Treatment of FIP in cats with Remdesivir

Original article: Treatment of FIP in cats with Remdesivir
Richard Malik DVSc PhD FACVSc FASM

Until recently, the diagnosis of FIP for a feline patient was a death sentence. Although omega-interferon and polyprenyl immunostimulant had some effects in some cases, most cats and kittens diagnosed with FIP died or euthanasia was required due to poor condition.

Figure 1. (A) BOVA Remdesivir reconstituted and ready for treatment. (B) The pathway that Remdesivir takes intracellularly to activate as GS-441524

That all changed a few years ago when the lifelong research of FIP Professor Niels C. Pedersen of UC Davis culminated. Niels first managed to save the lives of several cats with FIP with the protease inhibitor GC-376, and soon after showed that the nucleoside analog GS-441524 is even more effective in treating FIP, although the required dose depended on whether there was ocular or CNS involvement. . GS-441524 was a drug developed by the American company Gilead, which unfortunately did not show interest in further research into the molecule for veterinary use in the treatment of FIP. To fill the gap for effective FIP therapy, various companies have begun to manufacture GS-441524 and sell it on the black market. Although it was very expensive, the availability of quality GS-441524 provided determined cat owners with a way to save cats with wet or dry FIP, although obtaining this drug was complicated, usually associated with the help of a Facebook group. Unfortunately for cat lovers, APVMA and the Australian Veterinary Practitioner Board eventually made the import of GS-441524 and its use for veterinary purposes significantly more difficult, with repressive measures for veterinarians who wanted to help cats with FIP.

It is ironic that the COVID 19 pandemic has solved this problem. Gilead has developed remdesivir (GS-5734) for the treatment of human coronavirus disease. The drug received a temporary TGA marketing authorization in June 2020 for the treatment of SARS-Cov-2 infections in human patients. This process would normally take several years, but COVID accelerated it. Remdesivir is essentially GS-441524 with the addition of several additional phosphate groups to improve intracellular penetration (Figure 1B). Because remdesivir is an approved human drug, it can also be used off-label in veterinary practice, such as the treatment of FIP in cats. This circumvented problems with the use of an unlicensed medicine purchased on the black market and related problems with unproven efficacy, purity and consistency.

Figure 2. Dry FIP with pyogranulomatous inflammation of the intra-abdominal lymph nodes. Instead of exploratory laparotomy, lymph node biopsy, histology and immunohistology, it could be more cost-effective to try a 3-day intravenous Remdesivir treatment.

BOVA Aus was able to provide a reliable source of remdesivir. Studies in Australia have determined shelf life and confirmed in vitro efficacy against coronaviruses. We have been using it in clinical practice for the treatment of FIP for the last 6 weeks. Some of these cases were newly diagnosed cats, while others were cats that had already improved with GS-441524 obtained from the black market, which subsequently became unavailable. Several cases of wet and dry FIP have been treated. Even with the small number of cats, remdesivir appears to be very effective in treating FIP infections. Its subcutaneous administration is slightly easier compared to GS-441524, and it appears to be slightly less painful. It is supplied in a 100 mg vial, which is diluted with 9 ml of sterile water for injections to give a solution with a concentration of 10 mg / ml (10 ml vial after dilution).

In newly diagnosed cats with severe disease, we opted for the intravenous administration of remdesivir at a high starting dose (10 mg / kg dissolved in 10 ml saline and administered over 10 minutes) during the first 3 days of treatment, thus achieving a rapid onset of antiviral activity; The clinical signs of cats improved significantly during the initial therapy within 2-3 days. Cats then switch to subcutaneous treatment, usually at a lower dose. For common cases of FIP, we used 5-6 mg / kg once daily (SIUD) because remdesivir is thought to be approximately as effective as GS-441524 (Niels Pedersen, personal communication). In case of overt eye disease, a dose of 8 mg / kg SID is recommended and cats with neurological FIP with CNS symptoms are given 10 mg / kg SID. Treatment is then continued by daily subcutaneous injections for another 2-3 months. In cats for which SC injections were painful, we used gabapentin and / or buprenorphine for sedation / analgesia, and in some cases we introduced a new cephalic catheter every 5 days, which allowed the owners intravenous administration. In situations where owners could not afford the entire treatment, or when the injections were too painful, we used mefloquine (62.5 mg 2-3 times a week; obtained from BOVA or a local pharmacy) for initial work-based antiviral treatment after initial treatment with Remdesivir. Jacqui Norrisa and colleagues from the University of Sydney.

Figure 3. Which cat has FIP and is being treated with remdesivir?

The main advantage of FIP Remdesivir treatment is that the active substance we use is present in an approved medicine for human use. It is just a matter of writing a prescription with the name and address of the client, the name of the patient and the dose to be administered. BOVA can usually prepare and deliver vials to any veterinarian in Australia within 24-48 hours. At present, the cost per 100mg vial is $ 250 plus GST and postage, although it is possible that the price will decrease over time due to larger orders. We believe that most owners will feel much better if they get the product from a well-known Australian company than to send money abroad and hope that black market drugs will get safely from China to Australia.

Veterinarians who want to know more about this treatment option or have general questions about FIP can contact me by email (richard.malik@sydney.edu.au). The diagnosis of FIP is beyond the scope of this newsletter, but effusive cats are most easily diagnosed by cytology and effusion analysis, followed by immunohistochemistry at VPDS, University of Sydney (easily arranged via Vetnostics, QML, ASAP, VetPath, Gribbles or IDEXX). Dry FIP is more problematic because it usually requires an accurate aspiration biopsy of pyogranulomatous lesions in the liver, kidneys, or abdominal lymph nodes. We found that 3 days of intravenous Remdesivir therapy could be used as a cost-effective therapeutic test in cats with dry FIP as an alternative to biopsy of intra-abdominal structures in exploratory laparotomy, as FIP cases rapidly improve most clinical symptoms. If veterinarians do not want to start treatment with Remdesivir themselves, we can recommend veterinarians interested in FIP treatment who would like to accept such cases.

Resources

Kim, Y .; Liu, H .; Galasiti Kankanamalage, AC; Weerasekara, S .; Hua, DH; Groutas, WC; Chang, KO; Pedersen, NC Reversal of the progression of fatal coronavirus infection in cats by a broad-spectrum coronavirus protease inhibitor. PLoS Pathog. 2016, 12, e1005531.

Pedersen, NC; Kim, Y .; Liu, H .; Galasiti Kankanamalage, AC; Eckstrand, C .; Groutas, WC; Bannasch, M .; Meadows, JM; Chang, KO Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. J. Feline Med. Surg. 2018, 20, 378–392.

Murphy, BG; Perron, M .; Murakami, E .; Bauer, K .; Park, Y .; Eckstrand, C .; Liepnieks, M .; Pedersen, NC 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 .; Montgomery, E .; Murakami, E .; Liepnieks, M .; Liu, H. 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

Dickinson PJ, Bannasch M, Thomasy SM, et al. Antiviral treatment using the adenosine nucleoside analogue GS-441524 in cats with clinically diagnosed neurological feline infectious peritonitis. Journal of Veterinary Internal Medicine. 2020. doi: 10.1111 / jvim.15780.

McDonagh, P .; Sheehy, PA; Norris, JM Identification and characterization of small molecule inhibitors of feline coronavirus replication. Vet. Microbiol. 2014, 174, 438–447. Read "FIP remdesivirus treatment"

Thanks to COVID, veterinarians can now legally treat FIP in cats

Original article published on walkervillevet.com.au, 24.11.2020.

The nightmare is almost over. Until recently, there was a diagnosis infectious peritonitis in cats death sentence. Either a slow, persistent decline, or a decision to euthanize and end suffering. This happened to about 1% cats, mostly still kittens.

It was later found that certain antiviral drugs they can not only improve the symptoms, but can even lead to cure. But there was still a problem.

These antivirals were not licensed in Australia and therefore their import and use were illegal. The only cats that survived were therefore those whose owners and veterinarians were willing to take risks. My own veterinary association despite evidence of treatment effectiveness strongly warned against using them.

All the problems are over today.

Remdesivir: A new hope for the FIP

You must have heard of remdesivir. It was promptly approved by the TGA and the FDA due to promising results in the treatment of COVID-19. Importantly for remdesivire is that it is almost identical to black market drugs such as GS-441524.

It is now freely available with a valid prescription and meets all the strict criteria we expect from licensed drugs. Veterinarians still need to warn you that this is an off-label treatment, but it is the same as other cases where we use a human drug for treatment (which is often the case!).

Preliminary testing in Sydney has yielded excellent results. So now we have a cure for everyone. I estimate that fewer than 5% cats with FIP are currently undergoing treatment. Now all cat owners are offered a chance for treatment and most will seize it, although the cost problem still exists.

The cost of using remdesivir in cats

As you can imagine, it is an expensive medicine. I estimate that the 80-day treatment will cost around $ 4,800.

Is a however, this is very similar to the prices people currently pay for GS-441524 from the black market with unproven purity or efficiency. This time, if the cat is insured, it is likely that the treatment will even be covered by the insurance company.

Based on our previous observations, 84-day treatment should cure most affected cats. It is given as a subcutaneous injection once a day, but don't be put off. Everyone can do it and we will be happy to show you how.

Advice on the use of remdesivir for veterinarians

Australian veterinarians reading this article can contact me about a document that contains the recommended dosage, protocols based on the symptoms of the disease and how to obtain the drug itself. See the comments section below for some dosing notes. (translator's note - click on the link leading to the original article).

We are all committed to the work of Dr. Richard Malik DVSc PhD FACVSc FASM and the Feline Diseases Research Team at my alma mater The University Of Sydney.

We also thank the volunteer groups that helped many cats regain their health by taking risks. Their work is complete and we are grateful.

Andrew Spanner BVSc (Hons) MVetStud, a veterinarian in Adelaide, Australia. These blogs come from a series of regularly published e-mails and  Twitter.
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History of FIP research

Original article: History of FIP research; 19.10.2010; Translation 1.2.2021

Probably the oldest recorded case of FIP (Utrecht State Veterinary School, 1912/13); retrospective diagnosis is likely from the description of chronic exudative peritonitis, dyspnoea (pleurisy?), fever and eye symptoms. (Jacob, 1914).

The sudden occurrence of FIP in the late 1950s has been documented in long-term and thorough autopsy records at the hospital. Angell Memorial Animal Hospital in Boston. Therefore, the existence of FIP as a major disease before this time is questionable. The mention of a cat with a disease reminiscent of the FIP was published half a century earlier (1914 Jakob-Groot and Horzinek), but whether it was really the FIP is uncertain given the absence of reports of a similar disease in the following decades. The incidence of the disease has steadily increased since the 1960s and is currently one of the leading infectious causes of death in young cats from shelters and kennels. The reason for the sudden onset of FIP is unknown, but there are at least three possible explanations. First, coronaviruses may have specialized in cats over the last half century. Remarkably, FIP emerged ten years after the first mentions of porcine gastroenteritis (TGE) in North America. The causative FIP virus is closely related to porcine TGE virus and CCV (Canine Corona Virus), although they are still genetically distinguishable. However, recombinants are known to occur between these three viruses. At least one CCV strain can cause mild enteritis in cats and exacerbate subsequent FIPV infection, suggesting a strong resemblance to feline coronaviruses. Therefore, in this scenario, CCV may be a more likely precursor to FECV. Recombinant events are favored by the ease with which transcription units (RNAs) can be gained or lost during the divergent development of coronaviruses. Second, the FIP mutation may be selective for the FECV variant that emerged in the 1950s. This variant could also arise due to intraspecific and interspecific mutability of coronaviruses in general, and in this case FCoV in particular. The third explanation may include changes in the understanding of cats as pets and their breeding in this modern age. After World War II, there was a dramatic shift when cats began to behave like pets. The numbers of domestic cats have increased significantly, the breeding of purebred animals and cat breeding has become more popular, and more and more cats, especially kittens, have found themselves in shelters. These large, multi-cat enclosures are known to be a breeding ground for feline enteric coronavirus (FECV) and FIP infection. Interestingly, feline leukemia virus infection also spread among domestic cats during this period. FeLV infection was an important cofactor for FIP until it was pushed back into the wild in the 1970s and 1980s by testing, elimination / isolation, and possible vaccination.

Genetic relationships between different genotypes of feline and canine coronaviruses (FCoV and CCoV). Feline sequences are colored blue, canine sequences are colored orange, and porcine sequences are colored purple. Arrows indicate predicted recombination sites. Genes encoding polymerase polyprotein (Pol), structural peak (S), envelope (E), membrane (M) and nucleocapsid (N) proteins are indicated. Genes encoding helper proteins are indicated by numbers.

Sources:

Read FIP History
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