Acyclovir and Valacyclovir

Acyclovir is a synthetic analogue of the purine nucleoside deoxyguanosine (see Figure 7-1). In human patients, acyclovir is widely used to treat herpes simplex and varicella-zoster virus infections, both of which are α-herpesviruses. In small animal medicine, acyclovir has primarily been used to treat feline herpesvirus-1 (FHV-1) infections, although FHV-1 has a much lower susceptibility to the drug compared with the human herpesviruses.² Acyclovir has also been used to treat canine herpesvirus-1 (CHV-1) infections in puppies (see Chapter 16). Other nucleoside analogues (trifluridine, idoxuridine, cidofovir, ganciclovir, and penciclovir) show much greater activity than acyclovir against FHV-1 in vitro.^2–4

Topical acyclovir has been used with limited success to treat feline herpetic dermatitis⁵ and keratitis.⁶ Topical treatment requires frequent (>4 times a day) application for beneficial effect.⁶ The oral bioavailability of acyclovir is low in cats, and high doses are required to achieve adequate serum drug concentrations.⁷ Valacyclovir, the prodrug for acyclovir, is rapidly converted to acyclovir by a first-pass effect after oral administration, and administration of the prodrug results in improved oral bioavailability of acyclovir. Unfortunately, administration of high doses of acyclovir or valacyclovir to cats has resulted in significant toxicity, including myelosuppression, renal tubular necrosis, and hepatic necrosis, without effective suppression of viral replication.⁸ Thus the use of systemic acyclovir and valacyclovir to treat cats with herpesvirus infections is not recommended.

Penciclovir and Famciclovir

Of all antiviral drugs used to treat small animal patients, penciclovir and famciclovir have shown the greatest promise. Penciclovir is another guanosine analogue (see Figure 7-1). It is present at much higher concentrations and for longer duration in cells than is acyclovir, which permits less frequent dosing. In humans, the prodrug famciclovir is well absorbed orally and rapidly converted to penciclovir, leading to increased oral bioavailability of penciclovir. Most of the drug is eliminated unchanged in the urine, and so dose reduction may be required for animals with decreased kidney function. In human patients, the concurrent administration of food decreases peak plasma concentrations without affecting overall bioavailability. In humans with herpes simplex virus and herpes zoster infections, famciclovir is as effective as acyclovir. In contrast, penciclovir (and thus famciclovir) have been shown to be potent inhibitors of FHV-1 replication (which is not the case for acyclovir). Penciclovir-resistant mutants of FHV-1 with altered TK enzymes have been described.⁹

Administration of famciclovir to cats at dosages comparable to those used in other species results in much lower plasma concentrations and a longer time to development of peak plasma concentrations of penciclovir when compared with other animal species, which suggests altered absorption or metabolism of famciclovir in cats.¹⁰ High doses of famciclovir have been required to achieve adequate plasma drug concentrations. Nevertheless, famciclovir is well tolerated when administered orally to cats at doses that produce clinical responses.^5,10,11 Treatment of cats with experimentally induced FHV-1 conjunctivitis with famciclovir at 90 mg/kg PO q8h for 21 days resulted in lower clinical and pathologic disease scores and decreased viral shedding when compared with placebo-treated cats.¹¹ Clinical responses also occur in naturally infected cats with both acute and chronic manifestations of disease with negligible adverse effects.⁵ Because of saturation of the metabolism of famciclovir to penciclovir, equivalent serum and tear penciclovir concentrations can be achieved in cats with 40 or 90 mg/kg PO q8h of famciclovir, so 40 mg/kg PO q8h is considered equally efficacious.^12,13 Clinical improvement often occurs within a week of treatment.

Ganciclovir

Ganciclovir resembles acyclovir except that it has an additional hydroxymethyl group on its acyclic side chain (see Figure 7-1). In human patients, ganciclovir is widely used specifically for the treatment of human cytomegalovirus infections, which can be life threatening in the immunocompromised. Cytomegaloviruses are β-herpesviruses. Systemic administration of ganciclovir to human patients is associated with a high prevalence of adverse drug reactions, especially cytopenias and central nervous system (CNS) signs, and so the use of ganciclovir is limited to patients with life-threatening or sight-threatening infections. A topical ophthalmic gel formulation of ganciclovir (0.15%) is now available for treatment of keratitis caused by herpes simplex virus-1. Ganciclovir is highly inhibitory to FHV-1 replication in vitro.^4,14 Pharmacokinetic, safety, and efficacy studies in cats have not yet been performed, but topical ganciclovir holds promise for treatment of feline ocular herpesviral infections.

Cidofovir

Cidofovir is a nucleotide analogue of deoxycytidine monophosphate. Because the drug already has a monophosphate group, its metabolism to the active diphosphate form by host cellular enzymes is not dependent on viral TK, and so it has been used to treat acyclovir- and penciclovir-resistant infections. In human patients, cidofovir is primarily used to treat cytomegalovirus retinitis. Cidofovir also has efficacy against other DNA virus infections, such as poxvirus and papillomavirus infections, and has been used topically as a cream to treat viral warts in people. Because the oral bioavailability of cidofovir is extremely low (<5%), it is always administered intravenously, intravitreally, or topically. Cidofovir has a prolonged intracellular half-life, which enables infrequent parenteral dosing regimens in human patients (once weekly, and then every other week for maintenance therapy).

Like ganciclovir, cidofovir is highly active in vitro against FHV-1.4,14,15 Twice-daily administration of a 0.5% cidofovir ophthalmic solution significantly decreases viral shedding and the severity of clinical disease in cats with experimentally induced ocular FHV-1 infection (Table 7-2).¹⁶ Local irritation and scarring of the nasolacrimal duct has been reported with topical administration of cidofovir to humans and rabbits with keratoconjunctivitis.

Idoxuridine and Trifluridine

Idoxuridine and trifluridine are halogenated thymidine analogues that interfere with the replication of FHV-1 in vitro, although they are more potent inhibitors of herpes simplex virus replication.2,14 They have been used to treat herpesviral keratitis in humans and in cats.¹⁷ These drugs are highly toxic when given systemically, because host cell and viral DNA synthesis are equally affected. Frequent topical application is required (five to six times daily), and prolonged use can cause corneal irritation or ulceration. Trifluridine has better corneal penetration than idoxuridine and is available as a 1% ophthalmic solution. Unfortunately, trifluridine is expensive, and ocular administration of trifluridine is often extremely irritating to cats.¹⁸ In contrast, topical idoxuridine administration is generally well tolerated.

Vidarabine

Vidarabine is an adenosine analogue that is phosphorylated by host cellular enzymes to vidarabine triphosphate, which interferes with DNA synthesis by both the virus and host cells. It is effective against idoxuridine-resistant herpesviral strains because its mechanism of action differs from that of idoxuridine. It is reportedly well tolerated by cats when administered five to six times daily to cats as a 3% ophthalmic ointment.¹⁸

Lysine

Lysine is an amino acid that interferes with herpesviral replication by a poorly understood mechanism. Antagonism of arginine may somehow be involved, because a high lysine-to-arginine ratio appears to be important for efficacy. However, arginine itself was also shown to interfere with the replication of herpes simplex virus in vitro.¹⁹

Lysine has shown efficacy when administered as tablets to cats with FHV-1 conjunctivitis²⁰ and, in another study, it reduced shedding of reactivated virus by latently infected cats.²¹ When administered as tablets to cats in a shelter, there was no reduction in upper respiratory tract disease.²² There was concern that the stress of tablet administration may have contributed to disease in these cats. However, in two other studies, dietary supplementation with lysine was not effective for management of upper respiratory tract disease in a shelter.^23,24 In fact, cats that received the lysine-supplemented diet had more severe disease and more frequent viral shedding than cats that received a non-supplemented ration, despite having increased plasma lysine concentrations. The lysine-supplemented diet did not affect plasma arginine concentration, so altered arginine levels did not appear to contribute to the increased severity of disease.

Zidovudine and Fozivudine

Zidovudine (azidothymidine; AZT; Retrovir) is a thymidine analogue and was one of the first drugs shown to be effective against HIV. Inside host cells, it is converted to the active triphosphate form. AZT inhibits the replication of FIV, reduces plasma viral load, improves stomatitis, and increases CD4/CD8 ratios in cats naturally infected with FIV.27,28 Some FIV isolates are resistant as a result of mutations in the RT enzyme. Although AZT is active against FeLV in vitro, when compared with FIV-infected cats, it has not performed as well for treatment of naturally infected, sick cats with chronic FeLV infection. Nevertheless, improvement in stomatitis, reduced antigenemia, and reduction in development of lymphoma have been reported in studies of naturally and experimentally FeLV-infected cats that were treated with AZT.^28,29

AZT is available as a10 mg/mL syrup and a 10 mg/mL injection. It has good oral bioavailability and is well distributed to tissues, including the CNS. It is metabolized to an inactive form by the liver and excreted by the kidneys. Dosage reduction has been recommended for cats with renal failure. Unfortunately, some cats treated with AZT can develop dose-related hematologic adverse effects, most commonly nonregenerative anemia and neutropenia, so the CBC must be monitored during treatment. Adverse effects may be confused with retrovirus-induced cytopenias. In human patients with HIV infection, cytopenias are more likely to occur when disease is advanced.

Fozivudine is a thioether lipid-zidovudine conjugate that undergoes intracellular cleavage to zidovudine monophosphate and subsequent phosphorylation to the active triphosphate form. Cleavage preferentially occurs in lymphocytes and monocytes compared with RBC and marrow stem cells, and so hematologic toxicity is less likely to occur. Fozivudine reduces viremia in cats experimentally infected with FIV, without significant adverse effects.³⁰ Further study is required to evaluate this drug for treatment of chronic FIV and FeLV infections in cats.

Lamivudine

Lamivudine (3TC), a cytidine analogue, is synergistic when combined with AZT for treatment of HIV infection, and the combination is in common use in human medicine. AZT/3TC prevented FIV infection when given to cats shortly after experimental inoculation, but did not appear to be beneficial for treatment of cats with chronic FIV infection.³¹ In addition, severe hematologic adverse effects and fever occurred in some cats.

Other Antiretroviral Drugs

Raltegravir inhibits the retroviral integrase enzyme. Integrase incorporates transcribed viral DNA into the host chromosome. In human patients, raltegravir is approved for treatment of HIV infections and is used in combination with other antiretroviral drugs. Although expensive, raltegravir has shown great promise for treatment of FeLV infections in vitro and also in vivo.25,26 Other drugs that have shown promise in vitro for treatment of FeLV infections, with no evidence of toxicity to cell cultures, are the nucleoside analogues tenofovir, decitabine, and gemcitabine.²⁶ Tenofovir is used as part of combination therapy to treat HIV infections. It is administered as a prodrug. Decitabine and gemcitabine are cytidine analogues used in human patients to treat myelodysplastic syndromes and carcinomas, respectively. The use of combinations of gemcitabine and carboplatin to treat carcinomas in cats has been reported, but cytopenias and gastrointestinal toxicity occurred in some of the cats.³²

Plerixafor is a bicyclam derivative that selectively blocks the chemokine receptor, CXCR4. This receptor is used by FIV to enter cells (see Chapter 21). In a placebo-controlled, masked clinical trial, administration of plerixafor to cats with FIV infection for 6 weeks reduced proviral load but did not lead to improvement in clinical or immunologic variables.³³

Oseltamivir

Oseltamivir (Tamiflu) is the prodrug of oseltamivir carboxylate (GS4071), a potent inhibitor of influenza virus neuraminidase. Oseltamivir was developed because of the poor oral bioavailability of zanamivir, a neuraminidase inhibitor that is structurally similar to GS4071. Neuraminidase is a surface glycoprotein of both influenza A and influenza B viruses (see Figure 7-2). The viral neuraminidase cleaves sialic acid residues on the surface of infected cells, which allows new virus particles to be released from host cells. It also prevents aggregation of virus particles after they are released and facilitates spread of the virus through the mucus of the respiratory tract by cleaving sialic acid residues in mucin.

In humans and dogs, oseltamivir has high oral bioavailability.³⁵ Esterase enzymes in the liver then convert oseltamivir to its active form, which is well distributed to most body fluids, including surface epithelial cells throughout the upper and lower respiratory tract. Elimination of the drug relies on renal excretion. The drug is well tolerated in humans, with gastrointestinal signs being the most frequently reported adverse effects.

The prevalence of resistance to oseltamivir among influenza virus isolates is generally low (<5%). High-level resistance results from mutations in the viral neuraminidase. Neuraminidase inhibitors could play a critical role in prevention of mortality in human influenza virus pandemics, so strategies that minimize the selection of resistant mutants are important. The Centers for Disease Control and Prevention recommends prioritizing antiviral treatment to human patients at risk of complications of influenza, such as the very young and very old.³⁶

Oseltamivir has been used to treat canine parvovirus (CPV) enteritis in puppies, with anecdotal reports of improved outcome. A single prospective, randomized, masked, placebo-controlled trial of 35 dogs with CPV enteritis showed that dogs treated with oseltamivir (2 mg/kg PO q12h) had no significant drop in their white blood cell count, whereas untreated dogs had a significant drop in their white blood cell count in the first 5 days of hospitalization.³⁷ Treated dogs also gained weight during hospitalization, whereas untreated dogs lost weight. However, there was no difference in hospitalization time, treatments needed, clinical scores, morbidity, or mortality between the two groups, and the number of dogs in each group was small. No significant adverse drug effects were observed, but oseltamivir was administered as a 1:1 dilution with water, in order to reduce reactions to the taste of the drug and vomiting shortly after drug administration. The authors acknowledged that there were potential concerns that related to administration of an oral medication to dogs with enteritis, with variability in drug absorption.

As CPV has no neuraminidase, it was hypothesized that oseltamivir instead may act on the neuraminidases of bacteria that are normally responsible for secondary bacterial infections in CPV enteritis, which are primarily those of the gastrointestinal tract. The role of bacterial neuraminidases in the pathogenesis of enteric bacterial infections and bacterial translocation is unknown. Bacterial neuraminidase enzymes may play a role in biofilm formation and help bacteria to invade mucin layers of the respiratory tract.³⁸ It has been suggested that gut bacteria may use neuraminidase enzymes to cleave sialic acid residues on gastrointestinal epithelial cells, which exposes receptor sites for bacterial adherence.

A major concern that relates to treatment of CPV enteritis with oseltamivir is the possibility of selection for resistant mutants among influenza viruses if widespread use of the drug occurs in veterinary clinics. Given the restrictions on the use of this drug for treatment of human influenza virus infections, further investigation is required before the use of oseltamivir can be recommended for treatment of CPV enteritis.