The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset

Abstract

With up to 500,000 infections annually, Lassa virus (LASV), the cause of Lassa fever, is one of the most prevalent etiological agents of viral hemorrhagic fever (VHF) in humans. LASV is endemic in several West African countries with sporadic cases and prolonged outbreaks observed most commonly in Sierra Leone, Liberia, Guinea and Nigeria. Additionally several cases of Lassa fever have been imported into North America, Europe and Asia making LASV a global threat to public health. Despite this, currently no approved therapeutic or vaccine exists to treat or prevent LASV infections. Here, using a passaged strain of LASV that is uniformly lethal in Hartley guinea pigs, we demonstrate that favipiravir, a broad-spectrum antiviral agent and leading treatment option for influenza, has potent activity against LASV infection. In this model, once daily treatment with favipiravir significantly reduced viral titers in tissue samples and reduced mortality rates when compared with animals receiving vehicle-only or ribavirin, the current standard of care for Lassa fever. Favipiravir remained highly effective against lethal LASV infection when treatments were initiated nine days post-infection, a time when animals were demonstrating advanced signs of disease. These results support the further preclinical evaluation of favipiravir for Lassa fever and other VHFs.

Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses

“…Favipiravir, a pyrazine carboxamide derivative initially developed and approved for treatment against resistant influenza in Japan (10), is a relevant candidate, with several studies demonstrating its effectiveness against different HF viruses in vitro and in rodent models (10)(11)(12)(13)(14)(15)(16)(17)(18). This molecule is an RNA polymerase inhibitor, metabolized intracellularly into the active form favipiravir ribosyl triphosphate, which is thought to prevent viral RNA strand extension and induce lethal mutagenesis (10).…”

Favipiravir and Ribavirin Treatment of Epidemiologically Linked Cases of Lassa Fever

“…Treatment with ribavirin during the first 6 days of illness decreases mortality rates to 5% [4]. Favipiravir, a novel antiviral agent with broad-spectrum activity against RNA viruses, decreases levels of Lassa viremia and increases survival in animal models [5, 6]. We describe 2 cases of LF acquired via secondary spread from the same index case who survived after treatment with ribavirin and favipiravir.…”

Treatment of Lassa virus infection in outbred guinea pigs with first-in-class human monoclonal antibodies

“…Female outbred Hartley strain GP (~ 350-400 g, ~ 5-6 weeks old, Harlan Sprague Dawley, Houston, TX) were acclimatized for ~ 1 week prior to challenge intraperitoneally (IP) with 1000 plaque forming units of guinea pig adapted (GPA) LASV-Josiah (N=5/ treatment group). The GPA LASV infection model of outbred Hartley GP has been described recently for testing therapeutics against LASV (Safronetz et al, 2015). The advantage of using outbred animals to model human infection is inferred from the higher variability of immune responsiveness inherent in outbred populations allowing for increased countermeasure testing stringency versus those inbred for genetically tractable immune deficiencies which may, in turn, result in reduced predictive efficacy of the treatment in question by only testing a single immune phenotype rather than multiple at one time, as would be present in an outbred test population.…”