Hydroxychloroquine in COVID-19: The Study Points to Premature Decisions on Efficacy While Bells Ringing for Safety
Received 24 June 2020
Accepted for publication 4 August 2020
Published 17 August 2020 Volume 2020:12 Pages 115—121
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Arthur Frankel
Sitaram Khadka,1 Dhan Bahadur Shrestha,2 Pravash Budhathoki,3 Era Rawal4
1Department of Pharmacy, Shree Birendra Hospital; Nepalese Army Institute of Health Sciences, Kathmandu 44600, Nepal; 2Department of Emergency Medicine and General Practice, Mangalbare Hospital, Morang 56600, Nepal; 3Department of Emergency Medicine and General Practice, Dr Iwamura Memorial Hospital, Bhaktapur 44800, Nepal; 4Department of Emergency Medicine and General Practice, Kathmandu Medical College, Kathmandu 44600, Nepal
Correspondence: Sitaram Khadka
Department of Pharmacy, Shree Birendra Hospital; Nepalese Army Institute of Health Sciences, Kathmandu 44600, Nepal
Email [email protected]
Abstract: Coronavirus disease (COVID-19) pandemic has been a global disease burden. It has affected more than sixteen million people in the world within seven months of its first outbreak in Wuhan. Different treatment modalities, therapeutic and prophylactic agents for its therapy are underway. Until the proven therapy gets available, repurposing of drugs is a better way out. Hydroxychloroquine (HCQ) has been a potential recourse of treatment in this regard for COVID-19 management. As different episodes of cardiac adverse events of HCQ are reported, safety concerns are now a prime objective. The risk-benefit analysis is mandatory to address rational drug therapy even in such a global health crisis. In this article, we want to evaluate the safety and efficacy of HCQ in COVID-19 management.
Keywords: cardiac arrhythmia, COVID-19, drug repositioning, hydroxychloroquine, severe acute respiratory syndrome coronavirus-2
Coronavirus disease (COVID-19) pandemic has created strain over all the system on the globe. It has constituted a huge hurdle affecting millions of human beings.1 Though it has spread mostly around the developed world, the situation is worse in low- and middle-income countries (LMICs). The crawling progress in the health-care system and economy to thrive can be the factors behind this. No known treatment on hand leads to the reuse of the old concept of drug repurposing. In repurposing studies of drugs, anti-malarial agent, especially hydroxychloroquine (HCQ), is found to be significant as a potential treatment option.2,3 Its property to inhibit virus entry into the cells and to reduce the cytokine storm is considered a prime factor for COVID-19 management.4 More than 200 trials on this drug are going on all over the world.5 Meanwhile, a question on its clinical efficacy and safety concern is raised by larger studies regarding the treatment of COVID-19 cases. HCQ’s use can give rise to severe arrhythmias affecting multiple systems.6 QT-prolongation is the commonest cardiac consequence of HCQ, for which patients need to be monitored, especially if there is concomitant use of other QT-prolonging medications. Thus, COVID-19 cases under HCQ need to evaluate and monitor prior to the development of further consequences like ventricular arrhythmias.7
We searched databases like PubMed, Medline, Google Scholar, MedRxiv, Research Square, Cochrane Library, and Clinicaltrials.gov to find different articles regarding the use of HCQ in patients with COVID-19. We built search builder using appropriate medical search headings words and bullions as: (“coronavirus”[mh] OR “COVID 19”[tw] OR “SARS CoV 2”[All Fields] OR “novel coronavirus”[tw]) AND (“Hydroxychloroquine”[mh] OR “HCQ”[All Fields] OR “hydroxychloroquine”[tw]) for relevant papers in PubMed, Medline, and Cochrane Library. For search in Google Scholar, preprint sites and Clinicaltrials.gov “Hydroxychloroquine” and “COVID 19” used to search relevant papers. We included randomized controlled trials (RCTs), retrospective and prospective studies for our study that compared the use of HCQ with or without azithromycin in addition to standard of care compared to the patients receiving standard of care alone. We excluded reviews, commentaries, protocols, letter to editors, and editorials for this study.
Hydroxychloroquine – at a Glance
It is a synthetic derivative of 4-aminoquinoline which was synthesized as a drug in the mid-1940s.8 It has chemotherapeutic and antibiotic characteristics. It also has anti-inflammatory activity and is being used to treat autoimmune diseases like rheumatoid arthritis and lupus erythematosus.9 Being a weak base, it is supposed to elevate endosomal pH in host intracellular organelles thus prevent autophagosome-lysosome fusion and inactivate the enzymes required by the virus for replication.10 By increasing endosomal pH, it also affects the terminal glycosylation of the receptor angiotensin-converting enzyme-2. This results in the prevention of virus entry into the cells as this receptor is utilized by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to enter the cell.11 Significant cardiac adverse effects associated with HCQ such as QT-prolongation, ventricular arrhythmias, torsade de pointes (TdP), and cardiomyopathy are the prime concerns that require risk-benefit judgment in COVID-19 management.12–14
Apart from cardiac side effects, it has also the potential to cause bone marrow failure, hemolysis in glucose-6-phosphate dehydrogenase deficiency cases, retinopathy, gastrointestinal disorders, hepatobiliary disorders, metabolic disorders like hypoglycemia, skeletal muscle myopathy, neuromyopathy, psychiatric disorders, and exfoliative dermatitis.15
There are variable reports from laboratory to human use in RCTs regarding the effects of such 4-aminoquinolines in some viruses like the influenza virus, Zika virus, ebola virus, dengue virus, and chikungunya virus. Though showing somehow effective results in laboratory experiments, the insignificant result is reported in most of the human use. Such a response may be attributable to the drug’s complex pharmacokinetics that makes it difficult to extrapolate to humans.10
Outcome of HCQ
HCQ and standard of care in COVID-19 patients versus standard of care alone studies reported no significant differences in overall virological clearance between the two arms. The effectiveness of HCQ for such action drew attention by the study conducted by Gautret et al.16 While subsequent studies by Chen J. et al, Mallat et al and Tang et al did not demonstrate virological clearance.17–19 A similar type of study reported significant differences in radiological progression between two arms. The study by Chen Z. et al showed improvement in CT findings, while another study by Chen J. et al did not support such findings.17,20
Regarding mortality, a mixed type of result obtained with HCQ use. Rosenberg et al, Magagnoli et al, and Geleris et al showed increased risk of mortality among HCQ groups.21–23 In contrast to that, Yu et al, and Membrillo et al24,25 showed a decrease in mortality rate while the reports by Gautret et al, Lee et al, Mahevas et al, and Barbosa et al were inconclusive.16,26-28
Rosenberg et al, Geleris et al, and Barbosa et al reported an increase in intubation rate and mechanical ventilation.21,23,28 Whereas Magagnoli et al, Yu et al, and Lee et al demonstrated inconclusive results comparing hydroxychloroquine with the standard of care.22,24,26
Table 1: Studies regarding safety and efficacy of hydroxychloroquine with or without azithromycin in patients diagnosed with COVID-19.
Table 1 Studies Regarding Safety and Efficacy of Hydroxychloroquine with or Without Azithromycin in Patients Diagnosed with COVID-19
Tang et al, Rosenberg et al, and Mahevas et al19,21,27 notified an increased risk of overall adverse effects. While Gautret et al, Chen J et al, Chen Z et al, and Lee et al claimed less adverse profile of this agent.16,17,20,26 On top of that, Tang et al, Lee et al, and Mahevas et al advocated that there is no severe adverse effect of such agent.19,26,27
The significantly higher risk of cardiac adverse events like QT prolongation is found to be associated with the use of HCQ. Studies conducted by Rosenberg et al and Mahevas et al demonstrated such effects to a greater extent.21,27 The de-novo arrhythmias and QT prolongation are found to be aggravated by concomitant administration of azithromycin.7
Mild types of adverse reactions are reported in Chen Z et al study where one patient developed a rash and another one experienced headache.20 Similarly, transient diarrhea with abnormal liver function tests is reported by Chen J et al along with one severe case.17 Tang et al reported diarrhea, blurred vision, and thirst as adverse events in 30% of patients in his study and two of them reported severe events due to disease progression to upper respiratory tract infection.19 The cardiac adverse event is found significant among adverse reactions. QT prolongation and de novo ventricular arrhythmia are reported by many studies.7,21,27,29,30 In some studies, fewer adverse events are reported in the treatment group than the control group.26 Six patients on HCQ were lost in follow-up in a study conducted by Gautret et al.16 In this regard, HCQ cannot be considered safe to use for COVID-19 patients without evaluating risk–benefit ratio.
One a recent multinational registry-based cohort study by Mehra et al is not discussed above though it is of good size being it is kept under retraction notice because of methodical flaws and not meeting the basic requirement of the committee of publication ethics.31
Furthermore, with the revocation of the emergency use authorization for HCQ by the United States – Food and Drug Administration on 15 June 2020, its use in a clinical settings for COVID-19 management has been limited. It has been practiced in case of clear benefits that outweigh the risks to the patients.32
From the different studies, it can be concluded that the use of HCQ for COVID-19 is not free of associated risks. In such a global health crisis without approved treatment modalities, therapeutic or prophylactic agents, the use of HCQ as a possible treatment option is not an irrational choice. However, different studies report the increased risk of overall de-novo arrhythmias and significant QT-prolongation and mortality with the use of HCQ. Such incidences are more severe with its combination with a macrolide. Moreover, there was no improvement in survival, need for intubation following treatment. Despite some improvement in radiological progression in some studies, there were increased overall and severe adverse effects, though not statistically significant, among all studies. There is a need for the completion of ongoing substantial RCTs for the apropos evaluation of HCQ as a treatment option for COVID-19.
We greatly acknowledge Dr Robert Dohar (Medical Resident at the Department of Emergency Medicine, University of Toledo, United States) and Mr. Aavash Budhathoki (Budhanilkantha School, Nepal) for their support in proofreading the manuscript.
The authors report no conflicts of interest in this work.
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