Do we have enough evidence to use chloroquine/hydroxychloroquine as a public health panacea for COVID-19?

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel virus, was emerged in Wuhan, China, in December 2019. On March 11th, the World Health Organization (WHO) declared the outbreak of coronavirus disease 2019, and termed “COVID-19,” a pandemic. At that point, there were 118,000 confirmed cases and 4,291 victims worldwide (11. Novel Coronavirus (2019-nCoV) situation reports. Who.int. 2020 [cited April 14th, 2020]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/
https://www.who.int/emergencies/diseases...
). Since then, researchers around the world have been analyzing the genetic structure, multiplication patterns and the cellular mechanisms of SARS-CoV-2 in vitro and in vivo to identify possible drug targets (22. Monteiro WM, Brito-Sousa JD, Baía-da-Silva D, Melo GC, Siqueira AM, Val F, et al. Driving forces for COVID-19 clinical trials using chloroquine: the need to choose the right research questions and outcomes. Rev Soc Bras Med Trop. 2020;53:e20200155. https://doi.org/10.1590/0037-8682-0155-2020.
https://doi.org/10.1590/0037-8682-0155-2...
).

Four months after the onset of the outbreak, physicians from different countries and laboratories have proposed several empirical treatments for COVID-19. To date, there are over 335 COVID-19-related clinical trials registered on the National Institutes of Health (NIH) website (33. Search of: Interventional Studies | COVID19 - List Results - ClinicalTrials.gov https://clinicaltrials.gov/ct2/results?cond=COVID19&age_v=&gndr=&type=Intr&rslt=&Search=Apply
https://clinicaltrials.gov/ct2/results?c...
). The proposed drugs aim to prevent viral entry into host cells, interrupt viral replication, and attenuate virus-induced inflammatory responses. Examples of the drugs being tested for each of these mechanisms are recombinant human angiotensin converting enzyme 2 (RhACE2), the antiviral remdesivir, and the immunosuppressant, tocilizumab, respectively.

However, the most promising drugs appear to be old drugs, the antimalarial and immunomodulatory medication, chloroquine and its hydroxy analog, hydroxychloroquine. Chloroquine and hydroxychloroquine are by far the most popular drugs proposed for treatment and prophylaxis, appearing in 97 of the COVID-19 clinical trials registered on the NIH site. These aminoquinolines, which were discovered in 1934 and are inexpensively produced in several countries, and have well-known pharmacokinetic and pharmacodynamic properties. The antiviral mechanisms of chloroquine are based on its capacity to increase the endosomal pH. This prevents enveloped viruses, such as those belonging to the Coronaviridae family (e.g., SARS-CoV-2), from entering and releasing their genetic material into the host cells and from replicating their envelopes. Furthermore, in severe and complicated COVID-19 cases, the anti-inflammatory effects of chloroquine/hydroxychloroquine may also be of importance, as both medications can suppress the production and release of tumor necrosis factor (TNF) and interleukin 6 (IL-6) (44. Savarino A, Boelaert J, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003;3(11):722-7. https://doi.org/10.1016/S1473-3099(03)00806-5.
https://doi.org/10.1016/S1473-3099(03)00...
).

While the mechanisms of action of chloroquine/hydroxychloroquine are well-established, so are the side effects. Serious retinopathies and cardiopathies associated with bioaccumulation of the drugs are described in literature (55. Schroeder RL, Gerber JP. Chloroquine and hydroxychloroquine binding to melanin: Some possible consequences for pathologies. Toxicol Rep. 2014;1:963-968. https://doi.org/10.1016/j.toxrep.2014.10.019.
https://doi.org/10.1016/j.toxrep.2014.10...
). One study at the Clinics Hospital of the University of São Paulo evaluated 350 patients with systemic lupus erythematosus who were treated with chloroquine. The prevalence of side effects was 35.7%, with the most common being ocular alterations (17%), followed by gastrointestinal symptoms (10%), and dermatological (3.4%), neuromuscular (1.7%), and psychiatric alterations (0.3%) (66. Ponchet MR, Vilela MA, Sinahara KK, Dotto PF. Avaliação dos efeitos adversos desencadeados pelo uso de difosfato de cloroquina, com ênfase na retinotoxicidade, em 350 doentes com lúpus eritematoso. An Bras Dermatol. 2005;80(Supl 3):S275-82. https://doi.org/10.1590/S0365-05962005001000003.
https://doi.org/10.1590/S0365-0596200500...
). In Brazil, a phase 2 clinical trial on COVID-19 sponsored by the state of Amazonas was suspended after 25% of patients developed QT prolongation (>500 m/s) owing to cardiotoxicity (77. Borba MG, Val FF, Sampaio VS, Alexandre MA, Melo GC, Brito M, et al. Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study). 2020 [cited April 14th, 2020]. Available from: https://www.medrxiv.org/content/10.1101/2020.04.07.20056424v1
https://www.medrxiv.org/content/10.1101/...
).

Although chloroquine/hydroxychloroquine might yield promising results, they should not be announced as a cure by politicians and the mass media, as they have never been tested as treatments for Coronaviridae viruses. Clinical trials are ongoing during the course of this pandemic, yet no scientific evidence has been found to support the widespread use of these medications. Table 1 lists a few trials in advanced phases that have randomized allocation, double masking, and significant numbers of proposed participants. However, none of them have reported results as of yet.

Table 1
Ongoing randomized, double-blind clinical trials on the therapeutic and prophylactic use of chloroquine/hydroxychloroquine in COVID-19 patients.

Recent declarations by the President of Brazil recommending the indiscriminate use of chloroquine resulted in a shortage of the drug in several cities (88. BBC News Brasil. Bolsonaro volta a defender cloroquina em novo pronunciamento em rede nacional [Internet]. BBC News Brasil. 2020 [cited April 14th, 2020]. Available from: https://www.bbc.com/portuguese/brasil-52224256
https://www.bbc.com/portuguese/brasil-52...
). Aside from the lack of evidence supporting his proclamations, the president’s action hampered the treatment of patients who truly need chloroquine for systemic lupus erythematosus and rheumatoid arthritis. Pronouncements by the French president also appeared to have pressurized French doctors to prescribe the drug, despite its unconfirmed efficacy and many possible side effects (99. Sciama Y. Is France’s president fueling the hype over an unproven coronavirus treatment? [Internet]. 2020. [cited April 14th, 2020]. Available from: https://www.sciencemag.org/news/2020/04/france-s-president-fueling-hype-over-unproven-coronavirus-treatment
https://www.sciencemag.org/news/2020/04/...
). The same situation occurred in the United States (USA); the country’s president has endorsed chloroquine in a highly politicized debate over its use (1010. Thomas K, Sheikh K. Small Chloroquine Study Halted Over Risk of Fatal Heart Complications. Nytimes.com. 2020. [cited April 14th, 2020]. Available from: https://www.nytimes.com/2020/04/12/health/chloroquine-coronavirus-trump.html
https://www.nytimes.com/2020/04/12/healt...
).

A serious health system should not encourage protocols based on political beliefs or case reports. Scientific trial phases exist and are in constant review so we can guarantee some basic level of safety regarding prescription medications. Ignoring or skipping these phases can result in manmade medical disasters, such as the thalidomide-induced teratogenesis tragedies in the 20th century, which resulted in more than 10,000 children were born with debilitating malformations, leading to the scientific community being forced to rethink interventional studies and the approval process for new drugs (1111. Vargesson N. Thalidomide-induced teratogenesis: history and mechanisms. Birth Defects Res C Embryo Today. 2015;105(2):140-56. https://doi.org/10.1002/bdrc.21096.
https://doi.org/10.1002/bdrc.21096...
). Drug repositioning is possible and encouraged in case of pandemics, but chloroquine/hydroxychloroquine should not be recommended to the general population as if these medications were supported by grade 1a evidence (1212. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;350:g7647. https://doi.org/10.1136/bmj.g7647.
https://doi.org/10.1136/bmj.g7647...
). Affirmations of the drugs’ effectiveness, such as those by some of our world leaders in the middle of the pandemic will only spread fear and the erroneous belief in chloroquine/hydroxychloroquine as a panacea.

In summary, there are still no effective treatments for COVID-19. Though chloroquine/hydroxychloroquine may be promising, their use should be restricted to ongoing clinical trials until we have enough evidence to recommend it to the general population. We must consider the long-term consequences of chloroquine/hydroxychloroquine administration and respect the scientific approach. A well-established, evidence-based health care policy may save more lives than a swift implementation of unsupported recommendations.

REFERENCES

Publication Dates

  • Publication in this collection
    08 May 2020
  • Date of issue
    2020
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