Department of Surgical & Radiological Sciences, University of California Davis, Davis, CA, USA
Due to subclinical shedding, the diagnostic tests for feline herpesvirus type 1 (FHV-1) are not terribly reliable in individual cats. Meanwhile, a number of relatively safe and highly effective antiviral drugs have become available. As a result I have started to use response to therapy as a “diagnostic test.” This requires that I choose the optimum therapeutic approach possible for each cat.
Feline Herpetic Antiviral Therapy
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 systemically administered 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 use rather than systemic administration.
All antiviral agents currently used for cats infected with FHV-1 are virostatic. Therefore, they typically require frequent administration to be effective, should be initiated as early as possible in the disease course, and have no effect against the latent virus.
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 topically administered trifluridine is considered one of the most effective drugs for treating HSV-1 keratitis. This is in part due to its superior corneal epithelial penetration. It is also one of the more potent antiviral drugs for FHV-1. It is commercially available in the USA as a 1% ophthalmic solution that should be applied to the affected eye 5–6 times daily. Unfortunately, it is expensive and is often not well tolerated by cats, presumably due to a stinging reaction reported in humans.
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, if it can be obtained from a compounding pharmacist, should be applied to the affected eye 5–6 times daily.
Vidarabine (VDB) affects a viral replication step different from that targeted by idoxuridine. Therefore, vidarabine may be effective in patients whose disease seems resistant to idoxuridine. As a 3% ophthalmic ointment, vidarabine often appears to be better tolerated than many of the antiviral solutions. If it can be obtained from a compounding pharmacist, it should be applied to the affected eye 5–6 times daily.
Acyclovir (ACV) has relatively low antiviral potency against FHV-1, poor bioavailability, and is often toxic when systemically administered to cats. Oral administration of 50 mg/kg acyclovir to cats was associated with peak plasma levels of only approximately one third required for FHV-1. Common signs of toxicity are referable to bone marrow suppression. However, acyclovir is also available as a 3% ophthalmic ointment in some countries. In one study in which a 0.5% ointment was used 5 times daily, the median time to resolution of clinical signs was 10 days. Cats treated only 3 times daily took approximately twice as long to resolve and did so only once therapy was increased to 5 times daily.
Taken together, these data suggest that very frequent topical application of acyclovir may produce concentrations at the corneal surface that do exceed the reported concentration required for this virus but are not associated with toxicity. There are also in vitro data suggesting that interferon exerts a synergistic effect with acyclovir that could permit an approximately 8-fold reduction in acyclovir dose. In vivo investigation and validation of these data are needed.
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. Plasma concentrations of acyclovir that surpass the IC50 for FHV-1 can be achieved after oral administration of this drug to cats; however, it induced fatal hepatic and renal necrosis, along with bone marrow suppression, and did not reduce viral shedding or clinical disease severity. This shows how dangerous acyclovir is when notable plasma concentrations are achieved. Valacyclovir should never be used in cats. Ganciclovir (GCV) appears to be at least 10-fold more effective against FHV-1 compared with acyclovir. It is available for systemic (IV or PO) and intravitreal administration in humans, where it is associated with greater toxicity than acyclovir. Toxicity is typically evident as bone marrow suppression. It has been released as a new topical antiviral gel in humans. There are no reports of its safety or efficacy in cats as a systemic or topical agent, although anecdotal reports from Europe are very promising.
Famciclovir (Famvir® and generic) is a prodrug of penciclovir; however metabolism of famciclovir to penciclovir in humans is complex; requiring di-deacetylation, in the blood, liver, or small intestine, and subsequent oxidation to penciclovir by aldehyde oxidase in the liver. Unfortunately, hepatic aldehyde oxidase activity is nearly absent in cats. As a result, famciclovir pharmacokinetics in the cat are extremely complex and nonlinear. For example, an approximately 6-fold increase in dose produced only an approximately 3-fold increase in plasma concentration. This makes dose recommendation challenging; however, in a masked, prospective, placebo-controlled study of efficacy, experimentally infected cats, 90 mg/kg famciclovir given TID was associated with significantly reduced clinical signs, serum globulin concentrations, histologic evidence of conjunctivitis, viral shedding, and serum FHV-1 titers, as well as increased goblet cell density. Importantly, no important adverse clinical, hematologic or biochemical changes were associated with famciclovir administration. More recently, we have shown that 90 mg/kg PO BID produces almost identical plasma and tear concentrations as did the TID dose that was so successful. Do not compound this drug (it is very bitter and there are no reports of stability), and do not taper the dose when improvement is noted. Like all other antimicrobials, treat beyond clinical resolution and then stop. Transdermal famciclovir has not been investigated but, given the need for hepatic metabolism is unlikely to be successful.
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 (likely for this reason) it is not commercially available as a topical ophthalmic agent in humans. However, this side effect has not been noted in cats.
The literature regarding lysine has become very interesting recently with some data that at first glance appear contrary to earlier study outcomes which suggested efficacy. This requires a more detailed assessment. Lysine limits the in vitro replication of many viruses, including FHV-1. The antiviral mechanism is unknown; however, many investigators have demonstrated that concurrent depletion of arginine is essential for lysine supplementation to be effective. This finding suggests that lysine exerts its antiviral effect by antagonism of arginine. However, this effect is observed only at supraphysiologic concentrations of lysine. Meanwhile, results of 2 early independent in vivo studies in experimentally inoculated cats have supported a role for L-lysine. Lysine-treated cats undergoing primary herpetic disease had significantly less severe conjunctivitis than did cats that received placebo, while latently infected adult cats receiving lysine had reduced viral shedding. 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 shelter cats receiving oral boluses of 250 mg (kittens) or 500 mg (adult cats) of lysine once daily for the duration of their stay. No significant treatment effect was detected on the incidence of infectious upper respiratory disease (IURD), the need for antimicrobial treatment for IURD, or the interval from admission to onset of IURD. A subsequent pair of studies assessed the safety and efficacy of L-lysine incorporated into cat food. Perhaps not unexpectedly, food (and therefore lysine) intake decreased coincident with peak disease and viral presence. As a result, cats did not receive lysine at the very time they needed it most. Surprisingly though, clinical signs and viral shedding in cats fed the supplemented ration were worse than in cats fed the basal diet. Taking all of this into account, I discuss with owners of cats that have frequent recurrences their administering 500 mg lysine per os q 12 hours over the long term as an adjunctive prophylactic measure. Cats should receive lysine as a twice daily bolus; not sprinkled on food.