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Year : 2021  |  Volume : 46  |  Issue : 3  |  Page : 380-388

A systematic review on the therapeutic relevance of hydroxychloroquine/chloroquine in the management of COVID-19

1 Department of General Surgery, Glasgow Royal Infirmary; Department of General Surgery, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
2 Centre of Excellence for Biomedical and Biomaterials Research, University of Mauritius, Reduit, Mauritius

Date of Submission20-Jun-2027
Date of Acceptance21-Mar-2031
Date of Web Publication13-Oct-2021

Correspondence Address:
Dr. Dhruv Satya Sahni
Department of General Surgery, Lister Building, University of Glasgow, Glasgow Royal Infirmary, Glasgow
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijcm.IJCM_539_20

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Background: The coronavirus disease-2019 (COVID-19) pandemic is coming to the fore and has surfaced as a public health emergency of international concern. The lack of vaccines or an effective treatment has led to the global hunt for potential pharmaceuticals in adequately managing this disease. This systematic review highlights the efficacy of chloroquine and its derivative hydroxychloroquine in the treatment of COVID-19 and also explores the safety profile of these drugs. Methods: EMBASE, COCHRANE, and PubMed databases were searched for studies on the use of hydroxychloroquine or chloroquine in the treatment of COVID-19. Results: Twenty articles were selected including expert opinions, National Guidelines, three small randomized controlled trials, and one prospective study. Both hydroxychloroquine and chloroquine have shown promising results including reduction in hospital length of stay and overall mortality. Moreover, concomitant use with azithromycin seems to reduce viral load to a greater extent. Conclusions: Considering the known safety profile of these drugs in the treatment of other diseases, their availability and affordability, chloroquine and hydroxychloroquine are potential antiviral agents in the treatment of COVID-19. However, reported side effects of these drugs when used in conjunction with azithromycin in patients with comorbidities have raised significant safety concerns. High-quality randomized clinical trials are warranted to provide more comprehensive evidence of the safety of these drugs in patients infected with COVID-19.

Keywords: Chloroquine, coronavirus, coronavirus disease 2019, hydroxychloroquine, pneumonia, severe acute respiratory syndrome-CoV-2

How to cite this article:
Mccabe G, Sahni DS, Ramsaha S. A systematic review on the therapeutic relevance of hydroxychloroquine/chloroquine in the management of COVID-19. Indian J Community Med 2021;46:380-8

How to cite this URL:
Mccabe G, Sahni DS, Ramsaha S. A systematic review on the therapeutic relevance of hydroxychloroquine/chloroquine in the management of COVID-19. Indian J Community Med [serial online] 2021 [cited 2021 Dec 8];46:380-8. Available from: https://www.ijcm.org.in/text.asp?2021/46/3/380/328179

   Introduction Top

In December 2019, the first case of a novel disease was reported in Wuhan, in Hubei province of China. On further investigation, it was discovered that this was a new variant of Severe Acute Respiratory Syndrome (SARS) coronavirus or SARS-CoV. As of August 17, 2020, coronavirus disease 2019 (COVID-19) has spread across 215 countries and territories worldwide, with total cases crossing 21.8 million and a mortality of over 773,000.[1] It was deciphered that its main mode of transmission is from Human-Human via direct contact or droplets.[2],[3] However, airborne transmission of SARS-CoV-2 can also occur during medical interventions with aerosol-generating procedures.

Although a vast majority of cases showed mild flu-like symptoms such as fever, malaise, and cough, a significant proportion of these cases progressed to develop acute respiratory distress syndrome, respiratory failure, and multiple organ failure caused by uncontrolled cytokine storms.[3],[4] As the pandemic of coronavirus disease (COVID-19) continues to undermine public health in numerous countries, global efforts are being geared toward developing a vaccine against this virus. As of now, there is no known proven specific pharmacological treatment for the disease. Globally, the treatment has been focused on symptomatic and respiratory support.[5] Moreover, poor prognosis associated with the use of resuscitation fluids (hypotonic crystalloids, starches, or gelatine) and systemic corticosteroids, calls for the cautious use of positive end-expiratory pressure and intravenous fluids. Hence, significantly limiting the therapeutic options for COVID-19 pneumonia.[6]

In the hunt for an effective treatment to improve remission from COVID-19 infection and reduce mortality, multiple drugs including a range of antivirals and immunomodulators such as chloroquine and hydroxychloroquine are being validated for their efficacy and safety in numerous clinical trials. In vitro studies and smaller clinical trials held in China and France have suggested that chloroquine and hydroxychloroquine are effective in reducing viral replication and consequently decreasing viral load in numerous infections including those caused by SARS-associated coronavirus (CoV) and MERS-CoV.[7],[8],[9] Chloroquine has been widely used for over half a century for the treatment of malaria in different regions of the world and figures in the World Health Organization (WHO) list of essential medications.

Nonetheless, the efficacy and safety of this drug for treatment of SARS-CoV-2 pneumonia has not been sufficiently studied. Its high availability, low cost, and an established clinical profile makes it a potential candidate for treatment of this public health emergency.[10] In this perspective, this systematic review summarizes all the available evidence till date including opinions, guidelines, preliminary, and prospective studies evaluating the use of chloroquine and hydroxychloroquine in patients with COVID-19 and sheds light on the efficacy and safety profile of these drugs in treating this infection.

   Methods Top

A systematic search was carried out using EMBASE, COCHRANE, and PubMed databases from the onset of the COVID-19 epidemic to April 01, 2020 to identify articles discussing the use of hydroxychloroquine or chloroquine in the treatment of COVID-19. Two independent reviewers were involved in the identification and screening and extraction of information from these articles. We used the key words “SARS-CoV-2,” “2019-nCoV,” “COVID-19,” “Coronavirus,” “Wuhan,” and these were searched in conjunction with “Chloroquine,” “Hydroxychloroquine,” “Treatment,” “Therapeutics,” and “Therapy.” We also searched for any published data ranging from expert opinion to meta-analysis. Database searches were devoid of language restrictions considering that majority of the data and publications coming from China and Italy were in their native language. In addition, we used the snowballing method to review the references of the selected articles for further potential papers. We did not include any papers specifically discussing in vitro studies. The search was also expanded to the Chinese Clinical Trial Registry, Clinicatrial.Gov, and the International Clinical Trials Registry Platform (WHO) to retrieve data on ongoing trials and those planned in the near future. Official National Guidelines were also explored for information regarding drugs used in the management of COVID-19. The review team adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines.[11] Any discrepancies or doubts regarding the exclusion criteria were resolved by mutual consensus.

   Results Top

The initial search identified 958 results through the PubMed, EMBASE, and COCHRANE databases and 47 through other sources [Figure 1]. Following screening by title and text and removal of duplicates, we evaluated twenty articles in full text. These selected articles comprising expert opinions, National Guidelines, three small randomized controlled trials, and one prospective study, discussed the use or potential use of chloroquine or hydroxychloroquine in the treatment of COVID-19. The findings from these articles have been summarized in [Table 1]a,[Table 1]b,[Table 1]c. To date, 37 clinical trials have been recorded on the trial registries [Table 2]a,[Table 2]b,[Table 2]c,[Table 2]d.
Figure 1: PRISMA flow diagram for search outcome of systematic review on the use of chloroquine/hydroxychloroquine as a treatment option for COVID-19

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   Discussion Top

Among the 20 articles analyzed in this systematic review on chloroquine and hydroxychloroquine usage for the treatment of COVID 19, the majority were based on expert opinions and National Guidelines, with only three small randomized control trials and one prospective cohort study. All the National Guidelines recommended the use of these drugs in the treatment regimen of patients testing positive for COVID-19 [Table 1]a. In addition, the ICMR guidelines of India were the first to implement the use of hydroxychloroquine in asymptomatic health-care workers treating suspected or confirmed cases and household contacts of infected patients.[12]

The efficacy of chloroquine against other viral infections in in vitro studies was highlighted in an Editorial by French researchers, with the aim of encouraging the inclusion of this drug in clinical trials.[19] They further argued that the favorable risk–benefit balance, the high safety, and the relatively lower cost of this drug justifies its relevance in addressing the current COVID-19 pandemic. The expert consensus published by a multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province recommended the use of chloroquine phosphate in patients with SARS-CoV-2 pneumonia, classified as mild, moderate, or severe, provided there was no evidence of contraindications to this drug.[13]

Based on the apparent efficacy and acceptable safety of chloroquine phosphate in patients with COVID-19 pneumonia in multicenter clinical trials conducted in China, this drug was recommended for treating this infection in a larger population.[5] A letter from the Chinese researchers stated that the State Council of People's Republic of China had included the use of Chloroquine Phosphate in the 6th Edition of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19, for the treatment of novel coronavirus pneumonia.[5] Using a similar model, chloroquine/hydroxychloroquine was approved for treatment later by the respective control bodies in Italy, India, France, and USA after its trial use lead to patient recovery in multiple centers across these countries.

Nonetheless, recommendations from researchers in China advocate the use of hydroxychloroquine over chloroquine, considering the relatively severe side effects of the latter.[22] They also emphasized that hydroxychloroquine has a similar antiviral activity to chloroquine, while having a safer clinical profile, being more cost effective, and readily available than chloroquine. In addition, a randomized controlled trial conducted in China reported a significant reduction in time taken for clinical recovery and resolution of pneumonia in patients receiving hydroxychloroquine.[26] The expert opinions also suggested that hydroxychloroquine treatment can potentially improve outcomes in terms of decrease in length of stay in hospitals and decline in overall mortality [Table 1]b.

An open-label nonrandomized clinical trial documented a remarkable reduction in viral load of SARS-CoV-2, when hydroxychloroquine was concurrently administered with azithromycin [Table 1]c.[24] However, one randomized controlled trial in China and a prospective cohort study in France refuted these claims and reported no additional of using hydroxychloroquine over conventional treatment and no evidence of a strong antiviral activity from the combined therapy of hydroxychloroquine and azithromycin, respectively.[25],[27] Amidst the reports with promising results from the use of chloroquine and hydroxychloroquine in treatment of COVID-19, many researchers and clinicians have also expressed concern over the safety profile of these drugs, especially when used in conjunction with azithromycin and have cited the possibility of QTc prolongation, particularly in patients with underlying cardiovascular conditions.[29],[30]

The National Guidelines from Italy are contradictory in this aspect and suggest the use of chloroquine or hydroxychloroquine in a wide range of patients, ranging from those with mild respiratory symptoms and comorbidities to patients with severe respiratory failure.[14] Some reports also recommend practitioners to exercise caution when prescribing chloroquine/hydroxychloroquine for COVID-19 patients. For instance, a public document released by the Dutch Center of Disease control laid emphasis on the need to discontinue chloroquine after 5 days of treatment since the drug has a long half-life (30 h) and to minimize the risk of side effects.[17] This document also stated that it is crucial to differentiate between regimens based on chloroquine phosphate and chloroquine base due to the difference in composition of the active compound [Table 1]a.

The clinical trials identified from the trial registries comprise numerous randomized controlled trials with larger patient cohorts. The outcomes primarily assessed are mortality, viral load, and time to recovery [Table 2]a,[Table 2]b,[Table 2]c,[Table 2]d. Data from these trials are much awaited to provide greater insight into the effectiveness of chloroquine/hydroxychloroquine for treatment of COVID-19. Following completion of the randomized controlled trials underway, an updated systematic review or meta-analysis will enable a more accurate assessment of the risk–benefit balance of administering these drugs in COVID-19 patients. Although other drugs, in particular Remdesivir, Lopinavir-ritonavir have been identified as possible therapeutic options, the widespread availability and affordability of chloroquine/hydroxychloroquine makes them a more desirable candidate for treatment of this global pandemic, subject to proven efficacy and safety in clinical trials. Countries like India already have a high manufacturing capacity and considerable supplies of this widely proclaimed “game-changer” drug. This manufacturing capacity will be of immense aid if and when the off label use of chloroquine might lead to major drug shortage in the fight against Malaria.

   Conclusions Top

As the number of COVID-19 cases continue to increase exponentially in multiple regions of the world, it is imperative to develop an effective approach to stem this tide. The known clinical profile of chloroquine from its long-standing use, its low cost, and widespread availability has led to extensive research on its potential application in the management of COVID-19. In the light of preliminary data from recent randomized controlled trials suggesting potential improvement in clinical outcomes, both chloroquine and hydroxychloroquine are promising antiviral agents in the treatment of COVID-19 pneumonia. However, the reported side effects of these drugs when used in conjunction with azithromycin in patients with comorbidities have raised significant safety concerns and led to a need for further high-quality randomized clinical trials. Adequately coordinated clinical studies such as pan-continental multicentre trials, which include a larger cohort of patients, would not only provide more comprehensive evidence of the safety of these drugs in patients infected with COVID-19 but also increase the generalisability of the study.

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Conflicts of interest

There are no conflicts of interest.

   References Top

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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;14:72-3.  Back to cited text no. 5
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  [Figure 1]

  [Table 1], [Table 2]


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