Hydroxychloroquine and Chloroquine: Failed Remedies for COVID-19

Hydroxychloroquine (PLAQUENIL) is approved by the Food and Drug Administration (FDA) to treat rheumatoid arthritis and lupus erythematosus and to prevent or treat malaria that is not complicated by drug-resistant parasites or co-occurring brain or kidney disease.[1] Hydroxychloroquine is a derivative of and similar in structure to chloroquine (available in generic versions only), which is approved to treat malaria and another type of parasitic infection called extraintestinal amebiasis,[2] but hydroxychloroquine is newer and is less toxic to the liver.[3]

Early during the coronavirus pandemic, hydroxychloroquine and chloroquine were considered potentially useful treatments for coronavirus disease 2019 (COVID-19) because of their long history of being used to treat other infectious and inflammatory diseases in humans and because of early incomplete reports from China suggesting they might be effective COVID-19 treatments.[4] A poorly conducted, small study involving 30 patients by a maverick scientist in France, who claimed that hydroxychloroquine in combination with the antibiotic azithromycin (ZITHROMAX) had a 100% cure rate in COVID-19 patients, also encouraged use of these medications to treat COVID-19.[5],[6] Additionally, cell culture studies of hydroxychloroquine and chloroquine suggested that these drugs had potent activity against the novel coronavirus.[7]

Based largely on this preliminary and inadequate evidence, the FDA on March 28 issued an Emergency Use Authorization (EUA) permitting the limited use of the hydroxychloroquine and chloroquine from the Strategic National Stockpile for the treatment of seriously ill adolescents and adults with COVID-19 “for whom a clinical trial is not available.”[8] The EUA thereby temporarily allowed use of these drugs but only in the hospital setting and only if the patients could not be entered into a clinical trial testing these medications.

However, because these drugs can cause serious, potentially fatal adverse effects and because several well-designed randomized clinical trials subsequently showed that hydroxychloroquine is not effective for treating or preventing COVID-19, the FDA on June 15 revoked the EUA that allowed the use of hydroxychloroquine and chloroquine from the Strategic National Stockpile. In the agency’s EUA revocation letter, Dr. Denise Hinton, the agency’s chief scientist, stated the following:

[I]t is no longer reasonable tobelieve that the oral formulations of [hydroxychloroquine] and [chloroquine] 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.[9]

Safety concerns

Many reports have demonstrated the potential of hydroxychloroquine and chloroquine to cause harm. Most concerning, these drugs can cause QT prolongation,[10],[11] a change in the electrical activity of the heart that can lead to a fatal heart rhythm disturbance called torsades de pointes, which can cause cardiac arrest and sudden death. For years, the FDA-approved product labeling for hydroxychloroquine and chloroquine have warned about this and other serious cardiac risks.[12],[13] Moreover, a recent review of multiple studies found that the proportion of hospitalized COVID-19 patients who experienced severe QT prolongation during treatment with hydroxychloroquine ranged from 1% to 18% across studies.[14]

The product labeling for both medications also includes warnings about serious eye damage with long-term exposure and the acute adverse effects of diarrhea, nausea, abnormal liver function and severe hypoglycemia (low blood sugar, which may result in loss of consciousness).[15],[16]

Summary of recent evidence

After the FDA issued the EUA for the emergency use of hydroxychloroquine or chloroquine to treat hospitalized patients with COVID-19, results of several randomized clinical trials that assessed the risks and benefits of these drugs for treating or preventing COVID-19 were published.

Treatment of hospitalized COVID-19 patients

The first randomized, controlled trial, which was published in May in the British medical journal BMJ, was conducted in China and enrolled 150 patients hospitalized with COVID-19.[17] The disease was categorized as mild-to-moderate in 148 patients and severe in two patients. The patients were randomly assigned in equal numbers to receive either usual care only or usual care plus hydroxychloroquine at a dosage of 1,200 mg daily for three days followed by 800 mg daily for two to three weeks. A placebo was not available for the usual care control group patients.

In the hydroxychloroquine group for the BMJ trial, 85% of the patients tested negative for the coronavirus within 28 days of randomization, compared with 81% of the usual-care-only group. This difference was not statistically significant. Moreover, adverse events occurred in more patients in the hydroxychloroquine group than in the usual-care-only group (30% vs. 9%, respectively), and two hydroxychloroquine subjects experienced serious adverse events, compared with no such events in the usual-care-only group. The most common non-serious adverse event was diarrhea, which occurred in seven patients in the hydroxychloroquine group and none in the usual-care-only group.

The second randomized, controlled trial, which was published in April in the Journal of the American Medical Association (JAMA) Network Open and conducted in Brazil, demonstrated that high doses of chloroquine may be especially risky in hospitalized patients with severe COVID-19.[18] For this trial, researchers randomized 81 patients hospitalized for severe COVID-19 to receive either high-dose chloroquine (600 mg twice daily for 10 days) or low-dose chloroquine (900 mg on day one followed by 450 mg once daily for four days). All patients in both groups also received azithromycin. By 13 days after initiation of chloroquine, 39% of the 41 high-dose group patients died, compared with only 15% of the 40 low-dose group patients. Severe QT prolongation occurred in 19% of the high-dose patients, compared with 11% of the low-dose group patients. Originally, the Brazil researchers planned to randomize 440 subjects, but randomization of patients to the high-dose chloroquine group was halted after 81 subjects were enrolled because of the markedly higher death rate in the high-dose group.

The third and largest randomized clinical trial, which was conducted in the U.K., found that hydroxychloroquine provided no clinical benefit to hospitalized COVID-19 patients. Results of the trial, which were first announced in early June,[19] have not been published yet in a peer-reviewed journal, but were described in detail in a manuscript published online.[20] For this trial, researchers randomly assigned 3,155 hospitalized COVID-19 patients to usual care only and 1,561 patients to usual care plus hydroxychloroquine at a dosage of 800 mg initially and 6 hours later followed by 400 mg twice daily for up to 9 days. Within 28 days of randomization, 27% of hydroxychloroquine group patients died, compared with 25% of usual-care-only group patients, a difference that was not statistically significant.

Prevention trial

Another randomized clinical trial, which was conducted in the U.S. and published in the New England Journal of Medicine, assessed whether hydroxychloroquine use can prevent the development of COVID-19 after exposure to the coronavirus. For the trial, researchers enrolled 821 adults who experienced moderate-to-high-risk home or workplace contact with a COVID-19 case (defined as at least 10 minutes of exposure at a distance of less than six feet with no face mask or eye shield [high risk] or only a face mask but no eye shield [moderate risk]).[21] Those exposed individuals were randomized into two nearly equal groups, one receiving hydroxychloroquine (800 mg as an initial dose, 600 mg in the subsequent 6-8 hours and daily doses of 400 mg for an additional four days) and the other receiving a placebo. No statistically significant difference was seen in the subsequent rates of COVID-19 illness within 14 days of exposure (12% of hydroxychloroquine group subjects compared with 14% of placebo group subjects), but adverse effects in the hydroxychloroquine group subjects were significantly higher than in the placebo group subjects (40% versus 17%, respectively). The most common adverse effects were nausea or stomach upset, diarrhea, abdominal discomfort and vomiting. Serious adverse events, including abnormal heart rhythms, were not observed.

What You Can Do

Do not use hydroxychloroquine or chloroquine to treat or prevent COVID-19. These medications have been shown to be safe and effective options for treating rheumatoid arthritis, lupus and malaria, but be aware of adverse effects related to the eyes, liver and heart, and only use these medications for these approved uses under the direct care of your doctor.

References

[1] Concordia Pharmaceuticals. Label: hydroxychloroquine (PLAQUENIL). April 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=34496b43-05a2-45fb-a769-52b12e099341&type=display. Accessed September 9, 2020.

[2] Bayshore Pharmaceuticals. Label: chloroquine. April 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=4543d87b-6a1a-4e08-9cdd-33b4909c2c21&type=display. Accessed September 9, 2020.

[3] PubChem. Compound summary: Hydroxychloroquine. https://pubchem.ncbi.nlm.nih.gov/compound/3652. Accessed August 31, 2020.

[4] Meyerowitz EA, Vannier AGL, Friesen MGN, et al. Rethinking the role of hydroxychloroquine in the treatment of COVID-19. FASEB J. 2020;34(5):6027-6037.

[5] Rosendaal FR. Review of: "Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Gautret et al 2010, DOI:10.1016/j.ijantimicag.2020.105949. Int J Antimicrob Agents. 2020;56(1):106063.

[6] Sayare S. He was a science star. Then he promoted a questionable cure for COVID-19. The New York Times Magazine. May 21, 2020. https://www.nytimes.com/2020/05/12/magazine/didier-raoult-hydroxychloroquine.html?searchResultPosition=1. Accessed September 9, 2020.

[7] Meyerowitz EA, Vannier AGL, Friesen MGN, et al. Rethinking the role of hydroxychloroquine in the treatment of COVID-19. FASEB J. 2020;34(5):6027-6037.

[8] Food and Drug Administration. Letter to Dr. Rick Bright, Ph.D., regarding 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. March 28, 2020. https://www.fda.gov/media/136534/download. Accessed September 9, 2020.

[9] Food and Drug Administration. Letter to Gary L. Disbrow, Ph.D., Deputy Assistant Secretary, U.S. Department of Health and Human Services. June 15, 2020. https://www.fda.gov/media/138945/download. Accessed September 9, 2020.

[10] Chorin E, Dai M, Shulman E, et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nat Med. 2020; June;26(6):808-809.

[11] Pastick KA, Okafor EC, Wang F, et al. Review: Hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19). Open Forum Infect Dis. 2020;7(4):ofaa130.

[12] Concordia Pharmaceuticals. Label: hydroxychloroquine (PLAQUENIL). April 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=34496b43-05a2-45fb-a769-52b12e099341&type=display. Accessed September 9, 2020.

[13] Bayshore Pharmaceuticals. Label: chloroquine. April 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=4543d87b-6a1a-4e08-9cdd-33b4909c2c21&type=display. Accessed September 9, 2020.

[14] Hernandez AV, Roman YM, Pasupuleti V, et al. Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID-19: A living systematic review. Ann Intern Med. 2020;173(4):287-296.

[15] Concordia Pharmaceuticals. Label: hydroxychloroquine (PLAQUENIL). April 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=34496b43-05a2-45fb-a769-52b12e099341&type=display. Accessed September 9, 2020.

[16] Bayshore Pharmaceuticals. Label: chloroquine. April 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=4543d87b-6a1a-4e08-9cdd-33b4909c2c21&type=display. Accessed August 31, 2020.

[17] Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369 (May 14):m1849.

[18] Borba MG, Val FF, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: A randomized clinical trial. JAMA Netw Open. 2020;3(4):e208857.

[19] Statement from the chief investigators of the randomised evaluation of COVid-19 thERapY (RECOVERY) Trial on hydroxychloroquine. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19. June 5, 2020. 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. Accessed August 31, 2020.

[20] Horby P, Mafham M, Linsell L, et al. Effect of hydroxychloroquine in hospitalized patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial. medRxiv 2020.07.15.20151852; doi: https://doi.org/10.1101/2020.07.15.20151852. Preprint, not peer-reviewed.

[21] Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med. 2020;383(6):517-525.