BACKGROUND: 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.
METHODOLOGY/PRINCIPAL FINDINGS: 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 LD(50) 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.
CONCLUSIONS/SIGNIFICANCE: 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.