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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