Background

We are very clever at developing therapies against microorganisms... or rather hijacking them from bacteria. Many of the major classes of antibacterials, antifungals and anthelmintics are derived from prokaryotes. What we have not been so clever about is developing drugs to treat viral infections. This is largely a reflection of the most intimate relationship between a virus and its host. Not only do viruses replicate intracellularly, they also use many host cellular processes to complete their lifecycle. As such, attempts to interfere with viral growth can often be toxic to the host cell such that the therapeutic margins for antivirals are in many cases quite low. Despite these difficulties, many antiviral drugs are now being developed to treat human viral infections including human immunodeficiency virus (HIV), herpes simplex virus, and influenza virus.

The most commonly available antiviral drugs are generally the result of one of three processes. Interferons are natural chemicals produced by vertebrate cells that have quite general effects on viral replication. They represent the end result of an evolutionary process that has taken place over the millions of years of virus: host competition. Many other synthetic antivirals have been developed, often by trial and error. The properties which cause a drug to be anti-neoplastic will often enable the same drug to have antiviral activity, and this has formed another potential route for developing antiviral drugs. Increasingly, and in the future, antivirals will be designed on the basis of a deep understanding of the molecular interactions between important viruses and their infected cells, leading to the identification of crucial pathways that are required for viruses to complete their lifecycle. This scientific process is time consuming and costly, such that it is unlikely many antivirals will be specifically developed this way for the veterinary market. Rather, we will often have to make use of drugs first developed for human therapies.

For the cat, two factors have greatly influenced the clinical availability of antivirals, one positively and one negatively. Firstly, the close and fortuitous relationship between important viral pathogens of cats and humans, has meant that those drugs developed for human disease may also be useful for feline disease. Feline immunodeficiency virus (FIV) has been used as a model of HIV and has meant that many of the drugs that have been successfully developed to treat AIDS in people have also been tested on cats. Another example is feline herpesvirus (FeHV), which is very closely related to human herpes simplex virus, another virus for which antiviral therapy is routinely used in people. Secondly, the tendency of cats to find many drugs toxic has meant that although some drugs may have been shown to be beneficial in cell culture, they have proved too toxic in the cat, e.g.(8).

The main antiviral drugs available for cats are interferon, nucleoside analogues, and amino acids. Entry inhibitors, protease inhibitors, exit inhibitors and monoclonal antibodies are not yet available but will be mentioned for completeness because of their importance in treating human viral infections.

Interferons

Interferons are part of our natural innate immune response. They are rapidly induced in response to viral infection, much faster than the acquired immune response. They bind to cellular receptors leading to the induction of a so-called "antiviral" state. Their effects are mediated predominantly by two proteins. Double-stranded RNA activated protein kinase switches off protein translation (synthesis) in infected cells. Ribonuclease L chops DNA and RNA. There are two main types of interferon. Type I (αβω) and II (γ). Although interferons from one species may work in another (human interferon has been used in cats), they work best in more closely related species (feline interferon works in both cats and dogs). Virbagen omega (Virbac) is feline interferon omega produced by recombinant DNA technology in silkworm cells. It is licensed across Europe for the treatment of cats with feline leukaemia virus (FeLV) infection and / or FIV infection in the non-terminal stages of disease, and for canine parvoviral disease.

In one study, cats with FeLV +/- FIV were treated with 1MU/kg of Virbagen omega per day subcutaneously, for five days on three occasions starting on days 0, 14 and 60. Treated cats showed reduced mortality (39% compared to 59% of controls--relative risk of death in the interferon group is 1.6 lower than in the control group) (1). Generally, cats anaemic at the start of therapy that have shown no improvement in the anaemia by day 14 are considered unlikely to respond well to treatment.

There is also some evidence that oral human interferon α may have some beneficial effect against both FeLV and FIV infection. A low dose oral regime is preferable to parenteral routes of administration, as cats treated with the latter protocol seem to rapidly develop antibodies to the "foreign" interferon molecule, and become refractory to any beneficial effect. In a study of clinically affected FIV cats, low dose oral human interferon α was also shown to reduce clinical disease and prolong survival times compared to controls (7). However, there was no effect on the viral load in affected cats.

There is also some data to suggest a beneficial effect against feline infectious peritonitis (FIP) virus (2). In this study which was not controlled, 12 clinically ill cats previously diagnosed with FIP were treated with a combination of recombinant feline interferon (1 MU/kg s.c. e.o.d until remission, then weekly injections) and glucocorticoid (2mg/kg initially then reducing). Complete (> 2 yrs) remission (resolution of effusion) was seen in four cases, and partial remission (2 to 5 months) in four further cases.

Feline interferon is also licensed for the treatment of acute feline calicivirus disease in Japan & Australasia. Cats receive 2.5 MU/kg i.v. e.o.d. on three occasions. Treatment appears to be more effective when given early in disease. However, too my knowledge there are no widely available peer reviewed publications on its use.

Other possible (non-licensed) uses for feline interferon include outbreaks of FCV-associated virulent systemic disease, FeHV ocular disease, and feline parvovirus infection (based on licensed use for canine parvovirus--[4]). However, to the author's knowledge, controlled trials showing efficacy are lacking.

Nucleoside Analogues

The building blocks of DNA are the four nucleotides. Each consists of a sugar molecule with an attached base on one side (A, G, C or T) and phosphorylated on the other. Each nucleotide is made in the cell from a nucleoside, which is simply a nucleotide without the phosphate. Nucleoside analogues either contain a false sugar or a false base or both. They bind to the enzymes responsible for making new genetic information (polymerases) and inhibit their action. Clinically, they are used to inhibit tumour cells and viral replication. However, they can also interfere with normal cell turnover leading to their potential for toxicity.

Many nucleoside (and some nucleotide) analogues are now available for the treatment of HIV. Some are also useful in cats for the treatment of FIV and FeHV, however many are too toxic in cats. The nomenclature is confusing since each drug has a generic name, a chemical name and a trade name, e.g., Retrovir--brand name, AZT--commonly-used name (3'-azido-2',3'-dideoxythymidine), zidovudine (ZDV)--generic name.

Although there is a lot of data about the sensitivity of FIV and FeLV to nucleoside analogues in vitro (in cell culture), for most there is very little data about their clinical usefulness. Zidovudine (AZT) has been shown to be useful in FIV infected cats, and in early FeLV infection. However, non-regenerative anaemia is a common side effect which needs careful monitoring.

As is the case in HIV treatment, it is probable that these veterinary viruses will be swift to develop resistance to single drug therapies (e.g., [10]), and these may also be resistance to others drugs. This is likely to limit the clinical usefulness of monotherapies.

Numerous nucleoside analogs have been developed against human herpesviruses, mainly herpes simplex and varicella-zoster viruses. However, many are too toxic at therapeutic levels for oral administration to cats e.g., valacyclovir (5). The current treatment of FeHV keratitis is therefore based on the topical use of nucleoside analogues. Although in vitro, acyclovir is less efficacious than vidarabin, idoxuridin and trifluridin (6), it is often the most readily available of the drugs (e.g., Zovirax ophthalmic, GSK) (16). In one relatively small study of 17 cats variably treated with vidarabin, idoxuridin or trifluridin, no superior protocol could be identified (11). Human interferon alpha reduces viral replication and cell death in a corneal cell culture model (9), and has a synergistic effect with acyclovir (15), but evidence of its clinical utility in cats with FeHV is lacking.

Other antivirals such as ganciclovir, on the basis of in vitro studies, may prove useful in FeHV (14).

Ribavirin is used to treat respiratory syncytial virus infection in children. It has broad action against a variety of feline viruses including FeLV, FIV, calicivirus and coronavirus. However, it is to toxic for use in cats (8).

L-lysine

L-lysine is a normal amino acid that has an inhibitory effect against both human herpesvirus and FeHV infection. Oral supplementation (400mg of L-lysine in food once daily for 30 days) reduces the severity of experimentally-induced FeHV conjunctivitis when administered prior to infection (12) and the number of shedding episodes associated with reactivation of latent infection induced by re-housing (3). It may therefore be of use early in acute disease or as a means of reducing the amount of disease and virus shed at times of stress.

Other Drugs

Anti-flu drugs with specific activity against influenza viruses are particularly topical at the moment. Amantadine and rimantadine prevent the virus from uncoating, whereas zanamivir (Relenza) and oseltamivir (Tamiflu) prevent the release of viral particles from infected cells. Although cats can be infected with the H5N1 strain of influenza with severe consequences, it is uncertain whether these precious drugs would be made available for use in cats.

Protease inhibitors. Many viruses produce there own proteins as one large molecule that needs to be chopped by specific viral proteases to release the active proteins. This specific step is a key target for protease inhibitors against HIV. To the author's knowledge, no protease inhibitors are available for use in cats at the moment.

Monoclonal antibodies are specific antibody clones made in mice that target individual epitopes in their target antigen. Since they are made in mice they induce an immune response against themselves when injected into other species. Recently, these antibodies have been molecularly modified to make them immunologically acceptable in their new host and potentially useful as therapeutic agents. They are being developed for the treatment of cancers and infectious diseases in humans. In cats, there is some experimental evidence they will work against FCV and FeHV (13).

Summary

The general dogma that we can't treat viral infections is now gone, even for the cat. Unfortunately there are not many double blinded trials clearly demonstrating clinical efficacy but these will come. In the future, new drugs and new formulations of old drugs will be developed for humans and may be appropriate for use in the cat. Topical applications may abrogate toxic side effects of drugs given parenterally. Combination therapies give best clinical response in humans and this will probably be the case in the cat.

References

1.  de Mari K, Maynard L, Sanquer A, Lebreux B, Eun HM (2004). Therapeutic effects of recombinant feline interferon-omega on feline leukemia virus (FeLV)--infected and FeLV/feline immunodeficiency virus (FIV)-coinfected symptomatic cats. J Vet Intern Med, 18: 477-82.

2.  Ishida T, Shibanai A, Tanaka S, Uchida K, Mochizuki M (2004). Use of recombinant feline interferon and glucocorticoid in the treatment of FIP. J Feline Med Surg, 6: 107-9.

3.  Maggs DJ, Nasisse MP, Kass PH (2003). Efficacy of oral supplementation with L-lysine in cats latently infected with feline herpesvirus. Am J Vet Res, 64: 37-42.

4.  Martin V, Najbar W, Gueguen S, Grousson D, et al (2002). Treatment of canine parvoviral enteritis with interferon-omega in a placebo-controlled challenge trial. Vet Microbiol, 89: 115-27.

5.  Nasisse MP, Dorman DC, Jamison KC, Weigler BJ, Hawkins EC, Stevens JB (1997). Effects of valacyclovir in cats infected with feline herpesvirus 1. Am J Vet Res, 58:1141-4.

6.  Nasisse MP, Guy JS, et al (1989). In vitro susceptibility of FeHV to vidarabine, idoxuridine, trifluridine, acyclovir, or bromovinyldeoxyuridine. Am J Vet Res, 50: 158-60.

7.  Pedretti E, Passeri B, Amadori M, Isola P, Di Pede P, Telera A, Vescovini R, Quintavalla F, Pistello M (2006). Low-dose interferon-alpha treatment for feline immunodeficiency virus infection. Vet Immunol Immunopathol, 109: 245-54.

8.  Povey RC (1978). Effect of orally administered ribavirin on experimental FCV infection in cats. Am J Vet Res, 39: 1337-41.

9.  Sandmeyer LS, Keller CB, Bienzle D (2005). Effects of interferon-alpha on cytopathic changes and titers for FeHV in primary cultures of feline corneal epithelial cells. Am J Vet Res, 66: 210-6.

10. Smith RA, Remington KM, Preston BD, Schinazi RF, North TW (1998). A novel point mutation at position 156 of reverse transcriptase from FIV confers resistance to the combination of (-)-beta-2',3'-dideoxy-3'-thiacytidine and 3'-azido-3'-deoxythymidine. J Virol, 72: 2335-40.

11. Stiles J (1995). Treatment of cats with ocular disease attributable to herpesvirus infection: 17 cases (1983-1993). J Am Vet Med Assoc, 207: 599-603.

12. Stiles J, Townsend WM, Rogers QR, Krohne SG (2002). Effect of oral administration of L-lysine on conjunctivitis caused by feline herpesvirus in cats. Am J Vet Res, 63: 99-103.

13. Umehashi M, Imamura T, Akiyama S, Kimachi K, Tokiyoshi S, Mikami T (2002). Post-exposure treatment of cats with mouse-cat chimeric antibodies against FeHV and feline calicivirus. J Vet Med Sci, 64: 1017-21.

14. van der Meulen K, Garre B, Croubels S, Nauwynck H (2006). In vitro comparison of antiviral drugs against feline herpesvirus 1. BMC Vet Res, 2: 13.

15. Weiss RC (1989). Synergistic antiviral activities of acyclovir and recombinant human leukocyte (alpha) interferon on feline herpesvirus replication. Am J Vet Res, 50: 1672-7.

16. Williams DL, Robinson JC, Lay E, Field H (2005). Efficacy of topical aciclovir for the treatment of feline herpetic keratitis: results of a prospective clinical trial and data from in vitro investigations. Vet Rec, 157: 254-7.