Chloroquine and hydroxychloroquine during the COVID-19 pandemic

Chloroquine and hydroxychloroquine are anti-malarial medications also used against some auto-immune diseases.[1] Chloroquine, along with hydroxychloroquine, was an early experimental treatment for COVID-19.[2] Neither drug has been useful to prevent or treat SARS-CoV-2 infection.[3][4][5][6][7][8] Administration of chloroquine or hydroxychloroquine to COVID-19 patients, either as monotherapies or in conjunction with azithromycin, has been associated with deleterious outcomes, such as QT prolongation.[9][10] 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.[9]

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.[11] 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.[11]

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.[12][13] From April to June 2020, there was an emergency use authorization for their use in the United States,[14] and was used off label for potential treatment of the disease.[15] 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".[16]

Their use was withdrawn as a possible treatment for COVID-19 infection when it proved to have no benefit for hospitalized patients with severe COVID-19 illness in the international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.[17][18] 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".[19][20][21] 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.[1]

In 2021, hydroxychloroquine was part of the recommended treatment for mild cases in India.[22]

In 2020, the speculative use of hydroxychloroquine for COVID-19 threatened its availability for people with established indications (malaria and auto-immune diseases).[5]

  1. ^ a b "Chloroquine or Hydroxychloroquine". COVID-19 Treatment Guidelines. National Institutes of Health. Archived from the original on 28 August 2020. Retrieved 14 February 2021.
  2. ^ "Coronavirus (COVID-19) Update: Daily Roundup March 30, 2020". FDA. 30 March 2020. Archived from the original on 19 October 2020. Retrieved 28 February 2021.
  3. ^ Smit M, Marinosci A, Agoritsas T, Calmy A (April 2021). "Prophylaxis for COVID-19: a systematic review". Clinical Microbiology and Infection (Systematic review). 27 (4): 532–537. doi:10.1016/j.cmi.2021.01.013. PMC 7813508. PMID 33476807.
  4. ^ Meyerowitz EA, Vannier AG, Friesen MG, Schoenfeld S, Gelfand JA, Callahan MV, et al. (May 2020). "Rethinking the role of hydroxychloroquine in the treatment of COVID-19". FASEB Journal. 34 (5): 6027–6037. doi:10.1096/fj.202000919. PMC 7267640. PMID 32350928.
  5. ^ a b Juurlink DN (April 2020). "Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection". CMAJ. 192 (17): E450–E453. doi:10.1503/cmaj.200528. PMC 7207200. PMID 32269021.
  6. ^ "Assessment of Evidence for COVID-19-Related Treatments: Updated 4/3/2020". American Society of Health-System Pharmacists. Archived from the original on 14 April 2021. Retrieved 7 April 2020.
  7. ^ Yazdany J, Kim AH (June 2020). "Use of Hydroxychloroquine and Chloroquine During the COVID-19 Pandemic: What Every Clinician Should Know". Annals of Internal Medicine. 172 (11): 754–755. doi:10.7326/M20-1334. PMC 7138336. PMID 32232419.
  8. ^ Singh B, Ryan H, Kredo T, Chaplin M, Fletcher T, et al. (Cochrane Infectious Diseases Group) (February 2021). "Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19". The Cochrane Database of Systematic Reviews. 2021 (2): CD013587. doi:10.1002/14651858.CD013587.pub2. PMC 8094389. PMID 33624299.
  9. ^ a b Nag K, Tripura K, Datta A, Karmakar N, Singh M, Singh M, et al. (2024). "Effect of Hydroxychloroquine and Azithromycin Combination Use in COVID-19 Patients - An Umbrella Review". Indian J Community Med. 49 (1): 22–27. doi:10.4103/ijcm.ijcm_983_22. PMC 10900474. PMID 38425958.
  10. ^ Jankelson L, Karam G, Becker ML, Chinitz LA, Tsai M (2020). "QT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: A systematic review". Heart Rhythm. 17 (9): 1472–1479. doi:10.1016/j.hrthm.2020.05.008. PMC 7211688. PMID 32438018.
  11. ^ a b Jackson CB, Farzan M, Chen B, Choe H (January 2022). "Mechanisms of SARS-CoV-2 entry into cells". Nature Reviews. Molecular Cell Biology. 23 (1): 3–20. doi:10.1038/s41580-021-00418-x. PMC 8491763. PMID 34611326.
  12. ^ "Information for clinicians on therapeutic options for COVID-19 patients". US Centers for Disease Control and Prevention. 21 March 2020. Archived from the original on 8 April 2020. Retrieved 22 March 2020.
  13. ^ Hinton DM (28 March 2020). "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" (PDF). U.S. Food and Drug Administration (FDA). Archived from the original on 2 October 2020. Retrieved 30 March 2020.
  14. ^ "Coronavirus Disease 2019 (COVID-19)". Centers for Disease Control and Prevention. 11 February 2020. Archived from the original on 8 April 2020. Retrieved 9 April 2020.
  15. ^ Kalil AC (May 2020). "Treating COVID-19-Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics". JAMA. 323 (19): 1897–1898. doi:10.1001/jama.2020.4742. PMID 32208486.
  16. ^ "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". U.S. Food and Drug Administration (FDA). 24 April 2020. Archived from the original on 4 November 2020. Retrieved 28 February 2021.
  17. ^ Mulier T (17 June 2020). "Hydroxychloroquine halted in WHO-sponsored COVID-19 trials". Bloomberg. Archived from the original on 11 October 2020. Retrieved 17 June 2020.
  18. ^ "No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19". Recovery Trial, Nuffield Department of Population Health, University of Oxford, UK. 5 June 2020. Archived from the original on 8 October 2020. Retrieved 7 June 2020.
  19. ^ "Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine". U.S. Food and Drug Administration (FDA) (Press release). 15 June 2020. Archived from the original on 15 June 2020. Retrieved 15 June 2020.
  20. ^ Lovelace Jr B (15 June 2020). "FDA revokes emergency use of hydroxychloroquine". CNBC. Archived from the original on 11 October 2020. Retrieved 28 February 2021.
  21. ^ "Frequently Asked Questions on the Revocation of the Emergency Use Authorization for Hydroxychloroquine Sulfate and Chloroquine Phosphate" (PDF). U.S. Food and Drug Administration (FDA). 15 June 2020. Archived from the original on 15 April 2021. Retrieved 15 June 2020.
  22. ^ "Clinical Management Protocol for Covid-19 (in Adults)" (PDF). Ministry of Health and Family Welfare. 24 May 2021. Archived (PDF) from the original on 5 December 2021. Retrieved 10 July 2021. "Health ministry issues revised clinical management protocols for Covid-19 amid spurt in cases". Times of India. Press Trust of India. 13 June 2021. Archived from the original on 11 July 2021. Retrieved 10 July 2021.