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Evaluating treatments for feline herpesvirus type 1

Thomasy SM, Maggs DJ.  A review of antiviral drugs and other compounds with activity against feline herpesvirus type 1. Vet Ophthalmol 2016;19(S1):119-30.

Many cats are infected with feline herpesvirus type 1 (FHV-1); as with all herpesviruses, once an individual is infected, the virus often becomes latent but can never be eliminated from the body. FHV-1 is a common cause of ocular surface disease, dermatitis, respiratory disease, and potentially intraocular disease in felines.  Chronic-active infection with FHV-1 in cats is a source of frustration for owners and veterinarians alike, as it is common, may recur frequently in an individual, often appears uncomfortable or actually painful for the patient, and cannot be cured.

A number of antiviral therapies have been tried in feline patients with FHV-1.  Several decades ago a study reported that almost half of cats treated with the topical antiviral drugs trifluridine, idoxuridine, or vidarabine did not improve or actually worsened.  The most effective antiviral therapies for this infection target viral proteins responsible for DNA synthesis; however, not all potentially effective antiviral medications are safe for use in cats, even if they demonstrate safety in other species such as humans infected with herpes simplex type 1 (HSV-1), a herpesvirus very closely related to FHV-1.  The safety of a potentially effective antiviral drug is directly related to how specifically the drug targets viral DNA only.

As FHV-1 is an obligate intracellular organism which replicates within the cell nuclei of the host, antiviral agents effective against FHV-1 are likely to be toxic enough to permit topical application only, and as topicals may still trigger significant corneoconjunctival cytotoxicity.  Whether topical or systemic, these agents must be administered frequently, as all are virostatic rather than virucidal. Herewith is a list of antiviral medications that have been tried in cats with FHV-1:

a) Idoxuridine can be used topically only; it is a thymidine analogue and as such it will inhibit DNA synthesis in host cells as well as in the virus. As a topical, idoxuridine may also cause corneal toxicity. At this time it is only available from compounding pharmacies as an ointment or ophthalmic solution and must be administered every 4-6 hours.

b) Vidarabine, an adenosine analogue, is also nonselective in its effects and is considered to be toxic when administered systemically.  It is available as a 3% ophthalmic ointment applied every 4-6 hours and may be effective in patients whose disease does not respond to idoxuridine, and also better tolerated than antiviral solutions, including idoxuridine.

c) Trifluridine, a fluorinated nucleoside analogue of thymidine, is also too toxic for systemic administration.  Although it is quite effective in treating HSV-1 keratitis in humans, it often is associated with marked ocular irritation in cats.

d) Cidofovir, a cytosine analogue, is not commercially available as a topical ophthalmic agent, but has good safety data in people.  In one study of cats experimentally infected with FHV-1, a 0.5% cidofovir ophthalmic solution applied twice daily reduced viral shedding and clinical disease.  Nasolacrimal stenosis has been reported in humans using the drug, and cats receiving topical cidofovir should be monitored for this.

e) Acyclovir, a purine analogue requiring 3 phosphorlyation steps for activation, is not as efficiently phosphorylated by FHV-1 than HSV-1, so it is not very efficacious against FHV-1, and therefore systemic administration of this drug to cats is not recommended , especially because it can cause myelosuppression.  Topical application of the drug does not appear to be as toxic but it must be applied to the cat’s eye(s) at least five times daily to be effective.

f) Valacyclovir is a prodrug designed to increase the availability of acyclovir. A study of cats experimentally infected with FHV-1 and treated with this drug showed that it induced hepatic and renal necrosis as well as myelosuppression, and was not effective in ameliorating the severity of clinical disease.  This drug should never be used in cats.

g) Ganciclovir and its prodrug, valganciclovir, have not been well studied in cats; anecdotal reports of topical use of ganciclovir in cats in Europe sound promising, and it also has better in vitro efficacy against FHV-1 than acyclovir. Systemic use of ganciclovir in people is associated with significant toxicity.

h) Penciclovir is a deoxyguanosine analogue with a similar mechanism of action to acyclovir.  It has high in vitro and in vivo efficacy against FHV-1.  No commercial or compounded topical ophthalmic preparations of this drug are available.

i) Famciclovir is a highly bioavailable prodrug of penciclovir.  Famciclovir and its metabolites, BRL 42359 and penciclovir, appear to be systemically safe in cats, but the complex pharmokinetics of the drug have made it difficult to determine an optimum dose in cats.  After evaluating a number of pharmacokinetic studies, the authors suggest a dose of 90 mg/kg famciclovir orally twice daily as likely to be effective in treating cats with FHV-1.  Famciclovir is much safer for systemic use in cats than acyclovir or valacyclovir; nonetheless, feline patients receiving famciclovir should be monitored closely.  Animals with known concurrent disease and those expected to receive famciclovir for long periods of time should be monitored clincopathologically with a serum biochemistry panel, complete blood count, and urinanalysis.  Dose frequency but not dose magnitude, should be reduced in cats with renal insufficiency, just as in humans.

The authors recommend that famciclovir be used in conjunction with a mucomimetic agent such as hyaluronate, as this drug only partially mitigates the loss of conjunctival goblet cell density that is caused by FHV-1.

j) Foscarnet (phosphonoformate) is not recommended for cats due to its very low bioavailability in this species and poor in vitro activity against FHV-1.

Other compounds that have been evaluated for activity against FHV-1 are as follows:

a) Lysine has been widely used in cats with FHV-1 based on human HSV-1 in vitro data and clinical trials. Its use is controversial.  The authors’ analysis of laboratory and clinical studies on the use of lysine in FHV-1 lead them to conclude that use of this supplement is safe when orally administered to cats.  If administered as a bolus, which is potentially stressful to shelter cats, lysine may reduce viral shedding in latently infected cats and clinical signs in cats primarily exposed to the virus.  Data do not support dietary supplementation in any cats.  With regard to client-owned pet cats with recurrent chronic-active FHV-1, the group in which lysine is most commonly used, no clinical trials have been conducted.

b) Interferons, which occur in four types (alpha, beta, gamma, omega) and many subtypes, are cytokines with a variety of immunological and antiviral functions.  They can limit viral spreading to cells adjacent to a virally infected cell that has secreted interferons into the extracellular space which surrounds it. A review by the authors of multiple studies involving the use of interferons in FHV-1 infection led them to conclude that there is no strong support for their use in the management of feline herpetic disease.

c) Lambda-carrageenan, a seaweed extract, is well tolerated as a topical but did not reduce clinical signs of FHV-1 in a small, single study.

d) Leflunomide, an immunosuppressive agent, has demonstrated in vitro efficacy against FHV-1, but also some cytotoxicity.  No clinical studies have been performed.

e) Lactoferrin, an iron-binding glycoprotein with broad spectrum antipathogenic properties, has potent in vitro antiviral activity against FHV-1, but clinical studies are lacking.

f) Small interfering RNAs (siRNAs) are designed to transfect a cell and reduce expression of specific genes. Intracellular delivery of these agents in vivo, which is essential for their efficacy, is challenging. They are nontoxic in vitro and do not irritate the corneas of normal cats when applied topically.  However, in vivo topical application of siRNAs does not deliver these agents into corneal cells, possibly because tears remove them rapidly from the ocular surface.

g) Probiotics (Enterococcus faecium SF68) were investigated for efficacy in a clinical trial utilizing cats experimentally infected with FHV-1; no significant treatment effect was identified, but subjects had such minimal evidence of disease that a treatment effect could have been missed.

As with bacteria, under-dosing of antiviral agents has been shown in vitro to cause development of drug-resistant herpesviruses.  If antiviral agents are to be used, they must be given in doses known to be effective.

There is no clear information regarding duration of therapy for FHV-1 with antiviral agents, and no clear guidelines as to when antiviral agents should be started and stopped.  The authors recommend that antiviral agents be considered in cats with FHV-1 when signs are severe, resistant, or recurrent, particularly when there is corneal involvement, especially corneal ulceration.  Therapy should be continued for a period after the resolution of clinical signs; the length of this period should be determined based upon response to therapy, and duration and severity of clinical signs prior to treatment. No data are available to support dose reduction or tapering of antiviral drugs in cats. Doses of antiviral agents should not be reduced, especially not in magnitude but also usually in frequency, below their lowest effective virostatic levels. [PJS]

See also:
Thomasy SM, Covert JC, et al. Pharmacokinetics of famciclovir and penciclovir in tears following oral administration of famciclovir to cats: a pilot study.  Vet Ophthalmol 2012;15:299-306.