Original article: An update on treatment of FIP in the UK (1.2.2022)

dr. Sam Taylor BVetMed(Hons) CertSAM DipECVIM-CA MANZCVS FRCVS Prof. Séverine Tasker BVSc BSc DSAM PhD DipECVIM-CA FHEA FRCVS, Prof. Danielle Gunn-Moore BSc(Hon), BVM&S, PhD, MANZCVS, FHEA, FRSB, FRCVS Dr. Emi Barker BSc BVSc PhD PGCertTLHE DipECVIM-CA MRCVS, Dr. Stephanie Sorrell BVetMed(Hons) MANZCVS DipECVIM-CA MRCVS

Given the current situation, Sam Taylor, Séverine Tasker, Danièlle Gunn-Moore, Emi Barker and Stephanie Sorrell discuss treatment protocols to help doctors manage this viral disease.

Introduction

In August 2021, remdesivir (Figure 1) became legally available to UK vets to treat FIP in cats. Since then, many cats and kittens have been and are still being successfully treated. As with any new product, protocol modifications are adopted with experience, and in light of the recent release (November 2021) of oral GS-441524 (50 mg tablets) from a specialist UK manufacturer (Figure 2), this article has been drafted to support general practitioners in the use of remdesivir and GS-441524 in the treatment of FIP. It should be kept in mind that treatment may need to be tailored to the individual cat based on the client's response, compatibility and financial capabilities. The specific protocols below may help veterinarians and their clients, but will not be appropriate for all cases.

Treatment protocols (updated November 2021)

The dosage of the drugs has been increased compared to previous recommendations based on the experience of our Australian colleagues, who have treated more than 600 cats so far. Although some cats responded to previously recommended lower doses, they found that relapse was possible at or near the end of the 84-day (12-week) treatment period, leading to the need to extend treatment with a higher daily dosage. This was ultimately more expensive than starting treatment at a higher dosage.

With the use of remdesivir and/or GS-441524, treatment options are now available including a 12-week course of injectable remdesivir, switching from injectable remdesivir to oral GS-441524, or an exclusively oral GS-441524 protocol.

Suggested dosing, benefits, and limitations of each protocol are listed below. Remdesivir cannot be taken orally. The recommended dosage of drugs (Table 1) depends on the clinical picture - ie whether there is an effusion or not and whether there is eye and/or neurological involvement - this is due to differences in drug penetration into tissues. In case of doubt, it is more appropriate to use a higher dosage.

Please note that these dosages of oral GS-441524 are higher than reported in some publications - this is because these publications used so-called black market preparations of GS-441524 in which the amount of active ingredient administered to cats was not confirmed. The dosages given in this article are based on experience using an oral formulation of known GS-441524 that is legally available in the UK and Australia. Therefore, extrapolation cannot be used for other oral preparations for which the active ingredient and/or its concentration is not known or is not indicated by the manufacturer.

Combined injection and oral treatment protocols

The decision when to switch from injectable remdesivir to oral GS-441524 may depend on tolerability of injections (or oral tablets), differences in product cost (including cost of needles, syringes, sharps disposal, losses), owner preference, and finances.

Experience suggests that this transition may occur between days 7 and 14 after initiation of intravenous or subcutaneous remdesivir therapy. The change can be made directly; remdesivir is given for one day and GS tablets are started the next day.

The protocol chosen depends on the severity of the FIP disease in the cat. Dosage is shown in Table 1.

Serious condition

If the condition is severe (anorexia, dehydration, the cat is usually hospitalized):

• Initial treatment with remdesivir given once daily intravenously (Table 1) for three to four days – ie days 1, 2, 3 and/or 4. This will achieve the loading dose of the drug. Each day, dilute the required dose of remdesivir to a total volume of 10 mL with saline and administer slowly over 20 to 30 minutes by hand or pump.
• Subsequently, administer SC remdesivir once daily at the same dose (Table 1) until days 7 to 14.
• On days 8-15, switch to oral GS-441524 once (or twice) daily (Table 1) and continue until at least day 84.

Table 1: Overview of dosing recommendations for remdesivir and GS-441524

Less serious condition

Regarding a less severe condition (normal hydration, food intake):

• Initial treatment with remdesivir SC 1x a day (Table 1) until the 7th to the 14th day.
• Change to 1x (or 2x if a very high neurological dose is required) daily oral administration of GS-441524 (Table 1) on days 8-15 and continue until at least day 84.

An exclusively oral protocol

In the event that injectable treatment is not tolerated/financially feasible, only the oral GS-441524 treatment protocol is recommended:

• 1x (or 2x if a very high neurological dose is required) daily oral GS-441524 (Table 1) for at least 84 days.

Possible side effects of remdesivir:

Remdesivir appears to be well tolerated. However, the following side effects have been reported:

• Transient local discomfort/stinging on injection (see prevention later).
• Development/worsening of a pleural effusion (not always proteinaceous) during the first 48 hours of treatment, sometimes requiring drainage.
• Cats may be depressed or nauseous for several hours after intravenous administration.
• An increase in the activity of the enzyme alanine aminotransferase has been reported (whether due to the underlying disease of FIP or an adverse effect of the drug is unclear).
• Mild peripheral eosinophilia has been reported.

A note on weighing cats

During treatment, it is very important to weigh cats weekly using an accurate scale - with successful treatment, kittens will gain weight and/or grow, which will require a dose increase to ensure that the dose of antiviral given is still appropriate for the type of FIP being treated.

Options for clients with a limited budget

Please note that ideally, treatment should be administered using the recommended preparations and dosage for as long as possible (up to 84 days) to increase the likelihood of a cure.

Use the options below only when absolutely necessary, as a relapse may occur, which then requires longer treatment, leading to increased costs:

• Administer oral treatment with GS-441524 only for 84 days as above.
• Administer injectable remdesivir or oral GS-441524 for as many days as the owner can tolerate, then switch to oral mefloquine 62.5 mg two to three times weekly (in large cats three times weekly) or 20 mg to 25 mg orally once daily (if possible to change the composition of the tablets - for example, Novalabs) to complete the 84-day treatment protocol; mefloquine is less expensive than remdesivir and GS-441524, but further research is needed to assess its effectiveness in this setting.
• If it is necessary to increase the dose of remdesivir (for example, due to a neurological disease that appears during treatment), but it is not possible to afford it, mefloquine treatment can be added as an adjunctive treatment, because it is cheaper than remdesivir, although it is necessary to assess the effect of this combination further research.
• Feline interferon omega has also been used in the post-remdesivir/GS-441524 treatment period, but further research is needed to assess whether this combination is necessary.

Is the oral treatment given with or without food?

• GS-441524 is administered on an empty stomach (with some water) - food may be administered 30 minutes after administration of the drug.
• Mefloquine is given with food, otherwise vomiting often occurs.

Remember to support clients when giving oral medications, as this can also be challenging for them. Direct clients to the website iCatCare, where you can find information and videos.

How can I help owners with remdesivir SC application?

What can I expect during treatment?

• During the first two to five days, you should see an improvement in behavior, appetite, resolution of pyrexia, and a decrease in abdominal (Figure 3) or pleural fluid if an effusion is present (please note that in some cases pleural fluid may be transient in the first few days worsen - if the cat is at home, advise the owner to measure the resting respiratory rate and respiratory effort) - the effusion usually subsides within two weeks.
• If discharge is still present after two weeks, consider increasing the dosage.
• Serum albumin increases and globulin decreases (that is, normalizes) within one to three weeks, but note that globulins may initially increase when a large volume of effusion is absorbed.
• The resolution of lymphopenia and anemia may take longer, up to 10 weeks.
• Mild peripheral eosinophilia is a common finding and may be a favorable marker for disease resolution, similar to that seen in patients with COVID-19.
• The size of the lymph nodes will decrease within a few weeks.
• If progress is not as expected, consider reassessing the diagnosis (see below) and/or increasing the dosage.

What should be observed during treatment?

• Ideally, serum biochemistry and hematology after two weeks and monthly thereafter.
• For clients on a limited budget, monitor only weight/behavior/effusion/neurological signs/key biochemical abnormalities (for example, measuring only globulin and bilirubin).
• Note that the activity of the enzyme alanine transaminase (ALT) may increase - it is not clear whether this is due to the pathology of FIP or a reaction to the drug, and it is not usually a reason to stop treatment. It is not known whether the addition of hepatoprotective treatment (eg S-adenosyl-L-methionine) helps in these cases.
• Ultrasonography in the outpatient clinic to monitor the resolution of the effusion and/or the size of the lymph nodes.

If I observe a positive response to the treatment, when should I stop the treatment?

• Not earlier than after 84 days (12 weeks).
• Verify the disappearance of previous abnormalities (clinical, sono, biochemical and hematological examination).
• Discontinue treatment only after the cat has been normal (clinically, biochemically and hematologically) for at least two weeks (ideally four weeks).

What should I do if I have no or only a partial response to treatment?

• Make sure the cat actually has FIP - reevaluate the diagnosis, look for other pathologies, consider repeated sampling (eg, external laboratory analysis of any fluid; cytology or lymph node biopsy).
• If biochemical abnormalities (especially hyperglobulinemia and albumin to globulin ratio) remain present after 6 to 8 weeks, increase the dosage as for relapse (see below) by 3 mg/kg to 5 mg/kg daily and continue treatment, not stopping until parameters have normalized for at least 2 weeks, as indicated above under “when to stop treatment?” – This may mean extending treatment beyond 12 weeks.

What should I monitor after treatment?

• Advise the owner to monitor the cat closely for recurrence of the clinical condition - this monitoring should continue for 12 weeks after the end of treatment.
• Ideally, repeat serum biochemistry and hematology two weeks and one month after stopping treatment (to detect any changes that might indicate an early relapse).
• Note that relapse may occur with clinical symptoms but without any significant biochemical/hematological abnormalities.

Relapse

In case of relapse – e.g. recurrence of effusion, pyrexia, development of ocular or neurological symptoms, or return of hyperglobulinemia:

• Make sure the cat has FIP - reassess the diagnosis, consider other pathologies, consider repeat sampling (for example, external laboratory analysis of any fluid, cytology or lymph node biopsy).
• If relapse occurs during treatment, increase the dose of remdesivir or GS-441524 and monitor treatment as before, making sure that treatment is not stopped before the cat has been normal for at least two weeks. The increased dosage depends on the dosage the cat is receiving at the time of the relapse, the nature of the relapse and the financial possibilities, but can be up to the recommended dosage for neurological FIP (see above).
• If relapse occurs after stopping treatment, restart remdesivir or GS-441524 at a higher dose (usually 3 mg/kg to 5 mg/kg daily higher than previously used doses) and continue treatment for an additional 12 weeks. The increased dosage used depends on the dosage the cat was receiving at the time of the relapse and the nature (eg severity and/or development of neurological signs) of the relapse, but may be up to the dosage recommended for neurological FIP (20 mg/kg - see Table 1). It is possible that some cats will respond to a shorter treatment, but ideally relapse treatment is continued for the full 12 weeks after treatment has been completed to prevent relapse.
• If the dose of remdesivir or GS-441524 cannot be increased (for example, the highest neurologic dose of 20 mg/kg is already being used), consider mefloquine as adjunctive therapy (see above) while continuing remdesivir or GS-441524 at the same dose.

Castration and routine measures during the treatment of FIP

• If the cat responds to treatment, neutering should ideally be done one month after the treatment has been completed. However, if leaving the cat unneutered causes significant stress – for example, escape attempts or stress when the mother is in heat – it is advisable to neuter during treatment. If the latter option is required, neutering should ideally be done when the cat is responding well to treatment and has at least two weeks of treatment remaining after neutering (so that the antiviral treatment is given during the potential “stress” of post-neutering).
• There is no contraindication for routine deworming and flea treatment in cats treated with remdesivir or GS-441524.
• No information is available on vaccination of cats treated for FIP. If the cat is well during treatment, it should be vaccinated as usual, as it is still likely that the vaccination will have a protective effect. For cats that have completed the initial round, consider giving a third dose of vaccine after completing FIP treatment (see WSAVA Vaccination Guidelines).
• If veterinary procedures are required, the clinic stay should be minimized and protocols and handling should be implemented according to Cat Friendly Clinicto avoid stressing the cat.

Complementary treatment

• If a cat is receiving prednisolone, it should be discontinued during administration of remdesivir or GS-441524, and then discontinued completely, unless needed for short-term treatment of a specific immune-mediated disease resulting from FIP—for example, hemolytic anemia.
• Supportive therapy such as antiemetics, appetite stimulants, fluid therapy, and analgesics may be given along with remdesivir or GS-442415 as needed.

Possible future updates

We are constantly learning during treatment with these drugs, and recommendations may change over time. Other substances have been tested in cats, such as protease inhibitors (such as GC376) and other nucleoside analogues (such as molpurinavir), but these are not currently commercially available. How these agents and other immunomodulatory agents (such as polyprenyl immunostimulant) will fit into future protocols is currently unknown.

Translator's Note: The original article was published and updated in February 2022, since molnupiravir officially became available for the treatment of COVID-19 in humans, and there is also the possibility of its use in the treatment of FIP.

Acknowledgement

We thank Richard Malik and Sally Coggins for their advice in the preparation of this article.

dr. Richard Malik DVSc MVetClinStud PhD FASM graduated from the University of Sydney in 1981. He is a specialist in small animal internal medicine with a special interest in infectious diseases of dogs and cats. She works at the Center for Veterinary Education and helps organize CPD.

dr. Sally Coggins BVSc (hons I) MANZCVS (Feline Medicine) she graduated from the University of Sydney in 2007 with first class honours. Sally is currently investigating novel antiviral therapeutics for the treatment of feline infectious peritonitis and is conducting clinical trials open to national recruitment.

FIP advisory line

The above experts have come together to launch an email address ‘FIP advice’ (fipadvice@gmail.com) where they volunteer to answer questions about the new treatment and spread the word to vets and veterinary nurses in the UK. They have so far answered over 150 emails on the advice line.