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m Fine, I'll change it to something else, but "data" is more often than not treated as a mass noun and "this" is much more common than "these" in informal settings. We are making an encyclopedia, not a scientific paper. See WP:NOTTEXTBOOK.
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{{anchor|Chloroquine|Hydroxychloroquine}}
{{anchor|Chloroquine|Hydroxychloroquine}}
===Chloroquine and hydroxychloroquine===
===Chloroquine and hydroxychloroquine===
{{split section|Chloroquine and hydroxychloroquine during the COVID-19 pandemic|discuss=Talk:COVID-19 drug repurposing research#Split section on chloroquine and hydroxychloroquine?|date=February 2021}}
{{Excerpt|Chloroquine and hydroxychloroquine during the COVID-19 pandemic}}
{{see also|COVID-19 misinformation#Chloroquine and hydroxychloroquine}}

[[Chloroquine]] and [[hydroxychloroquine]] are [[anti-malarial]] medications also used against some [[auto-immune]] diseases.<ref name=":12">{{Cite web|last=|first=|date=|title=Chloroquine or Hydroxychloroquine|url=https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/chloroquine-or-hydroxychloroquine-with-or-without-azithromycin/|url-status=live|archive-url=|archive-date=|access-date=2021-02-14|website=COVID-19 Treatment Guidelines|publisher=[[National Institutes of Health]]|language=en}}</ref> Chloroquine, along with [[hydroxychloroquine]], was an early failed experimental treatment for [[Coronavirus disease 2019|COVID-19]].<ref name=":0">{{cite web|date=30 March 2020|title=Coronavirus (COVID-19) Update: Daily Roundup March 30, 2020|url=https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-march-30-2020|website=FDA}}</ref> They are not effective for preventing infection.<ref>{{cite journal|vauthors=Smit M, Marinosci A, Agoritsas T, Ford N, Calmy A|date=January 2021|title=Prophylaxis for COVID-19: a systematic review|journal=Clinical Microbiology and Infection|type=Systematic review|volume=|issue=|doi=10.1016/j.cmi.2021.01.013|pmid=33476807|doi-access=free}}</ref><ref name="Meyerowitz2020">{{cite journal|display-authors=6|vauthors=Meyerowitz EA, Vannier AG, Friesen MG, Schoenfeld S, Gelfand JA, Callahan MV, Kim AY, Reeves PM, Poznansky MC|date=May 2020|title=Rethinking the role of hydroxychloroquine in the treatment of COVID-19|journal=FASEB Journal|volume=34|issue=5|pages=6027–6037|doi=10.1096/fj.202000919|pmc=7267640|pmid=32350928}}</ref><ref name="Juurlink2020">{{cite journal|vauthors=Juurlink DN|date=April 2020|title=Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection|journal=CMAJ|volume=192|issue=17|pages=E450–E453|doi=10.1503/cmaj.200528|pmc=7207200|pmid=32269021}}</ref><ref name="ASHP2020COVID">{{cite web|title=Assessment of Evidence for COVID-19-Related Treatments: Updated 4/3/2020|url=https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx|access-date=7 April 2020|publisher=[[American Society of Health-System Pharmacists]]}}</ref><ref name="Yazdany2020">{{cite journal|vauthors=Yazdany J, Kim AH|date=June 2020|title=Use of Hydroxychloroquine and Chloroquine During the COVID-19 Pandemic: What Every Clinician Should Know|journal=Annals of Internal Medicine|volume=172|issue=11|pages=754–755|doi=10.7326/M20-1334|pmc=7138336|pmid=32232419}}</ref>

Several countries initially used chloroquine or hydroxychloroquine for treatment of persons hospitalized with COVID‑19 (as of March 2020), though the drug was not formally approved through clinical trials.<ref name="cdc3-212">{{cite web|date=21 March 2020|title=Information for clinicians on therapeutic options for COVID-19 patients|url=https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html|access-date=22 March 2020|publisher=US Centers for Disease Control and Prevention}}</ref><ref name="hinton2">{{cite web|date=28 March 2020|title=Request for Emergency Use Authorization For Use of Chloroquine Phosphate or Hydroxychloroquine Sulfate Supplied From the Strategic National Stockpile for Treatment of 2019 Coronavirus Disease|url=https://www.fda.gov/media/136534/download|access-date=30 March 2020|publisher=U.S. [[Food and Drug Administration]] (FDA)|format=PDF|vauthors=Hinton DM}}</ref> From April to June 2020, there was an [[emergency use authorization]] for their use in the United States,<ref>{{cite web|date=11 February 2020|title=Coronavirus Disease 2019 (COVID-19)|url=https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html|access-date=9 April 2020|website=Centers for Disease Control and Prevention}}</ref> and was used [[off label]] for potential treatment of the disease.<ref>{{cite journal|vauthors=Kalil AC|date=March 2020|title=Treating COVID-19-Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics|journal=JAMA|volume=323|issue=19|pages=1897–1898|doi=10.1001/jama.2020.4742|pmid=32208486|doi-access=free}}</ref> On 24 April 2020, citing the risk of "serious heart rhythm problems", the FDA posted a caution against using the drug for COVID‑19 "outside of the hospital setting or a clinical trial".<ref name="fda.gov">{{cite web|date=24 April 2020|title=FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems|url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or|website=U.S. [[Food and Drug Administration]] (FDA)}}</ref>

Their use was withdrawn as a possible treatment for COVID‑19 infection when it proved to have no benefit for hospitalized patients with severe COVID-19 illness in the international [[Solidarity trial]] and UK [[RECOVERY Trial]].<ref name="mulier2">{{cite news|date=2020-06-17|title=Hydroxychloroquine halted in WHO-sponsored COVID-19 trials|work=Bloomberg|url=https://www.bloomberg.com/news/articles/2020-06-17/hydroxychloroquine-testing-halted-in-who-sponsored-covid-trial|access-date=2020-06-17|vauthors=Mulier T}}</ref><ref name="rec-nobenefit3">{{Cite web|date=5 June 2020|title=No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19|url=https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19|access-date=7 June 2020|publisher=Recovery Trial, Nuffield Department of Population Health, University of Oxford, UK}}</ref> On 15 June, the FDA revoked its emergency use authorization, stating that it was "no longer reasonable to believe" that the drug was effective against COVID-19 or that its benefits outweighed "known and potential risks".<ref name="HCQ and CQ revocation PR2">{{cite press release|title=Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine|website=U.S. [[Food and Drug Administration]] (FDA)|date=15 June 2020|url=https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-chloroquine-and|access-date=15 June 2020}}</ref><ref name=":2">{{Cite news|author=Berkeley Lovelace Jr|date=15 June 2020|title=FDA revokes emergency use of hydroxychloroquine|website=CNBC|url=https://www.cnbc.com/2020/06/15/fda-revokes-emergency-use-of-hydroxychloroquine.html}}</ref><ref name="HCQ and CQ EUA revocation FAQ2">{{cite web|date=15 June 2020|title=Frequently Asked Questions on the Revocation of the Emergency Use Authorization for Hydroxychloroquine Sulfate and Chloroquine Phosphate|url=https://www.fda.gov/media/138946/download|access-date=15 June 2020|website=U.S. [[Food and Drug Administration]] (FDA)|format=PDF}}</ref> In fall of 2020, the [[National Institutes of Health]] issued treatment guidelines recommending against the use of hydroxychloroquine for treatment of COVID-19 in hospitalised patients.<ref name=":12" />

==== Background ====
[[Chloroquine]] is an [[anti-malarial]] medication that is also used against some [[auto-immune]] diseases. Hydroxychloroquine is more commonly available than chloroquine in the United States.<ref name="cdc3-212" /> Hydroxychloroquine is used as a [[Prophylaxis|prophylactic]] in India.<ref>{{Cite web|date=22 May 2020|title=Revised advisory on the use of Hydroxychloroquine(HCQ) as prophylaxis for SARS-CoV-2 infection(in supersession of previous advisory dated 23rd March, 2020)|url=https://www.icmr.gov.in/pdf/covid/techdoc/V5_Revised_advisory_on_the_use_of_HCQ_SARS_CoV2_infection.pdf|url-status=live|archive-url=https://archive.today/20200523092956/https://www.icmr.gov.in/pdf/covid/techdoc/V5_Revised_advisory_on_the_use_of_HCQ_SARS_CoV2_infection.pdf|archive-date=23 May 2020|access-date=3 July 2020|website=icmr.gov.in|publisher=[[Indian Council of Medical Research]]}}</ref><ref>{{Cite news|date=1 Jul 2020|title=Coronavirus and hydroxychloroquine: What do we know?|website=bbc.com|publisher=[[BBC]]|url=https://www.bbc.com/news/51980731|url-status=live|access-date=3 July 2020|archive-url=https://archive.today/20200703084208/https://www.bbc.com/news/51980731|archive-date=3 July 2020|vauthors=Goodman J, Giles C}}</ref>

Hydroxychloroquine and chloroquine have numerous, potentially serious, [[Side effect|side effects]], such as [[retinopathy]], [[hypoglycemia]], or life-threatening [[arrhythmia]] and [[cardiomyopathy]].<ref name="drugs-hydroxy">{{cite web|date=31 March 2020|title=Hydroxychloroquine sulfate|url=https://www.drugs.com/monograph/hydroxychloroquine-sulfate.html|access-date=5 April 2020|publisher=Drugs.com}}</ref> Both drugs have [[Drug interaction|extensive interactions]] with prescription drugs, affecting the therapeutic dose and disease mitigation.<ref name="drugs-hydroxy" /><ref name="drugs-chlor">{{cite web|date=31 March 2020|title=Chloroquine phosphate|url=https://www.drugs.com/monograph/chloroquine-phosphate.html|access-date=5 April 2020|publisher=Drugs.com}}</ref> Some people have [[Allergic reaction|allergic reactions]] to these drugs.<ref name="drugs-hydroxy" /><ref name="drugs-chlor" /> The NIH recommended against the use of a combination of hydroxychloroquine and azithromycin because of the resulting increased risk of sudden cardiac death.<ref>{{Cite news|date=April 21, 2020|title=NIH Panel Recommends Against Drug Combination Promoted By Trump For COVID-19|work=NPR|url=https://www.npr.org/sections/coronavirus-live-updates/2020/04/21/840341224/nih-panel-recommends-against-drug-combination-trump-has-promoted-for-covid-19|vauthors=Palca J}}</ref>

==== Timeline ====
Chloroquine was initially recommended by Indian, Chinese, South Korean and Italian health authorities for the treatment of COVID‑19,<ref>{{Cite web|date=2020-02-13|title=Physicians work out treatment guidelines for coronavirus|url=http://www.koreabiomed.com/news/articleView.html?idxno=7428|access-date=2020-03-18|website=Korea Biomedical Review|vauthors=Sung-sun K}}</ref> although these agencies and the US CDC noted [[Contraindication|contraindications]] for people with [[heart disease]] or [[diabetes]].<ref name="cdc3-212" /><ref>{{Cite web|title=Plaquenil (hydroxychloroquine sulfate) dose, indications, adverse effects, interactions... from PDR.net|url=https://www.pdr.net/drug-summary/Plaquenil-hydroxychloroquine-sulfate-1911|access-date=2020-03-19|website=Physicians' Desk Reference}}</ref> In February 2020, both drugs were shown to effectively reduce COVID‑19 illness, but a further study concluded that hydroxychloroquine was more potent than chloroquine and had a more tolerable safety profile.<ref name="cort">{{cite journal|vauthors=Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S|date=March 2020|title=A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19|journal=Journal of Critical Care|volume=57|pages=279–283|doi=10.1016/j.jcrc.2020.03.005|pmc=7270792|pmid=32173110|doi-access=free}}</ref><ref>{{cite journal|display-authors=6|vauthors=Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S, Lu R, Li H, Tan W, Liu D|date=March 2020|title=In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)|journal=Clinical Infectious Diseases|volume=71|issue=15|pages=732–739|doi=10.1093/cid/ciaa237|pmc=7108130|pmid=32150618}}</ref>

On 18 March, the [[World Health Organization]] (WHO) announced that chloroquine and the related [[hydroxychloroquine]] would be among the four drugs studied as part of the multinational [[Solidarity trial|Solidarity clinical trial]].<ref name="guardian" />

On 19 March, US President [[Donald Trump]] encouraged the use of chloroquine and hydroxychloroquine during a national press conference. These endorsements led to massive increases in public demand for the drugs in the United States.<ref>{{cite journal|vauthors=Liu M, Caputi TL, Dredze M, Kesselheim AS, Ayers JW|date=April 2020|title=Internet Searches for Unproven COVID-19 Therapies in the United States|journal=JAMA Internal Medicine|volume=180|issue=8|pages=1116–1118|doi=10.1001/jamainternmed.2020.1764|pmc=7191468|pmid=32347895}}</ref> Beginning in March 2020, US [[President Donald Trump]] began promoting hydroxychloroquine to prevent or treat [[COVID-19]], citing small numbers of [[Anecdote|anecdotal reports]].<ref name="piller3-20">{{cite journal|vauthors=Piller C|date=26 March 2020|title='This is insane!' Many scientists lament Trump's embrace of risky malaria drugs for coronavirus|url=https://www.sciencemag.org/news/2020/03/insane-many-scientists-lament-trump-s-embrace-risky-malaria-drugs-coronavirus|journal=Science|doi=10.1126/science.abb9021|access-date=4 August 2020}}</ref> Trump stated in June that he was taking the drug as a preventive measure,<ref name=":2" /> stimulating unprecedented worldwide demand and causing shortages of hydroxychloroquine for its prescribed purpose of preventing [[malaria]].<ref name="piller3-20" />

New York Governor [[Andrew Cuomo]] announced that New York State trials of chloroquine and hydroxychloroquine would begin on 24 March.<ref>{{cite news|date=23 March 2020|title=NY COVID-19 cases surge; Javits Center to house temporary hospitals|work=Fox 5|url=https://www.fox5ny.com/news/ny-covid-19-cases-surge-javits-center-to-house-temporary-hospitals}}</ref> On 28 March, the US [[Food and Drug Administration]] (FDA) authorized the use of hydroxychloroquine sulfate and chloroquine phosphate under an [[Emergency Use Authorization]] (EUA), which was later revoked due to the risk of cardiac adverse events.<ref name=":0" /><ref name="FDA EUA 20200328">{{cite web|date=28 March 2020|title=Chloroquine phosphate and hydroxychloroquine sulfate for treatment of COVID-19 Emergency Use Authorization|url=https://www.fda.gov/media/136534/download|access-date=14 June 2020|publisher=U.S. [[Food and Drug Administration]] (FDA)|format=PDF}} {{PD-notice}}</ref> The drug was authorized under the EUA as an experimental treatment for emergency use in hospitalized patients.<ref name=":0" /><ref name="FDA EUA 20200328" /><ref name=":3">{{cite web|title=Fact Sheet for Patients and Parent/Caregivers Emergency Use Authorization (EUA) of Chloroquine Phosphate for Treatment of COVID-19 in Certain Hospitalized Patients|url=https://www.fda.gov/media/136536/download|publisher=U.S. Food and Drug Administration (FDA)|format=PDF}}</ref>

On 28 March 2020 the FDA authorized the use of [[hydroxychloroquine]] and chloroquine under an [[emergency use authorization]] (EUA).<ref name=":0" /> The experimental treatment was first authorized only for emergency use for people hospitalized but unable to receive treatment in a clinical trial.<ref name=":3" />

On 1 April 2020, the [[European Medicines Agency]] (EMA) issued guidance that chloroquine and hydroxychloroquine are only to be used in clinical trials or emergency use programs.<ref>{{cite web|date=1 April 2020|title=COVID-19: chloroquine and hydroxychloroquine only to be used in clinical trials or emergency use programmes|url=https://www.ema.europa.eu/en/news/covid-19-chloroquine-hydroxychloroquine-only-be-used-clinical-trials-emergency-use-programmes|access-date=2 April 2020|website=[[European Medicines Agency]] (EMA)}}</ref>

On 9{{nbsp}}April, the [[National Institutes of Health]] began the first clinical trial to assess whether hydroxychloroquine is safe and effective to treat COVID‑19.<ref name="mh">{{cite news|last=Gross|first=Samantha J.|date=9 April 2020|title=As CDC drops guidance on chloroquine as COVID-19 therapy, doctors ask for research|work=Miami Herald|url=https://www.miamiherald.com/news/coronavirus/article241886271.html|name-list-style=vanc}}</ref><ref>{{cite web|title=Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease (ORCHID)|url=https://clinicaltrials.gov/ct2/show/NCT04332991|access-date=10 September 2020|website=ClinicalTrials.gov}}</ref> A [[Veterans Health Administration|Veterans Affairs]] study released results on 21 April suggesting COVID‑19-hospitalized patients treated with hydroxychloroquine were more likely to die than those who received no drug treatment at all, after correcting for clinical characteristics.<ref>{{cite web|title=Anti-malarial drug Trump touted is linked to higher rates of death in VA coronavirus patients, study says|url=https://www.washingtonpost.com/business/2020/04/21/anti-malarial-drug-trump-touted-is-linked-higher-rates-death-va-coronavirus-patients-study-says/|access-date=April 22, 2020|website=The Washington Post|vauthors=Rowland C|name-list-style=vanc}}</ref><ref>{{cite journal|vauthors=Magagnoli J, Narendran S, Pereira F, Cummings T, Hardin JW, Sutton SS, Ambati J|date=April 2020|title=Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19|journal=MedRxiv|doi=10.1101/2020.04.16.20065920|pmc=7276049|pmid=32511622|lay-url=https://www.eurekalert.org/pub_releases/2020-06/cp-meo060520.php}}</ref>

On 24 April, the FDA cautioned against using the drug outside a hospital setting or clinical trial after reviewing case reports of adverse effects including ventricular [[tachycardia]], ventricular [[fibrillation]] and in some cases death.<ref name="fda.gov" /> According to [[Johns Hopkins University|Johns Hopkins']] ABX Guide for COVID‑19, "Hydroxychloroquine may cause [[Long QT syndrome|prolonged QT]], and caution should be used in critically ill COVID‑19 patients who may have cardiac dysfunction or if combined with other drugs that cause QT prolongation".<ref>see under Treatment section of [https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540747/all/Coronavirus_COVID_19__SARS_CoV_2_#4.1 Coronavirus COVID‑19 (SARS-CoV-2); Johns Hopkins ABX Guide] (Retrieved 18 April 2020)</ref> Caution was also recommended as to the combination of chloroquine and hydroxychloroquine with treatments which might inhibit the [[CYP3A4]] enzyme (by which these drugs are metabolized). As such, combination might indirectly result in higher plasma levels of chloroquine and hydroxychloroquine, and thus enhance the risk for significant QT prolongation. CYP3A4 inhibitors include [[Azithromycin]], [[ritonavir]] and [[lopinavir]].<ref name="Heart Rhytm">{{cite journal|display-authors=6|vauthors=Wu CI, Postema PG, Arbelo E, Behr ER, Bezzina CR, Napolitano C, Robyns T, Probst V, Schulze-Bahr E, Remme CA, Wilde AA|date=March 2020|title=SARS-CoV-2, COVID-19, and inherited arrhythmia syndromes|journal=Heart Rhythm|volume=17|issue=9|pages=1456–1462|doi=10.1016/j.hrthm.2020.03.024|pmc=7156157|pmid=32244059}}</ref>

On 5 June, use of hydroxychloroquine in the UK [[RECOVERY Trial]] was discontinued when an interim analysis of 1,542 treatments showed it provided no mortality benefit to people hospitalized with severe COVID‑19 infection over 28 days of observation.<ref name="rec-nobenefit3" />

On 15 June, the FDA revoked the emergency use authorization for hydroxychloroquine and chloroquine, stating that although the evaluation of both these drugs under clinical trials continues, the FDA (after interagency consultation with the [[Biomedical Advanced Research and Development Authority]] (BARDA)) concluded that, based on new information and other information discussed "... it is no longer reasonable to believe that oral formulations of hydroxychloroquine (HCQ) and chloroquine (CQ) may be effective in treating COVID‑19, nor is it reasonable to believe that the known and potential benefits of these products outweigh their known and potential risks".<ref name="HCQ and CQ revocation PR2" /><ref>{{cite web|date=15 June 2020|title=EUA Archive|url=https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization-archived-information|access-date=15 June 2020|website=U.S. [[Food and Drug Administration]] (FDA)|quote=On June 15, 2020, based on FDA's continued review of the scientific evidence available for hydroxychloroquine sulfate (HCQ) and chloroquine phosphate (CQ) to treat COVID-19, FDA has determined that the statutory criteria for EUA as outlined in Section 564(c)(2) of the Food, Drug, and Cosmetic Act are no longer met. Specifically, FDA has determined that CQ and HCQ are unlikely to be effective in treating COVID-19 for the authorized uses in the EUA. Additionally, in light of ongoing serious cardiac adverse events and other serious side effects, the known and potential benefits of CQ and HCQ no longer outweigh the known and potential risks for the authorized use. This warrants revocation of the EUA for HCQ and CQ for the treatment of COVID-19.}}{{PD-notice}}</ref><ref>{{cite web|date=15 June 2020|title=HCQ and CQ revocation letter|url=https://www.fda.gov/media/138945/download|access-date=15 June 2020|website=U.S. [[Food and Drug Administration]] (FDA)|format=PDF}} {{PD-notice}}</ref><ref name="HCQ and CQ EUA revocation FAQ2" />[[File:Gfp-medicine-container-and-medicine-tablet.jpg|thumb|upright=0.8|left|A chloroquine tablet]]

On 23 July, results were published from a multicenter, randomized, open-label, three-group, controlled trial of 667 participants in Brazil which found no benefit from using hydroxychloroquine, alone or with azithromycin, to treat mild-to-moderate COVID‑19.<ref name="doi 10.1056/nejmoa2019014">{{cite journal|display-authors=6|vauthors=Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LC, Veiga VC, Avezum A, Damiani LP, Marcadenti A, Kawano-Dourado L, Lisboa T, Junqueira DL, de Barros e Silva GM, Tramujas L, Abreu-Silva EO, Laranjeira LN, Soares AT, Echenique LS, Pereira AJ, Freitas FG, Gebara OC, Dantas VC, Furtado RH, Milan EP, Golin NA, Cardoso FF, Maia IS, Hoffmann Filho CR, Kormann AP, Amazonas RB, Bocchi de Oliveira MF, Serpa-Neto A, Falavigna M, Lopes RD, Machado FR, Berwanger O|date=July 2020|title=Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19|journal=New England Journal of Medicine|volume=383|issue=21|pages=2041–2052|doi=10.1056/nejmoa2019014|pmc=7397242|pmid=32706953}}</ref> In July, the U.S President Donald Trump once again promoted the use of the drug contradicting various public health officials, including [[National Institute of Allergy and Infectious Diseases]] director Dr. [[Anthony Fauci]].<ref>{{Cite news|date=2020-07-29|title=Coronavirus: Hydroxychloroquine ineffective says Fauci|work=BBC|url=https://www.bbc.com/news/world-us-canada-53575964|access-date=2020-07-30}}</ref>

In fall of 2020, the [[National Institutes of Health]] issued treatment guidelines recommending against the use of chloroquine for treatment of COVID-19 in hospitalised patients.<ref name=":12" />

In November 2020, a U.S. National Institutes of Health clinical trial evaluating the safety and effectiveness of hydroxychloroquine for the treatment of adults with COVID-19 formally concluded that the drug provided no clinical benefit to hospitalized patients and recommended against its use.<ref name="NIH PR 20201109">{{cite press release|title=Hydroxychloroquine does not benefit adults hospitalized with COVID-19|website=National Institutes of Health (NIH)|date=9 November 2020|url=https://www.nih.gov/news-events/news-releases/hydroxychloroquine-does-not-benefit-adults-hospitalized-covid-19|access-date=9 November 2020}} {{PD-notice}}</ref><ref name="doi 10.1001/jama.2020.22240">{{cite journal|display-authors=6|vauthors=Self WH, Semler MW, Leither LM, Casey JD, Angus DC, Brower RG, Chang SY, Collins SP, Eppensteiner JC, Filbin MR, Files DC, Gibbs KW, Ginde AA, Gong MN, Harrell FE, Hayden DL, Hough CL, Johnson NJ, Khan A, Lindsell CJ, Matthay MA, Moss M, Park PK, Rice TW, Robinson BR, Schoenfeld DA, Shapiro NI, Steingrub JS, Ulysse CA, Weissman A, Yealy DM, Thompson BT, Brown SM, Steingrub J, Smithline H, Tiru B, Tidswell M, Kozikowski L, Thornton-Thompson S, De Souza L, Hou P, Baron R, Massaro A, Aisiku I, Fredenburgh L, Seethala R, Johnsky L, Riker R, Seder D, May T, Baumann M, Eldridge A, Lord C, Shapiro N, Talmor D, O'Mara T, Kirk C, Harrison K, Kurt L, Schermerhorn M, Banner-Goodspeed V, Boyle K, Dubosh N, Filbin M, Hibbert K, Parry B, Lavin-Parsons K, Pulido N, Lilley B, Lodenstein C, Margolin J, Brait K, Jones A, Galbraith J, Peacock R, Nandi U, Wachs T, Matthay M, Liu K, Kangelaris K, Wang R, Calfee C, Yee K, Hendey G, Chang S, Lim G, Qadir N, Tam A, Beutler R, Levitt J, Wilson J, Rogers A, Vojnik R, Roque J, Albertson T, Chenoweth J, Adams J, Pearson S, Juarez M, Almasri E, Fayed M, Hughes A, Hillard S, Huebinger R, Wang H, Vidales E, Patel B, Ginde A, Moss M, Baduashvili A, McKeehan J, Finck L, Higgins C, Howell M, Douglas I, Haukoos J, Hiller T, Lyle C, Cupelo A, Caruso E, Camacho C, Gravitz S, Finigan J, Griesmer C, Park P, Hyzy R, Nelson K, McDonough K, Olbrich N, Williams M, Kapoor R, Nash J, Willig M, Ford H, Gardner-Gray J, Ramesh M, Moses M, Ng Gong M, Aboodi M, Asghar A, Amosu O, Torres M, Kaur S, Chen JT, Hope A, Lopez B, Rosales K, Young You J, Mosier J, Hypes C, Natt B, Borg B, Salvagio Campbell E, Hite RD, Hudock K, Cresie A, Alhasan F, Gomez-Arroyo J, Duggal A, Mehkri O, Hastings A, Sahoo D, Abi Fadel F, Gole S, Shaner V, Wimer A, Meli Y, King A, Terndrup T, Exline M, Pannu S, Robart E, Karow S, Hough C, Robinson B, Johnson N, Henning D, Campo M, Gundel S, Seghal S, Katsandres S, Dean S, Khan A, Krol O, Jouzestani M, Huynh P, Weissman A, Yealy D, Scholl D, Adams P, McVerry B, Huang D, Angus D, Schooler J, Moore S, Files C, Miller C, Gibbs K, LaRose M, Flores L, Koehler L, Morse C, Sanders J, Langford C, Nanney K, MdalaGausi M, Yeboah P, Morris P, Sturgill J, Seif S, Cassity E, Dhar S, de Wit M, Mason J, Goodwin A, Hall G, Grady A, Chamberlain A, Brown S, Bledsoe J, Leither L, Peltan I, Starr N, Fergus M, Aston V, Montgomery Q, Smith R, Merrill M, Brown K, Armbruster B, Harris E, Middleton E, Paine R, Johnson S, Barrios M, Eppensteiner J, Limkakeng A, McGowan L, Porter T, Bouffler A, Leahy JC, deBoisblanc B, Lammi M, Happel K, Lauto P, Self W, Casey J, Semler M, Collins S, Harrell F, Lindsell C, Rice T, Stubblefield W, Gray C, Johnson J, Roth M, Hays M, Torr D, Zakaria A, Schoenfeld D, Thompson T, Hayden D, Ringwood N, Oldmixon C, Ulysse C, Morse R, Muzikansky A, Fitzgerald L, Whitaker S, Lagakos A, Brower R, Reineck L, Aggarwal N, Bienstock K, Freemer M, Maclawiw M, Weinmann G, Morrison L, Gillespie M, Kryscio R, Brodie D, Zareba W, Rompalo A, Boeckh M, Parsons P, Christie J, Hall J, Horton N, Zoloth L, Dickert N, Diercks D|date=December 2020|title=Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial|journal=JAMA|volume=324|issue=21|pages=2165–2176|doi=10.1001/jama.2020.22240|pmc=7653542|pmid=33165621|doi-access=free}}</ref><ref name=":12" />

====Combined with zinc and another antibiotic====
Due to the properties of zinc as a [[Cofactor (biochemistry)|cofactor]] in the [[immune response]] for producing antibodies during viral infections,<ref name="lpi">{{Cite web|date=2019-05-01|title=Zinc|url=https://lpi.oregonstate.edu/mic/minerals/zinc|access-date=2020-05-20|publisher=Micronutrient Information Center, Linus Pauling Institute, Oregon State University}}</ref> it is being included among multiple-agent "cocktails" for investigating potential treatment of people hospitalized with COVID‑19 infection.<ref name="upi">{{Cite news|author=Brian P. Dunleavy|date=2020-05-13|title=Zinc might boost effectiveness of malaria drug against COVID-19, experts say|work=United Press International|url=https://www.upi.com/Health_News/2020/05/13/Zinc-might-boost-effectiveness-of-malaria-drug-against-COVID-19-experts-say/2801589374701/|access-date=2020-05-20}}</ref> One such cocktail &ndash; hydroxychloroquine combined with a high dose of zinc (as a [[sulfate]], 220&nbsp;mg (50&nbsp;mg elemental Zn) per day for five days, a zinc dose ~4 times higher than the [[Reference Daily Intake|reference daily intake level]])<ref name="lpi" /> and an approved [[antibiotic]], either [[azithromycin]] or [[doxycycline]] &ndash; began in May as a [[Phases of clinical research|Phase{{nbsp}}IV trial]] in [[New York (state)|New York State]].<ref name="roslyn">{{cite web|title=Hydroxychloroquine and Zinc With Either Azithromycin or Doxycycline for Treatment of COVID-19 in Outpatient Setting|url=https://clinicaltrials.gov/ct2/show/NCT04370782|access-date=10 September 2020|website=ClinicalTrials.gov}}</ref> However, caution was recommended about the combination of chloroquine or hydroxychloroquine with [[CYP3A4]] inhibitors, such as azithromycin,<ref name="Heart Rhytm" /> a treatment combination found to be ineffective for preventing death in hospitalized people with COVID‑19.<ref>{{cite journal|display-authors=6|vauthors=Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, Weinberg P, Kirkwood J, Muse A, DeHovitz J, Blog DS, Hutton B, Holtgrave DR, Zucker HA|date=May 2020|title=Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State|journal=JAMA|volume=323|issue=24|pages=2493–2502|doi=10.1001/jama.2020.8630|pmc=7215635|pmid=32392282}}</ref> There is preliminary evidence that combining hydroxychloroquine and azithromycin for treating non-hospitalized ("outpatient") people with COVID‑19 infection with multiple [[Comorbidity|comorbidities]] was effective, but remains under preliminary research.<ref>{{cite journal|vauthors=Risch HA|date=May 2020|title=Early Outpatient Treatment of Symptomatic, High-Risk Covid-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis|journal=American Journal of Epidemiology|volume=189|issue=11|pages=1218–1226|doi=10.1093/aje/kwaa093|pmc=7546206|pmid=32458969|doi-access=free}}</ref>

[[Zinc deficiency]] &ndash; which decreases immune capacity to defend against pathogens &ndash; is common among elderly people, and may be a susceptibility factor in viral infections.<ref name="lpi" /> The mechanism for any potential benefit of including zinc in a cocktail treatment for recovery from severe COVID‑19 or any viral infection is unknown.<ref name="lpi" /><ref name="upi" />

====Prophylaxis====
Drugs used for treatment of infectious diseases may also be considered for use for post-exposure [[prophylaxis]]. On 22 May, ''[[The Lancet]]'' published a response to criticism of the Indian government's decision to allow [[chemoprophylaxis]] with hydroxychloroquine for some high risk persons who may have had exposure to COVID. Researchers supporting prophylactic administration of hydroxychloquine note that results from human trials have suggested that hydroxychloroquine may decrease the duration of both [[viral shedding]] and symptoms if the drug is administered early.<ref>{{cite journal|vauthors=Tilangi P, Desai D, Khan A, Soneja M|date=May 2020|title=Hydroxychloroquine prophylaxis for high-risk COVID-19 contacts in India: a prudent approach|journal=The Lancet. Infectious Diseases|volume=20|issue=10|pages=1119–1120|doi=10.1016/S1473-3099(20)30430-8|pmc=7255125|pmid=32450054}}</ref>

On 3 June, results were published from a randomized, double-blind, placebo-controlled trial of 821 participants which found that hydroxychloroquine did not prevent symptomatic COVID-19 illness when used for [[post-exposure prophylaxis]].<ref>{{cite journal|display-authors=6|vauthors=Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, Skipper CP, Nascene AA, Nicol MR, Abassi M, Engen NW, Cheng MP, LaBar D, Lother SA, MacKenzie LJ, Drobot G, Marten N, Zarychanski R, Kelly LE, Schwartz IS, McDonald EG, Rajasingham R, Lee TC, Hullsiek KH|date=June 2020|title=A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19|journal=The New England Journal of Medicine|volume=383|issue=6|pages=517–525|doi=10.1056/NEJMoa2016638|pmc=7289276|pmid=32492293|lay-url=https://www.nytimes.com/2020/06/03/health/hydroxychloroquine-coronavirus-trump.html|doi-access=free}}</ref><ref>{{cite journal|vauthors=Cohen MS|date=June 2020|title=Hydroxychloroquine for the Prevention of Covid-19 – Searching for Evidence|journal=The New England Journal of Medicine|volume=383|issue=6|pages=585–586|doi=10.1056/NEJMe2020388|pmc=7289275|pmid=32492298|doi-access=free}}</ref><ref>{{cite news|last1=McGinley|first1=Laurie|last2=Cha|first2=Ariana Eunjung|date=June 3, 2020|title=Hydroxychloroquine, a drug promoted by Trump, failed to prevent healthy people from getting covid-19 in trial|website=The Washington Post|url=https://www.washingtonpost.com/health/2020/06/03/hydroxychloroquine-clinical-trial-results/|access-date=June 5, 2020|name-list-style=vanc}}</ref>

British researchers are studying whether the drug is effective when used for prevention. 10,000 [[National Health Service]] (NHS) workers, along with 30,000 additional volunteers from Asia, South America, Africa, and other parts of Europe are participating in the global study. Results are expected by in 2021.<ref>{{cite news|date=May 21, 2020|title=Hydroxychloroquine: NHS staff to take drug as part of global trial|work=The Guardian|url=https://www.theguardian.com/world/2020/may/21/hydroxychloroquine-nhs-staff-take-drug-part-global-trial-coronavirus}}</ref><ref>{{Cite journal|last=University of Oxford|date=2020-10-01|title=Chloroquine/ Hydroxychloroquine Prevention of Coronavirus Disease (COVID-19) in the Healthcare Setting; a Randomised, Placebo-controlled Prophylaxis Study (COPCOV)|url=https://clinicaltrials.gov/ct2/show/record/NCT04303507}}</ref>

==== Controversy ====
{{see also|Trump administration communication during the COVID-19 pandemic#Chloroquine and hydroxychloroquine|Surgisphere#COVID-19|Didier Raoult#COVID-19}}Due to safety concerns and evidence of [[Arrhythmia|heart arrhythmias]] leading to higher death rates, the WHO suspended the hydroxychloroquine arm of the multinational [[Solidarity trial]] in May 2020.<ref name="who-suspend">{{Cite web|date=2020-05-25|title=WHO Director-General's opening remarks at the media briefing on COVID-19 – 25 May 2020|url=https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---25-may-2020|access-date=2020-05-27|publisher=World Health Organization}}</ref><ref>{{Cite news|date=2020-05-25|title=WHO pauses hydroxychloroquine coronavirus trial over safety concerns|work=Global News|publisher=The Associated Press|url=https://globalnews.ca/news/6983283/who-hydroxychloroquine-trial/|access-date=2020-05-27|vauthors=Cheng M, Keaten J}}</ref><ref>{{Cite news|date=2020-05-25|title=Coronavirus: WHO halts trials of hydroxychloroquine over safety fears|work=BBC News Online|url=https://www.bbc.com/news/health-52799120|access-date=2020-06-04}}</ref> The WHO had enrolled 3,500 patients from 17 countries in the Solidarity trial.<ref name="who-suspend" /> The research surrounding this suspension, provided by a company called [[Surgisphere]] based in [[Chicago]], came into question due to errors in the underlying data set.<ref name="stat1">{{cite web|last1=Herper|first1=Matthew|last2=Joseph|first2=Andrew|date=June 2, 2020|title=Top medical journals raise concerns about data in two studies related to Covid-19|url=https://www.statnews.com/2020/06/02/top-medical-journals-raise-concerns-about-data-in-two-studies-related-to-covid-19/|access-date=June 4, 2020|website=[[Stat (website)|Stat]]|name-list-style=vanc}}</ref><ref>{{cite journal|last1=Servick|first1=Kelly|date=2 June 2020|title=A mysterious company's coronavirus papers in top medical journals may be unraveling|journal=Science|doi=10.1126/science.abd1337|name-list-style=vanc}}</ref><ref>{{cite web|author=Melissa Davey|date=May 28, 2020|title=Questions raised over hydroxychloroquine study which caused WHO to halt trials for Covid-19|url=https://www.theguardian.com/science/2020/may/28/questions-raised-over-hydroxychloroquine-study-which-caused-who-to-halt-trials-for-covid-19|access-date=June 4, 2020|website=The Guardian}}</ref> The authors of the study corrected errors in the data later but initially remained firm on their conclusions.<ref name="stat1" /> Subsequently, a retraction of the study by three of its authors was published by ''The Lancet'' on 4{{nbsp}}June, 2020.<ref>{{cite journal|vauthors=Mehra MR, Ruschitzka F, Patel AN|date=June 2020|title=Retraction-Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis|journal=Lancet|volume=395|issue=10240|pages=1820|doi=10.1016/S0140-6736(20)31324-6|pmc=7274621|pmid=32511943}}</ref> The authors stated that their reason behind the retraction was because Surgisphere had failed to cooperate with an independent review of the data used for the study by not allowing any such review to take place.<ref>{{cite news|date=June 5, 2020|title=Coronavirus: Influential study on hydroxychloroquine withdrawn|website=BBC News Online|url=https://www.bbc.com/news/health-52929916|access-date=June 5, 2020}}</ref><ref>{{cite news|last1=Boseley|first1=Sarah|last2=Davey|first2=Melissa|date=4 June 2020|title=Covid-19: Lancet retracts paper that halted hydroxychloroquine trials|website=[[The Guardian]]|url=http://www.theguardian.com/world/2020/jun/04/covid-19-lancet-retracts-paper-that-halted-hydroxychloroquine-trials|access-date=4 June 2020|name-list-style=vanc}}</ref>

The WHO decided to resume the trial on 3{{nbsp}}June, after reviewing the safety concerns which had been raised. Speaking at a press briefing, WHO's director-general, [[Tedros Adhanom Ghebreyesus]] stated that the board had reviewed the available mortality data and had found "no reasons to modify the trial".<ref>{{cite web|author=Andrew Joseph|date=June 3, 2020|title=WHO resumes hydroxychloroquine study for Covid-19, after reviewing safety concerns|url=https://www.statnews.com/2020/06/03/who-resuming-hydroxychloroquine-study-for-covid-19/|access-date=June 4, 2020|website=[[Stat (website)|Stat]]}}</ref><ref>{{cite web|author=Shaun Lintern|date=June 3, 2020|title=Coronavirus: WHO re-starts hydroxychloroquine trials amid controversy over published research|url=https://www.independent.co.uk/news/health/coronavirus-hydroxychloroquine-trials-trump-who-lancet-a9546836.html|access-date=June 4, 2020|website=The Independent}}</ref>

On 4 July, the WHO discontinued the hydroxychloroquine trial based on evidence presented at the July WHO Summit on COVID-19 research and innovation. The WHO stated that "the interim results do not provide solid evidence of increased mortality was interrupted when interim results did not find significant mortality reduction in hospitalized patients.<ref>https://www.who.int/news/item/04-07-2020-who-discontinues-hydroxychloroquine-and-lopinavir-ritonavir-treatment-arms-for-covid-19</ref>


=== Ivermectin ===
=== Ivermectin ===

Revision as of 23:33, 28 February 2021

This article is about drugs that may be repurposed for treating COVID-19. For potential COVID-19 vaccine, see COVID-19 vaccine. For potential therapeutic drugs for COVID-19, see COVID-19 drug development.

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Drug repositioning (also known as drug re-purposing, re-profiling, re-tasking, or therapeutic switching) is the re-purposing of an approved drug for the treatment of a different disease or medical condition than that for which it was originally developed.[1] This is one line of scientific research which is being pursued to develop safe and effective COVID-19 treatments.[2][3] Other research directions include the development of a COVID-19 vaccine[4] and convalescent plasma transfusion.[5]

Several existing antiviral medications, previously developed or used as treatments for severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV/AIDS, and malaria, have been researched as potential COVID‑19 treatments, with some moving into clinical trials.[6][7][8]

In a statement to the journal Nature Biotechnology in February 2020, US National Institutes of Health Viral Ecology Unit chief Vincent Munster said, "The general genomic layout and the general replication kinetics and the biology of the MERS, SARS and [SARS-CoV-2] viruses are very similar, so testing drugs which target relatively generic parts of these coronaviruses is a logical step".[2]

Monoclonal antibodies

Monoclonal antibodies under investigation for repurposing include anti-IL-6 agents (Tocilizumab)[9] and anti-IL-8 (BMS-986253).[10] (This is in parallel to novel monoclonal antibody drugs developed specifically for COVID-19.)

Mavrilimumab is a human monoclonal antibody that inhibits human granulocyte macrophage colony-stimulating factor receptor (GM-CSF-R).[11][12] It has been studied to see if it can improve the prognosis for patients with COVID-19 pneumonia and systemic hyperinflammation. One small study indicated some beneficial effects of treatment with mavrilimumab compared with those who were not.[13]

In January 2021 in the United Kingdom, the National Health Service issued guidance that the immune modulating drugs tocilizumab and sarilumab were beneficial when given promptly to people with COVID-19 admitted to intensive care, following research which found a reduction in the risk of death by 24%.[14]

Tocilizumab

Tocilizumab is an interleukin 6 inhibitor authorized for use in several conditions, including rheumatoid arthritis, giant cell arteritis, systemic juvenile idiopathic arthritis and severe cytokine release syndrome.[15] Its use has been studied in several trials.

In March 2020, China approved the drug for the treatment of inflammation in COVID-19 patients but found no conclusive evidence whether the treatment is effective.[16] The Australasian Society for Clinical Immunology and Allergy recommend tocilizumab be considered as an off-label treatment for those with COVID-19 related acute respiratory distress syndrome.[17]

It is part of the RECOVERY Trial in the UK.[9] Hoffmann–La Roche and the WHO have also launched separate trials for its use in severe cases.[18] Roche announced on July 29 that its randomized double-blind trial of tocilizumab for the treatment of pneumonia in Covid patients had shown no benefits.[19]

The REMAP‑CAP study in the UK found that tocilizumab was beneficial in adults with severe COVID‑19, who were critically ill and receiving respiratory or cardiovascular organ support in an intensive care setting, when this was started within 24 hours of the need for organ support.[15] The use of tocilizumab and its place in therapy have been updated by UK NICE in January 2021.[15]

Antivirals

Considerable scientific attention has been focused on re-purposing approved antiviral drugs that have been previously developed against other viruses, such as MERS-CoV, SARS-CoV, and West Nile virus.[20] These include favipiravir,[20] remdesivir,[21] ribavirin,[22] triazavirin,[23] and umifenovir.[24]

It was announced on 3 April 2020 that artesunate/pyronaridine, the main components of a new ACT antimalarial drug sold under the brand name Pyramax,[25] showed an inhibitory effect on SARS-CoV-2 in vitro tests using Hela cells. Pyramax showed a virus titer inhibition rate of 99% or more after 24 hours, while cytotoxicity was also reduced.[26] A preprint published in July 2020 reported that pyronaridine and artesunate exhibit antiviral activity against SARS-CoV-2 and influenza viruses using human lung epithelial (Calu-3) cells.[27] It is currently in phase II clinical trial in South Korea[28][29][30] and in South Africa.[31]

GS-441524 is the nucleoside of the ProTide remdesivir. It has been shown to cure cats infected with Feline infectious peritonitis (FIP), a feline form of coronavirus with a 96% cure rate.[32][33] Studies have shown that even when remdesivir is administered, GS-441524 is the predominant metabolite circulating in serum due to rapid hydrolysis of the remdesivir pro-drugs, followed by dephosphorylation.[34][35][36][37][unreliable medical source?] Some researchers have suggested its utility as a treatment for COVID‑19,[34][38][39][40][41] noting easier synthesis, lack of first-pass metabolism in the liver, greater hydrophilicity and triphosphate formation in cell types irrespective of expression CES1 and CTSA, the enzymes required to bioactivate remdesivir.

Molnupiravir is a drug developed to treat influenza. It is in Phase II trials as a treatment for COVID-19.[42][43] In December 2020 scientists reported that the antiviral drug molnupiravir developed for the treatment of influenza can completely suppress SARS-CoV-2 transmission within 24 hours in ferrets whose COVID-19 transmission they find to closely resemble SARS-CoV-2 spread in human young-adult populations.[44][45]

Niclosamide was identified as a candidate antiviral in an in vitro drug screening assay done in South Korea.[46]

Protease inhibitors, which specifically target the protease 3CLpro, are being researched and developed in the laboratory such as CLpro-1, GC376, and Rupintrivir.[47][48][49]

Favipiravir

Favipiravir is an antiviral drug approved for the treatment of influenza in Japan.[50][20] There is limited evidence suggesting that, compared to other antiviral drugs, favipiravir might improve outcomes for people with COVID-19, but more rigorous studies are needed before any conclusions can be drawn.[51]

Chinese clinical trials in Wuhan and Shenzhen claimed to show that favipiravir was "clearly effective".[52] Of 35 patients in Shenzhen tested negative in a median of 4 days, while the length of illness was 11 days in the 45 patients who did not receive it.[53] In a study conducted in Wuhan on 240 patients with pneumonia half were given favipiravir and half received umifenovir. The researchers found that patients recovered from coughs and fevers faster when treated with favipiravir, but that there was no change in how many patients in each group progressed to more advanced stages of illness that required treatment with a ventilator.[54]

On 22 March 2020, Italy approved the drug for experimental use against COVID‑19 and began conducting trials in the three regions most affected by the disease.[55] The Italian Pharmaceutical Agency reminded the public that the existing evidence in support of the drug is scant and preliminary.[56]

On 30 May 2020, the Russian Health Ministry approved a generic version of favipiravir named Avifavir, which proved highly effective in the first phase of clinical trials.[57][58][59]

In June 2020, India approved the use of a generic version of favipravir called FabiFlu, developed by Glenmark Pharmaceuticals, in the treatment of mild to moderate cases of COVID‑19.[60]

Lopinavir/ritonavir

Genome of SARS-CoV-2: the grey wedges show where 3CLpro the main coronavirus protease cleaves the polyprotein.

In March 2020, the main protease (3CLpro) of the SARS-CoV-2 virus was identified as a target for post-infection drugs. The enzyme is essential for processing the replication-related polyprotein. To find the enzyme, scientists used the genome published by Chinese researchers in January 2020 to isolate the main protease.[61] Protease inhibitors approved for treating human immunodeficiency viruses (HIV) – lopinavir and ritonavir – have preliminary evidence of activity against the coronaviruses, SARS and MERS.[6][62] As a potential combination therapy, they are used together in two Phase III arms of the 2020 global Solidarity project on COVID‑19.[62][63] A preliminary study in China of combined lopinavir and ritonavir found no effect in people hospitalized for COVID‑19.[64]

One study of lopinavir/ritonavir (Kaletra), a combination of the antivirals lopinavir and ritonavir, concluded that "no benefit was observed".[64][65] The drugs were designed to inhibit HIV from replicating by binding to the protease. A team of researchers at the University of Colorado are trying to modify the drugs to find a compound that will bind with the protease of SARS-CoV-2.[66] There are criticisms within the scientific community about directing resources to repurposing drugs specifically developed for HIV/AIDS because such drugs are unlikely to be effective against a virus lacking the specific HIV-1 protease they target.[2] The WHO included lopinavir/ritonavir in the international Solidarity trial.[67]

On 29 June, the chief investigators of the UK RECOVERY Trial reported that there was no clinical benefit from use of lopinavir-ritonavir in 1,596 people hospitalized with severe COVID-19 infection over 28 days of treatment.[68][69]

A study published in October 2020 screening those FDA approved drugs which target SARS-CoV-2 spike (S) protein proposed that the current unbalanced combination formula of lopinavir might in fact interfere with the ritonavir's blocking activity on the receptor binding domain-human angiotensin converting enzyme-2 (RBD-hACE2) interaction, thus effectively limiting its therapeutic benefit in COVID-19 cases.[70]

Remdesivir

This section is an excerpt from Remdesivir.[edit]


Remdesivir, sold under the brand name Veklury,[71][72] is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences.[73] It is administered via injection into a vein.[74][75] During the COVID‑19 pandemic, remdesivir was approved or authorized for emergency use to treat COVID‑19 in numerous countries.[76]

Remdesivir was originally developed to treat hepatitis C,[77] and was subsequently investigated for Ebola virus disease and Marburg virus infections[78] before being studied as a post-infection treatment for COVID‑19.[79]

Remdesivir is a prodrug that is intended to allow intracellular delivery of GS-441524 monophosphate and subsequent biotransformation into GS-441524 triphosphate, a ribonucleotide analogue inhibitor of viral RNA polymerase.[80]

The most common side effect in healthy volunteers is raised blood levels of liver enzymes.[71] The most common side effect in people with COVID‑19 is nausea.[71] Side effects may include liver inflammation and an infusion-related reaction with nausea, low blood pressure, and sweating.[81]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[82]

Antiparasitics

Antiparasitics that have been investigated include chloroquine,[83] hydroxychloroquine,[84] mefloquine,[85][unreliable medical source?][86] ivermectin,[87] and atovaquone.[88]

Chloroquine and hydroxychloroquine

This section is an excerpt from Chloroquine and hydroxychloroquine during the COVID-19 pandemic.[edit]


A World Health Organization infographic that states that hydroxychloroquine does not prevent illness or death from COVID-19.

Chloroquine and hydroxychloroquine are anti-malarial medications also used against some auto-immune diseases.[89] Chloroquine, along with hydroxychloroquine, was an early experimental treatment for COVID-19.[90] Neither drug has been useful to prevent or treat SARS-CoV-2 infection.[91][92][93][94][95][96] Administration of chloroquine or hydroxychloroquine to COVID-19 patients has been associated with increased mortality and adverse effects, such as QT prolongation.[97][98] Researchers estimate that off-label use of hydroxychloroquine in hospitals during the first phase of the pandemic caused 17,000 deaths worldwide.[99] The widespread administration of chloroquine or hydroxychloroquine, either as monotherapies or in conjunction with azithromycin, has been associated with deleterious outcomes, including QT interval prolongation. As of 2024, scientific evidence does not substantiate the efficacy of hydroxychloroquine, with or without the addition of azithromycin, in the therapeutic management of COVID-19.[97]

Cleavage of the SARS-CoV-2 S2 spike protein required for viral entry into cells can be accomplished by proteases TMPRSS2 located on the cell membrane, or by cathepsins (primarily cathepsin L) in endolysosomes.[100] Hydroxychloroquine inhibits the action of cathepsin L in endolysosomes, but because cathepsin L cleavage is minor compared to TMPRSS2 cleavage, hydroxychloroquine does little to inhibit SARS-CoV-2 infection.[100]

Several countries initially used chloroquine or hydroxychloroquine for treatment of persons hospitalized with COVID-19 (as of March 2020), though the drug was not formally approved through clinical trials.[101][102] From April to June 2020, there was an emergency use authorization for their use in the United States,[103] and was used off label for potential treatment of the disease.[104] On 24 April 2020, citing the risk of "serious heart rhythm problems", the FDA posted a caution against using the drug for COVID-19 "outside of the hospital setting or a clinical trial".[105]

Their use was withdrawn as a possible treatment for COVID-19 infection when it proved to have no benefit for hospitalized patients with severe COVID-19 illness in the international Solidarity trial and UK RECOVERY Trial.[106][107] On 15 June 2020, the FDA revoked its emergency use authorization, stating that it was "no longer reasonable to believe" that the drug was effective against COVID-19 or that its benefits outweighed "known and potential risks".[108][109][110] In fall of 2020, the National Institutes of Health issued treatment guidelines recommending against the use of hydroxychloroquine for COVID-19 except as part of a clinical trial.[89]

In 2021, hydroxychloroquine was part of the recommended treatment for mild cases in India.[111]

In 2020, the speculative use of hydroxychloroquine for COVID-19 threatened its availability for people with established indications (malaria and auto-immune diseases).[93]

Ivermectin

In vitro, ivermectin has antiviral effects against several distinct positive-sense single-strand RNA viruses, including SARS-CoV-2.[112] Subsequent studies found that ivermectin could inhibit replication of SARS-CoV-2 in monkey kidney cell culture with an IC50 of 2.2–2.8 μM.[87][113] Based on this information, however, doses much higher than the maximum approved or safely achievable for use in humans would be required for an antiviral effect.[114] Aside from practical difficulties, such high doses are not covered by current human-use approvals of the drug and would be toxic, as the antiviral mechanism of action is considered to operate via the suppression of a host cellular process,[114] specifically the inhibition of nuclear transport by importin α/β1.[115]

In November 2020, a systematic review found weak evidence of benefit when ivermectin is used as an add-on therapy for people with non-severe COVID-19.[116] A randomized controlled trial (RCT) of 24 patients with non-severe COVID-19 and no risk factors found no difference in PCR-positive nasal swabs nor in viral load between patients who received ivermectin and those given placebo, thus failing the primary outcome of the study.[117] Merck, the company from which the drug originated, has said that there is no good evidence ivermectin is plausible or effective as a drug used against COVID-19, and that attempting such use may be unsafe.[118]

As of January 2021, the U.S. National Institutes of Health COVID-19 Treatment Guidelines state that the evidence for ivermectin is too limited to allow for a recommendation for or against its use.[119] Ivermectin is not approved by the FDA for anti-viral use.[119] Additional evidence from RCTs and dose-response studies are needed.[120] At least 45 such trials were listed as of January 2021.[117]

It was reported in June 2020 that despite the absence of high-quality evidence to suggest any efficacy, use of ivermectin for prevention or treatment of early-stage COVID-19 has become increasingly widespread especially in Latin America, raising concerns about self-medication, safety, and the feasibility of future clinical trials.[121][122] In response, the Brazilian Health Regulatory Agency, Brazilian Society of Infectious Diseases, and Brazilian Thoracic Society all issued position statements in July[123] or January 2021[124][125] advising against the use of ivermectin for this purpose, and the government of Peru rescinded a previous recommendation for the use of ivermectin (alongside azithromycin and hydroxychloroquine) in hospitalized patients,[126] although as of January 2021 it is still prescribed for outpatient use.[127]

Anticoagulants

Medications to prevent blood clotting have been suggested for treatment, and anticoagulant therapy with low molecular weight heparin appears to be associated with better outcomes in severe COVID‐19 showing signs of coagulopathy (elevated D-dimer).[128] Several anticoagulants have been tested in Italy, with Low-molecular-weight heparin being widely used to treat patients, prompting the Italian Medicines Agency to publish guidelines on its use.[129]

Scientists have identified an ability of Heparin to bind to the spike protein of the SARS-CoV-2 virus, neutralising it, and proposed the drug as a possible antiviral.[130]

A multicenter study on 300 patients researching the use of enoxaparin sodium at prophylaxis and therapeutic dosages was announced in Italy on 14 April.[131]

The anticoagulant dipyridamole is proposed as a treatment for COVID‑19,[132] and a clinical trial is underway.[133]

Interferons

Drugs with immune modulating effects that may prove useful in COVID‑19 treatment include type I Interferons such as Interferon-β, peginterferon alpha-2a and -2b.[134][135]

IFN-β 1b have been shown in an open label randomised controlled trial in combination with lopinavir/ ritonavir and ribavirin to significantly reduce viral load, alleviate symptoms and reduce cytokine responses when compared to lopinavir/ ritonavir alone.<Lancet 2020;395(10238):1695-1704> IFN-β will be included in the international Solidarity Trial in combination with the HIV drugs Lopinavir and Ritonavir.[134] as well as the REMAP-CAP[135] Finnish biotech firm Faron Pharmaceuticals continues to develop INF-beta for ARDS and is involved in worldwide initiatives[which?] against COVID‑19, including the Solidarity trial.[136] UK biotech firm Synairgen started conducting trials on IFN-β, a drug that was originally developed to treat COPD.[67]

Steroids

UK-Australia trial underway as of June 2020 examining budesonide as an early-intervention treatment for COVID-19, results expected in September 2020.[137] Patients previously prescribed inhaled corticosteroids have been observed to develop less serious illness when diagnosed with COVID-19, despite often having conditions such as asthma that might be thought to lead to more serious illness.[138][139]

Japan's National Center for Global Health and Medicine (NCGM) is planning a clinical trial for Teijin's Alvesco (ciclesonide), an inhaled corticosteroid for asthma, for the treatment of pre-symptomatic patients infected with the novel coronavirus.[140] Ciclesonide was identified as a candidate antiviral in an in vitro drug screening assay done in South Korea.[46]

In September 2020, a meta-analysis study published by the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group found hydrocortisone to be effective in reducing mortality rate of critically ill COVID-19 patients when compared to other usual care or a placebo.[141]

The use of corticosteroids can cause a severe and deadly "hyperinfection" syndrome for people with strongyloidiasis, which may be an underlying condition in populations exposed to the parasite Strongyloides stercoralis. This risk can be mitigated by the presumptive use of ivermectin before steroid treatment.[142]

Dexamethasone

See also: Dexamethasone § COVID-19
A vial of dexamethasone for injection

Dexamethasone is a corticosteroid medication in use for multiple conditions such as rheumatic problems, skin diseases, asthma and chronic obstructive lung disease among others.[143] A multi-center, randomized controlled trial of dexamethasone in treating acute respiratory distress syndrome (ARDS), published in February 2020, showed reduced need for mechanical ventilation and mortality.[144] Dexamethasone is only helpful in people requiring supplemental oxygen. Following an analysis of seven randomized trials,[145] the WHO recommends the use of systemic corticosteroids in guidelines for treatment of people with severe or critical illness, and that they not be used in people that do not meet the criteria for severe illness.[146]

On 16 June, the Oxford University RECOVERY Trial issued a press release announcing preliminary results that the drug could reduce deaths by about a third in participants on ventilators and by about a fifth in participants on oxygen; it did not benefit patients who did not require respiratory support. The researchers estimated that treating 8 patients on ventilators with dexamethasone saved one life, and treating 25 patients on oxygen saved one life.[147] Several experts called for the full dataset to be published quickly to allow wider analysis of the results.[148][149] A preprint was published on June 22[150] and the peer-reviewed article appeared on July 17.[151]

Based on those preliminary results, dexamethasone treatment has been recommended by the US National Institutes of Health (NIH) for patients with COVID-19 who are mechanically ventilated or who require supplemental oxygen but are not mechanically ventilated. The NIH recommends against using dexamethasone in patients with COVID-19 who do not require supplemental oxygen.[152] In July 2020, the World Health Organization (WHO) stated they are in the process of updating treatment guidelines to include dexamethasone or other steroids.[153]

The Infectious Diseases Society of America (IDSA) guideline panel suggests the use of glucocorticoids for patients with severe COVID-19; where severe is defined as patients with oxygen saturation (SpO2) ≤94% on room air, and those who require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).[154] The IDSA recommends against the use of glucocorticoids for those with COVID-19 without hypoxemia requiring supplemental oxygen.[154]

In July 2020, the European Medicines Agency (EMA) started reviewing results from the RECOVERY study arm that involved the use of dexamethasone in the treatment of patients with COVID-19 admitted to the hospital to provide an opinion on the results. It focused particularly on the potential use of the drug for the treatment of adults with COVID-19.[155]

In September 2020, the WHO released updated guidance on using corticosteroids for COVID-19.[156] The WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of people with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence).[156] The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID-19 (conditional recommendation, based on low certainty evidence).[156]

In September 2020, the European Medicines Agency (EMA) endorsed the use of dexamethasone in adults and adolescents (from twelve years of age and weighing at least 40 kg) who require supplemental oxygen therapy.[157] Dexamethasone can be taken by mouth or given as an injection or infusion (drip) into a vein.[157]

Vitamins

Vitamin C

Supplementation with micronutrients, including vitamin C, has been suggested as part of the supportive management of COVID-19, as levels of vitamin C in serum and leukocytes are depleted in the acute stage of infection owing to increased metabolic demands.[158] The use of high-dose intravenous vitamin C has been studied.[158] According to ClinicalTrials.gov, there are at least 34 ongoing clinical trials including vitamin C, which have completed or are recruiting people, hospitalized and severely ill with COVID‑19.[159]

Vitamin D

Oral vitamin D tablets

The National Institutes of Health (NIH) COVID-19 Treatment Guidelines stated in July 2020 that "there are insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19."[160]

There has been particular interest given the significant overlap in the risk factors for severe COVID-19 and vitamin D deficiency, including obesity, older age, and Black or Asian ethnic origin, noting that vitamin D deficiency is common in Europe and the United States particularly within these groups.[161] The general recommendation to take vitamin D supplements, particularly given the levels of vitamin D deficiency in Western populations, has been repeated.[162]

During the COVID-19 pandemic a number of clinical trials are being undertaken to examine any specific role for vitamin D in COVID-19 prevention and management.[163][164] Emerging results indicate a link between vitamin D deficiency and the severity of the disease. A systematic review and meta-analysis of 27 publications found that, although vitamin D deficiency was not associated with a higher probability of becoming infected with COVID-19, there were significant associations between vitamin D deficiency and the severity of the disease, including relative increases in hospitalization and mortality rates of about 80%.[165] As of February 2021, the English National Institute for Health and Care Excellence (NICE) continued to recommend small doses of supplementary vitamin D for people with little exposure to sunshine, but recommended that practitioners should not offer a vitamin D supplement solely to prevent or treat COVID‑19, except as part of a clinical trial.[162]

Many Phase II–IV clinical trials are underway to assess the use of oral vitamin D and its metabolites such as calcifediol for prevention or treatment of COVID‑19 infection, particularly in people with vitamin D deficiency.[163][166][161] A systematic review and meta-analysis of 27 publications, published in November 2020, showed that although vitamin D deficiency was not associated with a higher risk of getting COVID-19, there were positive associations between vitamin D deficiency and the severity of the disease, including increases of about 80% in hospitalization and mortality rates.[167]

Others

A form of angiotensin-converting enzyme 2, a Phase II trial is underway with 200 patients to be recruited from severe, hospitalized cases in Denmark, Germany, and Austria to determine the effectiveness of the treatment.[168][169]

Some antibiotics that have been identified as potentially re-purposable as COVID‑19 treatments,[170][171] including teicoplanin,[172] oritavancin,[173] dalbavancin,[173] monensin,[173] and azithromycin.[174] New York State began trials for the antibiotic azithromycin on 24 March 2020.[174]

On 31 July 2020, the U.S. Food and Drug Administration (FDA) authorized Revive Therapeutics to proceed with a randomized, double-blind, placebo-controlled confirmatory Phase III clinical trial protocol to evaluate the safety and efficacy of the antirheumatic agent bucillamine in patients with mild-moderate COVID-19.[175]

The oral JAK inhibitor baricitinib is also being studied for COVID-19 treatment.[176] In November 2020, the FDA granted emergency use authorization for baricitinib to be given to certain people hospitalized with suspected or confirmed COVID-19 (specifically, adults and children two years of age or older requiring supplemental oxygen, mechanical ventilation, or ECMO), but only in conjunction with remdesivir.[177] In a single clinical trial, this combination therapy was shown to have a small, but statistically significant effect on patient outcomes compared to administration of remdesivir alone.[178]

In 2021, the importance of drug repurposing for COVID-19 led to the establishment of broad-spectrum therapeutics.[179] Broad-spectrum therapeutics are effective against multiple types of pathogens.[180] Such drugs have been suggested as potential emergency treatments for future pandemics.[181][182]

Histamine H2 receptor antagonists are under investigation. Cimetidine has been suggested as a treatment for COVID-19.[132] Famotidine has been suggested as a treatment for COVID-19,[132] and a clinical study is underway.[183]

Researchers from the Montreal Heart Institute in Canada are studying the role of colchicine in reducing inflammation and pulmonary complications in patients suffering from mild symptoms of COVID‑19.[184] The study, named COLCORONA, is recruiting 6000 adults 40 and older who were diagnosed with COVID‑19 and experience mild symptoms not requiring hospitalization.[184][185] Women who are pregnant or breastfeeding or who do not have an effective contraceptive method are not eligible.[185]

Fenofibrate and bezafibrate have been suggested for treatment of life-threatening symptoms of COVID-19.[132][186]

A trial called "Liberate" has been started in the United Kingdom to determine the effectiveness of ibuprofen in reducing the severity and progression of lung injury which results in breathing difficulties for COVID‑19 patients. Subjects are to receive three doses of a special formulation of the drug – lipid ibuprofen – in addition to usual care.[187][188]

A clinical cohort study in Brazil found that COVID-19 patients who received a recent influenza vaccine needed less intensive care support, less invasive respiratory support, and were less likely to die.[189]

nanoFenretinide is nanoparticle sized fenretinide and repurposed oncology drug approved to enter the clinic for a lymphoma indication.[190] It was identified as a candidate antiviral in an in vitro drug screening assay done in South Korea.[46] Fenretinide's clinical safety profile also makes it an ideal candidate in combination regimens.[citation needed]

Sildenafil is proposed as a treatment for COVID-19,[132] and a Phase III clinical trial is underway.[191]

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Further reading

External links

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