Treatment of Late Stage Disease in a Model of Arenaviral Hemorrhagic Fever: T-705 Efficacy and Reduced Toxicity Suggests an Alternative to Ribavirin

PLoS One. 2008;3(11):e3725. doi: 10.1371/journal.pone.0003725. Epub 2008 Nov 14.

Abstract

A growing number of arenaviruses are known to cause viral hemorrhagic fever (HF), a severe and life-threatening syndrome characterized by fever, malaise, and increased vascular permeability. Ribavirin, the only licensed antiviral indicated for the treatment of certain arenaviral HFs, has had mixed success and significant toxicity. Since severe arenaviral infections initially do not present with distinguishing symptoms and are difficult to clinically diagnose at early stages, it is of utmost importance to identify antiviral therapies effective at later stages of infection. We have previously reported that T-705, a substituted pyrazine derivative currently under development as an anti-influenza drug, is highly active in hamsters infected with Pichinde virus when the drug is administered orally early during the course of infection. Here we demonstrate that T-705 offers significant protection against this lethal arenaviral infection in hamsters when treatment is begun after the animals are ill and the day before the animals begin to succumb to disease. Importantly, this coincides with the time when peak viral loads are present in most organs and considerable tissue damage is evident. We also show that T-705 is as effective as, and less toxic than, ribavirin, as infected T-705-treated hamsters on average maintain their weight better and recover more rapidly than animals treated with ribavirin. Further, there was no added benefit to combination therapy with T-705 and ribavirin. Finally, pharmacokinetic data indicate that plasma T-705 levels following oral administration are markedly reduced during the latter stages of disease, and may contribute to the reduced efficacy seen when treatment is withheld until day 7 of infection. Our findings support further pre-clinical development of T-705 for the treatment of severe arenaviral infections.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Absorption / drug effects
  • Administration, Oral
  • Alanine Transaminase / blood
  • Amides / administration & dosage
  • Amides / blood
  • Amides / therapeutic use*
  • Amides / toxicity*
  • Animals
  • Arenaviridae Infections / complications
  • Arenaviridae Infections / drug therapy*
  • Arenaviridae Infections / pathology
  • Arenaviridae Infections / virology
  • Aspartate Aminotransferases / blood
  • Cricetinae
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Hemorrhagic Fevers, Viral / complications
  • Hemorrhagic Fevers, Viral / drug therapy*
  • Hemorrhagic Fevers, Viral / pathology
  • Hemorrhagic Fevers, Viral / virology
  • Interferon Type I / blood
  • Liver Diseases / complications
  • Liver Diseases / pathology
  • Liver Diseases / virology
  • Mesocricetus
  • Pichinde virus / drug effects
  • Pyrazines / administration & dosage
  • Pyrazines / blood
  • Pyrazines / therapeutic use*
  • Pyrazines / toxicity*
  • Ribavirin / administration & dosage
  • Ribavirin / therapeutic use*
  • Survival Analysis
  • Treatment Outcome
  • Viral Load

Substances

  • Amides
  • Interferon Type I
  • Pyrazines
  • Ribavirin
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • favipiravir