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

Abstract

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.

Figure 1

Demographics of cats enrolled in the trial. (a–c) Pie charts summarizing the percentage of patients: by (a) age in months, (b) breed or (c) origin. (d) A bar graph showing the feline infectious peritonitis (FIP) forms of the enrolled patients. M = months; DSH = domestic shorthair; DLH = domestic longhair; MD = Maryland; OH = Ohio; Tx = Texas; FL = Florida; IL = Illinois; CT = Connecticut; CA = California

Figure 2

The time scale for treatment and clinical outcome of 20 cats entered into a field trial of GC376 protease inhibitor. Periods during which cats were treated are identified by solid lines. The date of the last day of treatment for the six cats that achieved a sustained clinical remission is indicated. Cat 21 was still on treatment at the time of writing. The remaining 13 cats succumbed to non-neurologic (FIP) or neurologic FIP (neuro-FIP) after being off primary or secondary treatments for 0–7 weeks

Figure 3

Appearance of the eyes of cat CT08 before starting treatment (a) and 1 week later (b). This cat developed severe neurologic signs 3 weeks after starting treatment

Figure 4

Antiviral treatment and body weight changes. (a) Cat CT04, a 6.8-year-old castrated male that presented with dry feline infectious peritonitis (FIP), received four rounds of antiviral treatment of increasing duration and as indicated by the dotted boxes. It lost weight preceding each relapse and gained increasingly more weight after subsequent treatment. (b) Weight gains of four kittens of 3.5–4.4 months of age during and following antiviral treatment are depicted by dots. A dotted box indicates the duration of antiviral treatment (12 weeks)

Figure 5

Mean and SD of absolute lymphocyte counts for treated patients with (a) wet or (b) dry feline infectious peritonitis (FIP). (a) Twelve cats (open circle) that presented with the abdominal or thoracic effusion and followed for up to 12 weeks. A thirteenth cat (CT16, closed circle) with abdominal effusion responded poorly to treatment. (b) Seven cats that presented with the dry or dry-to-wet forms of FIP and followed for up to 6 weeks of treatment

Figure 6

Mean and SD of total plasma protein levels among 20 cats over a 12 week period. Thirteen cats suffered fatal relapses at various weeks during treatment (W) and seven cats went into a sustained remission after 12 weeks of treatment (W-SV)

Figure 7

Relative baseline feline infectious peritonitis virus (FIPV) RNA levels in effusion samples from the enrolled patients prior to antiviral treatment. Quantitative real-time PCR was performed on the pretreatment effusion samples of the enrolled patients. The relative baseline viral RNA levels as fold differences compared with the pretreatment viral level of CT02, the cat with the lowest levels of RNA. The level of RNA transcripts was calculated for each patient using the ∆Ct method with a beta-actin reference gene

Figure 8

Reduction in feline infectious peritonitis virus RNA from sequential effusion samples during GC376 treatment of cats CT10, CT12, CT15, CT16, CT17, CT18 and CT23. Each point indicates the fold reduction of viral RNA level over that measured prior to treatment (day 0). Virus RNA levels were determined using quantitative real-time PCR by the ∆Ct method and a beta-actin reference gene

Figure 9

Section from the greatly thickened wall of resected colon from cat CT03. Immunoperoxidase (brown color) staining for feline infectious peritonitis virus antigen is seen in macrophages around the periphery of a granulomatous lesion. Virus persistence in the colon occurred in the presence of treatment and regression of other signs of disease (eg, effusive peritonitis)

Figure 10

A focal area of permanent hair loss caused by inadvertent deposition of GC376 in the epidermis of cat CT21. These areas were usually covered by hair and not outwardly visible

Figure 11

The adult dentition of cat CT17, which was treated for 12 weeks with GC376 starting at 4.4 months of age. There is retention of the upper left deciduous canine. The upper second and third premolars appear to be deciduous. Small permanent third premolars have partially erupted lingual to the deciduous third upper premolars. The gingiva surrounding the retained canine and premolars is inflamed. The adult canines also appear smaller than normal. The permanent right canine and fourth upper premolars appear to have erupted normally

Figure 12

Photomicrographs of a lesion in the brain of cat CT08. This cat developed severe neurologic disease while on initial GC376 treatment. (a) The fourth ventricle contains proteinaceous fluid admixed with numerous neutrophils and macrophages that multifocally extend into the surrounding rarefied neuropil. Large cuffs of lymphocytes and plasma cells surround blood vessels (*) (hematoxylin stain, × 20 magnification). (b) Multiple cells resembling peritoneal macrophages (outlined by the small rectange in box in Figure 4a) demonstrate positive immunoreactivity for feline infectious peritonitis antigen (hematoxylin counterstain, × 600 magnification)