Rationale of Old Antimalarial Drugs Against New Pandemic

426 views 7 04/01/2020 04/05/2020

Before COVID-19:

  1. Chloroquine has demonstrated its antiviral properties in vitro in the past against SARS-CoV-1 and MERS-CoV.1,2,3
  2. It inhibits replication of several viruses in pH-dependent steps including members of the flaviviruses, retroviruses and coronaviruses.2
  3. Immunomodulatory effects of chloroquine suppress the production/release of TNF-α and IL-6, which mediate the inflammatory responses in several viral diseases.2
  4. Hydroxychloroquine is an analogue of chloroquine but with less toxicity.2

 

During COVID-19 Outbreak:

  1. Chloroquine and hydroxychloroquine seem to be effective in vitro in reducing the replication of SARS-CoV-2.4,5
  2. Immunomodulatory effect of these drugs might play a role in controlling the cytokine storm that occurs in late phase in critically ill infected patient.5
  3. Hydroxychloroquine appears to have a more potent antiviral activity than chloroquine in vitro.5
  4. Chloroquine is reportedly associated with reduced progression of disease and decreased duration of symptoms according to a narrative letter by Chinese authors. No primary data are published to support these claims yet.1,7
  5. Preliminary data of a small sample-sized observational study (n=42) in France showed a significant viral load reduction or disappearance in COVID-19 from nasopharyngeal samples in patients receiving hydroxychloroquine. Its effect was reinforced when combined with azithromycin.8
  6. Despite encouraging results from limited data and some authorities including them in their management algorithm, no strong evidence to date confirms with certainty the effectiveness and role of chloroquine or hydroxychloroquine in the treatment of COVID-19.9

 

These statements come from multiple sources. Some are from a systematic review on the efficacy and safety of chloroquine for treatment of COVID-19 performed from inception to march 1st 2020. 234 sources were identified. Eight articles were evaluated, among which six were found relevant (one narrative letter, one research letter, one editorial, one expert consensus paper in Chinese, one national guideline document in Dutch and one in Italian).  During the review, twenty-three trials were found in trial registries, all from China. In vitro findings had encouraging results in antiviral activities of chloroquine against COVID-19. Based on these findings and still unpublished clinical experience, an expert consensus recommended the use of chloroquine phosphate in treatment guidelines from China’s National Health Commission. The Dutch Center of Disease Control and Italian Society of Infectious also suggested chloroquine as a treatment against COVID-19. 1,4,6 

In a narrative letter by Chinese authors, it was indicated that ‘‘chloroquine phosphate, an old drug for treatment of malaria, is shown to have apparent efficacy and acceptable safety against COVID-19 associated pneumonia in multicenter clinical trials conducted in China.’’  They also stated that these findings came from ‘‘more than 100 patients’’. However, no primary data supporting these claims were found in the trial registries.1,7

Preliminary data of a small sample-sized observational study (n=42) in France showed a significant viral load reduction or disappearance in COVID-19 from nasopharyngeal samples in patients receiving hydroxychloroquine. After 6 days, 70% of patients receiving hydroxychloroquine (n=14/20) had negative viral load vs 12.5% in the control group (n=2/16) (p=0.001). This effect was reinforced when azithromycin was associated with hydroxychloroquine within these patients, where the viral load was negative in 100% of patients in this group after 6 days (n=6/6). Azithromycin was added to prevent bacterial super-infection. Results suggest a synergistic effect of the combination of both. These preliminary data were published in regard to the promising results of the study in an urgent context of pandemic. These early findings come from a study with numerous limitations and should be interpreted with caution.8

Based upon limited in vitro and anecdotal data, and no current available data from randomized clinical trials, the regimens of chloroquine and hydroxychloroquine differ between jurisdictions around the world (if recommended). 9,10,11,12 The true efficacy of chloroquine or hydroxychloroquine as treatments or preventions are still currently under investigation worldwide.  More information on current clinical trials can be found at:  https://clinicaltrials.gov or https://apps.who.int/trialsearch/

Sources:

  1. Cortegiani A, Ingoglia Ippolito M, et al. (March 10 2020). A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. Journal of critical care 2020. https://doi.org/10.1016/j.jcrc.2020.03.005
  2. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R (November 1 2003). Effects of chloroquine on viral infections: an old drug against today’s diseases? Lancet Infect Dis. https://doi.org/10.1016/S1473-3099(03)00806-5
  3. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al (August 22 2005). Chloroquine is  a  potent inhibitor of SARS coronavirus infection and spread. Virology Journal 2005; 2:69. https://doi.org/10.1186/1743-422X-2-69
  4. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. (February 4 2020). Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research. https://doi.org/10.1016/S0140-6736(20)30183-5
  5. Yao X, Ye F, Zhang M, et al (March 9 2020). In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. https://doi.org/10.1093/cid/ciaa237
  6. Multicenter Collaboration Group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for Chloroquine in the Treatment of Novel Coronavirus Pneumonia. (February 20 2020). Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia [in Chinese]. Zhonghua Jie He He Hu Xi Za Zhi 2020;43:E019. https://doi.org/3760/cma.j.issn.1001-0939.2020.0019
  7. Gao J, Tian Z, Yang X (March 16 2020). Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. https://doi.org/10.5582/bst.2020.01047
  8. Gautret P,  Lagier  J-C,  Parola  P,  Hoang  VT,  Meddeb  L,  Mailhe  M,  et al (March 20 2020). Hydroxychloroquine  and  azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. https://doi.org/10.1016/j.ijantimicag.2020.105949
  9. COVID-19 et Chloroquine/hydroxychloroquine. Retrieved from https://www.inesss.qc.ca/covid-19/traitements-specifiques-a-la-covid-19/chloroquinehydroxychloroquine-mise-a-jour-completee-29-03-2020.html
  10. Consensus de cliniciens belges. Interim clinical guidance for patients suspected of/confirmed with covid-19 in Belgium. Retrieved from https://epidemio.wiv-isp.be/ID/Documents/Covid19/COVID-19_InterimGuidelines_Treatment_ENG.pdf
  11. Accessed on March 30th 2020: https://lci.rivm.nl/richtlijnen/covid-19#diagnostiek
  12. Handbook for the care of people with disease-COVID 19 Edition 2.0, March 13, 2020. Retrieved from https://drive.google.com/file/d /1eXE6espkYp6_k2XCyTf_6kgT6tFbnQjg/view
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