key: cord-1012338-v5cvm6j0
authors: Dickinson, Peter J.; Bannasch, Michael; Thomasy, Sara M.; Murthy, Vishal D.; Vernau, Karen M.; Liepnieks, Molly; Montgomery, Elizabeth; Knickelbein, Kelly E.; Murphy, Brian; Pedersen, Niels C.
title: Antiviral treatment using the adenosine nucleoside analogue GS‐441524 in cats with clinically diagnosed neurological feline infectious peritonitis
date: 2020-05-22
journal: J Vet Intern Med
DOI: 10.1111/jvim.15780
sha: 1ca12f01906147060ed4f004616eec77e8064b48
doc_id: 1012338
cord_uid: v5cvm6j0

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.

A domestic 8-month-old castrated male blue seal point Siamese cat obtained as a kitten from a rescue group was presented with a several-month history of lethargy and decreased appetite and a 1-month history of progressive pelvic limb ataxia that also was noted on neurological examination. The cat weighed 3.0 kg which was 1 kg less than a female sibling. Serum biochemistry abnormalities included an increased total protein concentration (8.9 g/dL; reference interval, 6.3-8.8 g/dL) with an AG ratio of 0.53 (albumin, 3.1 g/dL; reference interval, 2.6-3.9 g/dL; globulin, 5.8 g/dL; reference interval, 3.0-5.9 g/dL). Tests for FeLV and FIV and 

An 18-month-old spayed female domestic shorthair cat, obtained from an animal shelter, presented with a 3-month history of ocular disease, a 3-week progressive history of lethargy and inappetence and a several-day history of progressive pelvic limb paresis. The cat was treated with prednisolone acetate 1% eye drops OU, q6h for 5 days before presentation. On neurological examination, the cat had inappropriate behavior and hypersensitivity to cranial palpation. The cat was nonambulatory paraparetic with decreased pelvic limb reflexes.

Menace response was absent OU with anisocoria (mid-range pupil in the right eye [oculus dexter, OD], mydriasis OS). Pupillary light reflexes were absent OD because of posterior synechiae, and absent OS with direct or indirect illumination. Dazzle reflexes and vision were present OU and the cat appeared to have vision under photopic conditions.

Ophthalmic examination was consistent with uveitis and hyperviscosity syndrome OU. The cat weighed 2.6 kg. Serum biochemistry abnormalities included an increased total protein concentration (11.7 g/dL; reference interval, 6.3-8.8 g/dL) with an AG ratio of 0.2 (albumin, 2.0 g/dL; reference interval, 2.6-3.9 g/dL; globulin, 9.7 g/dL; reference interval, 3.0-5.9 g/dL). Tests for FeLV and FIV were negative, and FCoV antibody titer was positive at 1:6400. Abdominal ultrasound examination showed hepatosplenomegaly, small kidneys with indistinct corticomedullary junctions and enlarged mesenteric lymph nodes.

The cat was treated with 5 mg/kg GS-441524 SC, once daily for 15 weeks. After 1 month of treatment, uveitis was improved but still present, and the cat was ambulatory paraparetic with normal segmental reflexes. The cat weighed 3.3 kg and the AG ratio was 0.55.

After 2 months of treatment, subtle signs of active anterior uveitis were present OD, but there was only moderate improvement in the ambulatory paraparesis. Body weight had increased to 3.7 kg and the AG ratio was 0.67. After 15 weeks of treatment, there was minimal evidence of uveitis OD and improvement in the ambulatory paraparesis that had been static for the preceding 4 weeks. The cat Serum total protein concentration was still increased (8.6 g/dL) with an improved AG ratio of 0.72; lymphopenia and anemia had resolved. Because of the lack of weight gain and continued neurological deficits, the GS-441524 dosage was increased to 8 mg/kg SC, once daily for an additional 10 weeks (14 weeks in total). The cat also was given a 2-week course of prednisolone 1 mg/kg PO q24h. Increased activity and willingness to jump onto elevated surfaces was seen within 24 hours, and 1 week after cessation of GS-441524 treatment, neurological examination was unremarkable and no active ophthalmic disease was detected. Body weight had increased to 3 kg and serum total protein concentration was normal (7.6 g/dL) with an AG ratio of 0.8. Repeat MRI (Figure 1 ) showed minimal meningeal contrast enhancement, but ventriculomegaly had increased.

Repeat CSF RT-PCR for FCoV RNA was negative, and CSF TNCC was decreased from the previous count, but still high at 224/μL. Because of CSF analysis evidence that the infection was still active, GS-441524 dosage was further increased to 10 mg/kg SC, once daily for an additional 5 weeks (19 weeks in total). The cat remained clinically normal with increased activity over this period and body weight increased to 4.7 kg ( Figure 3 ). Immediately after cessation of treatment, neurological and 1, 2, 5, 6 However, preliminary studies suggested that treatment of ocular and CNS forms of FIP may be more difficult because of limited drug access through the blood-ocular and blood-brain barriers. 1, 2, 5, 6 High rates of FIP disease relapse involving the CNS were reported with protease inhibitor-based treatment, 5 whereas more hope was given to GS-441524 treatment of ocular and neurological FIP. The initial field trial of GS-441524 in naturally acquired, nonneurological FIP used doses of 2 mg/kg that appeared to be insufficient for cats that developed neurological signs during the course of treatment. 2 to prevent viral cytopathic effects was reported at 0.8 μM, with complete inhibition of viral replication at 10 μM and partial inhibition at 1 μM. 1 Limited pharmacokinetic studies in cats from the same study showed that concentrations of GS-441524 in CSF were approximately 20% that of plasma, and a 10 mg/kg dose resulted in CSF concentrations of 0.8 to 2.7 μM. These data are consistent with the limited efficacy associated with the 5 mg/kg doses in Cases 3 and 4 and the apparent efficacy associated with dose escalation to 8 to 10 mg/kg in Case 4. Expanded pharmacokinetic studies in healthy and affected cats with intact and compromised blood-brain barrier function will be necessary to further define the optimal dosage of GS-441524 in cats with neurological FIP. Similar to previous reports, 1, 2 adverse events associated with prolonged use of GS-441524 were limited. Local skin reactions and discomfort after SC injection were the only clinically relevant adverse events, but this was a major factor influencing the decision to euthanize Case 3. Although treatment responses were measurable by MRI, CSF analysis, and ocular imaging, the clinical response to treatment when appropriate dosages were used was equally useful, with rapid improvement in mentation, appetite and activity generally observed within 24 to 36 hours. Increased body weight and ability to jump onto elevated objects and surfaces also were seen as consistent indicators of effective treatment. GS-441524 is not available for routine clinical use, but the reported cases suggest that FIP affecting the CNS may be treatable using appropriate antiviral medications. Development of similar antiviral drugs for clinical application should be seen as a priority for this historically fatal disease.

Authors declare no conflict of interest.

Authors declare no off-label use of antimicrobials. 

The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies

Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis

An update on feline infectious peritonitis: diagnostics and therapeutics

A review of feline infectious peritonitis virus infection: 1963-2008

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

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

Authors declare human ethics approval was not needed for this study.

Peter J. Dickinson https://orcid.org/0000-0002-0037-2619