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So far unpublished work, which was published on the bioRxiv portal in November before being published in a peer-reviewed journal, offers preliminary answers to the question of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."
We had hoped that in 2023 one or more antivirals for cats would be legalized. With the exception of a few countries outside the US, this has not happened. Still, there is hope that studies being conducted at the University of California, Davis and elsewhere around the world will help advance conditionally and/or fully approved human drugs such as Remdesivir, Molnupiravir and Paxlovid for use by veterinarians. Even if drugs are approved for use in animals, drugs marketed for human use are not ideal because they must be purchased at the price set for humans. Therefore, the unapproved market will remain the main source of cheaper antivirals for many years to come. However, SOCK FIP appreciates the efforts of countless cat owners and lobbying industry and government agencies to allow the use of effective antivirals for cats. These efforts have had varying degrees of success in many countries outside the US.
FIP research at UC Davis in 2023 supported by SOCK FIP contributions
2023 continues to support SOCK FIP and feline coronavirus research at UC Davis, and we couldn't do it without the help of many donors. Two ongoing research projects receiving SOCK FIP funding are of particular interest. The first project involves testing antiviral drugs and is led by Drs Krystle Regan and Brian Murphy. Patients and owners were drawn from across the US. The first study compared two antiviral drugs in cats with wet FIP to test cure rates with either oral GS-441524 or Remdesivir (Gilead). This study, which was published, showed that oral Remdesivir worked as well as oral GS-441524. So if Remdesivir gets full approval in the United States, veterinarians can safely prescribe it to cats with wet FIP. Other studies comparing GS-441524 and Remdesivir in cats with dry FIP and Molnupiravir (Merck) in cats with wet FIP have also been completed. The results of these studies should be published in early 2024. The latest study involving Paxlovid (Pfizer) was recently fully approved and widely available in the United States, and if it proves to be a safe and effective treatment for cats with FIP, it will a third human antiviral drug to treat FIP that may one day be used by veterinarians. Drs Regan and Murphy also used their field test cases to study the causes of death during the first two weeks of treatment. This population represents up to 10 % treated cases worldwide. Necropsies showed the existence of serious complicating diseases, which often included bacterial sepsis, often with highly resistant organisms to antibiotics, as well as serious heart disease. More work is needed to determine the nature of the heart disease and how much of it may be pre-existing disease and how much is caused by the FIP virus.
The second major research project focused on the prevention of FIP is implemented by Dr. Patricia Pesavento, one of our veterinary pathologists, and her research team, which includes veterinary microbiologist Terza Brostoff, biomedical engineer Randy Carney, immunologist Dennis Hartigan O'Connor, and lab technician Ken Jackson. Their study involves the development of an mRNA vaccine against a portion of the nucleocapsid protein that is common to virtually all known feline coronavirus isolates. The theory is that an immune response to this protein, compared to the spike protein commonly used in COVID-19 vaccines, will protect cats exposed to the common enteric form of feline coronavirus from developing FIP. This would be analogous to the protection against severe and chronic forms of COVID-19 reported with mRNA vaccines. Team Dr. Pesaventa developed a vaccine based on ideal manufacturing parameters and tested it for safety and efficacy in a rodent model. The development of this mRNA vaccine will only be a first step as it will need to be further tested in a limited number of cats as a prelude to much more extensive field testing in larger populations of cats such as breeding stations or temporary/rescue stations experiencing ongoing cases of FIP.
Areas of future FIP research
The discovery of a cure for FIP does not end the need for further FIP research. We hope that veterinary scientists from around the world who are still active in academia and industry will consider some of the other promising areas of research. Such studies cover all aspects of FIP pathogenesis, from the basic enteric coronavirus, which is enzootic in virtually all healthy cat populations and exists in the lower intestinal tract, to mutant forms that have acquired the ability to infect monocytes/macrophages in and outside the abdominal cavity. The exact nature of immunity to feline coronaviruses, both the minimally pathogenic enteric form and the highly lethal form causing FIP, needs to be clarified. We know that immunity to both intestinal and extraintestinal forms of the virus is weak, short-lived and susceptible to weakening by internal and external stressors. Immunity to enteric coronavirus appears to involve locally produced antibodies, whereas immunity to FIP-causing mutant viruses involves more systemic lymphocyte-mediated (cellular) immune responses. Accurate knowledge of the strengths and weaknesses of both types of immunity will be essential for all future vaccine development efforts. Will you prevent FIP by attacking underlying enteric coronavirus infections or by attacking FIP-causing mutants when they emerge?
There is a great need to develop tests that can accurately determine when a cat has been cured by antiviral therapy. We know that some cats can heal in as little as 4-6 weeks, while others need up to 12 weeks. We suggest 12 weeks of treatment because this gives the maximum cure rate, but we know that some cats will be treated for an unnecessarily long time. The only current way to tell when a cat is cured is to stop the treatment and see if the disease returns. Regular complete blood counts and basic serum biochemistry are useful in conjunction with physical health indicators in monitoring and managing treatment, but return to normal test values and general health do not guarantee that treatment will not relapse. On the contrary, the persistence of minor abnormalities in the blood and health status is not always a sign that there has been no cure and that it is necessary to increase the dosage or prolong the treatment. This is especially true for cats with neurological FIP, where blood test results and the state of neurological deficits do not always indicate a cure.
Although there is hope that even more effective antiviral drugs will be found in the future, the well-documented safety and efficacy profiles of current drugs leave little room for further improvement. However, drug resistance is currently being observed in some cats. What is known about how drug resistance develops in chronic infections such as HIV/AIDS should be applied to FIP. The most effective way to combat drug resistance in HIV/AIDS is to combine two or more antivirals with different mechanisms of action before resistance develops.
It appears that some strains of feline coronavirus may be more neurotropic than others. A penchant for infecting the central nervous system can be developed by specific mutations in enteric strains of the coronavirus that are enzootic in the environment or by mutations that occur as part of the FIP biotype. The role of the blood-brain barrier and the apparent compartmentalization of immunity between the central nervous system and the rest of the organism are other areas that require study.
Most cat owners are currently aware of the large outbreak of FIP occurring on the island of Cyprus. It is still uncertain whether this outbreak qualifies as epizootic (epidemic) or enzootic (endemic). Preliminary research suggests that the outbreak is linked to closely related isolates of FIP virus serotype 2 (similar to canine coronavirus). It is clear that for cats in all parts of the world, whether this outbreak is related to the spread of the virus from cat to cat (ie, an epizootic disease) or to factors promoting the disease in the environment (ie, an enzootic disease) is important. The worst possible scenario is a panepizootic disease like COVID-19. Hopefully, researchers in Cyprus, the UK and elsewhere will be able to resolve the nature of this outbreak as quickly as possible.
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.
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:
Basic information Feline infectious peritonitis (FIP) is a viral disease of cats caused by certain strains of the coronavirus that has a high mortality rate.
The goal This case series reports the results of treatment of cats with FIP with molnupiravir.
The animals Eighteen cats diagnosed with FIP at You-Me Animal Clinic, Sakura-shi, Japan between January and August 2022 and whose owners gave informed consent for this experimental treatment.
Methods In this prospective observational study, molnupiravir tablets were prepared directly at the You-Me Animal Clinic. Owners administered 10-20 mg/kg PO twice daily. The standard duration of treatment was 84 days.
The results Of the 18 cats, 13 cats had effusive FIP and 5 cats had non-effusive FIP. Three cats had neurological or ocular signs of FIP before treatment. Four cats, all with effusive FIP, died or were euthanized within 7 days of starting treatment. The remaining 14 cats completed treatment and were in remission at the time of writing (139-206 days after initiation of treatment). Elevated serum alanine transaminase (ALT) activity was found in 3 cats, all on days 7–9, and all recovered without intervention. Two cats with jaundice were hospitalized, 1 during treatment (day 37) and 1 with severe anemia at the start of treatment.
Conclusions and clinical significance This case series suggests that molnupiravir may be an effective and safe treatment for domestic cats with FIP at a dose of 10–20 mg/kg twice daily.
1. Introduction
Feline infectious peritonitis (FIP) is a viral infectious disease occurring mainly in domesticated cats.1, 2 FIP is an aberrant immune response to infection with feline coronavirus (FCoV), which is ubiquitous, especially in breeding and rescue breeds, usually with no or mild clinical signs. Fecal-oral transmission of FCoV often occurs, especially in environments with multiple cats3 and the incidence of FIP in cats exposed to FCoV is up to 14 %.4, 5
Feline infectious peritonitis is usually classified as either effusive or non-effusive based on clinical presentation.1, 6, 7 Until the development of specific antiviral therapy, the case fatality rate associated with FIP was high, and most affected cats died within weeks to months of the onset of clinical signs.
Some nucleoside analogs, including remdesivir (GS-5734) and its active metabolite GS-4415248, inhibit viral RNA synthesis and have high antiviral activity against FCoV causing FIP in cats.9, 10 Despite the expectations of veterinarians and cat owners, the developer decided not to apply for approval of GS-441524 for the treatment of FIP. As a result, many cats with FIP are being treated with the unapproved drug GS-441524, and concerns have been raised about the quality, purity, and efficacy of the unapproved products available on the world market. Mutian has excellent efficacy and safety.11-14 Although the manufacturer did not disclose the chemical structure of the active substance and its exact concentration, its active substance is GS-441524.12
Molnupiravir is an oral nucleoside antiviral prodrug with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease (COVID-19). As of 2021, molnupiravir is approved in Japan to treat people with COVID-19. There are published reports on the efficacy and safety of molnupiravir in cats15 , but sufficient data on the use of molnupiravir in cats with FIP are lacking. Due to the lack of treatment options for FIP, we began offering molnupiravir to clients at our clinic, using small tablets prepared in-house for easy administration to cats. Here we present the results of the first 18 cats that underwent this FIP treatment in our clinic.
2 MATERIALS AND METHODS
2.1 Cats
All cats attending the You-Me Animal Clinic in Sakura-shi, Japan since January 2022 diagnosed with FIP and whose owners provided informed consent were included in this case series. Feline infectious peritonitis was diagnosed based on a combination of clinical signs (decreased appetite, enlarged abdominal lymph nodes, weight loss, fever, effusions, or uveitis) and laboratory test results for anemia and hyperglobulinemia, including the albumin-to-globulin (A/G) ratio and values of α1-acid glycoprotein (AGP). The presumptive diagnosis of FIP was based on the identification of FCoV RNA in samples from abdominal or pleural effusion (effusive FIP) or whole blood (non-effusive FIP), or from fine needle aspiration (FNA) of pyogranulomatous lesions. Virus detection was performed by reverse transcription polymerase chain reaction (RT-PCR) in the following testing laboratories: abdominal effusion and FNA samples at IDEXX, Japan (using a LightCycler 480 System II, Roche Diagnostics KK, Basel, Switzerland) and whole blood at Canine Lab., Japan (using CFX Connect, Bio-Rad Laboratories, Inc, Irvine, CA, USA). Abdominal or pleural effusion samples (1 ml each) were taken by ultrasound-guided abdominocentesis, respectively. by thoracentesis and were evaluated for the total number of nucleated cells, protein content, A/G ratio and cytology. Whole blood samples (1 ml) were collected and sent in ethylenediaminetetraacetic acid (EDTA) tubes.
2.2 Preparation of the medicine
Tablets containing molnupiravir 20 mg were prepared at the You-Me Animal Clinic. Briefly, molnupiravir powder was extracted from 20 commercially produced molnupiravir 200 mg capsules (MOVFORE, Lot No. HH2201001 [HETERO HEALTHCARE, Hyderabad, India]) and mixed with powdered cellulose (microcrystalline cellulose powder, NICHIGA, Takasaki, Japan) using a mortar and pestle (Matsuyoshi Medical Instruments Co, Ltd, Tokyo, Japan) to make a total of 12 g of powder mixture. The powder was shaped into approximately 200 6 mm wide sectional scored tablets using a generic tablet press made in China.
2.3 Treatment
Treatment with molnupiravir was initiated when FIP was highly suspected on the basis of clinical presentation or when FCoV RNA was detected by PCR; this date was marked as the first check. The following dosages were chosen: 20 mg/kg/d (10 mg/kg twice daily) for cats with effusive type, 30 mg/kg/d (15 mg/kg twice daily) for cats with non-effusive type and cats with pyogranulomatous lesions, and 40 mg/kg/d (20 mg/kg twice daily) for cats with neurological or ocular signs of FIP. Dosage may be increased or decreased in animals showing clinical deterioration or adverse reactions. Dosage was chosen based on estimated animal dosages listed on the Internet16, 17 and based on the adult human COVID-19 dose of molnupiravir, which is 800 mg every 12 hours.18 This would correspond to a dose per kilogram of 10 to 13.3 mg/kg twice daily for adults weighing 60 to 80 kg. As no pharmacokinetic information is available in relation to cats, we have chosen the dosage for cats based on the assumption that metabolism of drugs in cats is equivalent to metabolism in humans.
Owners were instructed to administer the tablets twice a day with 12 hours between doses. The expected standard duration of treatment was 84 days according to study GS-441524.10
2.4 Measurements
Owners were instructed to record body weight, body temperature, physical activity, appetite, and voiding/urinating daily and were asked to visit the clinic at 1, 2, 6, and 10 weeks. The following laboratory tests were required at each visit: red and white blood cell count, hemoglobin, hematocrit (HCT), AGP, total protein, albumin, aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, creatinine, blood urea nitrogen (BUN ) and the A/G ratio. Samples were analyzed in the clinic using a Catalyst One chemistry analyzer and a ProCyte One hematology analyzer (both IDEXX Laboratories, Westbrook, Maine). The A/G ratio was determined either from a whole blood plasma sample or from a fractionated protein sample. We performed abdominal and thoracic ultrasound evaluation of each cat at baseline and after 2, 6, and 10 weeks of treatment using a Prosound α7 (Aloka, Japan), including assessment of cardiac function (fractional shortening, left atrial to aortic diameter ratio, and valvular regurgitation).
2.5 Adverse Events
Any abnormal laboratory test values or medical events that occurred during treatment were considered adverse events and decisions were made to continue/discontinue treatment.
2.6 Statistical analysis
As this is a case series, no statistical calculations were performed other than descriptive statistics.
2.7 Ethics
All owners provided written informed consent prior to initiation of treatment. The experimental use of molnupiravir was approved by our Institutional Animal Study Review Committee.
3 RESULTS
3.1 Characteristics of the disease and treatment
Eighteen cats completed treatment by August 4, 2022 and are included in this summary report.
The presentation of the 18 cats is summarized in Table 1 and Table S1. The median age was 6.5 (range: 3-93) months. All 18 cats had a low serum A/G ratio, 16 cats had a loss of appetite, and 14 cats had mild to severe anemia by hemoglobin level and HCT. Thirteen cats had effusive FIP and 5 cats had non-effusive FIP. Neurological or ocular signs suggestive of FIP were present in 3 cats before treatment, including epileptic seizures/neurological signs (No. 8), blunted postural reflexes (No. 10), and slow pupillary reflex (No. 18) (Table S1). All but 2 cats (#8 and #15) were treated exclusively on an outpatient basis. Cat no. 8 was hospitalized from day 37 for 3 days due to jaundice. Cat no. 15 required hospitalization for 5 days after starting treatment due to anemia and jaundice accompanied by increased bilirubin concentration and ALT activity. During hospitalization, the cat received molnupiravir as scheduled, was hydrated with Ringer's solution, and treated with oral ursodeoxycholic acid (Towa, Japan) 10–15 mg twice daily to reduce bilirubin. There was no evidence of intravascular hemolysis (HCT remained stable), and microscopic examination of blood smears was negative for hemotropic mycoplasma infection.
TABLE 1. Basic characteristics of the cats in the described case series.
Age at disease onset, months, median (range)
6.5 (3-93)
Breed, n (%)
Housecat
9 (50.0)
Exotic shorthair
2 (11.1)
British Shorthair
2 (11.1)
Other
5 (27.8)
Sex, n (%)
Male not neutered/male neutered
4 (22.2)/7 (38.9)
Female not spayed/female spayed
2 (11.1)/2 (11.1)
Weight in kg, mean (SD)
2.72 (0.77)
Duration from onset of illness to initiation of treatment, days, median (range)
16.5 (2-49)
Effusive type, n (%)
13 (72.2)
Pyogranulomatous lesions in the abdominal cavity, n (%)
5 (27.8)
Neurological manifestations of FIP, n (%)
2 (11.1)
Ocular symptoms of FIP, n (%)
1 (5.6)
Temperature, °C, mean (SD)
39.3 (0.9)
Hematocrit, %, mean (SD)
27.3 (8.1)
Albumin/globulin ratio, mean (SD)
0.35 (0.10)
Sample type, n (%)
Abdominal effusion
11 (61.1)
Pleural effusion
1 (5.6)
FNA of a pyogranulomatous lesion
2 (11.1)
Full blood
3 (16.7)
None
1 (5.6)
The attending physician decided to extend the treatment to 99 days for cat no. 1. Consciousness disturbances appeared on day 8 in this cat and the dose was subsequently increased to 40 mg/kg. This symptom disappeared on the 15th day; however, the A/G ratio with the fractionated protein sample did not return to normal. On day 99, although the A/G ratio was still below the reference range (0.6), the clinician decided to stop treatment because the cat showed no clinical progression or deterioration.
3.2 Outputs
Clinical response in 14 cats was rapid. Dosing, findings during treatment, and outcomes in these animals are summarized in Tables S2 and S3. The fever subsided and the appetite returned within 2-3 days after the start of treatment. Remissions were also achieved in cats with severe clinical signs. Among them were cats no. 8, 17 and 18, which had pyogranulomatous lesions ≥ 2 cm in size, cat no. 4, which had severe anemia and a low A/G ratio, cat no. 14, which had a pleural effusion and difficulty breathing, and cat no. 15, who had an enlarged kidney. The pyogranulomatous lesions shrank or were undetectable on ultrasound in all 5 cases, and laboratory values returned to normal in all cats. Three cats had neurological signs of FIP before treatment. Cat no. 12 had no neurological symptoms of FIP before treatment, but had an epileptic seizure on day 7. The dosage was subsequently increased to 40 mg/kg. On the 2nd day, on the slit lamp at cat no. 7 found anisocoria that was probably related to uveitis. The dosage of molnupiravir was increased to 40 mg/kg from day 15, and all neurological or ocular signs of FIP resolved within 15 days.
Of the 14 cats that achieved remission, no relapses occurred through August 3, 2022, during 55 to 107 days of post-treatment follow-up. Three cats died (No. 2, No. 11 and No. 16) and one (No. 13) was euthanized; all these cats had the effusive form of FIP but had no neurological or ocular signs of the disease. All died within one week of starting treatment.
3.3 Security
Alanine transaminase activity higher than the reference value was found in 4 cats; the value of each of them was 286 U/l (cat #8 on day 37), 283 U/l (cat #9 on day 9), 154 U/l (cat #10 on day 7), and 117 U/l (cat No. 17 on the 9th day). Three cats with early ALT elevations on days 7 to 9 recovered without the need for intervention. In cat no. 8 developed jaundice on day 37 and was hospitalized for 3 days.
No abnormalities in BUN or creatinine concentrations were noted during treatment with molnupiravir.
4 DISCUSSION
In our series of cats with presumptive FIP treated off-label with a molnupivir compound, 14 of 18 cats achieved remission and remained in remission for up to 107 days of observation at the time of writing. Four cats showed signs of potential hepatic adverse effects; 3 cats developed ALT activity above the reference range during the first 7 to 9 days of treatment, all of which resolved without treatment, and 1 cat developed jaundice requiring hospitalization on day 37 of treatment.
The approved human formulation of molnupiravir is in 200 mg capsule form, but for animals it must be divided into smaller doses to facilitate administration of an appropriate dose based on body weight. We decided to prepare molnupiravir in the form of small tablets to simplify administration. We hypothesized that cats might refuse to swallow the drug in powder form or in aqueous solution, and it might be difficult for owners to administer the entire powder dose each time.
The minimum effective dose of molnupiravir in FIP is recommended to be 4.5 mg/kg PO every 12 hours for cats without neurological/ocular signs of disease, increasing to 12 mg/kg PO every 12 hours for cats developing ocular or neurological signs. symptoms of FIP.17 Others recommend a dose of 25 mg/kg every 24 hours for dry/wet FIP, 37.5 mg/kg every 24 hours for ocular FIP, and 50 mg/kg every 24 hours for neurological FIP.16 Since none of these recommended dosages have been established in prospective controlled studies, the dosage in this case series was determined by the author based on these estimates, adult dosages, and his experience. Nevertheless, the dosage used in our case series (10 mg/kg twice daily for cats with effusive FIP, 15 mg/kg twice daily for cats with non-effusive FIP or pyogranulomatous lesions, and 20 mg/kg twice daily for cats with neurological or ocular signs FIP) appears to be effective and safe and may help guide dosing in future clinical trials.
Four cats died during this study. Each of these cats had the effusive type of FIP; however, considering that some cats that survived had symptoms as severe or even more severe than those that died, no signs were found to predict early death. Unfortunately, the attending veterinarian was given little information about the deaths of the 3 cats that died at home, and no post-mortem examinations were performed. One cat (#2) died after vomiting the drug on day 6, so it is possible that this animal had swallowing problems.
The use of GS-441524 in 31 cats with FIP, of which 26 cats completed at least 12 weeks of treatment, resulted in remission in 25. 10 Eight of the 26 cats relapsed or became reinfected within 3 to 84 days after this period. . The length of observation in our case series is shorter than in study GS-44152410; however, observation of cats in our series is currently ongoing and more cats with FIP are being treated with molnupiravir. Further observation will provide data on longer-term efficacy. The major adverse events reported with injection in study GS-441524 were injection site reactions in 16 of 26 cats.10 Because the treatment in our study was administered orally, no injection site reactions occurred in any of the cats in our series. In our series, the most frequent adverse event during treatment was an increase in ALT activity. However, longer-term follow-up is necessary to more adequately assess liver-related reactions, and a larger group of animals is needed to more fully assess the adverse effects of molnupiravir.
Molnupiravir is active against SARS-CoV-2 and other RNA viruses19 and in cell culture it creates only low resistance.20 – 22 The efficacy of oral molnupiravir was evaluated in a phase 3 randomized control trial in 1,433 people with COVID-19, with a lower percentage of hospitalizations or deaths by day 29 in the molnupiravir group compared to placebo.18 Another important clinical question is whether molnupiravir-resistant viruses can develop and how many cats relapse or reinfection after treatment.
All owners who provided informed consent to participate were included in this study, so the risk of any bias should be minimal. Nevertheless, selection bias should be considered as this case series was enrolled in a single center in Chiba Prefecture, Japan. Another potential limitation of our case series is that the diagnosis of FIP was probable in all cases. Cats can have FCoV viremia without FIP, so RT-PCR detection of FCoV RNA is not specific for FIP.7 although this technique has a high sensitivity (90 %) and specificity (96 %) for FIP when applied to FNA specimens.23 In our series, the combination of RT-PCR with clinical signs and other serum biochemical tests, including a low A/G ratio, was highly suggestive of FIP.7 This case series suggests that molnupiravir may be an effective and well-tolerated treatment for FIP.
Table S1. Feline demographics and disease status before treatment. Table S2. Overview of the course of treatment. Table S3. Test values obtained at the first visit and the last test, based on which the decision was made to stop treatment.
References
Addie D, Belák S, Boucraut-Baralon C, et al. Feline infectious peritonitis. ABCD guidelines on prevention and management. J Feline Med Surg. 2009; 11: 594-604.
Wang YT, Su BL, Hsieh LE, Chueh LL. 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.
Addie DD, Toth S, Murray GD, Jarrett O. Risk of feline infectious peritonitis in cats naturally infected with feline coronavirus. Am J Vet Res. 1995; 56: 429-434.
Foley JE, Poland A, Carlson J, Pedersen NC. Risk factors for feline infectious peritonitis among cats in multiple-cat environments with endemic feline enteric coronavirus. J Am Vet Med Assoc. 1997; 210: 1313-1318.
Murphy BG, Perron M, Murakami E, et al. The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies. Vet Microbiol. 2018; 219: 226-233.
Pedersen NC, Perron M, Bannasch M, et al. Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. J Feline Med Surg. 2019; 21: 271-281.
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 (Basel). 2021; 11: 2257.
Krentz D, Zenger K, Alberer M, et al. Curing cats with feline infectious peritonitis with an oral multi-component drug containing GS-441524. Viruses. 2021; 13: 2228.
Katayama M, Uemura Y. Therapeutic effects of Mutian([R]) Xraphconn on 141 client-owned cats with feline infectious peritonitis predicted by total bilirubin levels. Vet Sci. 2021; 8: 328.
Katayama M, Uemura Y. Prognostic prediction for therapeutic effects of Mutian on 324 client-owned cats with feline infectious peritonitis based on clinical laboratory indicators and physical signs. Vet Sci. 2023; 10: 136.
Roy M, Jacque N, Novicoff W, Li E, Negash R, Evans SJM. Unlicensed molnupiravir is an effective rescue treatment following failure of unlicensed GS-441524-like therapy for cats with suspected feline infectious peritonitis. Pathogens. 2022; 11: 1209.
Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of Covid-19 in non-hospitalized patients. N Engl J Med. 2022; 386: 509-520.
Agostini ML, Pruijssers AJ, Chappell JD, et al. Small-molecule antiviral β-dN (4)-hydroxycytidine inhibits a proofreading-intact coronavirus with a high genetic barrier to resistance. J Virol. 2019; 93:e01348.
Dunbar D, Kwok W, Graham E, et al. Diagnosis of non-effusive feline infectious peritonitis by reverse transcriptase quantitative PCR from mesenteric lymph node fine-needle aspirates. J Feline Med Surg. 2019; 21: 910-921.
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.
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
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
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
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
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
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
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
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, 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.
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 type
GS-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 type
GS441524 - tablets with the specified real GS content
GS441524 - tablets with the stated equivalent GS content
Wet FIP (abdominal effusion, without ocular and neurological symptoms)
10-12 mg/kg once a day
6 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 day
8 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 day
10 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 day
6 mg/kg twice a day
Relapse of FIP (usually associated with neurological manifestations)
15 mg/kg twice a day
7.5 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 type
GC376 - 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 type
Remdesivir - 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 type
Molnupiravir
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 type
Mefloquine (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.
What is FIP? – FIP is caused by a common and mostly harmless enteric coronavirus, similar to those that cause the common cold in humans and diarrhea in foals, calves and poultry. Most cats are infected with feline enteric coronavirus (FECV) at around 9 weeks of age and may be reinfected before 3 years of age, when cycles of infection become less frequent. Specific mutations that allow FECV to escape from the cells lining the lower intestine and infect the most basic cell of the immune system, the macrophage, occur in about 10 % infections. However, this macrophage infection is eliminated in all but 0.3–1.4 % cats. Predisposing conditions that lead to disease in this small proportion of cats include young age, genetic susceptibility, sex, overcrowding, poor nutrition, and a number of stressful events in the environment. The site of initial onset of the disease is in the lymphoid tissue in the lower small intestine, cecum, and proximal colon. Infected macrophages leave these initial sites of disease and migrate locally and in the bloodstream to small veins in the lining of the peritoneal cavity, the uveal tract of the eye, the ependyma, and the meninges and spine. Symptoms of the disease appear within days, weeks, sometimes months, and rarely a year or longer. The form of the disease that manifests itself is simply referred to as wet (effusive) or dry (non-effusive). The two forms are easily distinguishable, although there may be intermediate forms between them. Some cats may have symptoms of dry FIP but later develop wet FIP, or vice versa. Overall, about two-thirds of cats have wet FIP and one-third have dry FIP. The duration of illness until death, usually by euthanasia, used to be only a matter of days or weeks. Fewer than 5 % diseased cats, especially those with milder forms of dry FIP, survive longer than one year with the best symptomatic care.
Manifestations and forms of FIP
Clinical manifestations of FIP – The clinical manifestations of wet (Table 1) and dry (Table 2) FIP differ depending on the site(s) in the body where the infected macrophages end up causing inflammation. The intensity and nature of the inflammation are responsible for the form of the disease. Wet FIP is a more acute and severe form of FIP and is characterized by the accumulation of inflammatory fluid in either the abdominal cavity and/or the chest cavity. Involvement of the central nervous system (CNS) and eyes is relatively rare in the wet form of FIP (Table 1). The dry form of FIP is not characterized by diffuse inflammation and fluid discharge, but rather by fewer and more tumor-like lesions (ie, granulomas) in organs (e.g., kidneys, cecum, colon, liver, lungs, lymph nodes) in the abdomen or chest cavity or in the eyes and brain (Table 2). While the brain and/or eyes are involved in only 9 % cases of the wet form, neurological and/or ocular disease is the main clinical sign in 70 % cats with the dry form of FIP.
TABLE 1. VARIABILITY OF CLINICAL SYMPTOMS OF THE EFFECTIVE (WET) FIP IN CATS AVOIDED AT UC DAVIS
Symptoms associated with:
occurrence (%)
Peritoneal cavity
58%
Peritoneal and pleural cavities
22%
Pleural cavity
11%
Peritoneal cavity, eyes
2,8%
Peritoneal cavity, CNS *
1,9%
Peritoneal and pleural cavity, CNS
0,9%
Peritoneal and pleural cavity, eyes
0,9%
Pleural cavity, CNS, eyes
0,9%
Peritoneal cavity, CNS, eyes
0,9%
* CNS - Central nervous system (brain, spine)
TABLE 2. VARIABILITY OF CLINICAL SYMPTOMS OF NON-FUSION (DRY) FIP IN CATS AVOIDED AT UC DAVIS
Symptoms associated with:
occurrence (%)
Peritoneal cavity
30%
CNS
22%
Eyes
14%
CNS and eyes
8%
Peritoneal cavity, eyes
7%
Peritoneal and pleural cavities
4%
Peritoneal and pleural cavity, CNS
3%
Peritoneal and pleural cavity, eyes
2%
Peritoneal cavity, CNS, eyes
2%
Pleural cavity
1%
Blood-brain and blood-eye barrier
Basic facts - The eye and central nervous system (CNS) are protected from harmful substances by blood-eye barriers (blood-eye barrier) and blood-brain (blood-brain barrier). These barriers are of great evolutionary importance because they protect brain and eye functions from the effects of systemic toxins and infectious agents. Such barriers have been developed over millions of years by positive selection of the most capable individuals. The blood-brain barrier in cats does not pass about 80% most drugs, while the blood-eye barrier about 70%. Therefore, if a given dose of a drug such as GS-441524 reaches an effective blood level (plasma) of 10 μM, the levels in the brain (cerebrospinal fluid) will be only 2 μM and the level in the eye (ventricular water) will only be 3 μM. However, higher levels are likely to be reached in inflamed tissues and will decrease as inflammation subsides. This may be one of the explanations for the rapid improvement that is often observed in the first days of treatment.
Several other aspects of these two blood barriers need to be considered. First, their impermeability of undesirable substances varies from individual to individual. Second, the effectiveness of this barrier decreases in inflamed tissues and increases as inflammation subsides. This is good for treatment in the early stages of the disease, but bad for treatment in the final stages when the inflammation disappears and only the virus remains. Third, there are no simple, safe or effective means of weakening these barriers, and the only way to increase the level of the drug in the brain or eyes is to increase their level in the blood plasma by administering a higher dose, either orally or parenterally.
How these barriers affect forms of FIP - Paradoxically, ocular and neurological forms of FIP are also a consequence of the same barriers, but in this case in neurological and / or ocular FIP, the main problem is the entry of antibodies and immune lymphocytes. The phenomenon of neurological disease after a common systemic viral infection is well known in humans and animals. A typical example is polio-encephalomyelitis in humans and canine distemper in dogs. Poliomyelitis virus (polio) is a common intestinal pathogen and usually causes a mild or mild intestinal infection. However, in some people, the virus also penetrates the brain and spinal cord. Humans develop a strong systemic immune response to the polio virus, which is highly effective in eliminating the virus in all parts of the body, except the nervous system, where the limits of the blood-brain barrier are an obstacle to immunity. These unfortunates develop a classic neurological form of infection. A similar phenomenon occurs in canine distemper. Canine distemper virus, which is closely related to the human measles virus, causes an acute respiratory infection in young dogs, which manifests 7-14 days after exposure and lasts one to two weeks. Most of these dogs recover completely, but some develop neurological disease in three or more weeks. This highly lethal secondary form of canine distemper is caused by a virus that has escaped from the body to the brain and spinal cord during the respiratory phase of the infection and is protected from the host's immune system by the blood-brain barrier.
The distribution of the disease between the CNS and other parts of the body may also explain why blood tests are rarely abnormal in cats with primary neurological disease or in those who have relapsed to these forms during or after treatment with non-neurological forms of FIP. It appears that inflammation at privileged sites such as the CNS may not elicit a systemic inflammatory response and may not cause significant changes in hematology, nor an increase in total protein and globulin, and a decrease in albumin to globulin A: G ratio.
Preliminary diagnosis of ocular and neurological FIP
Preliminary diagnosis – Eye and neurological diseases are much less common in cats with wet than with dry FIP (Tables 1, 2). They also occur in primary and secondary forms. Primary disease accounts for approximately one-third of cases of dry FIP (Table 2), and lesions outside the eyes and central nervous system (CNS) are either absent or not readily discernible. Secondary neurological and ocular forms of FIP become much more common as a result of antiviral therapy and occur either during the initial treatment of the common extra-ocular/CNS forms or as a relapse during the 12-week post-treatment observation period.
The initial suspicion of neurologic and/or ocular FIP is based on age, origin, and presenting clinical signs. FIP occurs mainly in cats under 7 years of age, three-quarters of them under 3 years of age and with the highest incidence between 16 weeks and 1.5 years. Common symptoms in both ocular and neurological FIP were stunted growth in kittens and adolescent cats, weight loss in adults, and vague signs of ill health often associated with fever.
It is believed that the diagnosis of FIP, especially the dry form, is difficult. However, a preliminary diagnosis is relatively easy to establish due to stereotypic signaling, clinical history and physical findings, and the rarity of disease confusion in the group with the highest risk of FIP. Neurological and/or ocular forms of FIP can be confused with systemic feline toxoplasmosis, so many cats with these forms of FIP are tested for toxoplasmosis and treated with clindamycin. However, systemic toxoplasmosis is an extremely rare disease in cats, especially compared to FIP. FIP is easily distinguished by the cat's origin (breeding station, foster/rescue station, shelter), signaling (age, sex, breed) and basic blood test results. Deep fungal infections (coccidioidomycosis, blastomycosis, histoplasmosis) can cause ocular and sometimes neurological symptoms similar to FIP, but are still rare even in their endemic areas. Lymphoma can also be a differential diagnosis of dry FIP, but this disease is usually sporadic and occurs in older cats. A number of congenital disorders can also present with progressive neurological signs, but these occur mainly in younger cats and are not associated with the inflammatory manifestations of infectious diseases such as FIP, toxoplasmosis or deep mycoses.
Symptoms of ocular FIP - Ocular disease occurs as the sole or primary symptom in about one-third of cats with dry FIP and in two-thirds of cases associated with extra ocular lesions (Table 2). Eye disease is an unusual manifestation in cats that initially had wet FIP (Table 1). The initial clinical manifestation is unilateral or bilateral anterior uveitis, manifested by a change in iris color, turbidity and remnants of flocculant in the anterior chamber, keratic clots on the back of the cornea, and anisocoria (unequal pupil size). In some cats, retinitis (inflammation of the retina) is an accompanying feature, and is manifested by focal wallpaper hyporeflectivity associated with local inflammation and microhemorrhage (minor bleeding) of the retinal vessels. Less than one-third of cats with ocular FIP also show indeterminate or overt neurological symptoms (Table 2). In some cases, glaucoma, usually unilateral, and panopthalmlitis (inflammation of all layers of the eye) occur, which can lead to enucleation (removal of the eye).
Symptoms of neurological FIP - the same prodromal signs have often been observed in cats with neurological signs, but include vague signs of dementia, aggressive behavior, compulsive licking of inanimate objects and other cats, reluctance to jump to high places, spontaneous muscle twitching, abnormal swallowing movements and occasional seizures. Later symptoms include posterior ataxia, inability to jump to high places, physical and auditory hyperesthesia, hyperreflexia, and cerebellar-vestibular signs (cruciate extensor reflex, loss of conscious proprioception), seizures, and increasing incoordination and dementia. Symptoms of spinal involvement often include fecal and/or urinary incontinence, paralysis of the tail and hind limbs, pain in the lower back. Catastrophic decerebral symptoms are also associated with sudden and severe herniation of the brain into the spinal cord.
Confirmatory tests of ocular and neurological FIP
Basic facts - The definitive diagnosis of FIP is based on the identification of the presence of viral antigen or RNA in macrophages in typical effusions or lesions by PCR or immunohistochemistry (IHC). Definitive diagnosis can be a difficult and expensive process in many cats, and PCR / IHC can be false negative in up to 30% samples. In most cases, however, it is not necessary to go that far because of the diagnosis. A comprehensive set of historical, physical, and less direct laboratory abnormalities may be sufficient to make a diagnosis.
Laboratory symptoms - The diagnosis of ocular and neurological FIP can usually be made by combining characteristic changes in cerebrospinal fluid (CSF) and aqueous humor (high protein, high cell counts, neutrophils, lymphocytes, macrophages) with significant abnormalities in history and history, physical examination, CBC ), biochemistry, or MRI. Total protein concentration is often increased (mean, 9.4 g / l; median 3.6 g / l; range 0.85-28.8 g / l) as well as increased erythroblast (NRBC) count (mean 196 / μL median 171 / μL; range 15–479 / μL). Neutrophils are the dominant inflammatory cell in most cats, while lymphocytes and a mixture of neutrophils and lymphocytes are observed in a smaller proportion.
MRI is a useful tool for diagnosing neurological FIP, especially in combination with routine signaling / history, typical clinical signs, and CSF analysis. MRI identified three different clinical syndromes in 24 cats with an autopsy confirmed by neurological FIP (Rissi DR, JVDI, 2018.30: 392–399): 1) T3-L3 myelopathy, 2) central vestibular syndrome, and 3) multifocal CNS disease. In all cases, MRI abnormalities were found, including increased meningeal contrast, increased ependymal contrast, ventriculomegaly, syringomyelia, and foramen magnum herniation. 15 cases showed hydrocephalus (10 cases), cerebellar herniation through the foramen magnum (6 cases), swelling of the brain with flattened gyri (2 cases) and fibrin accumulation in the ventricles (2 cases) or leptomening (1 case). Histologically, 3 main different distributions of neuropathological changes were observed, namely periventricular encephalitis (12 cases), rombencephalitis (8 cases) and diffuse leptomeningitis with superficial encephalitis (6 cases).
In one study, the most useful anti-mortem indicator of neurological FIP was the positive titer of IgG anti-coronavirus antibodies in the CSF. Antibody titers in CSF 1: 640 or higher were found only in cats with FIP and RT-PCR was always positive. Initial studies indicated that the antibody present in the CSF was produced, at least in part, in the CNS. However, in another study, the antibody was detected only in cats with serum titers of 1: 4096 to 1: 16384, and the researchers concluded that the antibodies in the CSF were obtained passively. In another attempt to measure local CNS antibody production in cats with FIP, the albumin quotient and IgG index were measured to determine if the proteins in the CSF were of blood origin or of local origin. Neither the albumin quotient nor the IgG index identified a pattern consistent with intrathecal IgG synthesis in cats with the CNS form of FIP. In conclusion, anti-coronavirus antibodies appear to enter the CSF at high levels, when they are also at high serum levels. Indeed, IFA serum coronavirus antibody titers in cats with ocular and neurological FIP are among the highest in any form of FIP.
PCR test performed from a sample of CSF and aqueous humor with a higher number of proteins and cells is highly sensitive and specific for ocular and neurological FIP. However, it is recommended that only a PCR test targeting the FCoV 7b gene be used, and no less sensitive PCR to FIPV specific mutations in the S gene. This FCoV gene is often used for PCR because it is the most abundant viral transcript and is therefore likely to that it will be detected. In some PCR assays, the FCoV M gene was targeted because it is highly conserved in all isolates, but transcripts are less numerous than in the 7b gene.
Immunohistochemistry on cells collected from spinal fluid is as sensitive and specific as PCR on samples with higher protein and cell counts. The antigen is localized specifically to macrophage-like cells.
The rapid FIP response to GS-441524 is being used as a confirmatory test increasingly. However, it should only be used in cases where there is other supporting evidence for a diagnosis of FIP. However, the truth is that there are probably no other simpler or cheaper means available at the moment to facilitate the diagnosis.
Treatment of neurological and ocular FIP
Difficulties in obtaining authorization for veterinary use of medicinal products for human use – Pharmaceutical companies such as Gilead Sciences and Merck have refused to compromise the development and approval processes of their promising anti-coronavirus drugs such as GS-5734 (Veklury®/Remdesivir) and EIDD-2801 (Molnupiravir®) or their respective biologically active forms GS-441524 and EIDD -1931. Out of desperation, cat owners around the world have turned to the Chinese black market for drugs like GS-441524. This black market was not entirely motivated by profit – China's FIP problem also grew at the same time as the domestic cat population. Moreover, even if Gilead Sciences had approved the use of GS-441524 in animals, the immediate need for an effective treatment for FIP has overtaken the official approval and commercialization process, which takes many years. Chemical companies and a dozen or more vendors of injectable and oral products have been able to satisfy the demand for GS from tens of thousands of desperate cat owners around the world. Veterinarians have been reluctant to pressure human pharmaceutical companies like Gilead to license their promising antiviral drugs for use in animals, but they are increasingly involved in helping owners with treatments. It therefore appears that the unapproved use of human drugs such as GS-441524, which are also desperately needed in veterinary species, will be the norm for many years to come.
(This paragraph comes from the original article from 1/4/2021.)
Virus-specific inhibitors – Inhibition of viral genes regulating specific stages of infection and replication has become the mainstay of treatment for chronic RNA virus infections in humans, such as HIV and hepatitis C virus. Currently, two classes of antiviral drugs have been shown to be effective against FIP. The first class consists of RNA synthesis inhibitors and includes the nucleoside analogs GS-441524 (the active ingredient in Remdesvir) and EIDD-2801 (molnupiravir). The second class of drugs consists of viral protease inhibitors, such as GC376 (prodrug of GC373) and Nirmatrelvir (prodrug of nitrile modification of GC373). Protease inhibitors are much less effective at crossing the blood-brain and blood-ocular barriers than nucleoside analogues and are not recommended for the treatment of neurological or ocular FIP.
Treatment with GS-441524 – GS-441524 has become the drug of first choice for the treatment of cats with all forms of FIP, and both injectable (SC) and oral forms are available in the off-label Chinese market. However, oral absorption is less than 50 % effective compared to injection, thus requiring twice the dosage of oral GS-441524. Suppliers of oral GS-441524 almost never disclose the actual concentration of GS-441524 in tablets or capsules, but rather label them as an equivalent injection dose. There is also an upper limit to the absorption efficiency of oral GS, making it difficult to achieve the higher blood levels needed to reach sufficient amounts of the drug in the brain and eyes. Therefore, if cats with ocular and neurological disease fail despite high equivalent doses of oral GS-441524, a switch to injectable GS-441524 should be considered before switching to a drug such as molnupiravir is considered.
The starting dose for cats with wet or dry FIP and no signs of ocular or neurological disease is 4-6 mg/kg daily for 12 weeks, with younger and wet cases tending towards the lower end and dry cases towards the higher end. Cats with eye lesions and no neurological signs are started at 8 mg/kg daily for 12 weeks. Cats with neurological signs are started at 10 mg/kg daily for 12 weeks. If cats with wet or dry FIP initially develop ocular or neurological signs, they are switched to the appropriate ocular or neurological doses. The dose of GS is adjusted weekly to account for weight gain. Weight gain can be huge in many of these cats, either because they are in poor condition to begin with or because their growth has been stunted. If the cat does not gain weight during treatment, this is considered a bad sign. The initial dosage is not changed unless there are serious reasons for this, such as ineffectiveness of treatment or improvement in blood test values, improvement is very slow, low activity level, initial clinical symptoms have not resolved, or the disease form has changed with the appearance of ocular or neurological symptoms. If there are good reasons to increase the dosage, it should always be from +2 to +5 mg/kg per day and for at least 4 weeks. If these 4 weeks exceed the original 12-week treatment time, the treatment time is extended. A positive response to any increase in dosage can be expected, and if you don't see an improvement, it means that the dosage is still not high enough, drug resistance is emerging, the GS mark is not what it should be, the cat does not have FIP, or there are other diseases that confuse the treatment.
One of the most difficult decisions is determining when to stop treatment. Although some cats, often younger with wet FIP, can be cured as early as 8 weeks and possibly earlier, the usual treatment period is 12 weeks. Some cats may even require dose adjustments and even longer treatment periods. Critical blood levels such as hematocrit, total protein, albumin and globulin levels and absolute lymphocyte counts usually return to normal in curing cats after 8 to 10 weeks, when there is often an unexpected increase in activity levels. We believe, but there is no evidence yet, that after 8-10 weeks, the cat will have its own immune response against the infection. This is a situation that occurs in the treatment of people with hepatitis C, which is also a chronic RNA virus infection that often requires antiviral treatment for up to 12 weeks or more.
Cats with ocular disease and no neurological impairment show a rapid response to GS, and complete recovery of vision with minimal or no residual damage is expected in as little as two weeks. Cats that develop neurological abnormalities, develop neurological disease during the treatment of other forms of FIP, or develop neurological symptoms during the 12-week post-treatment observation period also improve rapidly, but the dose is much higher, the duration of treatment often longer and the cure rate slightly lower. Treatment failures in cats with neurological FIP are due to either insufficient dose or the development of drug resistance.
Unfortunately, there is no simple blood test that can determine when a cat with neurological impairment has fully recovered. Many cats with neurologic FIP show minimal blood abnormalities, especially those with primary neurologic FIP, and the abnormalities often disappear by the end of treatment, even though residual sites of inflammation remain in the brain or spinal cord. In addition, some cats that recover from the infection will have mild to moderate neurological deficits that are residual effects of the previous illness. These facts make it difficult to use blood test results or residual neurological deficits as indicators of cure or undertreatment. Although a thorough eye examination can clearly rule out active signs of disease, the true state of the disease in the brain and spinal cord can only be determined by an MRI, ideally together with an analysis of the cerebrospinal fluid. These procedures are expensive, not available to everyone, and may not provide definitive proof that the infection in the CNS has been cleared.
Fear of relapses means that many people involved in GS treatment are too cautious about a single blood parameter that is slightly abnormal (eg, slightly high globulin or slightly low A: G ratio), or final ultrasound results suggesting suspiciously enlarged abdominals. lymph nodes, small amounts of abdominal fluid or blurred irregularities in organs such as the kidneys, spleen, pancreas or intestines. It should be borne in mind that the normal range of blood values applies to most animals, but it is a bell-shaped curve, and that there are a few non-standard patients who will have values at the edge of these curves. Ultrasonographers must consider the degree of pathology that can occur in the FIP of the affected abdomen and how scars and other permanent consequences can change the normal appearance of successfully treated cats. In situations where such questions arise, it is better to focus in more detail on the overall picture and not just on one small part. The most important outcome of treatment is a return to normal health, which has two components - external signs of health and internal signs of health. External signs of health include a return to normal activity levels, an appetite, adequate weight gain or growth, and coat quality. The latter is one of the best criteria for cat health. Internal health symptoms include the return of certain critical values to normal based on periodic complete blood count (CBC) monitoring and serum chemical profiles. The most important values in CBC are hematocrit and relative and absolute total white blood cell, neutrophil and lymphocyte counts. The most important serum values for chemical analysis (or serum electrophoresis) are total protein, globulin, albumin and A: G ratio levels. Bilirubin is often elevated in cats with effusive FIP and may be useful in monitoring the severity and duration of inflammation. There are many other values in the CBC panels and serum, and it is not uncommon for some of them to be slightly higher or lower than normal, and it is better to ignore these values unless they are significantly elevated and associated with clinical signs. For example, high BUN and creatinine, which is also associated with increased water consumption, excessive urination, and urinary abnormalities. The number of machine-counted platelets in cats is notoriously low due to the trauma of blood collection and platelet aggregation and should always be verified by manual examination of blood smears. The final decision to discontinue or extend treatment when faced with unclear doubts about different testing procedures should always be based on external manifestations of health than on any single test result.
(This paragraph comes from the original article from 1/4/2021.)
Relapses usually refer to infections that have escaped into the central nervous system (brain, spine, eyes) during treatment for wet or dry FIP that are not accompanied by neurological or ocular symptoms. Doses of GS-441524 used to treat these forms of FIP are often insufficient to effectively cross the blood-brain or blood-ocular barrier. The blood-brain barrier is even more efficient than the blood-ocular barrier, which explains why eye lesions are easier to heal than brain and/or spinal cord infections. Post-treatment relapses involving the eyes, brain, or spine are usually treated for at least 8 weeks at an initial daily dose at least 5 mg/kg higher than the dose used during primary treatment (eg, 10, 12, 15 mg/kg per day). Cats that fail to clear the infection at doses up to 15 mg/kg per day are likely to have developed varying degrees of resistance to GS-441524. Partial resistance may allow suppression of disease symptoms but not cure, while complete resistance is manifested by varying severity of clinical symptoms during treatment.
Different groups focused on the treatment of FIP have made various modifications in the treatment protocols. Some groups will treat with an extremely high dose of GS from the beginning and not increase the dose when indicated, or will recommend discontinuing or extending the high dose for the last two weeks in the hope that this will reduce the risk of relapse. In addition to GS, systemic prednisolone is often prescribed, but should only be used temporarily to stabilize serious illness. Systemic steroids reduce inflammation but tend to mask the beneficial effects of GS, and if used for an unreasonably long time and in high doses, can interfere with the development of immunity to FIP. Restoration of immunity to FIP is thought to be an important part of successful GS treatment. Therefore, some people advocate the use of interferon omega or non-specific immunostimulants to further stimulate the immune system, and some come up with other modifications. There is no evidence that using an extremely high dose will improve the cure rate. Also, interferon omega and non-specific immunostimulants have not been shown to have beneficial effects on FIP, whether given as a single treatment or as an adjunct to GS. The practice of adding another antiviral drug, the viral protease inhibitor GC376, to the treatment of GS in cats that develop resistance to GS is also emerging, but this still requires further research. Finally, it is common for owners, treatment groups and veterinarians to add many supplements, tonics or injections (eg B12) to increase hematopoiesis or to prevent liver or kidney disease. However, such supplements are rarely necessary in cats with pure FIP.
Molnupiravir (EIDD-2801) – Molnupiravir is very similar to GS-441524, but is a cytidine rather than an adenine nucleoside analog. It is widely used as an oral treatment for early cases of COVID-19 in humans, but in the last 1-2 years it has been increasingly used to treat cats with FIP. Due to the toxicity observed in cats at higher doses and as yet unknown chronic side effects, it is most often recommended for cats that developed resistance to GS-441524 during primary treatment or relapsed with neurological/ocular signs after treatment with high doses of GS- 441524. Fortunately, molnupiravir has a different resistance profile than GS-441524.
The safe and effective dosing of molnupiravir in cats with FIP has not been established in properly controlled and monitored field studies such as those performed for GC376 and GS-441524. However, the estimated starting dose of molnupiravir in cats with FIP was derived from published EIDD-1931 and EIDD-2801 in vitro cell culture studies and other laboratory and experimental animal studies. Molnupiravir (EIDD-2801) has an EC50 of 0.4 µM/µL against FIPV in cell culture, while the EC50 of GS-441524 is approximately 1.0 µM/µL. Molnupiravir begins to show cellular cytotoxicity at concentrations of 400 µM or higher, while GS-441524 is non-toxic at 400 µM. Both have similar oral absorption of around 40-50 %. The current recommended starting dose of molnupiravir for neurologic and ocular FIP is 8–10 mg/kg orally every 12 hours for 84 days. Depending on the response to treatment, it may be necessary to increase it to a maximum of 15 mg/kg orally every 12 hours. At higher doses, molnupiravir toxicity is likely to occur as indicated by changes in the complete blood count.
Causes of treatment failure
Incorrect dosage adjustments - It is important to start treatment with the appropriate dosage and to monitor it closely with regular checks on temperature, weight and external signs of improvement. The CBC and serum chemical analysis panel, which contains baseline protein values (total protein, albumin, globulin (TP - albumin = globulin) and A: G), should be performed at least once a month. with GS-441524 Expensive serum protein electrophoresis does not provide much more valuable information.
Low quality GS-441524 - GS-441524 is not approved for marketing in any country and is sourced from a small number of Chinese chemical companies which sell it to distributors as pure powder. Vendors dilute it into injectable solutions or prepare oral forms for sale under their trade names. There is no independent mechanism to ensure the quality of the final product sold to cat owners. Nevertheless, the main providers of dilute forms for injectable solutions and / or oral preparations are surprisingly honest, and some even offer limited guarantees if treatment with some of their products does not cure the disease. However, the batches sold by some providers appear to be counterfeit and some are not in the specified concentration. There may also be differences between batches, probably due to occasional problems with the supply of raw GS by retailers or problems with meeting the needs and expectations of the cat owner. Various groups of FIP Warriors have good information about the most reliable brands.
Drug resistance - resistance to GS-441524 may already exist at the time of diagnosis, but this is unusual. It occurs more frequently during treatment and is initially only partial and requires only higher doses. In some cats, it may become complete. Resistance is the biggest problem in cats with neurological disease, or they develop brain infections during treatment or within a few days or weeks after stopping treatment. Many cats with partial drug resistance may be "treated" for their symptoms, but they relapse as soon as treatment is stopped, as is the case with HIV treatment, for example. There are cats that have been able to partially or completely treat the symptoms of FIP for more than a year, but without a cure. Resistance eventually worsens and the symptoms of the disease worsen, treatment difficulties become unbearable for the owner or the owner's financial resources run out.
GS side effects
GS-441524 treatment is incredibly free of systemic side effects. It can cause mild kidney damage in cats without significant kidney damage, but does not lead to latent disease or kidney failure. Systemic drug reactions such as vasculitis have been observed in several cats and can be confused with injection site reactions. However, these drug reactions are in places where injections are not given, and often stop on their own or respond well to short-term low-dose steroids. The main side effect of GS treatment is pain at the injection sites, which varies from cat to cat and according to the abilities of the person giving the injections (usually the owner). Swelling or ulcers at the injection site sometimes occur in owners who do not change the application site often enough (do not stay between the shoulder blades) and do not inject into the muscular and nervous layers under the skin. I recommend choosing places starting one inch behind the shoulder blades, down from the back to 1 to 2 inches in front of the root of the tail and one third to half way down to the chest and abdomen. Many people use gabapentin to relieve pain before injections. Swollen spots and ulcers at the injection site should be stripped of surrounding hair and gently cleaned 4 or more times a day with sterile cotton swabs soaked in homemade hydrogen peroxide diluted 1: 5. They usually do not require any more complicated treatment and will heal in about 2 weeks.
Prognosis of treatment with GS441524
Exact cure rate data with GS-441524 are not yet available, but it seems possible to cure more than 80% cats with confirmed FIP. Treatment failure is due to misdiagnosis of FIP, inadequate treatment monitoring and dose adjustment, complicating diseases, poor GS, resistance to GS, or economic difficulties. The cure rate is slightly lower in cats with neurological forms of FIP and in older cats. Older cats are more susceptible to other chronic diseases, which either predispose cats to FIP or complicate overall health.
Cats with neurological FIP may suffer permanent residual symptoms of the disease. This is especially true for cats with spinal involvement and urinary and/or fecal incontinence or hind paralysis. Hydrocephalus and syringomyelia are common complications of neurological FIP and often persist to some extent after the infection has cleared. Fortunately, most cats with neurologic FIP recover normal or near-normal function despite persistent traces of hydrocephalus and syringomyelia.
Legal treatment for FIP?
We hope that the legal form GS-441524 will be available soon. The drug, called Remdesivir, is the greatest hope of the present because Remdsivir breaks down into GS when given intravenously to humans, mice, primates and cats. Remdesivir (Veklury®) has been fully approved by the US FDA and similar approval is likely to follow in other countries. If so, it can be prescribed by any licensed human physician as well as veterinarians. However, the use of Remdesivir in the United States was initially limited to a specific subset of patients with Covid-19 and only under controlled conditions and with ongoing data collection. Until all restrictions are lifted, it will not be easily accessible for human use. We have no experience in treating cats with Remdesivir instead of GS-441524. The molar basis of Remdesivir is theoretically the same as GS-441524. GS-441524 has a molecular weight of 291.3 g / M, while Remdesivir is 442.3 g / M. Therefore, 442.3 / 291.3 = 1.5 mg of Remdesivir would be required to obtain 1 mg of GS-441524. The diluent for Remdesivir is significantly different from the diluent used for GS-441524 and intended for intravenous use in humans. How diluted Remdesivir will behave when given by subcutaneous injection over 12 weeks or more is not known. Mild signs of hepatic and renal toxicity were observed in humans. GS-441524 causes mild and progressive renal toxicity in cats, but without apparent hepatic toxicity. It is uncertain whether renal toxicity observed in humans receiving Remdesivir is due to its active substance (ie GS-441524) or to chemical agents designed to increase antiviral activity.
The GC376 approval process for cats (and humans) is ongoing at Anivive, but will take two or more years. GC376 is a viral protease inhibitor and, unlike GS-441524, which inhibits the initial stage of viral RNA replication, GC376 prevents viral replication in the final stage of its replication process. Therefore, it is unlikely to have a significant synergistic viral inhibitory effect and its use in combination will be much more important in inhibiting drug resistance (e.g. in combination antiviral therapy for HIV / AIDS).
Improper use of GS-441524
Some veterinarians, in collaboration with major Chinese supplier GS-441524, have advocated its use to eliminate feline enteric coronavirus (FECV) infection. The reason is to prevent the occurrence of a mutant virus causing FIP (FIPV) and thus prevent FIP. This approach was supported by limited and highly controversial studies with shelter cats, which were naturally exposed to the FECV. Although this approach is attractive at first glance, it is a very incorrect use of GS-441524 in cats. FECV infection originally occurs in kittens and is not associated with any significant symptoms of the disease. Elimination lasts for weeks, months, and in some cases indefinitely, but in most cats, it eventually stops when immunity develops. Most cats over the age of three will no longer shed the virus. GS-441524 treatment is highly unlikely to result in more permanent immunity than is observed in nature and to eliminate cycles of infection and reinfection in younger cats.
Although our current knowledge of FECV infection seriously challenges this approach, there are even more compelling reasons why we will not treat healthy cats GS-441525 or other antiviral agents in the future. We already know from published studies that some primary strains of FIPV are resistant to GS-441524 (and GC376). We also know that drug resistance has become a long-term problem in cats with long-term treatment for GS-441524, especially in neurological forms of FIP. Therefore, the use of drugs such as GS-441524 in a large population of healthy cats will undoubtedly lead to widespread resistance to enzootic FECV. This resistance will also manifest itself in FIP-causing FECV (FIPV) mutations from these populations, making it impossible to use GS-441524 in more and more FIP cats. Unfortunately, veterinary medicine does not have the means of human medicine, it is not stimulated by potential benefits, which would lead to the discovery, testing and approval of more and more antiviral drugs to circumvent either natural or acquired drug resistance, which is already the case in HIV / AIDS treatment. achieved (at least on time).
(This part comes from the original article from 1/4/2021.)
Niels C. Pedersen, DVM PhD Distinguished Professor Emeritus UC Davis, Center for Animal Health Companion January 4, 2021, updated February 10, 2023
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