exclusion criteria were surveys with incomplete data or cats not diagnosed with FIP by a veterinarian.

3. Results

3.1 Demographic data

A total of 80 potential participants were identified through the FIP social media support group, and 37 questionnaire invitations were sent to those participants with available contact information. A total of 33 questionnaires were sent and follow-up emails were sent to 21 participants in order to obtain complete data from the questionnaires. Seventeen owners attached relevant documents to the sent questionnaires, and two other owners sent relevant documents to the study e-mail address, which included veterinary medical records, laboratory results and diagnostic images. These listed documents were used to document adverse reactions reported by one participant. One response was refusal to participate. Two cases were excluded because the cats did not have a veterinarian diagnosis of FIP (one was reportedly diagnosed based on the loss of a sibling to FIP, and the other was examined by a veterinarian who concluded that blood tests were not consistent with FIP). Thus, a total of 30 cats with suspected FIP were included in this study, 4 of which received no treatment prior to molnupiravir administration. These four cats were enrolled as a separate small cohort for first-line molnupiravir treatment. A block diagram of these cases is shown in Figure 1. The countries of origin represented were the United States (25), Germany (2), Poland (2), and Sweden (1). The sex/neuter status of the cats at the time of diagnosis was 40 % neutered males, 40 % spayed females and 20 % non-neutered males. The average age at diagnosis was 9.7 months, with a range from 1 month to 6 years. Most cats were of mixed or unknown breed (70 %); among them were seven purebred cats and two special crossbred cats (eg, a cross between a Balinese and ragdoll cat and a Siamese cat). Responses identifying the cat as "American Shorthair" or "American Longhair" were instead categorized as mixed breed, given the commonly reported confusion among American owners regarding the breed's nomenclature.

Figure 1. This flowchart represents the number of cases in each treatment block.

Regarding comorbidities, feline leukemia virus was reported in only one cat and calicivirus was reported in one cat. Several cats also had a history of external and/or internal parasitic infections (3), conjunctivitis/ocular infections (2), and bacterial skin infections (pyoderma) (1). A total of 16 cats had neurological signs of FIP. Three cats had both neurological and ocular manifestations of FIP, and two cats had only ocular manifestations of FIP. Of the remaining cases, seven were effusive, while five cases were non-effusive. The full breakdown of FIP types is shown in Table 1.

CatAge at diagnosis (months)Sex/castration status at diagnosisTribePrevious medical conditionsCountry of originFIP formDuration of initial treatment (weeks)Disease-free periodSecond therapyDuration of the second therapy (weeks)Disease-free periodThe third therapyDuration of the third therapy (weeks)Disease-free period
14MaleEuropean shorthairparasitic infections, URI at an early ageGermanyneurologicalinjectable oral GS-4415248noneinjectable and oral GS-44152415none
215neutered catBurmesenoneSwedeneffusive, non-effusive, neurologicalinjectable GS-44152412less than 4 weeksinjectable GS-4415241417 daysoral GS-4415245 weeksnone
39neutered catBritish ShorthairnonePolandeffusive, neurological, ocularinjectable GS-44152413less than 2 weeksinjectable GS-44152412more than 6 months, less than 1 year
45neutered catAbyssinianoneUSAeffusiveinjectable GS-44152412less than 2 weeksinjectable GS-44152414less than 4 weeks
54neutered catBalinese/Ragdol mixcalicivirus, conjunctivitis, giardiasis, tapeworm, URIUSAnon-effusiveinjectable GS-44152413less than 8 weeks
67neutered catSiamesenoneUSAneurologicalinjectable and oral GS-441524, injectable GC, injectable and oral molnupiravir12none
77neutered catAmerican ShorthairnoneUSAnon-effusiveinjectable and oral GS-4415245none
86neutered catAmerican Shorthair/Siamese mixtapeworm, FCoVUSAeffusive, neurologicalinjectable and oral GS-4415245none
94neutered catHomemade mixedbroken pelvisUSAeffusiveinjectable and oral GS-44152414less than 6 monthsoral GS-44152413less than 4 weeksoral GS-441524/injectable GC6 weeks in combination then 6 weeks of oral GSnone
104neutered catHomemade mixednoneUSAeffusiveinjectable GS-44152423less than 4 weeks
1172neutered catHomemade mixedFeLVUSAnon-effusiveoral GS-44152412less than 6 months
125MaleHomemade mixednoneUSAnon-effusive, neurological, ocularinjectable and oral GS-44152417none
1301.VMaleSavannahnoneUSAeffusive, neurologicalinjectable and oral GS-44152424less than 6 monthsinjectable and oral GS-44152412less than 4 weeks
144neutered catHomemade mixedSkin and eye infections, fleasPolandnon-effusive, neurologicalinjectable GS-44152412less than 2 weeksinjectable GS-44152417less than 4 weeks
1512neutered catAmerican ShorthairnoneUSAeffusiveinjectable GS-441524/GC01.Vnone
165neutered catHomemade mixednoneUSAeffusive, neurologicalinjectable GS-44152412less than 4 weeks
174MaleAmerican longhairnoneUSAocularinjectable and oral GS-441524, GC37613none
186neutered catHomemade mixednoneUSAeffusiveinjectable GS-44152412none
1912neutered catHomemade mixednoneUSAnon-effusiveinjectable and oral GS-44152412less than 2 weeksinjectable GS-44152412none
206neutered catUnknownnoneUSAnon-effusive, neurologicalinjectable GS-4415244noneoral GS-4415243none
214neutered catNorwegian forestnoneUSAneurologicalinjectable GS-44152412less than 6 monthsinjectable GS-44152401.VnoneMolnupiravir, GS-441524, GC12 weeksnone
226neutered catHomemade mixednoneUSAneurological, ocularoral GS-4415243none
2312neutered catUnknownnoneGermanyneurologicalinjectable GS-44152416less than 6 months
243MaleHomemade mixednoneUSAneurologicalinjectable GS-44152412less than 6 months
256neutered catAmerican ShorthairnoneUSAeffusiveoral GS-44152413less than 1 week
261MaleUnknownnoneUSAnon-effusiveinjectable GS-44152412less than 1 week
277neutered catHomemade mixednoneUSAnon-effusive, neurologicalMolnupiravir12less than 1 week*Molnupiravir
2824neutered catHomemade mixednoneUSAeffusiveMolnupiravir
2912neutered catHomemade mixednoneUSAnon-effusive, ocularMolnupiravir
3024neutered catHomemade mixednoneUSAneurologicalMolnupiravir
Table 1. Signaling and initial therapy characteristics of all 30 cats treated with unlicensed molnupiravir for suspected FIP.

3.2. Initial treatment before initiation of molnupiravir

A total of 26 of 30 cats received initial treatment for suspected FIP with unlicensed GS-441524 or a drug combination containing unlicensed GS-441524 as the main base drug (GS-441524-based). Half (13) of the cats were treated with injectable GS-441524. Only three cats were treated with oral GS-441524, while the other seven cats were treated with a combination of injectable and oral GS-441524 throughout the treatment period. Two cats were treated with a combination of the unlicensed drug GS-441524 and the unlicensed drug GC376. Cube no. 6 was treated with all previously mentioned drugs along with molnupiravir for 12 weeks of a very complicated regimen (Supplementary Data S2). Dosing of combination drugs used as part of primary therapy (eg, GC376 and molnupiravir) was not determined. Reported initial doses of the unlicensed GS-441524 ranged from 2 mg/kg to 10 mg/kg; the most frequently reported dosages were 5-6 mg/kg (eight cats) and 10 mg/kg (seven cats). Most (21) cats received a dose once a day. Only four were dosed twice daily, and one cat was dosed twice daily for one week at first, then switched to once daily dosing. The median duration of treatment based on GS-441524 was 12 weeks (IQR = 12-13). In fifteen cats, a change in daily doses was reported during treatment. For several cats, the daily dose was increased by body weight to maintain the same dosage in mg/kg. Others increased the mg/kg dosage because of insufficient clinical response or a change in route of administration (eg, from injectable to oral GS-441524). No participant reported dose reduction during treatment.

A total of 6 of 26 cats completed a shorter than average 12-week treatment with GS-441524 due to insufficient clinical response and were immediately started on another treatment. Two of the six cats initiated a different route or dose of unlicensed GS-441524 treatment as shown in Table 1. One cat switched from injectable to oral GS-441524 treatment on the second treatment. In the second cat, the dose of GS-441524 was simply increased during the second treatment. The remaining four cats started treatment with unlicensed molnupiravir at this time, as shown in Table 2. Of the 20 cats that completed at least 12 weeks of treatment with GS-441524, 16 experienced clinical remission. All 16 were in remission for less than 6 months, with 2 cats in remission for less than a week before clinical signs returned. All 16 started a second round of treatment, with 10 receiving a second round of GS-441524-based treatment and 6 starting molnupiravir at this time. Four cats that completed treatment with GS-441524 but did not achieve clinical remission were immediately started on molnupivir. A total of 26 cats received primary treatment with GS-441524 and all 26 relapsed or did not respond adequately. A total of 10 of 26 completed a second round of GS-441524-based treatment and 16 started molnupivir treatment.

CatClinical symptoms at the beginning of treatmentBrand nameInitial dosage and frequencyFinal dosage and frequencyDuration of treatment (weeks)Time to improvePersistent clinical symptomsThe resultAdverse effects
1diarrhea, vomitingAura Plus11 mg/kg twice daily11 mg/kg twice daily12less than 1 weeknoneclinical remissionnone
2none reportedAura12 mg/kg twice a day12 mg/kg twice a day12uncertainnoneclinical remissionnone
3anisocoria, colored spots in the eye, polydipsia, pica, weight lossAura 280128 mg/kg twice daily14 mg/kg twice a day12within 2 weeksnoneclinical remissionnone
4anorexia, lethargy, weight lossEIDD7 mg/kg twice a day7 mg/kg twice a day12less than 1 weeknoneclinical remissionnone
5colored spots in the eye, diarrhea, hiding and lack of socializationAura 28016 mg/kg once daily13 mg/kg once daily10within 2 weeksnoneclinical remissionnone
6anisocoria, constipation, anorexia, fecal and urinary incontinence, lethargy, paralysis, seizures, pale gums, weight lossAura 280120 mg/kg twice a day20 mg/kg twice a day11less than 1 weeknoneclinical remissionnone
7anorexia, difficulty walking, hiding, lack of socialization, jaundice, lethargyCapella EIDD9 mg/kg twice daily13 mg/kg twice a day10less than 1 weeknoneclinical remissionnone
8anorexia, difficulty walking, urinary incontinence, paralysisAura 280117 mg/kg twice a day17 mg/kg twice a day15less than 1 weekdifficulty walking persisted for 2 months, still not normal but has a normal lifeclinical remissionnone
9cough, anorexia, hiding, lack of socialization, polydipsia, weight lossAura 280112 mg/kg twice a day16 mg/kg twice a day13within 2 weekspolydipsia persisted for 1 weekclinical remissionnone
10anorexia, lethargy, weight lossAura 280112 mg/kg twice a day12 mg/kg twice a day16within 2 weeksnoneclinical remissionnone
11anorexia, lethargy, URI, weight lossAura 193112 mg/kg twice a day12 mg/kg twice a day12within 2 weeksnoneclinical remissionnone
12blindness, head bobbing, difficulty walkingAura 280110 mg/kg twice a day14 mg/kg twice a day12within 3 weeksnoneclinical remissionnone
13difficulty walking, hiding, lack of socialization, polyuria, lethargy, anorexia, paralysis, tremorsAura 280112 mg/kg twice a day12 mg/kg twice a day12less than 1 weeknoneclinical remissionnone
14anorexia, heavy walking, hiding, lack of socialization, lethargy, unusual timidityAura 280111 mg/kg twice daily16 mg/kg twice a day18more than 4 weeksnothing physical but the MRI is still not normalclinical remissionnone
15blindness, constipation, anorexia, diarrhea, enlarged abdomen, hiding, lack of socialization, lethargy, pale gums, weight lossAura 280116 mg/kg twice a day16 mg/kg twice a day12less than 1 weeknoneclinical remissionnone
16anorexia, difficulty walking, lethargy, seizures, tremors, weight lossAura 280114 mg/kg twice a day14 mg/kg twice a day12less than 1 weeknoneclinical remissionnone
17cough, anorexia, difficulty breathing, hiding, lack of socialization, lethargy, vomiting, weight lossAura 2801 and Aura 193112 mg/kg twice a day17 mg/kg twice a day20within 3 weeksanorexiaclinical remissionnausea/vomiting, anorexia
18constipation, anorexia, difficulty walking, hiding, lack of socialization, weight lossAura 280112 mg/kg twice a day12 mg/kg twice a day8within 2 weeksnoneclinical remissionnone
19lethargy, anorexiaAura 280112 mg/kg twice a day12 mg/kg twice a day7within 2 weeksnoneclinical remissionnone
20trembling/shakingAura 280110 mg/kg twice a day23 mg/kg two to three times a day10less than 1 weekin remission about 1 1 weeks before the onset of seizureseuthanasiadecreased appetite when dosed three times a day, severe leukopenia, loss of beard, scaly skin on ears
21difficulty walking, fecal incontinenceAura 2801 and Aura 193113 mg/kg twice a day30 mg/kg twice a day14less than 1 weekdifficult walking, difficult jumping, fecal incontinence persisted during the study (1 week post treatment)relapse and euthanasiadrooping ear tips, muscle weakness
22colored spots in the eye, anorexia, difficulty walking, hiding, lack of socialization, lethargyAura 280116 mg/kg twice a day19 mg/kg twice a day9within 2 weeksnoneclinical remissionnone
23difficulty walking, anorexia, loss of balanceEIDD aura12 mg/kg twice a day15 mg/kg three times a day10within 2 weeksheavy walkingclinical remissionnone
24blindness, colored spots in the mouth, anorexia, difficulty breathing, difficulty walking, enlarged abdomen, urinary incontinence, jaundice, lethargy, paralysis, tremorsAura 280115 mg/kg twice a day15 mg/kg twice a day16less than 1 weeknoneclinical remissionnone
25difficulty breathing, difficulty walking, hiding, lack of socialization, lethargy, URIAura 28017 mg/kg twice a day7 mg/kg twice a day16within 2 weeksnoneclinical remissionnone
26lethargy, anorexiaAura 280114 mg/kg twice a day14 mg/kg twice a day15less than 1 weekneurological twitches, elevated liver enzymesclinical remissionnone
Table 2. Treatment and outcome characteristics of 26 cats receiving unlicensed molnupiravir as rescue therapy.

3.3. The second round of treatment before the initiation of molnupiravir

Overall, 10 of 26 cats that received initial GS-441524 treatment and subsequently relapsed were reported to have received a second round of unlicensed GS-441524 treatment prior to initiation of molnupiravir. Again, most cats received injectable GS-441524 (6), with two receiving oral GS-441524 and two receiving both injectable and oral GS-441524. Reported dosages ranged from 4-5 mg/kg to 15 mg/kg; the most frequently used dosages were 7-8 mg/kg (two cats) and 15 mg/kg (two cats). Most cats were dosed once daily (seven cats), one cat was dosed twice daily and one cat was dosed three times daily. In most cats, the dose was varied during treatment. The two doses were weight-adjusted to maintain the same dosage in mg/kg. Dosing in mg/kg was increased in five cats that did not respond adequately or developed new clinical signs (eg, neurological signs).
The median duration of treatment was 12.5 weeks (IQR 9.75–14.25). Only two cats did not undergo at least 12 weeks of therapy. One of the two added GC376 and molnupiravir to current GS-441524 therapy, and the other started molnupiravir as sole therapy. Of the eight cats that completed at least 12 weeks of GS-441524 therapy, two did not achieve clinical remission. Both cats started treatment with unlicensed molnupiravir at that time. The remaining six cats were reported to achieve clinical remission after a second round of treatment with GS-441524. Five of the six cats were in remission for less than 4 weeks, with the exception of one cat that was in remission for more than 6 months but less than a year. Seven out of ten cats started taking unlicensed molnupiravir at this time.

3.4. The third round of treatment before starting molnupiravir

The remaining three cats received a final round of GS-441524-based treatment before switching to molnupiravir. Cat no. 2 received oral GS-441524 for 5 weeks prior to initiation of molnupiravir. Cat no. 9 was treated for 6 weeks with oral and injectable GS-441524 and then continued for 6 weeks with oral GS-442524 alone. Dosing and frequency in both cats are unknown, as the survey collected data on only two therapies prior to molnupivir. Cat no. 21 received a combination of GS-441524, GC376 and molnupiravir for 12 weeks. The dosage, frequency and duration of each varied radically over the course of 12 weeks (Supplementary Data S3). All three cats started treatment with molnupiravir without clinical remission from this third round of treatment.

3.5. Molnupiravir as rescue therapy

Of the 26 cats receiving unlicensed molnupiravir as rescue therapy, most were using the Aura brand, with only 2 cats using a different brand of molnupiravir. More than 81 % cats (18) were treated with Aura 2801, 1 cat was treated with Aura 1931, and another 2 cats were treated with both Aura preparations. The mean initial dosage was 12.8 mg/kg twice daily. One cat was dosed only once a day and two cats were dosed 2 to 3 times a day. The most commonly used initial dosage was 12 mg/kg twice daily. Dosage ranged from 6 to 28 mg/kg twice daily. 11 dosage changes were reported, all but one being an increase in dosage. Reduction of dosage in cat no. 3 was not explained in any way. The mean final dosage was 14.7 mg/kg twice daily, with the same three cats differing in dosing frequency. The most common final dosage was also 12 mg/kg twice daily. The dosage range was 7 to 30 mg/kg twice daily.

Median duration of treatment was 12 weeks (IQR 10-15). Overall, a wide range of 7-20 weeks was reported. Only eight cats were treated for less than 12 weeks. A cat that completed only 7 weeks of treatment was reported to have discontinued treatment due to achieving clinical remission. All 26 cats completed treatment at 7 weeks or longer and all 26 cats survived. No cases of missed doses of molnupiravir have been reported.

Owners reported improvement in clinical signs in more than 92 % cats within three weeks of initiation of molnupiravir treatment, with 84.6 % cats showing improvement within two weeks and nearly half (46.2 %) within one week. Only two cases were reported differently, with one cat showing no signs of improvement for up to 1.5 months, and the owner of the other cat being unsure of the timescale and degree of improvement in clinical signs. A total of seven cats with persistent clinical signs of FIP were reported. In one of them, the disappearance of clinical symptoms was reported after one week of the observation period. Others are thought to have had residual symptoms such as difficulty walking or jumping, tremors, MRI changes and fecal incontinence. The full range of persistent clinical signs is shown in Table 2. Only three cats reported adverse reactions in response to molnupiravir, including nausea/vomiting, anorexia, drooping ear tips (Figure 2), brittle whiskers, leukopenia, scaly skin and muscle wasting. At the time of publication, 24 of 26 cats are living in clinical remission of FIP after oral molnupiravir treatment. One cat reportedly died 1 week after discontinuation of molnupiravir due to a prolonged seizure, and the other cat (No. 21) was disease-free 4 weeks before relapse. Cat no. 21 then started a second round of molnupiravir at the same dose, but was subsequently euthanized due to insufficient response to treatment.

Figure 2. Dropped ear tips were reported as an adverse effect of unlicensed molnupiravir treatment in cat no. 21.

In cat no. Severe leukopenia was reported in 22 cases. Through veterinary records, it was found that cat no. 22 has moderate panleukopenia with lymphopenia, neutropenia, and normal hem and thrombograms on 4 of 5 sequential complete blood counts, which were confirmed through veterinary records of sequential complete blood counts. The initial white blood cell count recorded was 10,700 cells per microliter (reference range 3,500–16,000 cells per microliter). Four more complete blood tests showed white blood cell counts ranging from 1,200 to 1,900 cells per microliter. The initial neutrophil count was 8560 cells per microliter (reference range 2500-8500 cells per microliter). The other four neutrophil counts ranged from 696 to 1292 cells per microliter. The initial lymphocyte count was 1177 cells per microliter (reference range 1200-8000 cells per microliter). The other four lymphocyte counts ranged from 330 to 532 cells per microliter.

3.6. Molnupiravir as primary therapy

A small group of four cats were treated with unlicensed molnupiravir as sole therapy for suspected FIP, as shown in Table 3. Three of them reportedly chose molnupiravir over the unlicensed counterpart GS-441524 due to financial constraints. Cat no. 29 received 12 weeks of oral molnupiravir 12 mg/kg twice daily prior to the treatment shown in Table 3. This cat was disease-free for less than one week prior to restarting oral molnupiravir 19 mg/kg twice daily for 10 weeks.

CatClinical symptoms at the beginning of treatmentBrand nameInitial dosage and frequencyFinal dosage and frequencyDuration of treatment (weeks)Time to improvePersistent clinical symptomsConclusionAdverse effects
* 27Hiding, lack of socialization, lethargy, anorexia, URI, vomiting, weight lossAura 280119 mg/kg twice a day19 mg/kg twice a day10less than 1 weeknoneclinical remissionnone
28Anorexia, difficulty walking, distended abdomen, hiding, lack of socialization, lethargyAura 28018 mg/kg twice a day8 mg/kg twice a day13in two weeksnoneclinical remissionnone
29Anisocoria, blindness, eye color changes, anorexia, hiding, lack of socialization, urinary incontinence, lethargy,Aura 280110 mg/kg twice a day10 mg/kg twice a day13in two weeksnoneclinical remissionnone
30Hiding, lack of socialization, lethargy, pale gums, weight lossAura 280110 mg/kg twice a day12 mg/kg twice a day10in two weeksnoneclinical remissionnone
Table 3. Treatment and outcome characteristics of 4 cats receiving unlicensed molnupiravir as primary therapy.* They received two rounds of molnupiravir treatment; the first round is documented in Table 1.

All four cats were treated with oral molnupiravir Aura 2801 at a mean starting dose of 11.75 mg/kg twice daily (range 8-19 mg/kg) and a mean final dose of 12.25 mg/kg twice daily (range 8-19 mg/kg ). The median duration of treatment was 11.5 weeks (IQR 10-13), with two cats treated for 10 weeks and two cats treated for 13 weeks. A Mann-Whitney test was performed and no significant difference was found between the median duration of molnupivir as rescue therapy (12) and the duration of molnupivir as initial therapy (11.5) (p = 0.692). All owners reported seeing clinical improvement within two weeks and one cat showed improvement within one week. All cats survived the treatment, were disease-free at the time of publication, and no adverse effects of the treatment were reported.

3.7. Molnupiravir by type of FIP

The above information was collected for all 30 cats and then further divided according to the clinical forms of FIP. First, 16 cats with a reported neurological form of FIP were evaluated. Subsequently, the other cats were divided according to ocular (2), effusive (7) and non-effusive (5) forms. The mean starting dose of molnupiravir in the neurological form of FIP was 14.4 mg/kg twice daily, with two cats treated 2-3 times daily. The mean final dosage was 16.4 mg/kg twice daily, with two cats treated 2-3 times daily. The most commonly used initial and final dosage was 12 mg/kg twice daily. Median duration of treatment for neurological FIP was 12 weeks (IQR 10-12,641).

In the two remaining cases of ocular FIP, the mean initial dose was 11 mg/kg twice daily and the mean final dose was 13.5 mg/kg twice daily. The treatment lasted an average of 16.5 weeks. Seven cases of effusive disease were treated with a mean initial dose of 10.5 mg/kg twice daily and a mean final dose of 11.1 mg/kg twice daily. Treatment lasted an average of 13 weeks (IQR 12–16). Five non-effusive cases were treated with a mean initial dose of 10.6 mg/kg twice daily and a mean final dose of 12.8 mg/kg twice daily. One cat was treated once a day. The average duration of treatment was 10 weeks (IQR 8.5-13.5).

3.8. Costs and owner satisfaction

The majority of cats in this study were switched to unlicensed molnupiravir due to treatment failure/relapse or insufficient response. In addition to cats that relapsed or did not respond to unlicensed GS-441524-based treatment, one cat was intolerant to the injectable form of GS and three owners were cost-restricted. Owners were not required to disclose the financial costs of treatment; this information was provided on a voluntary basis only. In addition, “0” responses that were reported were not included in the calculation of the following averages due to the inability to distinguish whether “0” means no cost or unknown cost. The mean reported cost of the first round of GS-441524-based treatment was $3448.83, and similarly the mean reported cost of the second round of GS-441524-based treatment was $3509.09. Only 4 owners reported paying for molnupiravir treatment, while 16 others reported “0” (or no cost/cost unknown). The overall mean for the 20 owners who responded to the financial cost survey question (including “0” responses) for molnupiravir was $209. The average cost of the four owners who did not answer “0” was $1045. While 90 % owners reported being "very" or "somewhat" satisfied with their cat's experience of treating their cat with molnupiravir, three were "very dissatisfied" with their experience. Unfortunately, no explanation was provided for the reported dissatisfaction.

4. Discussion

In this work, we describe the first known use of unlicensed molnupiravir for the treatment of suspected FIP in cats based on owner-reported data. For the treatment of cats using unlicensed molnupiravir as primary therapy for suspected FIP, the combined data from this study suggests that dosing at 12 mg/kg twice daily for approximately 12 weeks is effective in achieving clinical remission. For the treatment of cats receiving molnupiravir as rescue therapy when failing or relapsing after GS-441524-based therapy, the combined data from this study suggests that dosing at 12-15 mg/kg twice daily for 12-13 weeks is effective in achieving clinical remission. However, when broken down by clinical form of FIP, it was found that neurological cases of FIP were generally treated with a higher dosage than the average for all types of FIP. Ocular, effusive and non-effusive cases were treated with a dosage of around 12 mg/kg twice daily, with some variations. Therefore, dosing of 15 mg/kg molnupiravir twice daily for 12 weeks appears to be effective for neurological cases of FIP. For ocular, effusive, and non-effusive cases, 12 mg/kg molnupiravir twice daily for 12–13 weeks appears to be effective.

These data are somewhat inconsistent with the proposed treatment protocol of the company producing unlicensed molnupiravir under the trade name HERO Plus 2801. The recommended dosage in the package insert is 25 mg/kg once daily for effusive and non-effusive FIP, 37.5 mg/kg once daily for ocular FIP and 50 mg/kg once daily for neurological FIP [9]. The package leaflet of HERO Plus 2801 also includes the preliminary results of the study "Effect of treatment with oral nutrition on survival time and quality of life in feline infectious peritonitis", which includes 286 cats with a diagnosis of FIP. According to this package insert, 28 cats were cured after 4 weeks of treatment and 258 cats were cured after 8 weeks of treatment, with no deaths at the time of reporting [9]. Data from this study have not yet been published in the scientific literature.

However, the cats in this study were using molnupiravir from a different supplier, Aura, which did not provide specific treatment recommendations. The treatment protocols used were therefore based on advice and information shared in groups on social networks, worksheets published on the Internet [10,11] and information on possible adverse effects contained in information published as part of human drug approval applications [12].

The molnupivir treatment protocol derived from this study more closely matches an independently designed protocol [10] published on the Internet. Based on data from in vitro cell cultures of EIDD-1931 and EIDD-2801, laboratory and field studies of GS-441524, and human pharmacokinetic studies, these authors extrapolated the effective dosage of oral molnupiravir [10]. Their calculations suggested a dosage of 4.5 mg/kg every 12 h for effusive and non-effusive FIP, 8 mg/kg every 12 h for ocular FIP, and 10 mg/kg every 12 h for neurological FIP [10]. Although the dosage in this study was generally higher than the dosage suggested by the cited authors, the high survival rate and low relapse rate at the time of the study termination suggest that the manufacturer's unlicensed recommendations may not represent the lowest effective dosage. Ultimately, controlled scientific experiments are greatly needed to evaluate the lowest effective dosage of molnupiravir in cats with suspected FIP.

Several cats were treated with Aura 1931, which is the active metabolite of molnupiravir, EIDD-1931. The reported dosages used were in a similar range to those reported for molnupiravir. Nominally, because the molecular weight of EIDD-1931 is lower than that of EIDD-2801, these cats received more active drug than cats using molnupiravir. However, a previous study showed decreasing oral bioavailability with increasing doses in mice. Therefore, the difference in bioavailability may not be proportional [13]. Pharmacokinetic studies of both molnupiravir and EIDD-1931 in cats are unfortunately unknown.

No adverse effects were reported in the package insert for HERO Plus 2801, which is contrary to what was reported in this study. Among the reported side effects of molnupiravir, the most prominent were drooping ears, hair loss, and severe leukopenia. No skin or follicular lesions have been reported in the human medical literature to match the whisker shedding or ear folding reported here. However, it should be noted that the cats that experienced these side effects received the two highest doses of molnupiravir shown in this study: 23 mg/kg three times daily and 30 mg/kg twice daily.

Severe bone marrow toxicity was reported in dogs during a 28-day study that was discontinued due to severe drug effects [12]. At the dosage of 17 mg/kg/day and 50 mg/kg/day, all hematopoietic cell lines were affected [12]. Cat no. 22 received a maximum dosage of 23 mg/kg three times daily, which was much higher than the toxic dosage in dogs of 17 mg/kg once daily. In the study group with a dose of 17 mg/kg, the possibility of reversibility was noted when the treatment was stopped [12].

There are concerns about the content of unlicensed brands of molnuviravir, as these brands are not currently regulated and often do not list the actual ingredients. The Hero brand (same manufacturer as HERO Plus 2801) shown in Figure 3 was analyzed by our group in December 2021 through Toxicology Associates Inc. (Columbus, OH). It was found to contain 97.3 % of molnupivirus, with no other contaminants detected. The Aura 2801 product used by the majority of participants in this study was analyzed in September 2022 by the same laboratory. It was found to contain 96.8 % of pure molnupivirus. A more controlled assessment of the actual content and purity of the unlicensed preparations of both GS-441524 and molnupiravir is of great interest to the veterinary community and is an active research topic in our group.

Figure 3. Images of Hero brand unlicensed molnupiravir packaging.

Some limitations of this study result from the retrospective nature and legality of the therapies used. First, all data used in this study were obtained based on owner reports. Working closely with the owners and administrators of the social media websites that supported this group enabled a better understanding and interpretation of many of the survey responses. Due to the lack of a definitive ante-mortem diagnosis of FIP available for practical use, it was also not possible to confirm that the cats included in this study had FIP. In addition, the data are likely to be biased toward positive outcomes and may be burdened by recall error. During the distribution phase, a potential study participant responded by requesting to be removed from our email list and stating that he did not wish to participate in the study. Their cat did not respond to molnupiravir treatment and was eventually euthanized. We assume that others may have had the same feeling, since three other potential participants did not respond to the invitation to the study. This may have narrowed the number of participants with an adverse outcome and falsely inflated apparent survival rates. Therefore, the data presented here are intended to serve as evidence of the feasibility of using molnupiravir as primary or rescue treatment for FIP, not as an indication of the true rate of efficacy.

In cats using unlicensed molnupiravir as rescue therapy, the cause of failure to respond or relapse after GS-441524-based therapy was not determined. It could be related to the quality of the drug, the resistance of the virus or another factor. As there is currently no testing or regulation in the US, unlicensed versions of GS-441524 or GC376 may be of insufficient purity or concentration, leading to treatment failure. Another possible cause is natural or acquired resistance to GS-441524. These two causes may also be linked, as acquired resistance may be promoted when an insufficient amount of antiviral is used in treatment, for example with low-quality drugs.

A recent paper found no drug-induced viral mutations of SARS-CoV-2 during molnupivir treatment [14]. This suggests that SARS-CoV-2 is unlikely to develop resistance to molnupiravir. Therefore, treatment with molnupiravir may be similarly unlikely to induce FIPV resistance, making it an attractive therapeutic option.

However, there is clearly a need for (1) a legal (in the United States and elsewhere) alternative to unlicensed treatment with GS-441524 and (2) the availability of alternative rescue drugs, either alone or in combination, after failure of GS-441524 treatment. Molnupiravir has the potential to fill both of these gaps, and this is the first known report of its use in cats in the literature. Nevertheless, unlicensed preparations may continue to be used for the treatment of FIP given the cost and the widely established networks available for their acquisition.

In conclusion, based on owner-reported data, unlicensed molnupiravir appears to be an effective treatment for suspected FIP as both first-line and salvage therapy. At a dosage of 12-15 mg/kg every twelve hours, minimal side effects are reported and it provides survival with clinical resolution of FIP symptoms. Although the experiences of these owners in treating and apparently curing cats from FIP are unconventional and potentially illegal, they are undeniably remarkable and we can learn a lot from the experiments these "citizen scientists" are conducting. By reporting these experiences, we aim to provide a starting point for investigating molnupiravir for use in cats with suspected FIP and to document a "herd health" phenomenon that our profession should not ignore.

Supplementary materials

The following supplementary information can be downloaded at https://www.mdpi.com/article/10.3390/pathogens11101209/s1 Supplementary Data S1: retrospective review of molnupiravir trials; additional data S2: abbreviated diary of clinical history cat. no. 6; supplementary data S3: Cat #21 abbreviated clinical history log.

References

  1. Felten, S .; Hartmann, K. Diagnosis of Feline Infectious Peritonitis: A Review of the Current Literature. Viruses 201911, 1068. [Google Scholar] [CrossRef] [PubMed]
  2. Pedersen, NC; Kim, Y.; Liu, H.; Kankanamalage, ACG; Eckstrand, C.; Groutas, WC; Bannasch, M.; Meadows, JM; Chang, K.-O. Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. J. Feline Med. Surg. 201820, 378–392. [Google Scholar] [CrossRef] [PubMed]
  3. Pedersen, NC; Perron, M .; Bannasch, M .; Montgomery, E .; Murakami, E .; Liepnieks, M .; Liu, H. Efficacy and safety of the nucleoside analog GS-441524 for the treatment of cats with naturally occurring feline infectious peritonitis. J. Feline Med. Surg. 201921, 271–281. [Google Scholar] [CrossRef] [PubMed]
  4. Jones, S.; Novicoff, W.; Nadeau, J.; Evans, S. Unlicensed GS-441524-Like Antiviral Therapy Can Be Effective for At-Home Treatment of Feline Infectious Peritonitis. Animals 202111, 2257. [Google Scholar] [CrossRef] [PubMed]
  5. Merck & Co., Inc. Authorized for Emergency Use in the Treatment of COVID-19. Lagevrio. 2022. Available online: https://www.lagevrio.com/patients/ (accessed on 26 August 2022).
  6. Gordon, CJ; Tchesnokov, EP; Schinazi, RF; Götte, M. Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template. J. Biol. Chem. 2021297, 100770. [Google Scholar] [CrossRef]
  7. Singh, AK; Singh, A.; Singh, R.; Misra, A. Molnupiravir in COVID-19: A systematic review of literature. Diabetes Metab. Syndr. Clin. Res. Rev. 202115, 102329. [Google Scholar] [CrossRef] [PubMed]
  8. Khoo, SH; Fitzgerald, R.; Fletcher, T.; Ewings, S.; Jaki, T.; Lyon, R.; Downs, N.; Walker, L.; Tansley-Hancock, O.; Greenhalf, W.; et al. Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: A Phase I, open-label, dose-escalating, randomized controlled study. J. Antimicrob. Chemother. 202176, 3286–3295. [Google Scholar] [CrossRef] [PubMed]
  9. FIP Warriors CZ/SK® (2022, May 20). Eidd-2801 (Molnupiravir). Available online: https://www.fipwarriors.eu/en/eidd-2801-molnupiravir/ (accessed on 26 August 2022).
  10. Pedersen, NC; Jacque, N. Alternative Treatments for Cats with FIP and Natural or Acquired Resistance to GS-441524. Sock it to Fip. Available online: https://sockfip.org/https-sockfip-org-wp-content-uploads-2022-03-approaches-to-drug-resistance-in-cats-treated-with-gs-441524-for-fip-v3-pdf/ (accessed on 26 August 2022).
  11. Pedersen, NC The Long History of Beta-d-n4-Hydroxycytidine and Its Modern Application to Treatment of COVID-19 in People and FIP in Cats. Sock it to Fip. Available online: https://sockfip.org/https-sockfip-org-wp-content-uploads-2022-04-the-long-history-of-beta-d-n4-hydroxycytidine-and-its-modern-application-to-treatment-of-covid-19-in-people-and-fip-in-cats-v2-pdf/ (accessed on 8 October 2022).
  12. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP) Assessment Report: Use of Mol-Nupiravir for the Treatment of COVID-19. 2022. Available online: www.ema.europa.eu/contact (accessed on 8 October 2022).
  13. Painter, GR; Bowen, RA; Bluemling, GR; DeBergh, J.; Edpuganti, V.; Gruddanti, PR; Guthrie, DB; Hager, M.; Kuiper, DL; Lockwood, MA; et al. The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal Venezuelan equine encephalitis virus infection. Antivirus. Res. 2019171, 104597. [Google Scholar] [CrossRef] [PubMed]
  14. Fletcher, T.; Ah Donovan-Banneld, I.; Penrice-Randal, R.; Goldswain, H.; Rzeszutek, A.; Pilgrim, J.; Bullock, K.; Saunders, G.; Northey, J.; Dong, X.; et al. Characterization of SARS-CoV-2 genomic variations in response to mol-nupiravir treatment in the AGILE Phase IIa clinical trial. Res. Sq. 2022. [Google Scholar] [CrossRef]
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