The current SARS-CoV-2 (COVID-19) coronavirus pandemic is posing many health management challenges with multiple uncertainties. One of the most relevant is focused on the most suitable pharmacological therapy for cure and prophylaxis. Currently, there is no specific drug treatment for COVID-19 that has demonstrated efficacy and safety in high- quality studies (1). However, different options are being proposed from an experimental approach. One of them is the use of chloroquine (CRQ) and its derivatives, basically hydroxychloroquine (HCQ).
On 16 April, the Spanish Agency for Medicines and Healthcare Products (AEMPS) updated a document analysing different available alternatives, existing presentations, degree of evidence, access requirements, proposed doses and most common adverse effects for every assessed drug (2). The chloroquine/hydroxychloroquine section provides interesting information taking into account these aspects, highlighting its important role against malaria, lupus or rheumatoid arthritis.
With regard to the scientific evidence, CRQ and HCQ have shown in vitro activity against SARS-CoV-2, but so far no published clinical trials have been carried out to confirm this effect. In other contexts, CRQ has not been shown to be effective in treating other viruses in animal or human models such as influenza, dengue or Chikungunya (2). Despite the limited evidence, the FDA has issued an emergency use authorization for the use of CRQ and HCQ in hospitalized patients with COVID-19 (3).
A CRITICAL READING OF THE CLINICAL EVIDENCE
At present, numerous clinical trials are underway with CRQ and HCQ (4) such as SOLIDARITY (5) or EPICOS (6), among the most important projects in Spain. Nevertheless, the first published article mentioning the use of CRQ in patients with COVID-19 was a letter to the editor (7) where no verifiable data is provided about its potential benefits in more than 100 infected patients, as stated in that document.
Nowadays, information can be extracted from three clinical trials (8,9,10), two of which have not been published yet, and five studies with an observational design (11,12,13,14,15), one of which has not been published yet (Table 1).
1. CLINICAL TRIALS
The study by Chen J et al. (8) must be emphasized because it is the first published trial in patients with COVID-19 that randomizes patients to receive HCQ or standard treatment. The protocol has not been accessed. The sample size is small, although basal characteristics appear to be balanced in both arms. At the end of the two-week follow-up, all patients improved their condition without differences in the estimated variables. The efficacy of HCQ against COVID- 19 remains unproven, although larger studies are needed to confirm the results.
On March 31, the results of another Chinese clinical trial, Chen Z et al., not published, were released (9). The process of randomization and blinding is unclear. The positive findings favouring HCQ in improving body temperature and cough do not seem convincing due to several aspects: 1) premature discontinuation of the study; 2) discrepancies between protocol (16) and article in the reported variables and age range of patients; 3) lack of results for the HCQ group 200mg/day. It is also a matter of discussion whether a placebo was finally used and if observed differences are or not clinically significant.
The results of another Chinese clinical trial, Tang W et al., not published, were released on 14 April (10). This is the study with the largest sample size whose results are known. There were no differences favouring HCQ in the main variable (viral clearance within 28 days) nor in most of the secondary variables (viral clearance at other time points, improvement in clinical symptoms and lymphocyte count). The proportion of adverse events was significantly higher in the HCQ group (30.0%, two of them were serious) than in the control group (8.8%). Potential post-hoc and C-reactive protein normalization findings should be confirmed in further studies.
2. OBSERVATIONAL STUDIES
The study by Gautret et al. (11) has significant limitations that need to be taken into account when considering its scientific contribution. Briefly, the following issues can be highlighted:
1. The main limitation stems from the fact that it was not originally conceived as a comparative study and it was eventually analysed as such. This decision is not in accordance with the published protocol (17) and should therefore be considered as a post-hoc analysis. The lack of randomization and blinding are additional shortcomings.
2. Secondly, the exclusion of six patients from the analysis does not seem adequately justified, favouring the HCQ group. All these patients received HCQ and five of them suffered a negative event (intensive care unit (ICU) admission, death or adverse event). No similar events occurred in the control group.
3. The three groups of participants to be compared (HCQ, HCQ+AZT, controls) are highly heterogeneous in terms of inclusion criteria, recruitment centres and age range. Furthermore, the criteria for adding AZT was optional, just depending on the clinical judgment of the professional.
4. The main variable is short-term and the measurement time points foreseen in the protocol were superseded with no justification. Lack of viral load data at a given time point were not treated equally for both groups.
5. It is not possible to confirm whether viral load data translate into more relevant clinical consequences (e.g. discharge, ICU admission, mortality, serious adverse events).
6. Finally, the publication presents significant conflicts of interest. One of the study authors (Rolain JM) is the editor-in-chief of the journal where the paper was published. Likewise, the institution promoting the study (Fondation Méditerranée Infection) has among its recognized partners Sanofi Aventis (18), who in turn markets HCQ in France (Plaquenil®).
The same research team has released a second study, not published yet, sharing some of the first article methodological concerns (12). The great majority (92%) of this uncontrolled cohort with 80 COVID-19 confirmed patients had low severity clinical symptoms. Some participants are used as a source of data in both articles, which is not recommended. Details of the study protocol are not provided. The final balance is poor, with no significant contribution to the previous publication. The study authored by Molina et al. presents a small cohort of 11 COVID-19 patients treated with the same therapeutic strategy previously used by Gautret et al. It obtained clearly discordant results, achieving a viral clearance at Day 5-6 in only two out of ten (20%) of total participants (13).
Other two observational propensity-score matched studies have recently provided information on 549 total patients, one of them with a retrospective design (14) and the other one emulating a clinical trial methodology (15). No differences have been found between HCQ, with or without AZT, and standard treatment groups.
In summary, up to now evidence is insufficient as to recommend CRQ and HCQ as a COVID-19 treatment (1).
RISK OF ADVERSE EVENTS
The prolongation of the QT interval has been associated with an increased risk of torsade de pointes and sudden death. Both CRQ and HCQ have the ability to prolong the QT interval, which can lead to a serious interaction when given with other drugs that have the same effect (e.g. azithromycin) (19). Currently there is very limited information on the safety of their concomitant use (20) and it is not recommended out of a clinical trial setting (1).
In this regard, a non-published study of a cohort with 84 COVID-19 hospitalized patients treated with HCQ + azithromycin has estimated that in 11% of the patients the QTc interval was prolonged above 500 msec, a threshold which usually represents the group with the greatest risk of arrhythmia (21). In addition, an analysis of the HCQ cardiovascular adverse events reported to the French pharmacovigilance database from 27 March to 10 April 2020 was performed. Forty-three events were recorded, some in combination with azithromycin, including seven sudden deaths [3 recovered by electroshock], a dozen arrhythmias/syncope and other cardiac problems that evolved favourably after the treatment was stopped (22). The AEMPS (23) and the European Medicines Agency (24) have warned that CRQ and HCQ can cause serious heart rhythm problems, mostly with high doses and if given simultaneously with other drugs sharing this same adverse effect. The FDA recommends not using it outside of the hospital setting or a clinical trial (25). Should HCQ were massively used in the future, it is foreseeable that some patients will suffer rare but potentially very serious adverse events, such as the aforementioned arrhythmias, skin reactions or fulminant liver failure (26).
CONFLICT OF INTEREST
The author declares no conflict of interest.
1. COVID-19 Treatment Guidelines. National Institutes of Health. Available at: https://covid19treatmentguidelines.nih.gov/therapeutic- options-under-investigation/
2. Tratamientos disponibles para el manejo de la infección respiratoria por SARS-CoV-2. Agencia Española del Medicamento y Productos Sanitarios [In Spanish]. 16/04/2020. Available at: https://www.aemps.gob.es/la- aemps/ultima-informacion-de-la-aemps-acerca-del- covid%e2%80%9119/tratamientos-disponibles-para-el-manejo-de- la-infeccion-respiratoria-por-sars-cov-2/
3. Hinton DM. Food and Drug Administration. FDA Emergency use authorization (EUA) of chloroquine and hydroxychloroquine. 28 Mar 2020. https://www.fda.gov/media/136534/download
4. Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. Journal of Critical Care 2020. Doi: 10.1016/j.jcrc.2020.03.005
5. Public health emergency SOLIDARITY trial of treatments for COVID-19 infection in hospitalized patients [Protocol]. Available at: https://doi.org/10.1186/ISRCTN83971151
6. EPICOS – Ensayo para la Prevención de la Infección por COronavirus en Sanitarios [Protocol in Spanish]. Code: 2020- 001385-11. Available at: https://reec.aemps.es/
7. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1):72-73. 2020 Feb 19. doi: 10.5582/bst.2020.01047
8. Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J of Zhejiang University. 2020;3. Doi: 10.3785/j.issn.1008-9292.2020.03.03.
9. Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial [NON PUBLISHED]. Available at: https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v2
10. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial [NON PUBLISHED]. Available at: https://www.medrxiv.org/content/10.1101/2020.04.10.20060558v1
11. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020. https://doi.org/10.1016/j.ijantimicag.2020.105949
12. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Sevestre J, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study [NON PUBLISHED]. Available at: https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID- IHU-2-1.pdf
13. Molina JM, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect 2020. https://doi.org/10.1016/j.medmal.2020.03.006
14. Magagnoli J, Narendran S, Pereira F, Cummings T, Hardin JW, Sutton SS, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. [NON PUBLISHED]. Available at: https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v2
15. Mahévas M, Tran VT, Roumier M, Chabrol A, Paule R, Guillaud C, et al. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen: results of a study using routinely collected data to emulate a target trial. [NON PUBLISHED]. Available at: https://www.medrxiv.org/content/10.1101/2020.04.10.20060699v1
16. Zhang Z. Therapeutic effect of hydroxychloroquine on novel coronavirus pneumonia (COVID-19). http://www.chictr.org.cn/showprojen.aspx?proj=48880
17. Treatment of Coronavirus SARS-Cov2 Respiratory Infections with Hydroxychloroquine. https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-000890-25/FR
19. Drug interaction results for hydroxychloroquine sulfate. Micromedex 2020. Available at: https://www.micromedexsolutions.com
20. Roden DM, Harrington RA, Poppas A, Russo AM. Considerations for Drug Interactions on QTc in Exploratory COVID-19 (Coronavirus Disease 2019) Treatment. Circulation 2020. 10.1161/CIRCULATIONAHA.120.047521
21. Chorin E, Dai M, Shulman E, Wadhwani L, Cohen RB, Barbhaiya C, et al. The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin [NON PUBLISHED]. Available at: https://www.medrxiv.org/content/10.1101/2020.04.02.20047050v1
22. Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM). Médicaments utilisés chez les patients atteints du COVID-19 : une surveillance renforcée des effets indésirables – Point d’information [In French]. 10/04/2020. Available at: https://www.ansm.sante.fr/S-informer/Actualite/Medicaments-utilises- chez-les-patients-atteints-du- COVID-19-une-surveillance-renforcee-des-effets-indesirables-Point-d-information
23. Cloroquina/Hidroxicloroquina: precauciones y vigilancia de posibles reacciones adversas en pacientes con COVID-19. Agencia Española del Medicamento y Productos Sanitarios [In Spanish]. 22/04/2020. MUH (FV) 07/2020. Available at: https://www.aemps.gob.es/informa/notasInformativas/medicamentosUsoHumano/seguridad/2020/docs/NI_MUH_FV-7-2020- Hidroxicloroquina.pdf?x50414
24. COVID-19: reminder of risk of serious side effects with chloroquine and hydroxychloroquine. European Medicines Agency. 23/04/2020. Available at: https://www.ema.europa.eu/en/documents/press-release/covid- 19-reminder-risk-serious-side-effects-chloroquine-hydroxychloroquine_en.pdf 25. 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. Disponible en: https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use- hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or
26. Ferner RE, Aronson JK. Chloroquine and hydroxychloroquine in covid-19. BMJ 2020;369:m1432 doi: 10.1136/bmj.m1432.