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Drug trials of chloroquine / hydroxychloroquine in the treatment of COVID-19 disease

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Chloroquine was one of the first drugs proposed as a treatment for COVID-19 in January 2020. As a licensed drug, with a well-established safety profile and an existing manufacturing process, it could be distributed rapidly and at scale. In June it was suspended from several large treatment trials. What is the science behind these events?

Why did we consider chloroquine as a potentially useful drug?

Chloroquine phosphate was used extensively in the 1980s and 1990s to treat falciparum malaria before drug-resistant parasites became widespread. Adding a hydroxyl group to the molecule creates hydroxychloroquine, which is less toxic in animal studies, and this is used in Europe and America to treat autoimmune disorders like rheumatoid arthritis. Chloroquine is taken up widely by cells in the body and it creates an alkaline environment which impedes the replication of viruses. Early in the pandemic, both drugs were shown to prevent the new coronavirus from invading and multiplying in monkey cells cultured on laboratory plates.[1][2] Several treatment trials were initiated in China but, as the epidemic was brought quickly under control locally, they were unable to recruit sufficient patients to resolve the value of chloroquine definitively.[3][4]

In March, researchers at a hospital in Marseille cited laboratory experiments where chloroquine had previously been shown to protect monkey cells from infection with the coronavirus that caused SARS in 2003[5] and they began to offer hydroxychloroquine to hospitalised COVID-19 patients. Twenty-six patients accepted the drug and they were compared with 16 patients who declined the drug. After six days of treatment, 70% of the hydroxychloroquine-treated patients had cleared the virus from their nose and throat but only 12% of the controls had cleared the virus.[6] Although the trial was small and was not randomised, it was widely reported as a hopeful development.

Randomised trials and routine hospital studies

In March, two large, randomised,multi-hospital trials were set up to evaluate different potential therapies; these were the SOLIDARITY trial run by the World Health Organization in several countries and the RECOVERY trial in the UK. On 27th April, the US Federal Drugs Administration approved the emergency use of hydroxychloroquine in the treatment of COVID-19 whilst awaiting trial results and several hospitals in America and France began to offer hydroxychloroquine to patients on a compassionate basis. Later, the outcomes of these treated patients were compared with those of patients who did not receive the drug. If drug allocation is not randomised, any difference in the outcome between those taking and those not taking the drug cannot be attributed entirely to the medication so the results have to be interpreted very cautiously. For example, differences in outcome may be attributable to subtle variations in disease severity at the outset, to the advice given to patients about whether to take the drug or not, or to the quality of care they are given throughout the illness.

In four large hospitals in France, researchers examined the case-notes of all COVID-19 patients who were sick enough to require oxygen. They compared 84 patients who had received hydroxychloroquine within 48 hours of hospital admission to 89 patients who had not. After adjusting for differences in the basic characteristics of the two groups at the start of the study they found no difference in the rates of deterioration or death between the two groups.[7] A study at a large hospital in New York also found no difference in the risk of dying and/or being ventilated between 811 patients who had received hydroxychloroquine and 565 who had not.[8]

Is chloroquine safe?

Chloroquine in high dose is known to increase the risk of an abnormal heart rhythm. In most of the studies above, chloroquine or hydroxychloroquine was used in a dose of 600 mg per day or less, often with a double dose on the first day. A research group in Brazil reasoned that sick patients, who do not absorb tablets well, would benefit from a double dose every day and they compared this high-dose with a low dose of chloroquine in a randomised trial of critically ill COVID-19 patients. At an interim analysis, one fifth of the way through the trial, the patients taking the high dose had a significantly higher risk of death (39%) than those taking the low-dose group (15%) and so they stopped the trial.[9]

On 22nd May 2020, a study was published in the Lancet medical journal, which reported an analysis of a commercial database of 96,032 hospitalised COVID-19 patients from 671 hospitals worldwide. The authors reported that patients treated with chloroquine or hydroxychloroquine were more likely to die in hospital than those not treated with these drugs, and that they were also more likely to experience an abnormal heart rhythm.[10] The academic community raised serious concerns about the veracity of the dataset used in the paper and, as it could not be properly audited, three of the four authors retracted their paper on 4th June.

In the interval between the publication and the retraction of this paper the World Health Organization suspended the hydroxychloroquine arm in the SOLIDARITY trial. Investigators at the RECOVERY trial analysed their interim results rapidly. Among 1542 patients randomised to hydroxychloroquine 25.7% had died within 28 days; among 3132 patients randomised to usual care 23.5% had died. The investigators reported that these results convincingly rule out any meaningful mortality benefit of hydroxychloroquine in patients hospitalised with COVID-19, and they have stopped further enrolment into the hydroxychloroquine arm of the study.[11] An analysis of the SOLIDARITY trial data reached a similar conclusion and the hydroxychloroquine arm in this trial has been stopped.[12]

Where next?

Over 200 research groups have registered that they are conducting trials of chloroquine for the prevention or treatment of COVID-19, including a large study of 2000 patients run by the US National Institutes of Health;[13] it is likely that much more data will emerge. However, from the evidence presented to date, it seems unlikely that chloroquine will have a large role in the treatment of hospitalised patients with COVID-19.

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References

  1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research. 2020 Mar;30(3):269-271. DOI: 10.1038/s41422-020-0282-0.

  2. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery. 2020 ;6:16. DOI: 10.1038/s41421-020-0156-0.

  3. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020 Mar. DOI: 10.1101/2020.03.22.20040758.

  4. Chen J, Liu D, Liu L, et al. [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19]. Zhejiang da xue xue bao (Journal of Zhejiang University, Medical Sciences). 2020 May;49(2):215-219. DOI: 10.3785/j.issn.1008-9292.2020.03.03.

  5. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virology Journal. 2005 Aug;2:69. DOI: 10.1186/1743-422x-2-69.

  6. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. 2020 Mar:105949. DOI: 10.1016/j.ijantimicag.2020.105949.

  7. Mahévas M, Tran VT, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020 May;369:m1844. DOI: 10.1136/bmj.m1844.

  8. Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. The New England Journal of Medicine. 2020 May. DOI: 10.1056/nejmoa2012410.

  9. Borba MGS, Val FFA, 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 Network Open. 2020 Apr;3(4):e208857. DOI: 10.1001/jamanetworkopen.2020.8857.

  10. Mehra MR, Desai SS, Ruschitzka F, Patel AN. RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet. 2020 May. DOI: 10.1016/s0140-6736(20)31180-6.

  11. Chief Investigators of the RECOVERY Trial. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19. Recovery: Randomised Evaluation of COVID-19 Therapy. 2020 Jun.

  12. “Solidarity” clinical trial for COVID-19 treatments. World Health Organization. 2020 June.

  13. NIH begins clinical trial of hydroxychloroquine and azithromycin to treat COVID-19. NIH News Releases. 2020 May.

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