Antiviral Chemotherapy in Veterinary Medicine
ACVIM 2008
Katrin Hartmann, Prof., Dr. med. vet., Dr. habil., DECVIM
Munich, Germany

Introduction

Antiviral chemotherapy is of increasing interest in veterinary medicine. Besides "true" antiviral chemotherapeutics and interferons, immunomodulators (or immunostimulatory agents or biological response modifiers) are commonly used to treat viral infections. It has been suggested that these agents benefit infected animals by restoring compromised immune function, thereby allowing the patient to control viral burden and recover from associated clinical syndromes. There is, however, no conclusive evidence from controlled studies that these drugs have any beneficial effect on health or survival of animals with virus infections. An unspecific stimulation of the immune system might even be contraindicated in some infections (e.g., in feline immunodeficiency virus (FIV) because these drugs can lead to an increased virus replication caused by activation of latently infected lymphocytes and macrophages, and therefore can effect a progression of disease, or in cats with feline infectious peritonitis (FIP) as clinical signs in FIP develop as a result of an overwhelming immune-mediated response).

Antivirals

Antivirals are compounds that interfere with one step (or several steps) in the viral replication cycle. Zidovudin (AZT) is a nucleoside analogue that blocks the reverse transcriptase of retroviruses. In cats, it should be used at a dosage of 5-10 mg/kg q12h PO or SC. Some cats may develop non-regenerative anemia during treatment that usually is reversible. AZT inhibits FIV and FeLV replication in vitro. It reduces plasma virus load, improves the immunological and clinical status of FIV-infected cats (e.g., in cats with stomatitis or neurological signs), increases quality of life, and prolongs life expectancy.1 In experimental trials, AZT has proved to be somewhat effective in treating cats experimentally infected with feline leukemia virus (FeLV) when treatment is initiated less than 3 weeks after infection. In a study of naturally FeLV-infected cats, however, 6 weeks of treatment with zidovudine did not lead to a statistically significant improvement of clinical, laboratory, immunologic, or virologic parameters.2

Several other nucleoside analogues with similar mode of action that are licensed for treatment of human immunodeficiency virus (HIV) infection have activity against FIV and FeLV. Stavudine (d4T) is active against FIV in vitro, but no in vivo data are available. Didanosine, 2',3'-dideoxyinosine, ddI, is also active against FIV and FeLV in vitro, but controlled in vivo studies confirming the efficacy are not available so far. Zalcitabine (ddC) has anti-FIV and anti-FeLV activity in vitro and has been used in experimental studies to treat FeLV-infected cats. Controlled release delivery of ddC inhibited de novo FeLV replication and delayed onset of viremia; however, when therapy was discontinued (after 3 weeks), an equivalent incidence and level of viremia were established rapidly. In a study evaluating the prophylactic antiviral activity against FeLV, high dosages of ddC were administered by continuous intravenous infusion but were extremely toxic (causing death in 8/10 cats), and lower dosages (still causing severe thrombocytopenia) were not effective in preventing infection. Lamivudine (3TC) is active against FIV in vitro. In experimentally FIV-infected cats, a high dose zidovudine/lamivudine combination (each drug 100 or 150 mg/kg/day) protected cats when the treatment was stared before experimental infection, but had no effect in chronically infected cats. Severe side effects occurred including fever, anorexia, and marked hematological changes.3

AMD3100, a bicyclam that inhibits virus entry, is not licensed as anti-HIV compound but as a stem cell activator for patients that undergo bone marrow transplantation. It acts as potent and selective antagonists of the chemokine receptor CXCR4, the main coreceptor for T-cell-line-adapted HIV strains. FIV also uses CXCR4 for cell fusion and viral entry, and a high degree of homology exists between the human and feline CXCR4. In a placebo-controlled double-blind study in which 40 naturally FIV-infected cats were treated for 6 weeks (0.5 mg/kg q12h SC), AMD 3100 caused a statistically significant improvement in the proviral load in FIV-infected cats. Patients receiving AMD3100 did not show side effects during treatment.

Some older drugs are effective against a variety of viruses but associated with severe side effects in cats. Ribavirin is active against a number of feline and canine viruses in vitro, including FIV, FeLV, feline herpesvirus (FHV-1), feline calicivirus (FCV), feline coronavirus (FCoV), Borna disease virus (BDV), and canine parainfluenzavirus (CPiV). In vivo, however, therapeutic concentrations are difficult to achieve due to toxicity (mainly dose-dependent hemolytic anemia). Foscarnet is a pyrophosphate analogue that has a wide spectrum of activity against DNA and RNA viruses. In vitro, foscarnet has been shown to be active against FIV and FeLV but no reliable data exist in vivo in cats and dogs, and its use in veterinary medicine is limited due to toxicity (e.g., nephrotoxicity, myelosuppression, mucous membrane ulcers, severe electrolyte changes). Suramin has been used as an antiparasitic agent and also has antiviral action but is also associated with severe side effects. In an uncontrolled study (with low number of cats), suramin was used in FeLV-infected cats in which anemia improved and serum viral infectivity ceased transiently.

Amantadine is a cyclic amine that acts against enveloped RNA viruses by blocking viral entry into host cells. It has also antidepressive effects in some patients; however, this have been attributed to its antiviral activity against human BDV infection which, to the belief of some authors, is frequently seen in patients with depressive episodes. Amantadine is effective against BDV in vitro. Only anecdotal reports exist from cats with BDV infection in Northern Europe that benefit from treatment with amantadine.

Acyclovir (AZV) is a nucleoside analogue that interferes with DNA replication of herpesviruses but is about 1000-fold less active against FHV-1 than against human herpes simplex virus (HSV). In cats, acyclovir should be given at a dose of 10 mg/kg q8h SC. When given in higher dosages systemically, AZV may cause obstructive nephropathy if diuresis is inadequate. If used topically in eye infections, frequent application (q4-6h) is recommended. Valacyclovir (VAZV) is a prodrug for acyclovir that has the same antiviral spectrum but has a 3- to 5-times higher oral bioavailability. In a placebo-controlled experimental study, high dose valacyclovir (60 mg/kg orally) did not suppress FHV-1 replication in acutely infected cats, but cats appeared to be uniquely sensitive to the toxic effects (e.g., renal tubular epithelium and hepatocellular necrosis, severe bone marrow suppression).4

There are a number of drugs with efficacy against FHV-1 that are mainly used topically because they are toxic if used systemically. Some of them are highly potent (trifuridine (TFT) > ganciclovir = idoxuridine (IDU) = cidofovir = penciclovir = vidarabin (ARA-A) > acyclovir >> foscarnet).5 Frequent application (q4h) is very important if used topically in cats with ocular FHV-1 infection. Case reports indicate that ARA-A might also be beneficial in dogs with canine herpesvirus (CHV) infection. ARA-A was given to 5 littermates of 2 puppies that had died from CHV infection, and all 5 survived. ARA-A also shows activity against FIP-causing FCoV strains in vitro, but there are no in vivo data to demonstrate efficacy in cats with FIP.

L-lysine may suppress the clinical manifestation of herpesvirus infection. The mechanism of action is reduced viral replication attributable to antagonism of arginine by excess lysine. L-lysine should be given at 500 mg per cat q12h PO. In an experimental placebo-controlled double-blind study including 8 cats, oral administration of L-lysine resulted in less severe manifestation of conjunctivitis caused by acute FHV-1 infection, compared to cats that received placebo.6 Additionally, significantly fewer viral shedding episodes and less clinical signs were identified in latently infected cats after a stress event of re-housing in the treatment group cats compared to the control group cats.7

Interferons

Interferons have immunomodulatory effect but also may act as true antiviral compounds. Human interferon-α is active against many DNA and RNA viruses. Two common treatment regimens exist in cats, SC injection of high-dose (104-106 IU/kg q24h) or PO application of low-dose (1-50 IU/kg q24h). When human interferon-α is given parenterally, it becomes ineffective after 3-7 weeks because of the development of neutralizing antibodies.8 When given PO, it is destroyed in the gastrointestinal tract, and no measurable serum levels develop. Given PO, however, it also has a systemic immunomodulatory effect through stimulation of the local lymphoid tissue in the oral cavity. Human interferon-α inhibits FeLV, FIV, FHV-1, and FCoV replication in vitro. In experimentally FeLV-infected cats, treatment with high dosages of human interferon-α (1.6 x 104 and 1.6 x 106 IU/kg SC) resulted in significant decreases in circulating FeLV p27 antigen. In a study of naturally FeLV-infected cats using a similar high-dose treatment regimen, however, treatment with human interferon-α did not lead to a statistically significant improvement of clinical, laboratory, immunologic, or virologic parameters.2 For oral low-dose interferon-α treatment in cats, 1-50 IU/kg are used (e.g., 30 IU/cat for 7 consecutive days on a one-week-on/one-week-off schedule being the most frequently recommended regimen). In a placebo-controlled study, treatment of ill client-owned FeLV-infected cats with low-dose oral interferon-α did not result in any statistically significant difference in FeLV status, survival time, clinical or hematologic parameters, or subjective improvement in the owners' impression when compared with a placebo group.9 In a recent study, natural human interferon-α was used in clinically-ill cats naturally infected with FIV (50 IU/kg on the oral mucosa daily for 7 days on alternating weeks for 6 months, followed by a 2-month break, and then repetition of the 6-month treatment). All but one of the 24 cats in the treatment group were alive at 18 months compared to only 1 of the 6 placebo-treated cats.10 In an experimental study in which 12 kittens infected with FHV-1 received either 108 IU/kg human interferon-α SC q12h for 2 days starting 1 day before the challenge or placebo, it reduced the clinical signs in the cats over a 14 day period. In vitro, antiviral activity against a FIP-causing FCoV strain was demonstrated. In 74 cats (52 treated, 22 controls) with experimentally induced FIP, prophylactic or therapeutic administration of high-dose (104 or 106 IU/kg) human interferon-α did not significantly reduce mortality in treated versus untreated cats, but the mean survival time in cats treated with 106 IU/kg interferon-α in combination with Propionibacterium acnes was significantly prolonged for 3 weeks. Interferon-α has been used in dogs (intralesional application) with viral papillomatosis but controlled studies are missing.

Feline interferon-ω, the corresponding feline interferon, was recently licensed for use in veterinary medicine in some European countries and Japan. Interferons are species-specific; therefore feline interferon-ω can be used for long periods without antibody development. Interferons of dogs and cats are closely related, and feline interferon-ω is almost as effective in canine cells as it is in feline cells, which justifies its use in dogs. Recommendation for treatment in cats and dogs are 2.5 x 106 IU/kg IV or SC q24h for 3 consecutive days in acute virus infections. In chronic virus infections, a treatment protocol of 106 IU/kg q24h SC on 5 consecutive days is suggested; this 5-day treatment period is repeated several times with 3-4 weeks without treatment in between. No severe side effects have been reported in cats or dogs. Feline interferon-ω is active against FIV, FeLV, FHV-1, FCV, feline panleukopenia virus (FPV), and canine parvovirus (CPV) in vitro. In a placebo-controlled field study in France including 48 cats with FeLV infection, a statistically significant difference was noted in the survival time of treated versus untreated cats.11 No virologic parameters, however, were measured throughout the study to support the hypothesis that the interferon actually had an anti-FeLV effect rather than inhibited secondary infections. Feline interferon-ω was also used in FIV-infected field cats but did not show higher survival rate when compared to a placebo group. Feline interferon-ω was used against FHV-1 and more effective treating FHV-1-infected corneal cells than human interferon-α.12 Therefore, it can be expected to have a good effect especially if applied topically in cats with FHV-1-induced ocular changes. In a recently performed randomized placebo-controlled double-blind treatment trial, 34 cats with FIP were treated with interferon-ω or placebo. In all cats, FIP was confirmed by histology and/or immunohistochemical or immunofluorescence staining of FCoV antigen in effusion or tissue macrophages. There was no statistically significant difference in the mean survival time of cats treated with interferon-ω or placebo.13 In an experimental placebo-controlled double-blind challenge trial including 10 beagle puppies inoculated with CPV that had developed clinical signs, all 5 dogs in the placebo group died within 10 days post-inoculation while in the treated group 4/5 dogs survived the challenge and recovered gradually. One field trial in France and a similar trial in Japan also demonstrated a significant reduction of mortality in dogs with parvovirus infection when treated with feline interferon-ω.14

Table 1. Treatment options for virus-infected cats and dogs (n.d. = not determined).

 

Efficacy
in vitro?

Controlled
studies
in vivo?

Efficacy
in vivo?

Forecast

Zidovudine (AZT)

FIV
FeLV

yes
yes

yes
yes

yes
no

Effective in some cats
Not effective in field cats

Stavudine (d4T)

FIV
FeLV

yes
n.d.

no
no

n.d.
n.d.

Possibly effective
Possibly effective

Didanosine (ddI)

FIV
FeLV

yes
yes

no
no

n.d.
n.d.

Possibly effective
Possibly effective

Zalcitabine (ddC)

FIV
FeLV

yes
yes

no
yes

n.d.
no

Toxic in high dosages
Toxic in high dosages

Lamivudine (3TC)

FIV
FeLV

yes
no

yes
no

no
n.d.

Toxic in high dosages
Toxic in high dosages

AMD3100

FIV
FeLV

yes
n.d.

yes
no

yes
n.d.

Some effect in field cats
Likely ineffective

Ribavirin

FIV
FeLV
FHV-1
FCV
FIP

yes
yes
yes
yes
yes

no
no
no
yes
yes

n.d.
n.d.
n.d.
no
no

Toxic in cats
Toxic in cats
Possibly as aerosol
Possibly as aerosol
Toxic in cats

Foscarnet

FIV
FeLV

yes
yes

no
no

n.d.
n.d.

Toxic
Toxic

Suramin

FIV
FeLV

n.d.
n.d.

no
no

n.d.
n.d.

Likely ineffective
Likely ineffective

Amantadine

BDV
CPiV

yes
no

No
no

n.d.
n.d.

Possibly effective
Possibly effective

Acyclovir (AZV)

FHV-1
CHV

yes
n.d.

yes
no

yes
n.d.

Some effect (e.g., topically)
Possibly effective

Valacyclovir (VAZV)

FHV-1
CHV

yes
n.d.

yes
no

no
n.d.

Toxic in high dosages
Toxic in high concentrations

Idoxuridine (IDU)

FHV-1
CHV

yes
n.d.

no
no

n.d.
no

Toxic, only topical use
Toxic if used systemically

Trifluridine (TFT)

FHV-1
CHV

yes
n.d.

no
no

n.d.
n.d.

Toxic, only topical use
Toxic if used systemically

Vidarabine (ARA-A)

FHV-1
FIP
CHV

yes
yes
n.d.

no
no
no

n.d.
n.d.
n.d.

Toxic, only topical use
Likely ineffective
Possibly effective

L-lysine

FHV-1
CHV

yes
n.d.

yes
no

yes
n.d.

Effective
Possibly effective

human interferon-α

--SC high dose

FIV
FeLV
FHV-1
FCV
FIP

yes
yes
yes
yes
yes

no
yes
yes
no
yes

n.d.
no
yes
n.d.
no

Likely ineffective
Not effective in field cats
Effective (e.g., topically)
Possibly effective
Not effective

--PO low dose

 

FIV
FeLV
FHV-1
FCV
FIP

yes
yes
yes
yes
yes

yes
yes
no
no
no

yes
no
n.d.
n.d.
n.d.

Some effect
Not effective in field cats
Likely ineffective
Likely ineffective
Contraindicated

Feline interferon-ω

FIV
FeLV
FHV-1
FCV
FIP
FPV
CPV

n.d.
yes
yes
yes
yes
n.d.
yes

yes
yes
no
no
no
no
yes

no
yes
n.d.
n.d.
n.d.
n.d.
yes

Ineffective
Some effect
Possibly effective
Possibly effective
Possibly effective
Likely effective
Effective

References

1.  Hartmann K, et al. Fel Pract 1995;6:13.

2.  Hartmann K, et al. Proceedings 20th ACVIM 2002;779.

3.  Arai M, et al. Vet Immunol Immunopathol 2002;85:189.

4.  Nasisse MP, et al. Am J Vet Res 1997;58:1141.

5.  Nasisse MP, et al. Am J Vet Res 1989;50:158.

6.  Stiles J, et al. Am J Vet Res 2002;63:99.

7.  Maggs DJ, et al. Am J Vet Res 2003;64:37.

8.  Zeidner NS, et al. J Acquir Immune Defic Syndr 1990;3:787.

9.  McCaw DL, et al. J Am Anim Hosp Assoc 2001;37:356.

10. Pedretti E, et al. Vet Immunol Immunopathol 2006;109:245.

11. De Mari K, et al. J Vet Intern Med 2004;18:477.

12. Siebeck N, et al. Am J Vet Res 2006;67:1406.

13. Ritz S, et al. J Vet Intern Med 2007;21:1193.

14. De Mari K, et al. Vet Rec 2003;152:105.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Katrin Hartmann, DMV, DH, DECVIM
Ludwig-Maximilians-Universität München
Munich, Bavaria, Germany


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