David J. Maggs, BVSc (Hons), DACVO
Professor, Veterinary Ophthalmology, University of California - Davis, Davis, CA, USA
I like to use response to therapy as a "diagnostic test". If we are to do this, we must choose the optimum therapeutic approach possible for each cat. This requires knowledge regarding:
1. General features of antiviral drugs
2. In vitro susceptibility of FHV-1 to each drug
3. How well tolerated and how safe each drug is in cats
4. Which tissues are reached following topical or systemic therapy
Antiviral Drugs in General
Although a large variety of antiviral agents exists for oral or topical treatment of cats infected with feline herpesvirus type 1 (FHV-1), some general comments regarding these agents are possible:
No antiviral agent has been developed for FHV-1. Agents highly effective against closely-related human herpesviruses are not predictably effective against FHV-1. All should be tested in vitro before they are administered to cats.
No antiviral agent has been developed for cats. Agents with acceptable safety in humans are not predictably non-toxic when administered to cats. All require safety and efficacy testing in vivo.
Many antiviral agents require host metabolism before achieving their active form. These agents are not 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, are unlikely to be effective against latent virus, and rely (in part) on the host clearing the virus.
Specific Comments Regarding Common Antiviral Drugs
The following 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.
Trifluridine (TFU) is too toxic to be administered systemically but can be administered topically. It has superior corneal epithelial penetration and is one of the most potent drugs against FHV-1. As a 1% ophthalmic solution, it should be applied to the affected eye at least 5–6 times daily. Unfortunately, it is often not well tolerated by cats, presumably due to a stinging reaction reported in humans.
Idoxuridine (IDU) acts via a similar mechanism as TFU and is similarly toxic if given systemically. However, it has been used as an ophthalmic 0.1% solution or 0.5% ointment. This drug is well tolerated by most cats and seems efficacious in many. It should be applied at least 5–6 times daily.
Vidarabine (VDB) affects a viral replication step different from that targeted by IDU and TFU. Therefore, VDB may be effective in patients whose disease seems resistant to IDU or TFU. As a 3% ophthalmic ointment, vidarabine appears to be very well tolerated. Like other virostatic drugs, it should be applied at least 5–6 times daily.
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 being associated with stenosis of the nasolacrimal drainage system components and, as yet, it is not commercially available as an ophthalmic agent in humans. Therefore, at this stage there are insufficient data to support its long term safety as a topical agent in cats.
Ganciclovir (GCV) appears to be at least 10-fold more effective against FHV-1 compared with acyclovir. It has recently been released as a new topical antiviral gel in humans. I am unaware of any reports of its safety or efficacy in cats as a systemic or topical agent.
Acyclovir (ACV) has relatively low potency against FHV-1, poor bioavailability, and is potentially toxic when systemically administered to cats. Oral administration of 50 mg/kg acyclovir to cats achieved peak plasma levels of only approximately 40% of target. Common signs of toxicity are referable to bone marrow suppression. However, acyclovir is also available as an ophthalmic ointment which appears safe and may be effective if applied at least 5 times daily.
Valacyclovir (VCV) is a prodrug of acyclovir that, in humans and cats, is more efficiently absorbed from the gastrointestinal tract compared with acyclovir and is converted to acyclovir by a hepatic hydrolase. When administered to cats, plasma acyclovir concentrations > IC50 1 can be achieved; however, in cats experimentally infected with FHV-1, valacyclovir induced fatal hepatic and renal necrosis, along with bone marrow suppression, and did not reduce viral shedding or clinical disease severity. Therefore, despite its superior pharmacokinetics, valacyclovir should never be used in cats.
Famciclovir is a prodrug of penciclovir - a drug that is highly effective against FHV-1; however metabolism of famciclovir to penciclovir is complex and requires a hepatic aldehyde oxidase that is nearly absent in cats. Data suggest that the pharmacokinetics of this drug are nonlinear with 40 mg/kg PO TID producing the same plasma concentrations as does 40 mg/kg PO TID. There is mounting evidence that famciclovir is very effective in cats with experimentally induced or spontaneous herpetic disease. Further studies are required before dose rates and frequency can be recommended.
The literature regarding lysine has become very interesting recently with some data that require more detailed assessment.
In vitro efficacy against FHV-1. Lysine limits the in vitro replication of FHV-1. The antiviral mechanism is unknown; however, it appears that lysine antagonism of arginine is important.
In vivo Research in Cats. Results of 2 early independent in vivo studies have supported the clinical use of l-lysine in cats. In the first of these studies, experimentally inoculated cats receiving 500 mg of lysine PO BID had significantly less severe conjunctivitis than cats receiving placebo. In the second study, latently infected cats receiving 400 mg of lysine PO SID shed FHV-1 less commonly compared with cats receiving placebo. In both studies, plasma arginine concentrations remained in the normal range, and no signs of toxicity were observed, despite notably elevated plasma lysine concentrations in treated cats.
A subsequent study examined the effects of lysine in 144 cats in a shelter. Cats received oral boluses of 250 mg (kittens) or 500 mg (adult cats) of lysine once daily for the duration of their stay at the shelter and outcomes were compared with those of an untreated control group. No significant treatment effect was detected. Since then, 3 studies have assessed the safety and efficacy of dietary lysine supplementation rather than bolus administration. While no nutritional safety issues have been identified to date, the virologic outcomes were surprising. In the first study, 50 cats with enzootic upper respiratory tract disease were fed a diet supplemented to approximately 1% (n = 25) or 5% (n = 25) lysine for 52 days while subjected to rehousing stress which is known to cause viral reactivation. Disease and viral shedding was more severe in cats fed the supplemented ration. A similarly designed experiment in a local human shelter with a more consistent "background" level of stress and with greater numbers enrolled revealed similar outcomes. Taken together, these data suggest that approximately 5% dietary lysine supplementation is not a successful means of controlling infectious upper respiratory disease within large multicat populations in which IURD is enzootic. In fact, it can lead to an increase in disease severity and the presence of FHV-1 DNA on oropharyngeal or conjunctival mucosa at certain points.
Although interferons may play important physiological roles in the control of viral infections, in vitro and clinical trials investigating potential therapeutic applications have produced conflicting results. In in vitro studies, 1 x 105 - 5 x 105 IU/ml of recombinant human IFNα or recombinant feline IFNω significantly reduced FHV-1 titer and/or cytopathic effect while not producing any detectable cytotoxic changes in the feline corneal cell line or CRFK cells on which the virus was grown. At higher concentrations, the effect the recombinant feline IFNω was greater than that of IFNα. In a separate in vitro study, notable synergistic activity against FHV-1 was demonstrated when acyclovir was combined with human recombinant IFNα.
I know of very few peer-reviewed, placebo-controlled, prospective clinical trials of IFN administration in cats infected with FHV-1. One study utilized 10,000 IU recombinant feline IFNω administered topically (OU) q 12 hours and 2,000 IU administered PO q 24 hours. No beneficial effects were shown. The effects of very high-dose systemic administration of IFNα prior to experimental FHV-1 infection have also been studied; 108 IU/kg were administered subcutaneously BID on two consecutive days prior to inoculation. Although disease was not prevented, cumulative clinical scores were lower for cats treated with IFNα. An abstract has also been presented detailing hopeful preliminary data using low oral doses.