| | | ivermectin use. After a discussion period, a vote was held on multiple aspects of the data on ivermectin, according to standard WHO guideline development processes. The Panel found the certainty of evidence for ivermectin's effects on survival to be strong and they recommended unconditional adoption for use in the prophylaxis and treatment of COVID-19.
In summary, based on the totality of the trials and epidemiologic evidence presented in this review along with the preliminary findings of the Unitaid/WHO meta-analysis of treatment RCTs and the guideline recommendation from the international BIRD conference, ivermectin should be globally and systematically deployed in the prevention and treatment of COVID-19.
Go to:
Footnotes
G. U. Meduri's contribution is the result of work supported with the resources and use of facilities at the Memphis VA Medical Center. The contents of this commentary do not represent the views of the US Department of Veterans Affairs or the US Government.
The authors have no conflicts of interest to declare.
Contributed byP. Kory and G. U. Meduri have contributed equally to this work.
Contributed byStudy conception and design: P. Kory and G. . Meduri. Acquisition of data: Paul Marik and Jose Iglesias. Analysis and interpretation of data: Paul Marik, P. Kory, and Jose Iglesias. Drafting of manuscript: P. Kory. Critical revision: G. U. Meduri and Joseph Varon.
Off-Label Use: This manuscript includes discussion of off-label use in COVID-19 of the FDA-approved medication ivermectin.
Go to:
REFERENCES
1. Hermine O, Mariette X, Tharaux PL, et al. . Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181:32–40. [ PMC free article] [ PubMed] [ Google Scholar]
2. Salvarani C, Dolci G, Massari M, et al. . Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181:24–31. [ PMC free article] [ PubMed] [ Google Scholar]
3. Agarwal A, Mukherjee A, Kumar G, et al. . Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020;371:m3939. [ PMC free article] [ PubMed] [ Google Scholar]
4. Consortium WST. Repurposed antiviral drugs for covid-19— interim WHO solidarity trial results. New Engl J Med. 2020;384:497–511. [ PMC free article] [ PubMed] [ Google Scholar]
5. World Health Organization. Corticosteroids for COVID-19: living guidance. World Health Organization, September 2, 2020. Available at: apps.who.int.
6. Horby P, Lim WS, Emberson JR, et al. . Dexamethasone in hospitalized patients with Covid-19-preliminary report. New Engl J Med. 2020;384:693–704. [ PMC free article] [ PubMed] [ Google Scholar]
7. Crump A, Omura S. Ivermectin,‘wonder drug’from Japan: the human use perspective. Proc Jpn Acad Ser B. 2011;87:13–28. [ PMC free article] [ PubMed] [ Google Scholar]
8. Tambo E, Khater EI, Chen JH, et al. . Nobel prize for the artemisinin and ivermectin discoveries: a great boost towards elimination of the global infectious diseases of poverty. Infect Dis Poverty. 2015;4:58. [ PMC free article] [ PubMed] [ Google Scholar]
9. Atkinson SC, Audsley MD, Lieu KG, et al. . Recognition by host nuclear transport proteins drives disorder-to-order transition in Hendra virus V. Sci Rep. 2018;8:358. [ PMC free article] [ PubMed] [ Google Scholar]
10. Yang SNY, Atkinson SC, Wang C, et al. . The broad spectrum antiviral ivermectin targets the host nuclear transport importin a/ß1 heterodimer. Antivir Res. 2020;177:104760. [ PubMed] [ Google Scholar]
11. Götz V, Magar L, Dornfeld D, et al. . Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. Sci Rep. 2016;6:23138. [ PMC free article] [ PubMed] [ Google Scholar]
12. Lv C, Liu W, Wang B, et al. . Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antivir Res. 2018;159:55–62. [ PubMed] [ Google Scholar]
13. Mastrangelo E, Pezzullo M, De Burghgraeve T, et al. . Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J Antimicrob Chemother. 2012;67:1884–1894. [ PMC free article] [ PubMed] [ Google Scholar]
14. Tay MYF, Fraser JE, Chan WKK, et al. . Nuclear localization of dengue virus (DENV) 1–4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antiviral Res. 2013;99:301–306. [ PubMed] [ Google Scholar]
15. Varghese FS, Kaukinen P, Gläsker S, et al. . Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses. Antivir Res. 2016;126:117–124. [ PubMed] [ Google Scholar]
16. Wagstaff Kylie M, Sivakumaran H, Heaton Steven M, et al. . Ivermectin is a specific inhibitor of importin a/ß-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012;443:851–856. [ PMC free article] [ PubMed] [ Google Scholar]
17. King CR, Tessier TM, Dodge MJ, et al. . Inhibition of human adenovirus replication by the importin a/ß1 nuclear import inhibitor ivermectin. J Virol. 2020;94:94. [ PMC free article] [ PubMed] [ Google Scholar]
18. Caly L, Druce JD, Catton MG, et al. . The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antivir Res. 2020;178:104787. [ PMC free article] [ PubMed] [ Google Scholar]
19. Bray M, Rayner C, Noël F, et al. . Ivermectin and COVID-19: a report in Antiviral Research, widespread interest, an FDA warning, two letters to the editor and the authors' responses. Antiviral Res. 2020;178:104805. [ PMC free article] [ PubMed] [ Google Scholar]
20. Schmith VD, Zhou J, Lohmer LR. The approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19. Clin Pharmacol Ther. 2020;103:214–216. [ PMC free article] [ PubMed] [ Google Scholar]
21. Dayer M.R. Coronavirus (2019-nCoV) deactivation via spike glycoprotein shielding by old drugs, bioinformatic study. Preprints. 2020. doi: 10.20944/preprints202005.0020.v1. [ Google Scholar]
22. Maurya DK. A combination of ivermectin and doxycycline possibly blocks the viral entry and modulate the innate immune response in COVID-19 patients. ChemRxiv. 2020. doi: 10.26434/chemrxiv.12630539.v1. [ Google Scholar]
23. Hussien MA, Abdelaziz AEM. Molecular docking suggests repurposing of brincidofovir as a potential drug targeting SARS-CoV-2 ACE2 receptor and main protease. Netw Model Anal Health Inform Bioinform. 2020;9:56–18. [ PMC free article] [ PubMed] [ Google Scholar]
24. Suravajhala R, Parashar A, Malik B, et al. . Comparative docking studies on curcumin with COVID-19 proteins. Preprints. 2020. doi: 10.20944/preprints202005.0439.v1. [ Google Scholar]
25. Nallusamy S, Mannu J, Ravikumar C, et al. Shortlisting phytochemicals exhibiting inhibitory activity against major proteins of SARS-CoV-2 through virtual screening. Res Square. 2020. Doi: 10.21203/rs.3.rs-31834/v1. [ Google Scholar]
26. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2. Vivo. 2020;34:3023–3026. [ PMC free article] [ PubMed] [ Google Scholar]
27. Scheim D. From cold to killer: how SARS-CoV-2 evolved without hemagglutinin esterase to agglutinate, then clot blood cells in pulmonary and systemic microvasculature. SSRN. 2020. Doi: 10.2139/ssrn.3706347. [ CrossRef] [ Google Scholar]
28. Dasgupta J, Sen U, Bakshi A, et al. . Nsp7 and spike glycoprotein of SARS-CoV-2 are envisaged as potential targets of vitamin D and ivermectin. Preprints. 2020. doi: 10.20944/preprints202005.0084.v1. [ Google Scholar]
29. Sen Gupta PS, Biswal S, Panda SK, et al. . Binding mechanism and structural insights into the identified protein target of COVID-19 and importin-alpha with in-vitro effective drug ivermectin. J Biomol Struct Dyn. 2020:1–10. [ PMC free article] [ PubMed] [ Google Scholar]
30. Swargiary A. Ivermectin as a Promising RNA-dependent RNA Polymerase Inhibitor and a Therapeutic Drug against SARS-CoV2: Evidence from in Silico Studies. Res Square. 2020. Doi: 10.21203/rs.3.rs-73308/v1. [ Google Scholar]
31. Arevalo AP, Pagotto R, Porfido J, et al. . Ivermectin reduces coronavirus infection in vivo: a mouse experimental model. bioRxiv. 2020. doi:10.1101/2020.11. [ Google Scholar]
32. de Melo GD, Lazarini F, Larrous F, et al. . Anti-COVID-19 efficacy of ivermectin in the golden hamster. bioRxiv. 2020. doi: 10.1101/2020.11.21.392639. [ Google Scholar]
33. Perera RA, Tso E, Tsang OT, et al. . SARS-CoV-2 virus culture from the upper respiratory tract: correlation with viral load, subgenomic viral RNA and duration of illness. MedRXiv. 2020. doi: 10.1101/2020.07.08.20148783. [ Google Scholar]
34. Polak SB, Van Gool IC, Cohen D, et al. . A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression. Mod Pathol. 2020;33:2128–2138. [ PMC free article] [ PubMed] [ Google Scholar]
35. Young BE, Ong SW, Ng LF, et al. . Viral dynamics and immune correlates of COVID-19 disease severity. Clin Infect Dis. 2020. Available at: bookcafe.yuntsg.com. [ PMC free article] [ PubMed] [ Google Scholar]
36. Li Y, Chen M, Cao H, et al. . Extraordinary GU-rich single-strand RNA identified from SARS coronavirus contributes an excessive innate immune response. Microbes Infect. 2013;15:88–95. [ PMC free article] [ PubMed] [ Google Scholar]
37. Zhang X, Song Y, Xiong H, et al. . Inhibitory effects of ivermectin on nitric oxide and prostaglandin E2 production in LPS-stimulated RAW 264.7 macrophages. Int Immunopharmacol. 2009;9:354–359. [ PubMed] [ Google Scholar]
38. Ci X, Li H, Yu Q, et al. . Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway. Fundam Clin Pharmacol. 2009;23:449–455. [ PubMed] [ Google Scholar]
39. Zhang X, Song Y, Ci X, et al. . Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res. 2008;57:524–529. [ PubMed] [ Google Scholar]
40. Héctor C, Roberto H, Psaltis A, et al. . Study of the efficacy and safety of topical ivermectin+ iota-carrageenan in the prophylaxis against COVID-19 in health personnel. J Biomed Res Clin Investig. 2020;2. [ Google Scholar]
41. Behera P, Patro BK, Singh AK, et al. Role of ivermectin in the prevention of COVID-19 infection among healthcare workers in India: a matched case-control study. medRxiv. 2020. [ PMC free article] [ PubMed] [ Google Scholar]
42. Hellwig MD, Maia A. A COVID-19 Prophylaxis? Lower incidence associated with prophylactic administration of Ivermectin. Int J Antimicrob Agents. 2021;57:106248. [ PMC free article] [ PubMed] [ Google Scholar]
43. Bernigaud C, Guillemot D, Ahmed-Belkacem A. et al. Bénéfice de l'ivermectine: de la gale à la COVID-19, un exemple de sérendipité,. Annales de Dermatologie et de Vénéréologie. 2020;147:A194. [ Google Scholar]
44. Shouman WM, Hegazy AA, Nafae RM, et al. . Use of Ivermectin as a Potential Chemoprophylaxis for COVID-19 in Egypt: A Randomized Clinical Trial. J Clin Diagn Res. 2021;15. [ Google Scholar]
45. Elgazzar A, Hany B, Youssef SA, Hafez M, Moussa H, eltaweel A. Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic. Res Square. 2020. Doi: 10.21203/rs.3.rs-100956/v3. [ Google Scholar]
46. Prophylaxis Chala. Covid-19 in healthcare agents by intensive treatment with ivermectin and iota-carrageenan (Ivercar-Tuc). ClinicalTrials.gov. 2020:NCT04701710. [ Google Scholar]
47. Alam M, M R, G PF, et al. . Ivermectin as pre-exposure prophylaxis for COVID 19 among healthcare providers in a selected tertiary hospital in Dhaka an observational study. Eur J Med Health Sci. 2020;2:1–5. [ Google Scholar]
48. Chamie J. Real-world evidence: the case of Peru. In: Causality between Ivermectin and COVID-19 Infection Fatality Rate; 2020. [ Google Scholar]
49. Mahmud R. A Randomized, Double-Blind Placebo Controlled Clinical Trial of Ivermectin Plus Doxycycline for the Treatment of Confirmed Covid-19 Infection ClinicalTrials.gov. 2020. Available at: clinicaltrials.gov. [ Google Scholar]
50. Carvallo HE, Hirsch RR, Farinella ME. Safety and Efficacy of the combined use of ivermectin, dexamethasone, enoxaparin and aspirin against COVID-19. medRxiv. 2020. Available at: medrxiv.org. [ Google Scholar]
51. Khan MSI, Khan MSI, Debnath CR, et al. . Ivermectin treatment may improve the prognosis of patients with COVID-19. Archivos de Bronconeumología. 2020;56:828–830. [ PMC free article] [ PubMed] [ Google Scholar]
52. Gorial FI, Mashhadani S, Sayaly HM, et al. . Effectiveness of ivermectin as add-on therapy in COVID-19 management (pilot trial). medRxiv. 2020. doi: 10.1101/2020.07.07.20145979. [ Google Scholar]
53. Hashim HA, Maulood MF, Rasheed AM, et al. . Controlled randomized clinical trial on using Ivermectin with Doxycycline for treating COVID-19 patients in Baghdad, Iraq. medRxiv. 2020. doi: 10.1101/2020.10.26.20219345. [ Google Scholar]
54. Chowdhury AT, Shahbaz M, Karim MR, et al. . A randomized trial of ivermectin-doxycycline and hydroxychloroquine-azithromycin therapy on COVID19 patients. Res Square. 2020. doi: 10.21203/rs.3.rs-38896/v1. [ Google Scholar]
55. Podder CS, Chowdhury N, Sina MI, et al. . Outcome of ivermectin treated mild to moderate COVID-19 cases: a single-centre, open-label, randomised controlled study. IMC J Med Sci. 2020;14:1–8. [ Google Scholar]
56. Cadegiani FA, Goren A, Wambier CG, et al. . Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in outpatient settings significantly reduced symptoms compared to known outcomes in untreated patients. medRxiv. 2020. doi: 10.1101/2020.10.31.20223883. [ Google Scholar]
57. Chaccour C, Casellas A, Blanco-Di Matteo A, et al. . The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial. EClinicalMedicine. 2021;32:100720. [ PMC free article] [ PubMed] [ Google Scholar]
58. Espitia-Hernandez G, Munguia L, Diaz-Chiguer D, et al. . Effects of Ivermectin-Azithromycin-Cholecalciferol Combined Therapy on COVID-19 Infected Patients: A Proof of Concept Study; 2020. [ Google Scholar]
59. Babalola OE, Bode CO, Ajayi AA, et al. . Ivermectin shows clinical benefits in mild to moderate Covid19 disease: a randomised controlled double blind dose response study in Lagos. medRxiv. 2021;hcab035. doi: 10.1093/qjmed/hcab035. [ PMC free article] [ PubMed] [ Google Scholar]
60. Ravikirti, Roy R, Pattadar C, et al. . Ivermectin as a potential treatment for mild to moderate COVID-19 – a double blind randomized placebo-controlled trial. medRxiv. 2021. doi: 10.1101/2021.01.05.21249310. [ Google Scholar]
61. Morgenstern J, Redondo JN, De Leon A, et al. . The use of compassionate Ivermectin in the management of symptomatic outpatients and hospitalized patients with clinical diagnosis of COVID-19 at the Medical Center Bournigal and the Medical Center Punta Cana, Rescue Group, Dominican Republic, from may 1 to august 10, 2020. medRxiv. 2020. Doi: 10.1101/2020.10.29.20222505. [ Google Scholar]
62. Robin RC, Alam RF, Saber S, et al. . A case series of 100 COVID-19 positive patients treated with combination of ivermectin and doxycycline. J Bangladesh Coll Physicians Surgeons. 2020;38:10–15. doi: 10.3329/jbcps.v38i0.47512.[published Online First: Epub Date]|. [ CrossRef] [ Google Scholar]
63. Rajter JC, Sherman MS, Fatteh N, et al. . Use of ivermectin is associated with lower mortality in hospitalized patients with COVID-19 (ICON study). Chest. 2021;159:85–92. [ PMC free article] [ PubMed] [ Google Scholar]
64. Spoorthi VSS. Utility of ivermectin and doxycycline combination for the treatment of SARS-CoV2. Int Arch Integrated Med. 2020;7:177–182. [ Google Scholar]
65. Niaee MS, Gheibi N, Namdar P, et al. . Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: A randomized multi-center clinical trial. Res Square. 2020. doi: 10.21203/rs.3.rs-109670/v1. [ Google Scholar]
66. Portmann-Baracco A, Bryce-Alberti M, Accinelli RA. Antiviral and anti-inflammatory properties of ivermectin and its potential use in covid-19. Arch Bronconeumol. 2020;56:831. [ PMC free article] [ PubMed] [ Google Scholar]
67. Ahmed S, Karim MM, Ross AG, et al. . A five day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect Dis. 2021;103:214–216. [ PMC free article] [ PubMed] [ Google Scholar]
68. Chachar AZK, Khan KA, Asif M, et al. . Effectiveness of ivermectin in SARS-CoV-2/COVID-19 patients. Int J Sci. 2020;9:31–35. [ Google Scholar]
69. Soto-Becerra P, Culquichicón C, Hurtado-Roca Y, et al. . Real-world effectiveness of hydroxychloroquine, azithromycin, and ivermectin among hospitalized COVID-19 patients: results of a target trial emulation using observational data from a nationwide healthcare system in Peru. SSRN. 2020. Available at: ssrn.com.
70. Budhiraja S, Soni A, Jha V, et al. . Clinical Profile of First 1000 COVID-19 cases admitted at tertiary care hospitals and the correlates of their mortality: an Indian experience. medRxiv. 2020. doi: 10.1101/2020.11.16.20232223. [ Google Scholar]
71. Rubin R. As their numbers grow, COVID-19 “long haulers” stump experts. JAMA. 2020;324:1381–1383. [ PubMed] [ Google Scholar]
72. Callard F, Perego E. How and why patients made Long Covid. Soc Sci Med. 2021;268:113426. [ PMC free article] [ PubMed] [ Google Scholar]
73. Siegelman JN. Reflections of a COVID-19 long hauler. JAMA. 2020;324:2031–2032. [ PubMed] [ Google Scholar]
74. Aguirre-Chang G. Post-Acute or prolonged COVID-19: treatment with ivermectin for patietns with persistent, or post-acute symptoms ResearchGate. 2020. Available at: researchgate.net.
75. Kircik LH, Del Rosso JQ, Layton AM, et al. . Over 25 Years of clinical experience with ivermectin: an overview of safety for an increasing number of indications. J Drugs Dermatol. 2016;15:325–332. [ PubMed] [ Google Scholar]
76. Gardon J, Gardon-Wendel N, Demanga N, et al. . Serious reactions after mass treatment of onchocerciasis with ivermectin in an area endemic for Loa loa infection. Lancet. 1997;350:18–22. [ PubMed] [ Google Scholar]
77. Guzzo CA, Furtek CI, Porras AG, et al. . Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42:1122–1133. [ PubMed] [ Google Scholar]
78. Veit O, Beck B, Steuerwald M, et al. . First case of ivermectin-induced severe hepatitis. Trans R Soc Trop Med Hyg. 2006;100:795–797. [ PubMed] [ Google Scholar]
79. Sparsa A, Bonnetblanc JM, Peyrot I, et al. . Systemic adverse reactions with ivermectin treatment of scabies. Annales de Dermatologie et de Venereologie. 2006;133:784–787. [ PubMed] [ Google Scholar]
80. Chandler RE. Serious neurological adverse events after ivermectin—do they occur beyond the indication of onchocerciasis?. Am J Trop Med Hyg. 2018;98:382–388. [ PMC free article] [ PubMed] [ Google Scholar]
81. Anglemyer A, Horvath HT, Bero L. Healthcare outcomes assessed with observational study designs compared with those assessed in randomized trials. Cochrane Database Syst Rev. 2014:MR000034. [ PMC free article] [ PubMed] [ Google Scholar]
82. Dahabreh IJ, Sheldrick RC, Paulus JK, et al. . Do observational studies using propensity score methods agree with randomized trials? A systematic comparison of studies on acute coronary syndromes. Eur Heart J. 2012;33:1893–1901. [ PMC free article] [ PubMed] [ Google Scholar]
83. Kitsios GD, Dahabreh IJ, Callahan S, et al. . Can we trust observational studies using propensity scores in the critical care literature? A systematic comparison with randomized clinical trials. Crit Care Med. 2015;43:1870–1879. [ PubMed] [ Google Scholar]
84. Lonjon G, Boutron I, Trinquart L, et al. . Comparison of treatment effect estimates from prospective nonrandomized studies with propensity score analysis and randomized controlled trials of surgical procedures. Ann Surg. 2014;259:18–25. [ PubMed] [ Google Scholar] |
|
