Introductory Philosophy

Feline herpesvirus (FHV-1) is a ubiquitous virus whose strains do not vary greatly in their clinical virulence worldwide. And yet, we see a huge range of clinical signs in cats infected with this virus. There are probably a large number of reasons for this; however, principal among these is likely the host's response to this virus. FHV-1-naïve kittens infected in the first few weeks of life against a backdrop of waning maternal immunity almost inevitably get severe upper respiratory and ocular disease, and experience high morbidity but rare mortality. By contrast, adult cats can undergo viral reactivation, shed virus, and infect in-contact cats; all without demonstrating any clinical signs. Of course, many other disease syndromes are noted along a spectrum between these 2 extremes. With such a wide range of clinical manifestations and with normal animals shedding virus, diagnostic testing is fraught with difficulty and has very low sensitivity and specificity. I no longer conduct laboratory tests for FHV-1 or Chlamydophila felis (the major infectious differential diagnosis) in individual cats with keratoconjunctivitis. Rather, my "diagnostic tests" now are (i) the history and clinical exam findings followed by (ii) response to therapy. This requires acceptance of a couple of critical facts: first I have to be willing to be wrong when making an educated guess regarding the etiological diagnosis, and second, I have to use the absolute best therapeutic trial and demand excellent owner compliance in executing that trial.

Diagnosing Keratoconjunctivitis Using Clinical Signs as Your Guide

Using clinical signs of surface ocular disease as a "diagnostic assay" requires a philosophical approach that I liken to adding pebbles to one of two sides of an old-fashioned scale or balance. I start with the paradigm that feline keratoconjunctivitis is infectious till proven otherwise, and that, by far and away, the most commonly implicated infectious organisms are FHV-1 and Chlamydophila felis. I then consider the clinical signs outlined in the following table. Using each feature as a discerning feature, I aim to place one of my "diagnostic pebbles" on the herpetic or chlamydial sides of the balance, thereby making a clinical judgment at the end of the examination, as to which of these 2 organisms is more likely to be the cause of the disease seen.

Note that both agents cause some of the signs and that it is a weighted assessment. This introduces a notable element of subjectivity into the assessment. I unashamedly tell clients this and explain that I believe that it is better than currently available laboratory tests. I also use this time to introduce the concept that the clients themselves will form the critical next step in the diagnostic process - "response to therapy."

Treatment

If we are to use response to therapy as a "diagnostic test," then we must choose the optimum therapeutic approach possible for each cat. This requires knowledge regarding:

1.  Susceptibility of FHV-1 to each drug

2.  How well tolerated and how safe each drug is in cats

3.  Which tissues are reached following topical or systemic therapy

4.  The owner preferences

Antiviral Drugs in General

Although a large variety of antiviral agents exists for oral or topical treatment of cats infected with FHV-1, some general comments regarding these agents are possible:

 No antiviral agent has been developed for FHV-1; although many have been tested for efficacy against this virus. Agents highly effective against closely-related human herpesviruses are not necessarily or predictably effective against FHV-1 and all should be tested in vitro before they are administered to cats.

 No antiviral agent has been developed for cats; although some have been tested for safety in this species. Agents with a reasonable safety profile in humans are not always or predictably non-toxic when administered to cats and all require safety and efficacy testing in vivo.

 Many antiviral agents require host metabolism before achieving their active form. These agents are not reliably or predictably metabolized by cats and pharmacokinetic studies in cats are required.

 Antiviral agents tend to be more toxic than do antibacterial agents since viruses are obligate intracellular organisms and co-opt or have close analogues of the host's cellular "machinery." This limits many antiviral agents to topical (ophthalmic) rather than systemic use.

 All antiviral agents currently used for cats infected with FHV-1 are virostatic. Therefore, they typically require frequent administration to be effective.

Specific Comments Regarding Common Antiviral Drugs

A number of antiviral agents have been studied to varying degrees for their efficacy against FHV-1, their pharmacokinetics in cats, and/or their safety and efficacy in treating cats infected with FHV-1. The following are my "favourites."

Idoxuridine (IDU) is a nonspecific inhibitor of DNA synthesis, affecting any process requiring thymidine. Therefore, host cells are similarly affected, systemic therapy is not possible, and corneal toxicity can occur. It has been used as an ophthalmic 0.1% solution or 0.5% ointment. This drug is reasonably well tolerated by most cats and seems efficacious in many. It is no longer commercially available in the USA, but can be obtained inexpensively from a compounding pharmacist. It should be applied to the affected eye at least 5–6 times daily.

Famciclovir is a prodrug of penciclovir (PCV); however, metabolism of famciclovir to penciclovir is complex and requires di-deacetylation followed by oxidation to penciclovir by a hepatic aldehyde oxidase. Unfortunately, hepatic aldehyde oxidase activity is nearly absent in cats. This necessitates cautious extrapolation to cats of data generated in other species. Our data to date in normal and experimentally infected cats suggest that the pharmacokinetics of this drug is extremely complex and likely results from nonlinear famciclovir metabolism. Despite this, there is mounting evidence that suggests famciclovir is very effective in some cats with experimentally induced or suspected spontaneous herpetic disease. Further studies of this drug's pharmacokinetics, safety and efficacy are required before dose rates and frequency can be recommended; however, we have recently demonstrated that cats receiving 90 mg famciclovir/kg PO TID and experimentally infected with FHV-1 had marked reduction in disease and viral shedding. In a subsequent study, we were able to show that administration of 40 mg/kg PO TID achieved similar plasma penciclovir concentrations to those achieved with 90 mg/kg PO TID. Finally, we have now published data that show that cats receiving 40 mg/kg famciclovir PO TID achieve penciclovir concentrations in their tears likely to be effective against FHV-1 for about 4 hours following each administration (i.e., for about 12 hours per day).

Cidofovir (CDV) is commercially available only in injectable form in the USA, but has been studied as a 0.5% solution applied topically twice daily to cats experimentally infected with FHV-1. Its use in these cats was associated with reduced viral shedding and clinical disease. Its efficacy at only twice daily (despite being virostatic) is believed to be due to the long tissue half- lives of the metabolites of this drug. There are occasional reports of its experimental topical use in humans or rabbits being associated with stenosis of the nasolacrimal drainage system components and, as yet, it is not commercially available as an ophthalmic agent in humans.

Lysine administration has not been studied in client-owned cats with herpetic disease and there are no published data on dose, frequency of administration, course of therapy, or timing of lysine administration relative to spontaneous disease episodes. However, there have been a number of studies of lysine in experimental models of the disease. I currently recommend 500 mg lysine PO BID therapeutically at the time of recrudescent disease and encourage owners of cats that have frequent recurrences to administer this same dose over the long term as a prophylactic measure. Based on recent experimental studies in which diets were supplemented with lysine, I strongly recommend that client-owned animals receive lysine as a twice daily bolus; not sprinkled on food. Unlike the protocol for HSV-1-infected humans, owners of cats receiving L-lysine for FHV-1 should not be advised to restrict their cat's arginine intake. There is no evidence to support the use of lysine in shelters; in fact some studies suggest a worsening of disease in cats receiving dietary lysine supplementation.