Friday, April 3, 2020

COVID-19: Hydroxychloroquine mechanism and role in management of SARS-CoV-2 infection

Hello everyone, this post aims to highlight all the important aspects of the recently famous drug hydroxychloroquine in the management of COVID-19.

Mechanism of action: In a study by Aartjan et al, zinc ions (Zn2+) in high intracellular concentrations have been shown to inhibit viral RNA polymerase. However, zinc being an ion cannot enter the cell through the plasma membrane, so it needs ionophores such as pyrithione (PT) to enter the cell, where, in high concentrations, it can efficiently impair the replication of a variety of RNA viruses. Chloroquine can also act as an ionophore that can increase zinc ions transport into the cell.
According to Harrison’s principles of internal medicine, “Infection of tissue culture cells by viruses such as Semliki Forest virus, vesicular stomatitis virus, and certain strains of influenza virus can be prevented by chloroquine, an agent that blocks the function of lysosomes. Chloroquine is a weak base that diffuses into lysosomes and becomes protonated, raiding the pH and ionic strength of the lysosome. When the pH rises, the lysosomal enzymes fail to function. Viruses that require acid pH to fuse with cell membranes can no longer do so in the presence of chloroquine, and the cells are protected from infection.”

Studies revealed that it also has potential broad-spectrum antiviral activities by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. The anti-viral and anti-inflammatory activities of chloroquine may account for its potent efficacy in treating patients with COVID-19 pneumonia.

Chloroquine can also prevent orf1ab, ORF3a, and ORF10 from attacking the heme to form the porphyrin and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a certain extent, effectively relieving the symptoms of respiratory distress. The infectivity of the nCoV pneumonia was not completely prevented by the drugs, because the binding of E2 glycoprotein and porphyrin was not inhibited. You can read more about this on our previous post on: Coronavirus and hemoglobin https://www.medicowesome.com/2020/04/covid-19-coronavirus-and-hemoglobin.html


Current place in the management of COVID-19


1. In India, ICMR has recommended this drug for prophylaxis to healthcare workers dealing with infected patients and asymptomatic contacts of infected people at a dose of 400 mg per week. Besides AIIMS(New Delhi) has recommended this drug for the treatment of moderate to severe cases who are admitted in the hospital at a dose of 400 mg BD for 1 day which is followed by 200 mg BD for 5 days.

2. Chen et al in an unpublished RCT of 30 patients did not find HCQ provided benefit. The study suggests that if it has an impact, it is likely small. 

3. Gautret et al in a non-RCT of 36 patients suggested that HCQ reduced the duration of viral shedding in infected patients. 6 patients in a post-hoc analysis who received HCQ in combination with azithromycin showed further reduction in the viral carriage. However, this was not statistically significant and groups were not well balanced at baseline. 

4.  Chen et al in a double-blind RCT of 62 patients showed that HCQ can significantly shorten the time to clinical recovery and promote the absorption of pneumonia among patients with COVID-19. However, this study has not yet been certified by peer review. 

5. The Marseille study, an unblinded, non-randomized study of 26 infected patients showed a significant reduction in viral load with HCQ. And the number of positive cases was spectacularly reduced by the combination of HCQ with azithromycin. However, this study was full of flaws, there wasn’t adequate matching between the two groups, there were 6 dropouts who weren’t accounted in the study, patients in the control group didn’t have uniform testing, and the patients in the HCQ group had more severe symptoms and were further along in their clinical course. Apparently, this was the study, based on which President Trump promoted the use of HCQ!

6. The patients taking HCQ should be closely monitored for toxicity, in particular, QT prolongation; especially if it is used with azithromycin. Combining lopinavir/ritonavir with HCQ or chloroquine can cause serious arrhythmias and drug interactions due to the increased QT interval. 


Effect of the pandemic on drug supplies for Rheumatology patients


Hydroxychloroquine has been in use since the 1940s for the treatment of rheumatological conditions such as RA, SLE, and Sj√∂gren’s syndrome. The sudden interest in this drug has led to shortages for patients who rely on it for the treatment of their autoimmune conditions. The Lupus Foundation of America has called on drug manufacturers to increase the production of HCQ, in order to ensure that patients with SLE are still able to access it without much difficulty.

Overall, no agent has proven efficacy for COVID-19. A number of approaches are being investigated based on in vitro or extrapolated evidence, including remdesivir, hydroxychloroquine, chloroquine, interleukin-6 pathway inhibitors, and convalescent plasma. When treatment of COVID-19 is being considered, patients should be referred to a clinical trial whenever possible. A registry of international clinical trials can be found at clinicaltrials.gov. 

Thank you! :) 

-Vinayak

References:
1. CHEN J. ,LIU D. et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci), 2020, 49(1): 0-0.
2. 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. Int J Antimicrob Agents. 2020. [PMID:32205204]
3. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020. [PMID:32020029]
4. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. Zhaowei Chen, Jijia Hu, et al. medRxiv 2020.03.22.20040758; doi: https://doi.org/10.1101/2020.03.22.20040758
5.te Velthuis AJ, et al. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS
Pathog. 2010 Nov 4;6(11):e1001176. doi: 10.1371/journal.ppat.1001176. PubMed
PMID: 21079686; PubMed Central PMCID: PMC2973827.

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