key: cord-347186-tbtmqmpr
authors: Acharya, Yogesh; Sayed, Abida
title: Chloroquine and hydroxychloroquine as a repurposed agent against COVID-19: a narrative review
date: 2020-08-04
journal: Ther Adv Infect Dis
DOI: 10.1177/2049936120947517
sha: 
doc_id: 347186
cord_uid: tbtmqmpr

The predicament arising from the coronavirus disease 2019 (COVID-19) pandemic has become one of the most significant modern public health challenges. Despite uncertainties in the viral determinants and pathogenesis, it is crucial to accurately inspect all available evidence to construct accurate clinical guidelines for optimised patient care. This study aims to discuss the available evidence for the use of chloroquine (CQ) and hydroxychloroquine (HCQ) against COVID-19. Early in vitro studies of CQ/HCQ against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are convincing. But contradictory evidence exists on the clinical use of CQ/HCQ, either alone or in combination with azithromycin. As of now, there is no compelling clinical evidence on CQ, HCQ, and azithromycin in COVID-19 and the available evidence is limited to methodologically inferior non-randomised studies. Studies have also shown detrimental drug reactions to CQ and ‘HCQ plus azithromycin’, mainly cardiac side effects in hospitalised patients with coexisting cardiovascular comorbidities. Therefore, we recommend that physicians avoid high doses and exercise extreme caution in the compassionate use of CQ/HCQ, either alone or in combination with other antiviral drugs.

The sudden outbreak of Coronavirus Disease 2019 (COVID- 19) , stemming from a novel coronavirus originating from Wuhan, China, has grown into a global pandemic as the third major outbreak of the virulent coronavirus family after Severe Acute Respiratory Syndrome (SARS) and Middle Eastern Respiratory Syndrome (MERS). 1 Despite radical containment efforts, the SARS Coronavirus 2 (CoV 2) continues to spread globally. Currently, therapeutic tactics are only supportive as there are no proven pharmacological agents active against the virus. 2 International efforts are focussed on searching for effective therapies to counter the disease's effects. One strategy is to search for Nobel agents by repurposing older drugs with known antiviral activity that have been studied in the past. 3 In this regard, chloroquine (CQ) and hydroxychloroquine (HCQ) have garnered much attention as they were well studied during previous coronavirus epidemics with SARS and MERS. 4 This study aims to discuss the general properties and antiviral history of CQ and HCQ, and to analyse the available evidence against COVID-19, either alone or in combination with other drugs.

A literature review was performed using PubMed and Google Scholar to identify all relevant English language scientific studies based on our study objectives. Non-specific combinations of the search strings included (Coronavirus OR Severe Acute Respiratory Syndrome OR SARS OR Chloroquine and hydroxychloroquine as a repurposed agent against COVID-19: a narrative review CQ and HCQ share similar pharmacokinetics, with rapid absorption from the gastro-intestinal surfaces, and are renally and hepatically eliminated. As they are weak bases, they increase the pH of acidic vesicles. 6 Notably, HCQ increases intracellular pH levels by inhibiting lysosomal activity in immune cells to prevent downstream immune cell interaction, antigen processing, and cytokine responses. Furthermore, the increment in the pH interferes with viral entry into endosomes and blocks viral-endosome fusion. 6 Although CQ and HCQ are relatively well-tolerated, both drugs are associated with systemic adverse effects, including QT syndrome, hypoglycemia, hepatitis, pancreatitis, neutropenia, retinopathy, anaphylaxis, and cardiac toxicities. 7 The United States Food and Drug Administration (FDA) has issued warnings on CQ/HCQ, particularly based on the associated cardiac side-effects. 8 The CQ/HCQ, either alone or in combination with other drugs like azithromycin, can cause possible cardiac complications, including conduction defects, such as bundle branch blocks, atrioventricular blocks, QT prolongation, torsades de point (TdP), and even dangerous ventricular arrhythmias. Although the CQ and HCQ use during pregnancy and in lactating mothers are believed to be safe, [9] [10] [11] they should be avoided in children due to narrow therapeutic and toxic windows. Children can suffer from apnea, seizures, and arrhythmias if they exceed the recommended therapeutic dose. 12 Antiviral activity: SARS, MERS and others Clark, in 1952, conducted studies depicting the potential anti-microbial activity of CQ by effective inhibition of deoxyribonucleic acid (DNA) synthesis on a protozoan parasite, Plasmodium gallinaceum. 13 This led to further investigations by Schellenberg and Coatney in 1960, 14 who demonstrated CQ-induced inhibition of the incorporation of radioactively labelled nucleic acid substituents in DNA and ribonucleic acid (RNA) of Plasmodium gallinaceum. These studies showed that CQ could inhibit the nucleic acid, and this nucleic-acid inhibitory potential could be utilised in viruses.

Mallucci conducted one of the first animal studies in 1966 to demonstrate the antiviral activity of CQ on lysosomes of hepatitis virus-infected mouse cells. 15 The mechanism of inhibition was unknown before the animal studies, and CQ was believed to lower virus yield, hypothesised by the prevention of new viral synthesis or viral uncoating. In 1972, Shimizu et al. investigated the antiviral effects of CQ on non-oncogenic viruses in animal cell culture. 16 26, 27 These inhibitory effects were noted with CQ treatment both before and after exposure to the SARS virus, suggesting its prophylactic as well as therapeutic utility. Vincent et al. 27 found that CQ interferes with the terminal glycosylation process of cellular receptors, particularly angiotensinconverting enzyme 2 (ACE2), with the potential to prevent virus-receptor interaction, and interferes with viral spreading by increasing vesicular pH levels.

In 2006, Savarino et al. pointed out the importance of the CQ as a broad-spectrum antiviral agent. 28 They stated, 'the broad-spectrum antiviral effects of chloroquine deserve particular attention in a time in which the world is threatened by the possibility of a new influenza pandemic, and the availability of effective drugs would be fundamental during evaluation of an effective vaccine.'

In 2009, Keyaerts et al. further investigated both the in vitro and in vivo antiviral activities of CQ against human CoV strain OC43 (HCoV-OC43) in newborn mice. 29 They concluded that CQ interferes with the in vitro replication of HCoV-OC43, and showed 100% survival in newborn mice treated pre-partum with CQ. Their result showed that CQ could be immensely useful against HCoV-OC43.

Although there were some promising results concerning CQ/HCQ in SARS/MERS, most of these credible pieces of evidence were based on in vitro studies. Only a few clinical studies were available, which were methodologically inferior with small sample size, high dropout rates, variable baseline viral loads compared with monotherapy, and combination therapy of CQ/HCQ and differences in toxicities, which impacted the quality and validity of the results obtained. 30 As the SARS/ MERS outbreaks were limited within a particular region and lasted for a short time, there were no follow ups, more extensive observational studies, or controlled clinical trials to support this evidence.

Since the beginning of the COVID- 19 The CQ and HCQ duo was one of the very first contenders in the race against COVID-19.

Although there was no high-quality clinical evidence of CQ/HCQ against SARS and/or MERS, the in vitro and in vivo results of CQ/HCQ were promising. Therefore, as SARS-CoV 2 shared genetics and pathological similarities with SARS/ MERS within the coronavirus families, CQ/HCQ were considered to be initial candidates for drug repurposing in COVID-19. [32] [33] [34] [35] We have summarised these in vitro and in vivo studies in Table 1 , and each of these studies is described in brief based on the sequential unfolding of the evidence.

On 4 February 2020, an editorial in Springer Nature ® conducted by Wang et al. was one of the first to describe the effects of CQ in conjunction with other five antiviral drugs in Vero E6 cells infected with nCoV2019BetaCoV. 35 They performed a standard in vitro assay in 2019-nCoV clinical specimens to elucidate the antiviral activity in terms of cytotoxicity, virus yield, and infection rate. Notably, their time-of-addition assay showed that CQ blocked the virus at low concentrations during both entry and post-entry phases of cellular infection. They concluded that CQ has a high prospect in 2019-nCoV as it is a standard drug with known safety profile, is relatively cheap, achieves a wide volume of distribution after oral intake, and can easily attain the EC90 seen in Vero E6 (6.90 μM) with standard 500 mg dose.

On 19 February, a Chinese briefing reported CQ as a successful treatment regimen in greater than 100 patients infected with COVID-19. 53 The patients showed improvements in lung function demonstrated by radiological evidence, viral clearance, and slowing of disease progression. They recommended CQ to be listed in the standard Guidelines for management of COVID-19associated pneumonia in the National Health Commission, China, based on the successful outcomes in terms of safety and efficacy within the country.

Another in vitro study conducted by Yao et al. 36 On 29 April 2020, Saleh et al. conducted a prospective observational safety study to evaluate the effect of CQ, HCQ, and azithromycin in association with QT interval and risk of TdP and sudden cardiac death in COVID-19 patients. 44 In this extensive cohort study to date with CQ/HCQ/ azithromycin, no TdP or sudden death due to arrhythmia was noted. These medications did prolong the QT interval but did not lead to the discontinuation of therapy. They concluded that further research is needed to establish drug safety before a definitive recommendation can be made. In addition, a retrospective observational cohort safety study conducted by van den Broek et al. on 29 April 2020, investigated CQ-induced QT prolongation in COVID-19 patients. 45 They concluded that CQ leads to QT prolongation and recommended ECG monitoring of all patients taking CQ.

Similarly, on 1 May 2020, Mercuro et al. in Boston, Massachusetts, investigated the risk of QT prolongation with the use of HCQ with or without azithromycin used in combination in COVID-19 confirmed-patients. 46 They observed that patients receiving HCQ as a treatment for COVID-19 pneumonia were at significant risk for QT prolongation and that parallel treatment with azithromycin further elevated the risk. They emphasised extreme caution and careful monitoring of the patients with a careful weighing of both risk and benefits before initiation of the treatment with HCQ/azithromycin. On 2 May 2020, a rapid systematic review consisting of clinical trials carried out by Chowdhury, Rathod and Gernsheimer showed inadequate evidence to encourage the use of CQ/HCQ in COVID-19. 58 They concluded that healthcare professionals should dissuade from the clinical use of CQ/HCQ until the ongoing studies provide more evidence on efficacy and safety profiles. Similarly, on 5 May 2020, Jain et al. conducted a safety study to establish an improved ECG monitor system of COVID-19 patients undergoing pharmaceutical treatment associated with a risk of QT prolongation. 47 They created a tool called Situation Background Assessment Recommendation (SBAR) that identifies patients requiring ECG monitoring and tags QT prolongation within the ECGs. They showed that SBAR efficiently identified QT prolongation, with 95.1% being related to QT-prolonging medications.

Furthermore, on 7 May 2020, Geleris et al. conducted an observational study to determine an association between HCQ and the need for intubation or risk of death. 48 Based on the observations of 1376 consecutive patients with COVID-19 who received HCQ (600 mg twice daily on initial admission followed by 400 mg daily for 5 days), they conclude that there was no significant association of HCQ with lowering the risk of intubation or death (HR 1.04; 95% CI 0.82-1.32). Geleris et al. 48 concluded that HCQ should only be used within clinical trial settings unless its efficacy can be thoroughly tested and established. This study had many potential limitations, including missing data and inaccurate health record-keeping, incomplete documentation on smoking, and comorbidity status on patients as well as a single-centre design, limiting the generalisability of the study data.

An open-labeled randomised controlled trial was published on 7 May 2020, by Tang 

Apart from a general warning, the FDA has cautioned against the indiscriminate use of CQ/ HCQ, either alone or in combination with azithromycin, in COVID-19 patients due to the potential linkage to cardiac toxicities, including severe complications like rhythm disturbances. 60 While the FDA continues to explore these adverse events and will communicate their findings with the public once more information becomes available, the latest COVID-19 NIH Treatment Guidelines Panel recommends 'against using high-dose chloroquine (600 mg twice daily for 10 days) for the treatment of COVID-19 (AI), because the high dose carries a higher risk of toxicities than the lower dose'. 61 Similarly, the EMA has advised the close monitoring of the COVID-19 patients receiving CQ/HCQ. 54

Current clinical recommendations on CQ/HCQ in COVID-19 are not backed by substantial evidence, and most of the studies are methodologically inferior. In this unique circumstance, we are made to decide between providing medical care or producing reliable and scientifically valid data. This dilemma may lead to compromising the generation of evidence-based and clinically reliable results. In many cases, drugs like CQ and HCQ are being given compassionately due to the severe nature of the disease, despite the discrepancies and safety warnings. As there is insufficient clinical evidence to either refute or accept the use of CQ/HCQ in COVID-19, we would like to advise physicians across the globe to avoid high dose and exercise extreme caution in the compassionate use of CQ/HCQ, particularly in patients with cardiac comorbidities.

Understandably, there is an overwhelming need to identify plausible treatment options against a devastating and deadly disease like COVID- 19 .

In their quality analysis of the existing studies of CQ/HCQ in COVID-19, Alexander et al., reported that the majority of the existing studies on COVID-19 are general, biased, and methodologically non-rigorous. 62 They concluded that the available clinical studies have many limitations, including sample size, unclear reporting of study methodology, no blinding and/or randomisation, missing clinical data, inconsistencies in treatment versus control groups such as groups taken from different healthcare centers, lack of control groups, lack of matching and stratification, inconsistent and low event rates, and an unadjusted analysis. Observational studies can lead to biases, like selection, collider, and confounding bias, that can significantly influence studies outcomes, making them challenging to interpret and/or replicate. 63, 64 This is mostly due to the high demand for evidence on ongoing pandemics and uncertainty regarding the virus.

Although we did not perform the quality assessment of the available studies, the majority of the available studies were case-based small studies that are often not controlled with randomisation and/or standardisation. There is no denial that high-quality research, such as RCTs or extensive registry-based observational studies, are still warranted to have conclusive evidence before reaching any consensus. Despite these methodological challenges, it is still up to the research community and clinicians to accurately appraise studies and prioritise the publication of credible evidence. 65

Given the promising early in vitro results of CQ/ HCQ in SARS-CoV 2 and existing therapeutic dilemmas, the compassionate use of CQ/HCQ can be an option in the ongoing crisis despite the absence of convincing clinical evidence in COVID-19. However, physicians should avoid high doses of CQ/HCQ and exercise caution, particularly in patients with existing cardiovascular disease. We suggest that clinicians and researchers regularly update and adhere to the available credible evidence and findings of the ongoing clinical trials.

• Given the promising early in vitro results and therapeutic dilemma, the compassionate use of CQ/HCQ in COVID-19 can be an option. • However, there is no convincing clinical evidence to support the use of CQ and HCQ, either alone or in combination with azithromycin, in COVID-19. • Misuse of CQ/HCQ or use beyond the prescription can result in serious health problems, including cardiac toxicity and even death. • It is recommended to avoid high dose CQ/ HCQ and exercise extreme caution while using CQ/HCQ even in hospitalised patients. • Clinicians and researchers should regularly update and adhere to the available credible evidence and findings of the ongoing clinical trials.

YA and AS made substantial contributions to the conception and study design, data acquisition and interpretation. All authors were involved in drafting the manuscript as well as the revision process. All authors have approved the final version of the manuscript.

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The authors declare that there is no conflict of interest.

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The authors received no financial support for the research, authorship, and/or publication of this article.

Yogesh Acharya https://orcid.org/0000-0003-1829-5911