Efficacy of the early administration of valacyclovir hydrochloride for the treatment of neuropathogenic equine herpesvirus type-1 infection in horses

Lara K. Maxwell Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078

Search for other papers by Lara K. Maxwell in
Current site
Google Scholar
PubMed
Close
 DVM, PhD
,
Bradford G. Bentz Hagyard Equine Medical Institute, 4250 Iron Works Pike, Lexington, KY 40511.

Search for other papers by Bradford G. Bentz in
Current site
Google Scholar
PubMed
Close
 VMD, MS
,
Lyndi L. Gilliam Department of Veterinary Clinical Sciences, Oklahoma State University, Stillwater, OK 74078

Search for other papers by Lyndi L. Gilliam in
Current site
Google Scholar
PubMed
Close
 DVM
,
Jerry W. Ritchey Department of Pathobiology, Oklahoma State University, Stillwater, OK 74078

Search for other papers by Jerry W. Ritchey in
Current site
Google Scholar
PubMed
Close
 DVM, PhD
,
Nicola Pusterla Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

Search for other papers by Nicola Pusterla in
Current site
Google Scholar
PubMed
Close
 DVM, PhD
,
R. Eberle Department of Pathobiology, Oklahoma State University, Stillwater, OK 74078

Search for other papers by R. Eberle in
Current site
Google Scholar
PubMed
Close
 PhD
,
Todd C. Holbrook Department of Veterinary Clinical Sciences, Oklahoma State University, Stillwater, OK 74078

Search for other papers by Todd C. Holbrook in
Current site
Google Scholar
PubMed
Close
 DVM
,
Dianne McFarlane Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078

Search for other papers by Dianne McFarlane in
Current site
Google Scholar
PubMed
Close
 DVM, PhD
,
Grant B. Rezabek Center for Veterinary Health Sciences, the Oklahoma Animal Disease Diagnostic Laboratory, Oklahoma State University, Stillwater, OK 74078

Search for other papers by Grant B. Rezabek in
Current site
Google Scholar
PubMed
Close
 DVM, MPH
,
James Meinkoth Department of Pathobiology, Oklahoma State University, Stillwater, OK 74078

Search for other papers by James Meinkoth in
Current site
Google Scholar
PubMed
Close
 DVM, PhD
,
Chase Whitfield Department of Veterinary Clinical Sciences, Oklahoma State University, Stillwater, OK 74078

Search for other papers by Chase Whitfield in
Current site
Google Scholar
PubMed
Close
 DVM
,
Carla L. Goad Department of Statistics, College of Arts and Sciences, Oklahoma State University, Stillwater, OK 74078

Search for other papers by Carla L. Goad in
Current site
Google Scholar
PubMed
Close
 PhD
, and
George P. Allen Department of Veterinary Science, College of Agriculture, Food, and Environment, University of Kentucky, Lexington, KY 40546.

Search for other papers by George P. Allen in
Current site
Google Scholar
PubMed
Close
 PhD

Abstract

OBJECTIVE To determine whether prophylactic administration of valacyclovir hydrochloride versus initiation of treatment at the onset of fever would differentially protect horses from viral replication and clinical disease attributable to equine herpesvirus type-1 (EHV-1) infection.

ANIMALS 18 aged mares.

PROCEDURES Horses were randomly assigned to receive an oral placebo (control), treatment at detection of fever, or prophylactic treatment (initiated 1 day prior to viral challenge) and then inoculated intranasally with a neuropathogenic strain of EHV-1. Placebo or valacyclovir was administered orally for 7 or 14 days after EHV-1 inoculation or detection of fever (3 horses/group). Effects of treatment on viral replication and clinical disease were evaluated. Plasma acyclovir concentrations and viremia were assessed to determine inhibitory concentrations of valacyclovir.

RESULTS Valacyclovir administration decreased shedding of virus and viremia, compared with findings for control horses. Rectal temperatures and clinical disease scores in horses that received valacyclovir prophylactically for 2 weeks were lower than those in control horses. The severity of but not the risk for ataxia was decreased by valacyclovir administration. Viremia was decreased when steady-state trough plasma acyclovir concentrations were > 0.8 μg/mL, supporting the time-dependent activity of acyclovir.

CONCLUSIONS AND CLINICAL RELEVANCE Valacyclovir treatment significantly decreased viral replication and signs of disease in EHV-1–infected horses; effects were greatest when treatment was initiated before viral inoculation, but treatment was also effective when initiated as late as 2 days after inoculation. During an outbreak of equine herpesvirus myeloencephalopathy, antiviral treatment may be initiated in horses at various stages of infection, including horses that have not yet developed signs of viral disease.

Abstract

OBJECTIVE To determine whether prophylactic administration of valacyclovir hydrochloride versus initiation of treatment at the onset of fever would differentially protect horses from viral replication and clinical disease attributable to equine herpesvirus type-1 (EHV-1) infection.

ANIMALS 18 aged mares.

PROCEDURES Horses were randomly assigned to receive an oral placebo (control), treatment at detection of fever, or prophylactic treatment (initiated 1 day prior to viral challenge) and then inoculated intranasally with a neuropathogenic strain of EHV-1. Placebo or valacyclovir was administered orally for 7 or 14 days after EHV-1 inoculation or detection of fever (3 horses/group). Effects of treatment on viral replication and clinical disease were evaluated. Plasma acyclovir concentrations and viremia were assessed to determine inhibitory concentrations of valacyclovir.

RESULTS Valacyclovir administration decreased shedding of virus and viremia, compared with findings for control horses. Rectal temperatures and clinical disease scores in horses that received valacyclovir prophylactically for 2 weeks were lower than those in control horses. The severity of but not the risk for ataxia was decreased by valacyclovir administration. Viremia was decreased when steady-state trough plasma acyclovir concentrations were > 0.8 μg/mL, supporting the time-dependent activity of acyclovir.

CONCLUSIONS AND CLINICAL RELEVANCE Valacyclovir treatment significantly decreased viral replication and signs of disease in EHV-1–infected horses; effects were greatest when treatment was initiated before viral inoculation, but treatment was also effective when initiated as late as 2 days after inoculation. During an outbreak of equine herpesvirus myeloencephalopathy, antiviral treatment may be initiated in horses at various stages of infection, including horses that have not yet developed signs of viral disease.

Contributor Notes

Dr. Bentz's present address is Equine Medicine and Surgery, 7991 E Texas St, Bossier City, LA 71111.

Address correspondence to Dr. Maxwell (lk.maxwell@okstate.edu).

Deceased.

  • 1. Allen GP. Risk factors for development of neurologic disease after experimental exposure to equine herpesvirus-1 in horses. Am J Vet Res 2008; 69: 15951600.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2. Henninger RW, Reed SM, Saville WJ, et al. Outbreak of neurologic disease caused by equine herpesvirus-1 at a university equestrian center. J Vet Intern Med 2007; 21: 157165.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3. Goehring LS, van Winden SC, van Maanen C, et al. Equine herpesvirus type 1-associated myeloencephalopathy in the Netherlands: a four-year retrospective study (1999–2003). J Vet Intern Med 2006; 20: 601607.

    • Search Google Scholar
    • Export Citation
  • 4. Sawtell NM, Bernstein DI, Stanberry LR. A temporal analysis of acyclovir inhibition of induced herpes simplex virus type 1 in vivo reactivation in the mouse trigeminal ganglia. J Infect Dis 1999; 180: 821823.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Murray MJ, del Piero F, Jeffrey SC, et al. Neonatal equine herpesvirus type 1 infection on a Thoroughbred breeding farm. J Vet Intern Med 1998; 12: 3641.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Garré B, Shebany K, Gryspeerdt A, et al. Pharmacokinetics of acyclovir after intravenous infusion of acyclovir and after oral administration of acyclovir and its prodrug valacyclovir in healthy adult horses. Antimicrob Agents Chemother 2007; 51: 43084314.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Maxwell LK, Bentz BG, Bourne DW, et al. Pharmacokinetics of valacyclovir in the adult horse. J Vet Pharmacol Ther 2008; 31: 312320.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Rollinson EA, White G. Relative activities of acyclovir and BW759 against Aujeszky's disease and equine rhinopneumonitis viruses. Antimicrob Agents Chemother 1983; 24: 221226.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Tearle JP, Smith KC, Platt AJ, et al. In vitro characterisation of high and low virulence isolates of equine herpesvirus-1 and -4. Res Vet Sci 2003; 75: 8386.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Garré B, van der Meulen K, Nugent J, et al. In vitro susceptibility of six isolates of equine herpesvirus 1 to acyclovir, ganciclovir, cidofovir, adefovir, PMEDAP and foscarnet. Vet Microbiol 2007; 122: 4351.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Hedge J, Wagoner D. Horse conformation: structure, soundness, and performance. Guilford, Conn: The Lyons Press, 2004.

  • 12. Allen GP, Breathnach CC. Quantification by real-time PCR of the magnitude and duration of leucocyte-associated viraemia in horses infected with neuropathogenic vs. non-neuropathogenic strains of EHV-1. Equine Vet J 2006; 38: 252257.

    • Search Google Scholar
    • Export Citation
  • 13. Mayhew IG, deLahunta A, Whitlock RH, et al. Spinal cord disease in the horse. Cornell Vet 1978; 68(suppl 6):1207.

  • 14. FDA. Freedom of Information summary: original new animal drug application. NADA 141–268: Protazil antiprotozoal pellets. Silver Spring, Md: FDA, 2007.

    • Search Google Scholar
    • Export Citation
  • 15. Crabb BS, MacPherson CM, Reubel GH, et al. A type-specific serological test to distinguish antibodies to equine herpesviruses 4 and 1. Arch Virol 1995; 140: 245258.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16. Heldens JG, Hannant D, Cullinane AA, et al. Clinical and virological evaluation of the efficacy of an inactivated EHV1 and EHV4 whole virus vaccine (Duvaxyn EHV1,4). Vaccination/challenge experiments in foals and pregnant mares. Vaccine 2001; 19: 43074317.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17. Pusterla N, Wilson WD, Conrad PA, et al. Cytokine gene signatures in neural tissue of horses with equine protozoal myeloencephalitis or equine herpes type 1 myeloencephalopathy. Vet Rec 2006; 159: 341346.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18. Pusterla N, Mapes S, Wilson WD. Diagnostic sensitivity of nasopharyngeal and nasal swabs for the molecular detection of EHV-1. Vet Rec 2008; 162: 520521.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19. Pusterla N, Mapes S, Wilson WD. Prevalence of equine herpesvirus type 1 in trigeminal ganglia and submandibular lymph nodes of equids examined postmortem. Vet Rec 2010; 167: 376378.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20. Wada Y, McCright IJ, Whitby FG, et al. Replacement of loop II of VP1 of the DA strain with loop II of the GDVII strain of Theiler's murine encephalomyelitis virus alters neurovirulence, viral persistence, and demyelination. J Virol 1998; 72: 75577562.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21. Brush LA, Black DH, McCormack KA, et al. Papiine herpesvirus 2 as a predictive model for drug sensitivity of macacine herpesvirus 1 (monkey B virus). Comp Med 2014; 64: 386393.

    • Search Google Scholar
    • Export Citation
  • 22. Nasisse MP, Dorman DC, Jamison KC, et al. Effects of valacyclovir in cats infected with feline herpesvirus 1. Am J Vet Res 1997; 58: 11411144.

    • Search Google Scholar
    • Export Citation
  • 23. Eberle R, Black DH, Lehenbauer TW, et al. Shedding and transmission of baboon herpesvirus papio 2 (HVP2) in a breeding colony. Lab Anim Sci 1998; 48: 2328.

    • Search Google Scholar
    • Export Citation
  • 24. Azab W, Tsujimura K, Kato K, et al. Characterization of a thymidine kinase-deficient mutant of equine herpesvirus 4 and in vitro susceptibility of the virus to antiviral agents. Antiviral Res 2010; 85: 389395.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25. Boyd MR, Bacon TH, Sutton D, et al. Antiherpesvirus activity of 9-(4-hydroxy-3-hydroxy-methylbut-1-yl)guanine (BRL 39123) in cell culture. Antimicrob Agents Chemother 1987; 31: 12381242.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26. De Clercq E, Holy A, Rosenberg I, et al. A novel selective broad-spectrum anti-DNA virus agent. Nature 1986; 323: 464467.

  • 27. de la Fuente R, Awan AR, Field HJ. The acyclic nucleoside analogue penciclovir is a potent inhibitor of equine herpesvirus type 1 (EHV-1) in tissue culture and in a murine model. Antiviral Res 1992; 18: 7789.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28. Rollinson EA. Comparative efficacy of three 2′-fluoropyrimidine nucleosides and 9-(1,3-dihydroxy-2-propoxymethyl) guanine (BW B759U) against pseudorabies and equine rhinopneumonitis virus infection in vitro and in laboratory animals. Antiviral Res 1987; 7: 2533.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29. Smith KO, Galloway KS, Hodges SL, et al. Sensitivity of equine herpesviruses 1 and 3 in vitro to a new nucleoside analogue, 9-[[2-hydroxy-1-(hydroxymethyl) ethoxy] methyl] guanine. Am J Vet Res 1983; 44: 10321035.

    • Search Google Scholar
    • Export Citation
  • 30. Fang J, Jadhav PR. From in vitro EC50 to in vivo dose-response for antiretrovirals using an HIV disease model. Part II: application to drug development. J Pharmacokinet Pharmacodyn 2012; 39: 369381.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31. Tod M, Lokiec F, Bidault R, et al. Pharmacokinetics of oral acyclovir in neonates and in infants: a population analysis. Antimicrob Agents Chemother 2001; 45: 150157.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32. Garré B, Gryspeerdt A, Croubels S, et al. Evaluation of orally administered valacyclovir in experimentally EHV1-infected ponies. Vet Microbiol 2009; 135: 214221.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33. Goehring LS, Wagner B, Bigbie R, et al. Control of EHV-1 viremia and nasal shedding by commercial vaccines. Vaccine 2010; 28: 52035211.

    • Crossref
    • Search Google Scholar
    • Export Citation

Advertisement