Ebola virus disease treatment research

Researcher working with the Ebola virus while wearing a BSL-4 positive pressure suit

Ebola virus disease (research) or simply Ebola, is a disease that affects humans and other primates caused by ebolaviruses; there is no cure or specific treatment that is currently approved,[1] treatment is primarily supportive in nature.[2]

Overview

In March 2014, the World Health Organization (WHO) reported a major Ebola outbreak in Guinea, a western African nation.[3] The disease then rapidly spread to the neighboring countries of Liberia and Sierra Leone. The 2014 West African Ebola outbreak is the largest Ebola outbreak ever documented, and the first recorded in the region.[3]

The director of the US National Institute of Allergy and Infectious Diseases has stated that the scientific community is still in the early stages of understanding how infection with the Ebola virus can be treated and prevented.[4] The unavailability of treatments in the most-affected regions has spurred controversy, with some calling for experimental drugs to be made more widely available in Africa on a humanitarian basis, and others warning that making unproven drugs widely available would be unethical, especially in light of past experimentation conducted in developing countries by Western drug companies.[5][6] As a result of the controversy, on 12 August an expert panel of the WHO endorsed the use of interventions with as-yet-unknown effects for both treatment and prevention of Ebola, and also said that deciding which treatments should be used and how to distribute them equitably were matters that needed further discussion.[7]

Conventional trials to study efficacy by exposure of humans to the pathogen are obviously not feasible in this case. For such situations, the FDA has established the "Animal Efficacy Rule" allowing limited licensure to be approved on the basis of animal model studies that replicate human disease, combined with evidence of safety. A number of experimental treatments are being considered for use in the context of this outbreak, and are currently or will soon undergo clinical trials.[8] A distributed computing project, Outsmart Ebola Together, has been launched by World Community Grid in collaboration with the Scripps Research Institute to help find chemical compounds to fight the disease. It uses the idle processing capacity of volunteers' computers and tablets.[9]

The Centre for epidemic and microbiological research and treatment was constructed in the Guinean Kindia province. The Centre was designed and created by RUSAL specialists with the assistance of Rospotrebnadzor scientists (RUSAL has invested $10m).[10]

Experimental treatments being researched

Antibodies

  • ZMapp is a combination of three chimeric monoclonal antibodies effective in Ebola-infected monkeys.[11] Due to a limited supply of the antibody preparation, it was used to treat a small number of individuals infected with the Ebola virus early in the 2014-5 West Africa outbreak; although some individuals recovered, the outcome is not considered statistically significant.[12][13] The National Institutes of Health announced on 27 February 2015 the commencement of a randomized controlled trial of ZMapp to be conducted in Liberia and the United States.[14] From March 2015 through November 2015, 72 individuals infected with the Ebola virus were enrolled in the trial; investigators stopped enrolling new subjects in January 2016, having failed to reach its enrollment goal of 200 due to the waning of the Ebola outbreak. As a result, although a 40% lower risk of death was calculated for those who received ZMapp, the difference was not statistically significant and ultimately it could not be determined whether the use of ZMapp was superior to the optimized standard of care alone. However, ZMapp was found to be safe and well-tolerated.[15][16][17]
  • The mAb114 monoclonal antibody was derived from an EVD survivor of the 1995 DRC outbreak in Kikwit. It binds to the glycoprotein cap of the virus. As of 2016 it had not not been tested in humans, but been tested in three non-human primates; it worked less well at preventing disease when given alone than in combination with another mAb.[18][19][20]

Antivirals and other drugs

  • Favipiravir (Avigan) is a broad-spectrum antiviral drug, used to treat influenza,[17] which in a mouse model appears to be useful in treating Ebola disease.[21][22] A phase two clinical trial started in Guinea during December 2014,[23][24] with early reports indicating that it has some benefit.[25]
  • Ribavirin, an antiviral drug, delayed death and increased survival rate in both mouse and monkey models; adverse effects, such as birth defects and red blood cell breakdown, limit its use.[17]
  • BCX4430 is a broad-spectrum nucleoside analog antiviral drug developed by BioCryst Pharmaceuticals.[26] A phase one trial started in December 2014.[27][28] The drug was effective in Ebola-infected monkeys.[29]
  • Brincidofovir, an antiviral drug, has been granted an emergency FDA approval as an investigational new drug for the treatment of Ebola after it was found to be effective against Ebola virus in in vitro tests.[30] A phase two trial started during January 2015 in Liberia, but was subsequently discontinued due to a lack of suitable subjects.[31][32][33]
  • TKM-Ebola is an RNA interference drug candidate; a Phase II trial started on 11 March 2015 and stopped enrolling new subjects on 19 June 2015 after it appeared not to work; statistical analysis was ongoing at the time.[34][35]
  • AVI-7537 is an antiviral drug developed by Sarepta Therapeutics, which was effective in Ebola-infected monkeys.[36][37] A phase one trial May 2010 to November 2011 showed that the drug was safe in healthy adults;[38][39] however, a later phase one trial was withdrawn due to funding constraints.[40]
  • JK-05 is an antiviral drug developed by Sihuan Pharmaceutical along with Academy of Military Medical Sciences. In tests on mice, JK-05 shows efficacy against a range of viruses, including Ebola. It is claimed to have a simple molecular structure, which should be readily amenable to synthesis scale-up for mass production. The drug has been given preliminary approval by the Chinese authorities to be available for Chinese health workers involved in combating the outbreak, and Sihuan are preparing to conduct clinical trials in West Africa.[41][42]

Blood products

The WHO has stated that transfusion of whole blood or purified serum from Ebola survivors has the greatest potential to be implemented immediately, and has issued an interim guideline for this therapy.[43] A study in Sierra Leone started in November 2014, and preliminary results show an 80 percent survival rate.[44] Trials in Liberia and Guinea started in January 2015, with funding from the Gates Foundation.[45] Blood transfusions were also used in a 1995 outbreak in the Democratic Republic of the Congo, and 7 out of 8 patients survived.[46]

Existing drugs without anti-Ebola activity

Ribavirin is also known to be ineffective against ebolaviruses despite its effectiveness against other viral hemorrhagic fevers such as Lassa fever.[47] Interferon therapies have been tried as a form of treatment for EVD, but were found to be ineffective.[48]

Potential diagnostic tests

One issue which hinders control of Ebola is that diagnostic tests which are currently available require specialised equipment and highly trained personnel. Since there are few suitable testing centres in West Africa, this leads to delay in diagnosis. In December, a conference in Geneva will aim to work out which diagnostic tools could identify Ebola reliably and more quickly. The meeting, convened by the WHO and the non-profit Foundation for Innovative New Diagnostics, seeks to identify tests that can be used by untrained staff, do not require electricity or can run on batteries or solar power and use reagents that can withstand temperatures of 40 °C.[49]

As of February  2015 a number of diagnostic tests are under trial:

  • Diagnostics-in-a-Suitcase, based on recombinase polymerase amplification (RPA). The new equipment, about the size of a laptop and solar-powered, allows testing to be done in remote areas; testing commenced in Guinea during January 2015.[50]
  • In December 2014, the FDA approved LightMix (R) Ebola Zaire rRT-PCR Test for emergency use on patients with symptoms of Ebola.[51]
  • Massachusetts Institute of Technology has developed a 10-minute Ebola test using Matrix Multiplexed Diagnostic (MMDx) technology. This still has to complete testing to gain FDA approval.[52]
  • Corgenix Medical Corp announced on 26 February that health regulators had approved its rapid Ebola test for emergency use. The ReEBOV Antigen Rapid Test involves putting a drop of blood on a paper strip and waiting for at least 15 minutes for a reaction.[53]
  • On 29 March, a new rapid Ebola virus diagnostic kit/test was developed by British military scientists and NHS in Sierra Leone.[54]

Hemopurifier

The Hemopurifier is a single-use disposable cartridge designed for use with dialysis machines and other blood circulatory pumps. It functions to selectively remove harmful substances from the blood, giving a potential method of addressing diseases. During October 2014 the Hemopurifier was used as an adjunct in the treatment of a patient who was suffering from Ebola, who subsequently recovered.[55] The FDA has subsequently approved the device for testing in up to 20 infected Ebola cases in the United States.[56]

See also

References

  1. ↑ Choi JH, Croyle MA (December 2013). "Emerging targets and novel approaches to Ebola virus prophylaxis and treatment". BioDrugs. 27 (6): 565–83. doi:10.1007/s40259-013-0046-1. PMC 3833964. PMID 23813435.
  2. ↑ Clark DV, Jahrling PB, Lawler JV (September 2012). "Clinical management of filovirus-infected patients". Viruses. 4 (9): 1668–86. doi:10.3390/v4091668. PMC 3499825. PMID 23170178.
  3. 1 2 "Guidelines for Evaluation of US Patients Suspected of Having Ebola Virus Disease". CDC. 1 August 2014. Retrieved 5 August 2014.
  4. ↑ Roberts, Dan. "Ebola CDC director warns Ebola like 'forest fire' as Congress readies for hearing - Ebola crisis live updates". The Guardian. Retrieved 1 October 2014.
  5. ↑ "Three leading Ebola experts call for release of experimental drug". Los Angeles Times. 6 August 2014.
  6. ↑ "In Ebola Outbreak, Who Should Get Experimental Drug?". The New York Times. 8 August 2014.
  7. ↑ "Ethical considerations for use of unregistered interventions for Ebola viral disease (EVD)". World Health Organization. 12 August 2014.
  8. ↑ Briggs H (7 August 2014). "Ebola: Experimental drugs and vaccines". BBC News, Health. Retrieved 1 August 2014.
  9. ↑ Park A (19 December 2014). "How Your Tablet Can Help Find an Ebola Cure". Retrieved 19 December 2014.
  10. ↑ "Ebola 2.0 – Lessons Learned in 2014 May Not Suffice". Africa Times. 2017-05-22. Retrieved 2017-05-25.
  11. ↑ Seppa N (29 August 2014). "ZMapp drug fully protects monkeys against Ebola virus". Science News. Society for Science & the Public. Retrieved 1 October 2014.
  12. ↑ Tosh PK, Sampathkumar P (December 2014). "What clinicians should know about the 2014 Ebola outbreak". Mayo Clinic Proceedings. 89 (12): 1710–7. doi:10.1016/j.mayocp.2014.10.010. PMID 25467644.
  13. ↑ Kroll D (26 August 2014). "How will we know if the Ebola drugs worked?". Forbes. Retrieved 1 October 2014.
  14. ↑ "Liberia-U.S. clinical research partnership opens trial to test Ebola treatments". National Institutes of Health (NIH). Retrieved 27 February 2015.
  15. ↑ "Press release: Study Finds Ebola Treatment ZMapp Holds Promise, Although Results Not Definitive | NIH: National Institute of Allergy and Infectious Diseases". National Institute of Allergy and Infectious Diseases. October 12, 2016.
  16. ↑ Bixler SL, Duplantier AJ, Bavari S (2017). "Discovering Drugs for the Treatment of Ebola Virus". Current Treatment Options in Infectious Diseases. 9 (3): 299–317. doi:10.1007/s40506-017-0130-z. PMC 5570806. PMID 28890666.
  17. 1 2 3 Dhama K, Karthik K, Khandia R, Chakraborty S, Munjal A, Latheef SK, et al. (2018). "Advances in Designing and Developing Vaccines, Drugs, and Therapies to Counter Ebola Virus". Frontiers in Immunology. 9: 1803. doi:10.3389/fimmu.2018.01803. PMC 6095993. PMID 30147687.
  18. ↑ Moekotte AL, Huson MA, van der Ende AJ, Agnandji ST, Huizenga E, Goorhuis A, et al. (November 2016). "Monoclonal antibodies for the treatment of Ebola virus disease". Expert Opinion on Investigational Drugs. 25 (11): 1325–1335. doi:10.1080/13543784.2016.1240785. PMID 27676206.
  19. ↑ Hayden EC (25 February 2016). "Ebola survivor's blood holds promise of new treatment". Nature. doi:10.1038/nature.2016.19440.
  20. ↑ Corti D, Misasi J, Mulangu S, Stanley DA, Kanekiyo M, Wollen S, et al. (March 2016). "Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody". Science. 351 (6279): 1339–42. doi:10.1126/science.aad5224. PMID 26917593.
  21. ↑ Gatherer D (August 2014). "The 2014 Ebola virus disease outbreak in West Africa". The Journal of General Virology. 95 (Pt 8): 1619–24. doi:10.1099/vir.0.067199-0. PMID 24795448.
  22. ↑ Oestereich L, Lüdtke A, Wurr S, Rieger T, Muñoz-Fontela C, Günther S (May 2014). "Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model". Antiviral Research. 105: 17–21. doi:10.1016/j.antiviral.2014.02.014. PMID 24583123.
  23. ↑ "Guinea: Clinical Trial for Potential Ebola Treatment Started in MSF Clinic in Guinea". AllAfrica – All the Time. Retrieved 28 December 2014.
  24. ↑ "Efficacy of Favipiravir Against Ebola (JIKI)". ClinicalTrials.gov. U.S. National Institutes of Health. Retrieved 1 August 2015.
  25. ↑ "Fujifilm's Toyama unit set to publish promising early clinical results in treating Ebola". Retrieved 7 February 2015.
  26. ↑ Kroll D (29 August 2014). "BioCryst to Launch NHP Ebola Drug Safety, Efficacy Studies 'Within Weeks'". Forbes. Retrieved 5 October 2014.
  27. ↑ "DURHAM: BioCryst receives additional funding for Ebola drug". WNCN. 18 September 2014. Retrieved 5 October 2014.
  28. ↑ "A Phase 1 Study to Evaluate the Safety, Tolerability and Pharmacokinetics of BCX4430". ClinicalTrials.gov. U.S. National Institutes of Health. Retrieved 1 August 2015.
  29. ↑ "BioCryst's Ebola drug shows promise in animal study". Reuters. Retrieved 27 December 2014.
  30. ↑ Staff (3 September 2014). "Chimerix experimental drug shows promise in fighting Ebola virus". WNCN. Retrieved 7 October 2014.
  31. ↑ "Trials of untested Ebola drugs begin in West Africa". Reuters. Retrieved 6 January 2015.
  32. ↑ "Chimerix's Brincidofovir Selected for Use in Ebola Clinical Trial in West Africa by International Consortium". Chimerix, Inc. Retrieved 1 August 2015.
  33. ↑ "Chimerix Ends Brincidofovir Ebola Trials To Focus On Adenovirus And CMV". Forbes. Retrieved 31 January 2015.
  34. ↑ Kupferschmidt K (11 March 2015). "New Ebola drug trial starts in Sierra Leone". Science Magazine. AAAS. Retrieved 1 August 2015.
  35. ↑ Vogel G, Kupferschmidt K (19 June 2015). "In setback for potential Ebola drug, company halts trial". news.sciencemag.org. Retrieved 24 June 2015.
  36. ↑ Blum K. "Drug Targeting Ebola Virus Protein VP24 Shows Promise in Monkeys". mBiosphere. American Society for Microbiology. Retrieved 1 August 2015.
  37. ↑ "AVI 6002 (AVI-7537) Drug Therapy (Sarepta Therapeutics) for Treating Ebola Virus Disease". ECRI Institute. Retrieved 1 August 2015.
  38. ↑ Heald AE, Iversen PL, Saoud JB, Sazani P, Charleston JS, Axtelle T, et al. (November 2014). "Safety and pharmacokinetic profiles of phosphorodiamidate morpholino oligomers with activity against Ebola virus and Marburg virus: results of two single-ascending-dose studies". Antimicrobial Agents and Chemotherapy. 58 (11): 6639–47. doi:10.1128/AAC.03442-14. PMC 4249403. PMID 25155593.
  39. ↑ "Safety Study of Single Administration Post-Exposure Prophylaxis Treatment for Ebola Virus". ClinicalTrials.gov. U.S. National Institutes of Health. Retrieved 1 August 2015.
  40. ↑ "A Study to Assess the Safety, Tolerability and Pharmacokinetics of AVI-7537 in Healthy Adult Volunteers". ClinicalTrials.gov. U.S. National Institutes of Health. Retrieved 1 August 2015.
  41. ↑ "China approves Ebola drug for emergency use. Kristine Yang, Bioworld.com". BioWorld.
  42. ↑ "China sends Ebola drug to Africa, eyes clinical trials". Reuters. Retrieved 31 October 2014.
  43. ↑ "Use of convalescent whole blood or plasma collected from patients recovered from Ebola virus disease Empirical treatment during outbreaks". WHO. Retrieved 4 October 2014.
  44. ↑ Maxmen A (16 February 2015). "Blood transfusions show early promise as possible Ebola cure". Al Jazeera America. Retrieved 1 August 2015.
  45. ↑ Butler D (15 December 2014). "First trials of blood-based Ebola therapy kick off". Nature News. Retrieved 1 August 2015.
  46. ↑ Mupapa K, Massamba M, Kibadi K, Kuvula K, Bwaka A, Kipasa M, et al. (February 1999). "Treatment of Ebola hemorrhagic fever with blood transfusions from convalescent patients. International Scientific and Technical Committee". The Journal of Infectious Diseases. 179 Suppl 1 (s1): S18–23. doi:10.1086/514298. PMID 9988160.
  47. ↑ Goeijenbier M, van Kampen JJ, Reusken CB, Koopmans MP, van Gorp EC (November 2014). "Ebola virus disease: a review on epidemiology, symptoms, treatment and pathogenesis". The Netherlands Journal of Medicine. 72 (9): 442–8. PMID 25387613.
  48. ↑ Chippaux JP (October 2014). "Outbreaks of Ebola virus disease in Africa: the beginnings of a tragic saga". The Journal of Venomous Animals and Toxins Including Tropical Diseases. 20 (1): 44. doi:10.1186/1678-9199-20-44. PMC 4197285. PMID 25320574.
  49. ↑ "Ebola Experts Seek to Expand Testing". Scientific American. Retrieved 11 December 2014.
  50. ↑ Paddock C (9 January 2015). "'Lab in a suitcase' set to improve Ebola virus control". Medical News Today. Retrieved 11 April 2015.
  51. ↑ Falconi M (29 December 2014). "Roche Secures Emergency Approval by U.S. Regulators for Ebola Test". WSJ. Retrieved 29 December 2014.
  52. ↑ "MIT designs 10-minute ebola test". gizmag.com. Retrieved 26 February 2015.
  53. ↑ "FDA approves Corgenix's Ebola test for emergency use". Reuters. Retrieved 27 February 2015.
  54. ↑ O'Carroll L. "Ebola rapid diagnostic kit developed by UK scientists in Sierra Leone". the Guardian. Retrieved 10 April 2015.
  55. ↑ "New Ebola Treatment Filters Virus Out of the Blood". Time. Retrieved 3 January 2015.
  56. ↑ "FDA allows testing of Aethlon device in Ebola patients". Reuters. 2 January 2015. Retrieved 2 January 2015.

Further reading

  • "Ebola virus disease Information for Clinicians in U.S. Healthcare Settings | Ebola Hemorrhagic Fever | CDC". www.cdc.gov. Centers for Disease Control and Prevention. Retrieved 19 July 2016.
  • Nelson EA, Barnes AB, Wiehle RD, Fontenot GK, Hoenen T, White JM (August 2016). "Clomiphene and Its Isomers Block Ebola Virus Particle Entry and Infection with Similar Potency: Potential Therapeutic Implications". Viruses. 8 (8): 206. doi:10.3390/v8080206. PMID 27490565.
  • Morais V (26 August 2016). "An Old Solution for a New Problem: Antiserum against Emerging Infectious Diseases". Frontiers in Public Health. 4: 178. doi:10.3389/fpubh.2016.00178. PMC 5000394. PMID 27617259.
  • "Ebola/Marburg Research". www.niaid.nih.gov. NIH: National Institute of Allergy and Infectious Diseases. Retrieved 29 August 2016.
  • "Medscape: Ebola Virus RNA Evident in Semen for a year or longer". www.medscape.com. Medscape. Retrieved 1 September 2016.
  • Leligdowicz A, Fischer WA, Uyeki TM, Fletcher TE, Adhikari NK, Portella G, Lamontagne F, Clement C, Jacob ST, Rubinson L, Vanderschuren A, Hajek J, Murthy S, Ferri M, Crozier I, Ibrahima E, Lamah MC, Schieffelin JS, Brett-Major D, Bausch DG, Shindo N, Chan AK, O'Dempsey T, Mishra S, Jacobs M, Dickson S, Lyon GM, Fowler RA (July 2016). "Ebola virus disease and critical illness". Critical Care. 20 (1): 217. doi:10.1186/s13054-016-1325-2. PMID 27468829.
  • Davey RT, Dodd L, Proschan MA, Neaton J, Neuhaus Nordwall J, Koopmeiners JS, et al. (October 2016). "A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection". The New England Journal of Medicine. 375 (15): 1448–1456. doi:10.1056/NEJMoa1604330. PMC 5086427. PMID 27732819.
  • González VM, Martín ME, Fernández G, García-Sacristán A (December 2016). "Use of Aptamers as Diagnostics Tools and Antiviral Agents for Human Viruses". Pharmaceuticals. 9 (4): 78. doi:10.3390/ph9040078. PMID 27999271.
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