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Favipiravir Treatment of Lassa: A Broad-Spectrum RNA Antiviral

Amesh A. Adalja, MD, FACP, FACEP, FIDSA, June 27, 2018

One of the challenges with most of the high-consequence viral infectious diseases is that very few specific antiviral medications are available for their treatment. The reason for this lack of countermeasures is multifactorial and is largely influenced by the fact that many of these infections are rare, unpredictable, and do not present a lucrative market opportunity. One means to overcome some of these difficulties is to repurpose other antiviral agents that may have broader spectrums of activities that allow them to have effects on more than one viral family. A new study just published in Emerging Infectious Diseases reports on the use of the influenza antiviral favipiravir for Lassa fever and provides an example of this strategy.1 

 

Lassa: An Endemic Hemorrhagic Fever

Lassa fever is a viral hemorrhagic fever endemic in parts of West Africa. The disease is primarily spread to humans through exposure to rodents, but nosocomial spread can also occur. It confers a considerable morbidity and mortality, with severe disease occurring in 20% of diagnosed cases, leading to 5,000 deaths per year. The current accepted treatment is intravenous ribavirin. 

In the study in EID, Rosenke and colleagues assessed the impact of favipiravir on Lassa fever in a cynomolgus macaque model that largely replicates the human experience with the virus. Lethal doses of Lassa were injected into 4 animals, while 4 others served as controls. Treatment was begun 4 days post-infection. Dosing was 300 mg/kg, and the initial dose was intravenous, with subsequent dosing subcutaneous. The drug was administered daily for 14 days. Clinical scoring was lower in the treatment group, all of whom survived. The control group all reached an endpoint that prompted euthanasia by day 12. Additionally, no infectious virus was isolated from the blood or autopsy specimens of treated macaques.1 

 

A Broad-Spectrum RNA Virus Antiviral?

Favipiravir is an antiviral compound licensed in Japan for the treatment of influenza and whose mechanism of action is thought to block the viral RNA-dependent polymerase enzyme.2 Its activity is thought to be useful against a wide range of RNA viruses. The current study, coupled with the successful recent use of oral favipiravir in combination with ribavirin in 2 human Lassa cases,3 raises the possibility of a new treatment for Lassa fever. More important in my analysis is that the modest success of this drug against Lassa fever, in addition to its efficacy against a virus from a distinct family (influenza), is proof-of-concept that at least a pan-RNA antiviral might be feasible. Although favipiravir did not appear to have efficacy against the RNA Ebola virus during the West African Ebola outbreak (possibly related to dosing), its activity against other RNA viruses might prove useful. Determining the optimal dosing protocol specific to each viral agent, which will each have disparate favipiravir inhibition concentrations, will be necessary, as will studies looking at its use in combination with other antivirals, such as ribavirin, when treating Lassa.

In a recent report that my colleagues and I released on the characteristics of pandemic pathogens, we identified RNA viruses as posing the highest risk of causing a global catastrophic biological event. We also issued a recommendation for broad-spectrum antiviral agents whose activity spans ranges of viruses.4 This study is an important contribution to that effort and should be further investigated. 

 

References

  1. Rosenke K, Feldmann H, Westover JB, et al. Use of favipiravir to treat Lassa virus infection in macaques. Emerg Infect Dis 2018;24(9).https://wwwnc.cdc.gov/eid/article/24/9/18-0233_article. Accessed June 27, 2018.
  2. Sissoko D, Laouenan C, Folkesson E, et al.; JIKI Study Group. Experimental treatment with favipiravir for Ebola virus disease (the JIKI Trial): a historically controlled, single-arm proof-of-concept trial in Guinea. PLoS Med 2016;13(6):e1002066.
  3. Raabe VN, Kann G, Ribner BS, et al. Favipiravir and ribavirin treatment of epidemiologically linked cases of Lassa fever. Clin Infect Dis 2017;65:855-859.
  4. Adalja AA, Watson M, Toner ES, Cicero A, Inglesby TV. The Characteristics of Pandemic Pathogens. Baltimore, MD: Johns Hopkins Center for Health Security; 2018. http://www.centerforhealthsecurity.org/our-work/pubs_archive/pubs-pdfs/2018/180510-pandemic-pathogens-report.pdf. Accessed June 26, 2018.