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      Antiviral treatment using the adenosine nucleoside analogue GS‐441524 in cats with clinically diagnosed neurological feline infectious peritonitis

      case-report

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          Abstract

          Feline infectious peritonitis (FIP) is caused by a mutant biotype of the feline enteric coronavirus. The resulting FIP virus (FIPV) commonly causes central nervous system (CNS) and ocular pathology in cases of noneffusive disease. Over 95% of cats with FIP will succumb to disease in days to months after diagnosis despite a variety of historically used treatments. Recently developed antiviral drugs have shown promise in treatment of nonneurological FIP, but data from neurological FIP cases are limited. Four cases of naturally occurring FIP with CNS involvement were treated with the antiviral nucleoside analogue GS‐441524 (5‐10 mg/kg) for at least 12 weeks. Cats were monitored serially with physical, neurologic, and ophthalmic examinations. One cat had serial magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis (including feline coronavirus [FCoV]) titers and FCoV reverse transcriptase [RT]‐PCR) and serial ocular imaging using Fourier‐domain optical coherence tomography (FD‐OCT) and in vivo confocal microscopy (IVCM). All cats had a positive response to treatment. Three cats are alive off treatment (528, 516, and 354 days after treatment initiation) with normal physical and neurologic examinations. One cat was euthanized 216 days after treatment initiation following relapses after primary and secondary treatment. In 1 case, resolution of disease was defined based on normalization of MRI and CSF findings and resolution of cranial and caudal segment disease with ocular imaging. Treatment with GS‐441524 shows clinical efficacy and may result in clearance and long‐term resolution of neurological FIP. Dosages required for CNS disease may be higher than those used for nonneurological FIP.

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          Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis

          Objectives The safety and efficacy of the 3C-like protease inhibitor GC376 was tested on a cohort of client-owned cats with various forms of feline infectious peritonitis (FIP). Methods Twenty cats from 3.3–82 months of age (mean 10.4 months) with various forms of FIP were accepted into a field trial. Fourteen cats presented with wet or dry-to-wet FIP and six cats presented with dry FIP. GC376 was administered subcutaneously every 12 h at a dose of 15 mg/kg. Cats with neurologic signs were excluded from the study. Results Nineteen of 20 cats treated with GC376 regained outward health within 2 weeks of initial treatment. However, disease signs recurred 1–7 weeks after primary treatment and relapses and new cases were ultimately treated for a minimum of 12 weeks. Relapses no longer responsive to treatment occurred in 13 of these 19 cats within 1–7 weeks of initial or repeat treatment(s). Severe neurologic disease occurred in 8/13 cats that failed treatment and five cats had recurrences of abdominal lesions. At the time of writing, seven cats were in disease remission. Five kittens aged 3.3–4.4 months with wet FIP were treated for 12 weeks and have been in disease remission after stopping treatment and at the time of writing for 5–14 months (mean 11.2 months). A sixth kitten was in remission for 10 weeks after 12 weeks of treatment, relapsed and is responding to a second round of GC376. The seventh was a 6.8-year-old cat with only mesenteric lymph node involvement that went into remission after three relapses that required progressively longer repeat treatments over a 10 month period. Side effects of treatment included transient stinging upon injection and occasional foci of subcutaneous fibrosis and hair loss. There was retarded development and abnormal eruption of permanent teeth in cats treated before 16–18 weeks of age. Conclusions and relevance GC376 showed promise in treating cats with certain presentations of FIP and has opened the door to targeted antiviral drug therapy.
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            Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis

            Objectives The aim of this study was to determine the safety and efficacy of the nucleoside analog GS-441524 for cats suffering from various forms of naturally acquired feline infectious peritonitis (FIP). Methods Cats ranged from 3.4–73 months of age (mean 13.6 months); 26 had effusive or dry-to-effusive FIP and five had non-effusive disease. Cats with severe neurological and ocular FIP were not recruited. The group was started on GS-441524 at a dosage of 2.0 mg/kg SC q24h for at least 12 weeks and increased when indicated to 4.0 mg/kg SC q24h. Results Four of the 31 cats that presented with severe disease died or were euthanized within 2–5 days and a fifth cat after 26 days. The 26 remaining cats completed the planned 12 weeks or more of treatment. Eighteen of these 26 cats remain healthy at the time of publication (OnlineFirst, February 2019) after one round of treatment, while eight others suffered disease relapses within 3–84 days. Six of the relapses were non-neurological and two neurological. Three of the eight relapsing cats were treated again at the same dosage, while five cats had the dosage increased from 2.0 to 4.0 mg/kg q24h. The five cats treated a second time at the higher dosage, including one with neurological disease, responded well and also remain healthy at the time of publication. However, one of the three cats re-treated at the original lower dosage relapsed with neurological disease and was euthanized, while the two remaining cats responded favorably but relapsed a second time. These two cats were successfully treated a third time at the higher dosage, producing 25 long-time survivors. One of the 25 successfully treated cats was subsequently euthanized due to presumably unrelated heart disease, while 24 remain healthy. Conclusions and relevance GS-441524 was shown to be a safe and effective treatment for FIP. The optimum dosage was found to be 4.0 mg/kg SC q24h for at least 12 weeks.
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              The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies

              Highlights • GS-441524 inhibited replication of serotype II FIP virus (FIPV) in CRFK cell cultures at an EC50 of approximately 1 uM and no toxicity at 100 uM. • GS-441524 inhibited wildtype FIPV replication in macrophage cultures from ascitic fluid of two cats with naturally occurring FIP. • GS-441525 is triphosphorylated by CRFK cells in vitro and PBMC in vivo. • Pharmacokinetic studies in laboratory cats demonstrated effective blood levels over 24 h after a single dose of 5 mg/kg SC or IV. • Severe experimental effusive FIP was successfully treated with 2 or 5 mg/kg GS-441524 SC q24 h for two weeks.
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                Author and article information

                Contributors
                pjdickinson@ucdavis.edu
                Journal
                J Vet Intern Med
                J. Vet. Intern. Med
                10.1111/(ISSN)1939-1676
                JVIM
                Journal of Veterinary Internal Medicine
                John Wiley & Sons, Inc. (Hoboken, USA )
                0891-6640
                1939-1676
                22 May 2020
                July 2020
                : 34
                : 4 ( doiID: 10.1111/jvim.v34.4 )
                : 1587-1593
                Affiliations
                [ 1 ] Department of Surgical and Radiological Sciences School of Veterinary Medicine Davis California USA
                [ 2 ] Veterinary Medical Teaching Hospital, School of Veterinary Medicine Davis California USA
                [ 3 ] Department of Ophthalmology and Vision Science University of California‐Davis Davis California USA
                [ 4 ] Department of Pathology, Microbiology and Immunology School of Veterinary Medicine Davis California USA
                [ 5 ] Center for Companion Animal Health School of Veterinary Medicine Davis California USA
                Author notes
                [*] [* ] Correspondence

                Peter J. Dickinson, Department of Surgical and Radiological Sciences, University of California‐Davis, School of Veterinary Medicine, Davis, CA 95616.

                Email: pjdickinson@ 123456ucdavis.edu

                Author information
                https://orcid.org/0000-0002-0037-2619
                Article
                JVIM15780
                10.1111/jvim.15780
                7379040
                32441826
                9e0122bf-b391-4e72-a8ee-b6ad2e58ee5f
                © 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 20 December 2019
                : 24 March 2020
                : 26 March 2020
                Page count
                Figures: 3, Tables: 0, Pages: 7, Words: 3810
                Funding
                Funded by: Center for Companion Animal Health (CCAH), University of California, Davis School of Veterinary Medicine
                Funded by: SOCK FIP
                Categories
                Case Report
                SMALL ANIMAL
                Case Reports
                Infectious Disease
                Custom metadata
                2.0
                July 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:24.07.2020

                Veterinary medicine
                antiviral,cat,corona virus,ophthalmology
                Veterinary medicine
                antiviral, cat, corona virus, ophthalmology

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