Medicine, Surgery and Wildlife, Marathon Veterinary Hospital, Marathon, FL, USA
Since FIP is in part immune-mediated in pathogenesis, treatment aimed at controlling the immune response has been used, using prednisolone at 2–4 mg/kg/day, with a tapering of dose slowly if the cat responds to treatment. However, there are no controlled studies to prove any beneficial effect of corticosteroids, although they are frequently used.
One uncontrolled study suggested that feline interferon omega (IFN-w) (given with glucocorticoids) treatment could be beneficial in FIP but the diagnosis was not confirmed in those cats that survived,1 and a subsequent randomized placebo-controlled double-blind treatment study in 37 cats with confirmed FIP2 showed no benefit of IFN-w and immunosuppressive levels of glucocorticoids than glucocorticoids alone, although the cases treated were likely very late in the course of disease.
As long ago as 2009, a small study3 described the use of oral polyprenyl immunostimulant (PPI), which upregulates Th-1 cytokines, in the treatment of 3 cases of non-effusive FIP. In two of the cats the FIP diagnosis was based on the finding of pyogranulomatous lymphadenitis on lymph node aspirates whereas the third was confirmed as FIP by positive FCoV antigen immunostaining on histopathology of a lymph node. Two of the three cats remained alive and well on treatment 2 years after diagnosis whilst the third cat survived 14 months but was treated for only 4.5 months. A larger study evaluating oral PPI treatment three times per week in 60 non-effusive FIP cases (16 gastrointestinal, 18 mixed, 11 non-localised, 9 ocular, 5 neurological, 1 with no clinical signs) was recently published;4 this study did not include untreated controls for ethical reasons. In this study the diagnosis of non-effusive FIP was largely made by the attending 1st opinion veterinarian, sometimes with the help of veterinary specialists, but only 13 of the 36 cats that had so-called specialised laboratory testing had FCoV immunostaining performed, although it is recognised that sampling for the diagnosis of non-effusive FIP cases is notoriously difficult. Of the 60 cats, 8 survived for over ~6 months, including 1 cat for 2 years and 1 cat for just over 5 years. During this study, cats could be treated with additional drugs, and it was found that the survival of the cats that were given corticosteroids concurrently with PPI was significantly shorter than those given PPI without corticosteroids. No side effects were reported with PPI treatment. The author recommend that a controlled study is performed to verify PPI’s benefit. PPI is commercially available, although costly.
Recent studies have focused on the use of novel anti-viral agents as treatment. These anti-viral agents have included protease inhibitors, which inhibit proteases that normally process FCoV polyproteins into mature proteins during FCoV replication, and nucleoside analogues, that act as an alternative substrate for RNA synthesis for FCoVs, resulting in RNA chain termination during viral RNA transcription. None of the in vivo studies with protease inhibitors or nucleoside analogues described later have included untreated control cats for ethical reasons.
Protease inhibitor agents, such as 3CLpro inhibitors, have been shown to have activity against FCoV in vitro,5,6 prompting in vivo studies.7 One 3C-like protease inhibitor compound, GC376, showed great promise in an experimental study in young cats with effusive FIP7 where 6 of 8 cats with induced clinical FIP recovered from disease following 2–3 weeks of 5–10 mg/kg BID SQ GC376 treatment. The 6 recovered cats all remained healthy during an observation period of 8 months, although a subsequent publication documented that one of these cats had succumbed to neurological FIP 6 months later.8 It is know that experimentally induced FIP differs markedly from naturally occurring FIP (e.g., experimental infection is usually induced by intraperitoneal inoculation of a laboratory-derived FIP-associated FCoV which results in acute effusive disease in 80–100% of infected cats, rather than naturally occurring FIP which arises following initial enteric FCoV infection in up to 10% of infected cats and can take weeks to develop and manifests in different forms of FIP). Thus it is important to evaluate potential treatments in naturally occurring FIP and GC376 treatment was thus then evaluated in naturally occurring FIP.8
In the study of naturally occurring FIP, 20 cats with effusive or non-effusive FIP8 were recruited. Cats were confirmed as having FIP based on signalment, history, prior test results, clinical examination, repeat of blood and effusion testing and ultrasonography and ophthalmological examinations when necessary. The study describes that the presence of ‘FIP virus’ was confirmed by reverse-transcriptase (RT-)PCR in effusions at admission or at post-mortem examination. But the number of cats on which these diagnostic methods were used was not stipulated and a lack of reference to the use of histopathology or effusion cytology and immunostaining for diagnosis is a possible limitation of the study.
However, the difficulties in obtaining a definitive diagnosis in such a study is acknowledged. The 20 cats with FIP were administered GC376 SQ BID; the dose (15 mg/kg) used was higher than that used in the experimental FIP study7 due to treatment failure occurring after 9 days of treatment in the 1st of the natural cases of FIP treated. The 1st 5 cats in the study were treated for 2 weeks, similar to the experimental study, but due to relapse of clinical signs (typically 1–7 weeks after primary treatment), repeat treatments, and longer treatment courses (of ≥ 12 weeks), were used on cats showing relapses and in newly recruited cases. Of the 20 treated cats in the study, 6 cats (these were mostly young acute effusive FIP cases) showed long-term remission of ≥ 18 months (this duration was stipulated in a subsequently published study9 rather than being in the original paper) following GC376 treatment. Those successfully treated cats had usually had a long course (12 weeks) of GC376 treatment. A sustained remission was not seen in all cats following GC376 treatment and some side effects were reported; injection reactions and abnormal eruption of permanent teeth. The cats that showed relapses of FIP often showed signs of neurological FIP.
A more recent study9 has described treatment using the nucleoside analogue GS-441524 in an experimental study in young cats with effusive FIP. In this study 10 cats that developed effusive FIP were treated with GS441524 SQ SID for 2 weeks and showed a rapid reversal of clinical signs. Two of the 10 treated cats required a 2nd treatment course following a relapse at 4 and 6 weeks post-treatment, respectively, and both improved again. All 10 treated cats remained clinically healthy until the time of publication, at least 8 months post-infection. No signs of toxicity were noted besides a transient “stinging” injection reaction in some cats9 and a treatment dosage of 2 mg/kg SQ SID was recommended for use in future studies.
This GS-441524 treatment has just been evaluated in a field study of 31 cats with FIP10. Cats were confirmed as having FIP based on signalment, history, clinical examination, prior test results, repeat testing and/or effusion analysis, with FCoV RT-PCR performed on effusions when possible. Cat with neurological or ocular signs were discouraged from the trial due to previous concerns of poor penetration of GS-441524 into the brain and/or eye.9 Of the 31 cats with FIP recruited into this study,10 26 had evidence of effusion. Cats ranged from 3.4–73 months of age (mean 13.6 months). The cats were started with a primary treatment course of GS441524 at a dosage of 2 mg/kg SQ SID for ≥ 12 weeks (with>12 weeks of treatment given if serum protein levels remained elevated). The dosage was increased to 4 mg/kg SQ SID for secondary treatments later in the trial for when cats showed a relapse or when a ≥ 12-week treatment course was deemed necessary due to persistence of clinical signs.
Five of the 31 cats died or were euthanized within 26 days of primary treatment. The remaining 26 cats completed ≥ 12 weeks of GS-441524 treatment and showed rapid clinical improvement within 2 weeks. Of these 26 cats, 18 remained healthy, while eight others showed FIP relapses (6 non-neurological and 2 neurological) at a mean of 23 days following treatment. Three of the eight relapsed cats were treated again with GS-441524 at 2 mg/kg SQ SID; one of these three cats relapsed with neurological disease and was euthanized whilst the two remaining cats responded well but relapsed with FIP again and were treated again with GS-441524 but at a higher dosage of 4 mg/kg SQ SID. Of the original 31 cats, 25 long-time survivors that underwent successful treatment were described, but one of these cats was subsequently euthanized due to presumed unrelated heart disease, while 24 remain healthy at the time of publication (published February 2019, and some of the cats had started on the trial spring 2017).
Neither GC376 nor GS-441524 are currently available but both are undergoing approval for commercial sale. However illegal/non-licensed production of these products has been reported in some parts of the world but the lack of biological safety data and information on the purity of such compounds means that their use cannot be recommended.
References are available upon request.