Ebola virus treatment: A practical approach

health-care workers in 2014 ebola virus outbreal

Health-care workers treating Ebola virus patients

Attempts to stop the current Ebola virus outbreak has reveled both a dearth of commercially available antivirals with which to treat the infection and the glacial rate of governmental drug approval. Both have impeded resolution of the current Ebola crisis. While drug safety should always be foremost, given the increasing rates of new infection and death, one must ask: “Are there no Ebola virus treatment option(s) for use singly or in combination that are readily available, found safe and proven effective in reversing the course of Ebola virus infection?”

Summarized below is a listing of approved or late clinical stage anti-Ebola virus antivirals that one might consider for treatment of Ebola virus infections.

Drug (class) Mode of action  Treatment
 Best utilized  Survival rates (animal model) Pros Cons Current status
rVIIa/tissue factor inhibitor(biologic) reduces coagulation, fibrinolysis, and cytokine inflammation Daily injections <1 days after infection 33%rhesus monkey Alleviates major vascular symptomslow toxicity Does not stop virus replication Approved for human use
Anti-Ebola IgG (biologic) Blocks virion glycoprotein attachment to cell Alternate days injections < 6days after infection 43%rhesus monkey Low toxicitySpecific to Ebola virus Long lead times (months) to manufacture and process   Pre-clinical
iRNAs (Oligonucleotide) Targets virus RNAs that encode VP24, VP35, RNA polymerase L Daily injections Upon suspected infection   70%rhesus monkey Ease of manufactureHigh specificity inefficient tissue targetinghigh doses required ~6mg/kg/dose/day  Pre-clinical
Clomiphene / Toremifene(estrogen receptor antagonists) Inhibits virus entry and internalization Dailyoral Pre or stage 1 symptoms < day 2 90%Clomiphene
70% Toremifenemouse
low virus specificity  FDA approved
Favipiravir (T-705) (purine nucleotide analog) misincorporation leads to lethal virus mutation Dailyoral < 6 days after symptoms occur 100%mouse Virus RNA polymerase specificlow effective dose:IC90: 100 ?Molar  Phase 2 &3approval for use as an influenza virus antiviral

References

1. Furuta, Y., B. B. Gowen, K. Takahashi, K. Shiraki, D. F. Smee, and D. L. Barnard. 2013. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 100:446-454. PubMed
2. Geisbert, T. W., L. E. Hensley, P. B. Jahrling, T. Larsen, J. B. Geisbert, J. Paragas, H. A. Young, T. M. Fredeking, W. E. Rote, and G. P. Vlasuk. 2003. Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet 362:1953-1958. PubMed
3. Geisbert, T. W., A. C. Lee, M. Robbins, J. B. Geisbert, A. N. Honko, V. Sood, J. C. Johnson, J. S. de, I. Tavakoli, A. Judge, L. E. Hensley, and I. Maclachlan. 2010. Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Lancet 375:1896-1905. PubMed
4. Johansen, L. M., J. M. Brannan, S. E. Delos, C. J. Shoemaker, A. Stossel, C. Lear, B. G. Hoffstrom, L. E. Dewald, K. L. Schornberg, C. Scully, J. Lehar, L. E. Hensley, J. M. White, and G. G. Olinger. 2013. FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection. Sci.Transl.Med. 5:190ra79. PubMed
5. Oestereich, L., A. Ludtke, S. Wurr, T. Rieger, C. Munoz-Fontela, and S. Gunther. 2014. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res. 105:17-21. PubMed
6. Olinger, G. G., Jr., J. Pettitt, D. Kim, C. Working, O. Bohorov, B. Bratcher, E. Hiatt, S. D. Hume, A. K. Johnson, J. Morton, M. Pauly, K. J. Whaley, C. M. Lear, J. E. Biggins, C. Scully, L. Hensley, and L. Zeitlin. 2012. Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques. Proc.Natl.Acad.Sci.U.S A 109:18030-18035. PubMed
7. Qiu, X., J. Audet, G. Wong, L. Fernando, A. Bello, S. Pillet, J. B. Alimonti, and G. P. Kobinger. 2013. Sustained protection against Ebola virus infection following treatment of infected nonhuman primates with ZMAb. Sci.Rep. 3:3365. PubMed
8. Warfield, K. L., D. L. Swenson, G. G. Olinger, D. K. Nichols, W. D. Pratt, R. Blouch, D. A. Stein, M. J. Aman, P. L. Iversen, and S. Bavari. 2006. Gene-specific countermeasures against Ebola virus based on antisense phosphorodiamidate morpholino oligomers. PLoS.Pathog. 2:e1. PubMed

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