Effective Oral Favipiravir (T-705) Therapy Initiated after the Onset of ClinicalDisease in a Model of Arenavirus Hemorrhagic Fever
PLoS Neglected Tropical Diseases
Lassa and Junín viruses are the most prominent members of the Arenaviridae family of viruses that cause viral hemorrhagic fever syndromes Lassa fever and Argentine hemorrhagic fever, respectively. At present, ribavirin is the only antiviral drug indicated for use in treatment of these diseases, but because of its limited efficacy in advanced cases of disease and its toxicity, safer and more effective antivirals are needed.
Here, we used a model of acute arenaviral infection in outbred guinea pigs based on challenge with an adapted strain of Pichindé virus (PICV) to further preclinical development of T-705 (Favipiravir), a promising broad-spectrum inhibitor of RNA virus infections. The guinea pig-adapted passage 19 PICV was uniformly lethal with an LD50 of ∼5 plaque-forming units and disease was associated with fever, weight loss, thrombocytopenia, coagulation defects, increases in serum aspartate aminotransferase (AST) concentrations, and pantropic viral infection. Favipiravir (300 mg/kg/day, twice daily orally for 14 days) was highly effective, as all animals recovered fully from PICV-induced disease even when therapy was initiated one week after virus challenge when animals were already significantly ill with marked fevers and thrombocytopenia. Antiviral activity and reduced disease severity was evidenced by dramatic reductions in peak serum virus titers and AST concentrations in favipiravir-treated animals. Moreover, a sharp decrease in body temperature was observed shortly after the start of treatment. Oral ribavirin was also evaluated, and although effective, the slower rate of recovery may be a sign of the drug's known toxicity.
Our findings support further development of favipiravir for the treatment of severe arenaviral infections. The optimization of the experimental favipiravir treatment regimen in the PICV guinea pig model will inform critical future studies in the same species based on challenge with highly pathogenic arenaviruses such as Lassa and Junín.
Several viruses in the Arenaviridae family cause severe life-threatening hemorrhagic fever syndromes, which are considered neglected tropical diseases in endemic areas of Africa and South America. Ribavirin, the only licensed antiviral indicated for use has limited efficacy when treating advanced cases of disease and is associated with toxicity. In the present study, we use a model of acute arenaviral disease in guinea pigs based on infection with an adapted strain of the Pichindé arenavirus (PICV) to further preclinical development of a promising broad-spectrum antiviral drug candidate, favipiravir. Oral favipiravir was highly effective in the treatment of sick animals with marked fevers, as all recovered fully from lethal PICV infection even when therapy was initiated one week after virus challenge. Antiviral activity and reduced disease severity was evidenced by dramatic reductions in serum virus loads and serum aspartate aminotransferase, an enzyme released into the bloodstream following tissue damage and a marker for severe arenaviral infections. Moreover, a sharp decrease in fever was observed shortly after the onset of treatment. Our findings support further development of favipiravir for the treatment of severe arenaviral infections, for which there are presently no safe and effective therapies for treating advanced cases of disease.
Mendenhall M, Russell A, Smee DF, Hall JO, Skirpstunas R, Furuta Y, and Gowen BB. (2011) Effective Oral Favipiravir (T-705) Therapy Initiated after the Onset of Clinical Disease in a Model of Arenavirus Hemorrhagic Fever. PLoS Negl Trop Dis 5(10): e1342. doi:10.1371/journal.pntd.0001342. 2011.