Chloroquine and Hydroxychloroquine in Coronavirus Disease 2019 (COVID-19). Facts, Fiction & the Hype. A Critical Appraisal.

Highlights of this review include

• Chloroquine/hydroxychloroquine (CQ/HCQ) have suffered from significant fictions and resultant hype during COVID-19 pandemic.

• CQ and HCQ share same drug profile except HCQ has better safety record.

• CQ/HCQ have lysosomotropic property, prevent the conversion of toxic heme into non-toxic hemozoin, have immunoregulatory effect and downregulate pro-inflammatory cytokines.

• CQ/HCQ have been in clinical use for malaria with recent setback due widespread drug resistance.

• HCQ is the cornerstone in managing rheumatic diseases including rheumatoid arthritis and systemic lupus erythematosus.

• CQ/HCQ have convincing strong in vitro antiviral activity against SARS-CoV-2.

• CQ/HCQ in managing COVID-19 is a dynamic phenomenon and is rapidly evolving with results of ongoing trials.

• CQ/HCQ have widespread drug interactions.

• HQ/HCQ prolong QTc, may rarely cause Torse de Pointes and sudden cardiac deaths. Addition of Azithromycin may potentiate this adverse effect.

•HCQ therapy should follow a defined algorithm to reduce adverse drug reactions.

Abstract

The coronavirus infection (COVID-19) has turned in to a global catastrophe and there is an intense search for effective drug therapy. Of all the potential therapies, chloroquine and hydroxychloroquine have been the focus of tremendous public attention. Both drugs have been used in the treatment and prophylaxis of malaria and long-term use of hydroxychloroquine is the cornerstone in the treatment of several auto-immune disorders. There is convincing evidence that hydroxychloroquine has strong in vitro antiviral activity against SARS-CoV-2. Few small uncontrolled trials and several anecdotal reports have shown conflicting results of such drug therapy in COVID-19. However, as of today, the results of large scale randomized controlled trials are not available. Despite the lack of such evidence, hydroxychloroquine is used as a desperate attempt for prophylaxis and treatment of COVID-19. The drug has wide-ranging drug interactions and potential cardiotoxicity. Indiscriminate unsupervised use can expose the public to serious adverse drug effects.

Keywords

Chloroquine

Hydroxychloroquine

COVID-19

SARS-CoV-2

Coronavirus

Pandemic

1. Introduction

The coronavirus infection which originated from Wuhan, China in December 2019 has turned in to a global catastrophe (1). The virus has been designated as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) and the disease caused by the agent as Coronavirus Disease 2019 (COVID-19) (2). WHO pronounced the disease as a pandemic on March 11, 2020 (3). The world community has responded to the challenge with resilience and determination (4). There has been a major understanding of the disease as well as the pathogen in a matter of days and weeks rather than years and decades, an unprecedented occurrence in the history of medicine. It has led to the sharing of knowledge, preparedness measures to be implemented, containment measures to mitigate against the virus morbidity & mortality, and collaborative research to quickly address critical gaps in knowledge (5).

2. Drugs for COVID-19

During this COVID-19 pandemic, there have been intense attempts to explore drug therapy for prophylaxis and treatment of SARS-CoV-2 infection (6, 7, 8, 9). Several drugs have been identified based on their differing modes of action on the virus and various pathways it traverses and includes several antivirals (lopinavir/ritonavir combination, remdesivir, favipiravir), two antimalarials (chloroquine and hydroxychloroquine), ACE2 inhibitor (losartan), immunosuppressive agents (tocilizumab, leronlimab and corticosteroids), TMPRSS2 inhibitor (camostat mesylate), anti-parasitic drugs (ivermectin & nitazoxanide), Gold-containing drug auranofin, an immunomodulator used in sepsis and leprosy (Sepsivac-Mycobacterium w heat-killed injections), allogeneic PLacental eXpanded (PLX) cells, and convalescent plasma (6, 7, 8, 9, 10) (Table 1). As of today, there is no medication or vaccine proven to be effective for the treatment or prevention of COVID-19 (11, 12, 13).

Table 1. List of Some Potential Drugs Explored in the treatment of for COVID-19.

Class/DrugDoseRationaleTrialsAntiviralsLopinavir/Ritonavir (LPV/RTV)i

LPV 400 mg/RTV 100 mg BID PO x 14d

LPV 400 mg/RTV 100 mg PO BID x 21d

iii

LPV 400 mg/RTV 100 mg PO x 14d ± Ribavirin (loading dose 4g, 1.2g x 8 hourly PO)

HIV protease inhibitor. In vitro activity vis-à-vis SARS-CoV & NERS-CoV. No data vis-à-vis SARS-CoV-2.Randomized trial-not effective. A Cohort study and anecdotal experience-results inconsistentRemdesiviri

200mg IV x d1; 100 mg IV x d2-5.

200mg IV x d1; 100 mg IV x d2-10

iii

200mg IV x d1; 100mg IV x daily up to 10 days.

Nucleoside analogue Broad-spectrum antiviral against coronavirusesGilead: Several randomized trials initiated. Compassionate use.Favipiravir (Avigan)200 mg tablets (1200 mg PO first dose; 400 mg PO x d1; 400 mg BID PO xd2-5).Activity against RNA viruses & indicated in Influenza resistant to Tamiflu. It has a teratogenic effect.Chinese non-randomized trial-effectiveAntimalarialsChloroquine (CQ)500 mg BID PO x 10dImmunomodulatory effect & reduce the production of cytokines. In vitro antiviral activity vis-à-vis SARS-CoV-2; HCQ is more potent and less toxic.Chinese & French trials; non-randomized; results inconclusive. Anecdotal reports. Included for treatment and prophylaxis in protocols.Hydroxychloroquine (HCQ)i

400 mg BID PO x d1; 200 mg BID PO x d2-5

200 mg TID PO x 10 days (French trial).

iii

400 mg BID PO x d1; 400 mg PO once weekly x 3-7 wk. (ICMR, prophylaxis)

Antihypertensive drugLosartan50 mg QID POiHypothetical: may block ACE2 receptors & inhibit virus binding. can also upregulate ACE2 which may harm host?Clinical trial underwayImmunosuppressive drugsTocilizumabIV infusion: 4-8 mg/kg x 60 min; if needed repeat at 12 hr. (max dose 800 mg)Recombinant humanized monoclonal antibody against IL-6 receptor. To treat cytokine storm syndrome.Case study & series, rapid improvement in cytokine related symptoms.CorticosteroidsParenteralAnti-inflammatory to treat extended cytokine response; treatment ARDS & sepsisUse controversial (not intended to treat pneumonia). Treat shock and/or ARDSAntibioticAzithromycini

500 mg QID PO x d1; 250 mg QID PO x d2-5.

500 mg PO QID x 7 days

iii

500 mg PO x QID 5 days

Macrolide & Antibacterial Immunomodulators, downregulate inflammatory response; reduce cytokine production, and inhibit cytokine actions. No antiviral effect is known.French trial as an adjunct to HCQ. MERS-CoV: large retrospective analysis-no advantageConvalescent PlasmaPlasma from recovered COVI-19 patients.Convalescent COVID-19 patients may have high titer antibodies (titer>1:320).Trials to treat severe/life-threatening disease (not allowed for prevention).

3. The Hype

Of all the potential therapies against SARS-CoV-2 infection, antimalarials namely chloroquine (CQ) and hydroxychloroquine (HCQ) have been the focus of tremendous public attention (14, 15, 16, 17, 18, 19). There have been sharp differences of opinion as to the role of these 2 drugs in the prevention and treatment of SARS-CoV-2 infection. On one extreme, these drugs have been touted as "biggest game-changers in the history of medicine" (17, 20), while at the other end these drugs have been trolled as “useless and dangerous” (18, 21, 22).

There have been interesting developments related to the role of CQ and HCQ to COVID-19 in the United States. Taking leads from the French trial (23), President Donald Trump has given several press briefings including tweets in support of the drug. These have not been corroborated by his experts and the FDA. Despite all this, FDA on March 29, 2020, has issued emergency authorization for use of HCQ for hospitalized teen and adult patients with COVID-19 (24). This move was supported by the White House, despite the scant evidence. US Govt. has made huge quantities of HCQ available, procured from pharma companies, and other countries including India (24, 25). India has also taken a not less interesting position on the role of CQ/HCQ to COVID-19. National Task Force for COVID constituted by ICMR on March 22, 2020, recommended the use of HCQ for prophylaxis of SARS-CoV-2 infection for healthcare workers and household contacts of COVID-19 patients (15). The decision has been based on available preclinical and clinical data and anecdotal reports (15, 26). Amongst all this controversy, several events have surfaced mainly based on pinning the hope that HCQ may be effective against an invisible python that is ravaging the world. Hoarding of these drugs has left a drug shortage in the market (27). Patients with systemic lupus erythematosus and other autoimmune disorders who are on lifelong HCQ therapy find it difficult to get their daily supplies (28). Several deaths have been reported due to the self-use of HCQ to prevent coronavirus infection and consequent drug-related cardiotoxicity (29, 30). Pharmaceuticals have received bulk orders and large quantities of the drug have been supplied to many countries including the USA (31, 32).

4. Pharmacology of 4-Aminoquoliloes (4AQ's)

CQ was discovered in 1934 as an anti-malarial drug and is on the WHO Model List of Essential Medicines 2019 (33). HCQ was developed during the second world war and is more potent than CQ with less severe side effects (34). Both CQ (C18H26ClN3; molecular mass 320 g/mol) & HCQ (C18H26ClN3O; molecular mass 336 g/mol) are 4-aminoquinolones (4AQ's) (35). HCQ differs from CQ only by one hydroxy group (OH). They resemble each other in their pharmacokinetics, mode of action, indications, and type of drug toxicity. CQ is administered as phosphate whereas HCQ is administered as sulfate. Given differing molecular weights of CQ and HCQ (320 versus 336 respectively) equivalent doses of the two drugs are different. 4AQ's retinopathy occurs more often with CQ than HCQ (36). HCQ is the only molecule available at present in the US market. However, CQ is available and continues to in use in most other countries. Both drugs are cheap, easily available, and easy to administer (33).

CQ & HCQ are weak bases and occur as enantiomers (R and S isomers). After oral intake, drugs are quickly absorbed in the upper intestinal tract, with high bioavailability (0.7-08) and a large volume of distribution in the blood. The drug half-life is comparatively long (40 to 60 days). Both CQ and HCQ are lysosomotropic and get deposited in acidic vesicles namely lysosomes and endosomes and bind to melanin (skin and eyes). CQ and HCQ are 60% bound to plasma proteins and following administration are dealkylated in the liver via cytochrome p450 (CYP) into active metabolites and both the parent drug and the active metabolites are excreted by the kidneys and feces (35, 37) (Table 2).

Table 2. Pharmacology of Chloroquine and Hydroxychloroquine.

ParameterChloroquineHydroxychloroquineDiscovery year19341946Basic compound4-aminoquinoline4-aminoquinolineDrug ClassAnti-malarialAnti-malarialDrug FormulaC18H26ClNO3C18H26ClNO3OMol weight320 g/mol336 g/molChemical natureWeak baseWeak baseSalt for therapeuticsPhosphateSulfateAvailability250 mg (150 mg base); 500 mg (300 mg base)200 mg (155 mg base)Brand nameAralen (US),Plaquenil (US)AbsorptionUpper intestinal tract; 2-4 hr.; 89%; not affected by food.Upper intestinal tract; 2-4 hr.; 74%; not affected by food.Bioavailability0.7-0.80.7-0.8DistributionLarge; 60,000 lLarge; 47,257 lTerminal Half life45± 15 days41 ± 11 daysResidence time≈ 900 h≈ 1,300 hMetabolismUnmetabolized 62%; rest is dealkylated in Liver; Enzyme Cytochrome 450; active metabolite Desethylchloroquine 39%.Unmetabolized 58%; rest is dealkylated in Liver; Enzyme Cytochrome 450; active metabolites Desethylchloroquine (18%) & Desethylhydroxychloroquine (16%).ClearanceKidney (51%) & LiverKidney (21%) & LiverToxicityAnimal2-3 times more toxic than Chloroquine (Albino rats)SaferCardiacSameSameOphthalmicMore (≈ 20% in 5-7 yr.)Less (≈ 1 % in 5-7 yr.)Drug-drug interactionSameSamePregnancy & LactationSafeSafeIndicationMalaria treatmentYesYesMalaria prophylaxisYesYesRheumatologyNot recommendedDrug of choiceStatus for COVID-19In vitro antiviral activityLess potent in vitroHydroxychloroquine is more potent in vitro than chloroquineTreatmentUsed in studiesUsed in studiesProphylaxis-Yes (ICMR)

5. Indications of 4AQ's

Both CQ and HCQ have been used for long in the treatment of malaria and now are being used extensively in rheumatic diseases. Despite the lack of evidence, hydroxychloroquine is used as a desperate attempt for prophylaxis and treatment of COVD-19.

5.1. Malaria

Both CQ and HCQ have been used in the treatment and prophylaxis of malaria (35, 38). As antimalarial, they have marked schizonticidal and gametocidal activity and work against an asexual form of the malarial parasite in the stage of its life cycle within the red blood cells. The drugs do not act against the intrahepatic forms of the parasite. The mechanism of action of CQ and HCQ is related to their lysosomotropic property. The drugs get accumulated within the food vacuole (lysosome-like organelle) of the parasite and prevent the conversion of toxic heme (released from digestion of hemoglobin by parasite proteases) into non-toxic hemozoin (the malarial pigment) (Fig 1). The parasite detoxifies heme in the food vacuole via a biocrystallization process in which heme is sequestered into large insoluble crystals namely hemozoin. The drugs bind heme and prevent heme from being incorporated into crystals. The accumulated free heme lyses membranes and leads to parasite death (39). Of late, as a result of extensive mass use of these drugs, there has been the emergence and spread of resistance and its use is limited to regions with no known resistance (40). The chloroquine resistance is due to decreased accumulation of chloroquine in the food vacuole. The drug resistance is mediated primarily by mutant forms of the ‘chloroquine Resistance Transporter’ (PfCRT), that cause efflux of chloroquine from the digestive vacuole (41) and possibly ‘Multi-Drug Resistance 1 (PfMDR1) gene’ (42). These drugs are not recommended for the treatment of Plasmodium falciparum due to widespread resistance to it.

Fig 1. Mode of action of chloroquine in malaria and the mechanism of chloroquine drug resistance. Chloroquine (CQ) accumulates in the food vacuole of the parasite. The drug inhibits the formation of hemozoin (non-toxic) from the heme (toxic) released by the digestion of hemoglobin. The accumulated heme lyses membranes and leads to parasite death. Chloroquine résistance is due to a decreased accumulation of chloroquine in the food vacuole. The drug resistance is mediated primarily by mutant forms of the ‘chloroquine Resistance Transporter’ (PfCRT), that cause efflux of chloroquine from the digestive vacuole.

5.2. Rheumatic Diseases

Today the antimalarial drugs have a major therapeutic role in Rheumatology. Here HCQ is preferred to CQ, as such patients need long term therapy and HCQ has a lower incidence of retinopathy when compared to CQ (43). HCQ is used in active rheumatoid arthritis (early mild disease or adjuvant therapy to other disease-modifying anti-rheumatic drugs – the DMARDs), systemic and discoid lupus erythematosus, Sjogren's syndrome, Sarcoidosis, Antiphospholipid syndrome, and photosensitive dermatosis (44, 45, 46, 47, 48, 49). The drug has become a cornerstone in managing patients with systemic lupus erythematosus (50). The therapeutic effect of HCQ in rheumatic disorders is related to inhibition of various processes in innate and adaptive immunity (Fig 2). The drug has an immunoregulatory effect and downregulates pro-inflammatory cytokines namely Interleukin 1 (IL-1), Interleukin-6 (il-6), Interferons (IFNα and IFNγ), tumor necrosis factor (TNF) and B-cell activating factor (BAFF). The drug is lysosomotropic and accumulates within lysosomes and endosomes and raises their pH. The drug inhibits lysosomal enzymes and inhibits autophagy pathway and endocytosis. This, in turn, downregulates autoantigen presentation (MHC Class II-mediated), T-cell activation, differentiation, and expression of co-stimulatory molecules (such as CD154) and release of cytokines. In endosomes, the drug prevents TLR signaling and cGAS-STING signaling and downregulates the production of proinflammatory cytokines (37, 51, 52).

Fig 2. Basis of Hydroxychloroquine (HCQ) Use in Rheumatic Diseases. The drug, in antigen processing cells (APC) namely plasmacytoid dendritic cells, monocytes, macrophages, and B cells, interferes with TLR-mediated activation, signaling, and cytokine production. In APC such as plasmacytoid dendritic cells and B cells, the drug inhibits antigen processing and subsequent MHC class II-mediated antigen presentation to T cells. This prevents T cell activation, production of proinflammatory molecules, and reduces the production of cytokines.

5.3. COVID-19

CQ and HCQ have several effects that can potentially prevent SARS-CoV-2 infection and also reduce its progression (Fig 3). The drugs may interfere with the entry of the virus into cells. Coronaviruses highjack the ACE2 receptors for its entry into the cell (53). The SARS-CoV-2 RBD (Receptor Binding Domain) has much more affinity (15-fold) to bind ACE2 compared with SARS-CoV RBD, resulting in much higher infectivity. Both drugs are known to interfere in the glycosylation of ACE2 (54). This can make Spike protein-ACE2 binding less efficient and impede the entry of the virus into the cells. The drugs are lysosomotropic, are weak bases, enter the cell organelle namely acidic endosomes and lysosomes, and increase their pH (55). This can interfere with viral activity in many ways. The virus fusion process within the host cell and replication can be prevented. Within antigen processing cells (APC), drugs can interfere with antigen processing and MHC class II-mediated antigen presentation. This, in turn, can interfere with T cell activation, expression of CD154, and downregulate cytokine production. Both drugs disrupt TLR-nucleic acid sensor cGAS and downregulate pro-inflammatory genes (37).

Fig 3. Proposed Sites of Action of hydroxychloroquine in SARS-CoV-2 Infection. The flow diagram shows stages of SARS-CoV-2 infection in the human host and subsequent mechanism of effects leading to target organ damage. The possible sites HCQ may act is shown by the red arrows.

5.3.1. Systematic Review

The use of CQ and HCQ in COVID-19 has been a focus of tremendous public attention. To scrutinize this, we performed a systematic review to identify studies wherein CQ and HCQ have been used to treat COVID-19. A PRISMA checklist was used to conduct a systematic review (56). To do so, we searched MEDLINE (National Library of Medicine, Bethesda, MD, USA) and EMBASE (Elsevier, New York, NY, USA) from inception till April 18, 2020, using keywords chloroquine AND COVID-19, and hydroxychloroquine AND COVID-19, to find articles providing information on the efficacy and safety of these formulations in patients with SARS-CoV-2 infection. The search included articles related to in-vitro studies as well. There was no language barrier employed and searches were expanded using a snowballing method to retrieve relevant papers. We also searched for several clinical trial registries to identify published results from ongoing trials. Articles available in press and media were scrutinized to search the published source articles. Articles were also searched in preprint repositories namely medRxiv (Cold Spring Harbor Laboratory), ResearchGate (Berlin, Germany), figshare (UK), etc. We did not register the systematic review protocol due to the urgency of the matter. Two authors (AS, MK) independently screened the databases, and the trial registries and extracted relevant information. Discrepancies and doubts about the relevance of the sources were solved by consensus with inputs from all the authors (AS, MK, MSK).

The initial search identified 293 articles (188 from PubMed, 80 EMBASE, and 25 from other sources). Several trials are on the offering which amongst others include: i. WHO mega trial, ii. The trial at Columbia University, iii. The trial at the University of Minnesota, New York, iv. 23 registered ongoing trials in China. However, results of none of these trials are available as of today. Following the screening of titles and abstracts and removing duplicates, we evaluated 17 articles about HQ and/or HCQ in coronavirus infection (Table 3). This included 4 in vitro studies and 13 clinical trials. Two of these trials have evaluated the prophylactic use of HCQ in COVID-19 (57, 58).

Table 3. In vitro Studies and Clinical Trials of Chloroquine and Hydroxychloroquine in SARS-CoV-2 Infection.

Author/refDrugStudy groupDesign/ExperimentsOutcomeIn Vitro studiesVincet/59CQVero E6 cell modelSARS-CoVViral inhibitionWang /60CQVero E6 cell modelSARS-CoV-2Viral inhibition at entry & post-entry infection.Liu/61CQ, HCQVero E6 cell modelSARS-CoV-2Viral inhibition, CQ more potent than HCQYao/62CQ, HCQVero E6 cell modelSARS-CoV-2Viral inhibition, HCQ more potent than CQ, HCQ dose estimation doneTherapeutic clinical TrialsGao/63CQ, HCQ100 patientsObservational with historical controlsInhibits pneumonia progression, improves lung function, shortens disease courseGautret/23HCQ, ± AZT42 patientsObservational with historical controlsHastens viral clearance at day 6 (70% vs. 12.5%), AZT enhances viral clearanceGautret/65HCQ ± AZT80 patientsObservationalViral clearance at day - 83%, hospital stay- 4.6 days.CHEN/66HCQ30 patientsSmall randomized studyNo effect on viral clearance at day 7 (86.7% vs. 93.3%)Chen/67HCQ62 patientsRandomizedSignificant effect on time to clinical recovery, body temperature recovery time, and the cough remission time.Magagnoli/68HCQ, HCQ + AZT368 patientsRetrospectiveMortality HCQ 27%, HCQ + AZT 22.1%, Controls 11.4%. Need for ventilation- no difference in three groups.Borba/69HCQ400 patients (interim analysis 80 patients)Parallel double blind with 2 dosage regimens planned and terminated after interim analysisMortality higher (17%) with higher HCQ dosage regimen.RECOVERY TRIAL/72HCQ4674 patients (Interim analysis)Large Randomized Controlled28 mortality 25.7% vs. 23.5%, No effect on hospital stay.Tang/73HCQ150 patientsRandomizedViral clearance day 28 (85.4% vs. 81.3%)Molina/70HCQ + AZT11 patientsObservationalViral clearance at day 6- 20% onlyMahevas/71HCQ181 patientsObservational with historical controlsTransfer to ICU within 7 days-20.2% vs. 22.1%, death 2.8% vs. 4.8%.Prophylactic clinical TrialsBoulware/58HCQ821 asymptomatic with high risk exposureLarge randomized double-Blind studyPost-exposure incidence 11.8% vs. 14.3%.Chatterjee/57HCQ (4 doses)Health care workersCase control studySignificant decline in chances of getting infected (AOR: 0.44; 95% CI: 0.22-0.88).CQ=Chloroquine, HCQ=Hydroxychloroquine, AZT=Azithromycin

5.3.2. In Vitro Studies

There are several in vitro studies done on Vero E6 cells have that evaluated the antiviral efficacy of CQ and HCQ against coronaviruses. All these studies have shown strong antiviral activity of CQ as well as HCQ against coronaviruses. The authors believed that antiviral activity was due to the well-known lysosomotropic property of the drug, causing high endosomal pH and interfering with virus-cell fusion. Besides, the drug was found to interfere with virus entry due to interference with the terminal glycosylation of ACE2. Vincent et al (59) from CDC studied in vitro antiviral properties of CQ on SARS-Coronavirus namely SARS-CoV on primitive Vero E6 model. CQ showed a strong inhibitory effect on the virus. Recently, Wang et al (60) from Beijing China showed that CQ at low micromolecular concentrations to be highly effective with high selectivity index in blocking SARS-CoV-2 infection in vitro, both at entry and post-entry stages of infection. Seven drugs were tested in the experiments which included Ribavirin, Penciclovir, Favipiravir, Nafamostat, Nitazoxanide, Remdesivir, and CLQ. Of the seven drugs, only 2 drugs namely Remdesivir and CQ potently blocked virus infection at low molecular concentration and showed a high selectivity index. The fact that drugs demonstrated anti-viral effects at low concentrations could favourably show clinical response in human infection. Anti-viral activity of CQ at entry and post-entry of infection suggests that drugs can be used both for prophylaxis as well as curative. Liu et al (61) from Wuhan China compared the antiviral potency in vitro of CQ and HCQ against SARS-CoV-2, the causative agent of COVID-19. The results showed that HCQ was less potent than CQ in its anti-SARS-CoV-2 activity. However, Yao et al (62) from Beijing China reported on the anti-SARS-CoV-2 activity of HCQ and CQ and found HCQ was more potent than CQ in its antiviral activity. Based on a physiologically-based pharmacokinetic model (PBPK), they calculated the therapeutic dose of HCQ as 400 mg given twice on the first day followed by 200 mg twice daily for 4 days for SARS-CoV-2 infection.

5.3.3. Clinical studies

The above-mentioned in vitro studies have connivingly shown that CQ and HCQ have strong antiviral activity against coronavirus. However, the same is not true for clinical trials. As of today, there is no convincing randomized controlled trial published to show that CQ and/or HCQ is beneficial in prophylaxis and/or treatment of SARS-CoV-2 infection. Till that it is worth evaluating the results of a few six trials and anecdotal reports.

Gao et al (63) from Qingdao, China reported on efficacy and safety of CQ or HCQ in the treatment of COVID-19 associated pneumonia in 100 patients enrolled from 10 hospitals. CQ/HCQ was superior to the control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course. Severe adverse reactions to CQ/HCQ were not noted in the aforementioned patients. The authors supported their conclusions on an audio transcript of the news (in Chinese) briefing held by the State Council of China on February 17, 2020. Reference was also made of the Chinese Clinical Trial Registry which enrolled these patients and which authors had accessed on Feb 18, 2020. The evidence of such data in the trial registries has been reviewed and none is available or found. So, it is impossible to comment on or confirm the validity of the above observations, conclusions, and recommendations.

Gautret et al (23) from Marseille, France recruited 42 patients with COVID-19 to evaluate the role of HCQ. Six of the treated patients were excluded (death-1, ICU admission-3, ADR-1, and refusal to therapy-1) and only 36 patients were included in the final analysis. This included 20 patients who received HCQ 200 mg TID PO. Six of the 20 patients in the HCQ group received azithromycin as well to treat infections and supplement the antiviral activity of HCQ. Sixteen patients in the control group were recruited from other hospitals or those who refused drug treatment. Of the 36 patients evaluated, 6 patients had no symptoms, 22 complained of throat symptoms and 8 had a pneumonic disease. The primary endpoint of the study was viral clearance (throat swab negative by RT-PCR) at day 6th post-inclusion and the secondary endpoint included serial viral load, clinical follow, and adverse drug reactions. The viral clearance at day 6 (primary outcome) occurred in 14 (70%) patients in HCQ treated group compared to 2 (12.5%) patients in the control group (P<0.001). HCQ treated patients had faster viral clearance than the control group. All the six patients in whom azithromycin was added to HCQ cleared the virus on day 6. This trial is fraught with major issues. The patient's enrolment was not randomized, which is essential for making dependable comparisons. Six of the treated patients who did poorly (one died, 3 were admitted to ICU, one had drug adverse effects and one refused treatment) were not included in the analysis, thus skewing the outcome. The protocol for virus testing was faulty, as viral clearance was declared only at 6 days and not beyond. Six patients received HCQ with azithromycin. Both drugs can cause prolonged QTc intervals and enhance the chances of deaths related to torsade de Pointes (TdP) (64). The paper did not undergo peer review and was published within 24 hours of submission.

Recently Gautret et al (65) reported on an observational study on 80 patients with relatively mildly infected patients with SARS-CoV-2 who received HCQ 200 mg TDS PO x10d plus azithromycin 500 mg QD PO x d1, followed by 250 mg QD PO x4d. One patient died and the second patient was admitted to ICU. All other patients had rapid clinical improvement, with a rapid fall of nasopharyngeal viral load (negative at day 7th in 83% and day 8th in 93%). Viral cultures from respiratory samples became negative in 97.5% by 5th day. The mean hospital stay was only 5 days. This study has a major limitation as it is an observational single-arm study and without a comparative group who do not receive the drug, it is not possible to comment on the beneficial effects of the drug, especially in a cohort of patients with mild clinical disease.

CHEN et al (66) from Fudan University, Shanghai, China reported a pilot study on the role of HCQ in COVID-19 patients. The study is published in the Chinese journal “J. Zhejiang Univ. (Med Sci)” and only abstract is available in English. The authors recruited 30 patients with COVID-19. Patients were randomized into 2 groups, 15 received HCQ, 400 mg per day for 5 days along with supportive treatment while another 15 patients received supportive treatment alone. The primary endpoint was negative throat swabs for SARS-CoV-2 by RT-PCR at day 7. One patient on HCQ treatment developed severe disease. There was no significant difference in the 2 groups in the percentage of viral clearance (86.7% versus 93.3%; p>0.05) or median duration of viral clearance (4 days versus 2 days, P>0.05) Both groups did equally when assessed by clinical and radiologic parameters. The authors concluded that the prognosis of COVID-19 patients enrolled in this study was good and further studies need to be with a larger sample size to evaluate the role of HCLQ HCQ in SARS-CoV-2 infection. The trial is published in the Chinese language and has been reproduced in English. The sample size is so small that the power of the study is very low. It is not known whether the published data has been peer-reviewed for ethical, scientific, and statistical errors, etc.

Chen et al (67) from Renmin Hospital in Wuhan University posted results of a randomized trial as a preprint in medRxiv. 62 patients with COVID-19 were randomized into 2 groups, 31 patients received HCQ 400 mg QD x 5d in addition to supportive treatment while another 31 patients received supportive treatment alone. Patients in the HCQ group did significantly better in time to clinical recovery, the body temperature recovery time, and the cough remission time. Radiological improvement in pneumonia occurred in 25/31 (80.6%) in the HCQ group and 17/31 (54.8%) in the control group. Four patients progressed to severe illness and all belonged to the control group. It was concluded that HCQ treatment in COVID-19 shorten clinical recovery and promotes the absorption of pneumonia. It is difficult to evaluate the results of this trial as it is open-labeled trial amenable to bias and has been published as a preprint and has not gone through a review process.

Magagnoli et al (68) performed a retrospective analysis of date from patients hospitalized with COVID-19 and posted results as a preprint in medRxiv. A total of 368 patients were evaluated which fell into 3 groups namely HCQ alone (n=97), HCQ plus azithromycin (n=113), and no HCQ (n=158). Two primary outcomes namely death and the need for mechanical ventilation were evaluated. The death rates in HCQ alone, HCQ plus azithromycin, and no HCQ were 27.8%, 22.1%, 11.4% respectively. The need for mechanical ventilation occurred in 13.3%, 6.9%, 14.1% in the three groups respectively. The death rates in HCQ were higher than no HCQ group (p<0.030), while there was no difference in the need for ventilation in 3 groups. In this study, the authors found no evidence that the use of HCQ, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with HCQ alone. This large retrospective study in a large cohort of patients has put doubts on the efficacy of HCQ in COVID-19. The results of randomized controlled trials are immensely awaited to sort out this controversy.

The CloroCovid-19 study was initiated in Manaus, Amazonas, Brazil as a parallel, double-blind, randomized, phase IIb trial with two doses of CQ namely high dose (600 mg CQ BID PO x 10d or total dose 12g) versus low dose (450 mg BID PO x d1, followed by 450 mg QD PO for 4d or total dose 2.7g) (69). Besides, all patients received ceftriaxone and azithromycin. Out of a pre-defined 440 patients sample size, 81 patients were enrolled and the study had to be terminated. High dose CQ was associated with a high occurrence of long QTc (25%) and higher mortality (17%) than the low dose. The fatality rate was in patients on CQ was similar to those of historical controls not using CQ. Only one of the 14 patients tested showed negative RT-PCR for SARS-CoV-2 in respiratory samples on day 5.

The results from several therapeutic trials have been reported of late in the interim period (69, 70, 71, 72, 73). However, none of these have shown conclusive evidence for or against the use of HCQ in COVID-19. The two trials on the prophylactic role of HCQ to protect healthcare workers (57) or individuals with high-risk exposure (58) have shown contradictory results.

There have been several anecdotal reports about the efficacy of HCQ in COVID-19 available online secondary to media reports. Reports from Jaipur, India were of an Italian couple and 2 doctors with severe COVID-19 who received a combination of drugs including lopinavir/ritonavir, oseltamivir, and CQ and made eventual recovery (74, 75). Medanta Hospital, New Delhi reported on 14 Italian tourists with COVID-19 who were treated with lopinavir, azithromycin, and CQ and made eventual recovery (76). These and other anecdotal reports on the use of CQ are non-contributory. The drug has been used in combinations with antiviral drugs and there is no evidence that CQ was affective as SARS-CoV-2 infection in these patients.

We believe and so do many, that we need multiple well-designed and conducted randomized clinical trials to evaluate the role of CQ/HCQ in SARS-CoV-2 infection. The study should include patients with a broad range of clinical presentations including asymptomatic carriers, mildly symptomatic, severe disease, and those with Cytokine Storm Syndrome with ARDS and on ventilator support. Patients with cardiac and hepatic disease should be included in trials. The trials have to have varying drug dosages. Trials have to be randomized, blinded with placebo in the control arm, and should have an adequate sample size. The trials should be registered and under constant review for exceptional results for early termination. Also, trials that shall evaluate the prophylactic role of chloroquine need to be done. These trials also need to be randomized controlled studies with adequate sample size. Once these trials are available, only then the role of CQ and HCQ in SARS-CoV-2 infection can be defined. At present we are clueless and it is impossible to make guess as to the role of these drugs in COVID-19.

6. Drug Toxicity

Both CQ and HCQ have been used widely and have had a reasonable margin of safety. The drugs functions as immunomodulators and have no immunosuppressant activity (77). Thus, the use of these drugs is not associated with a higher risk of infections and or cancers (37, 78). Common adverse reactions include nausea, vomiting, diarrhea, and abdominal discomfort (79). However, these drugs can cause cardiotoxicity, myopathy, and retinopathy (80, 81, 82, 83) (Table 4).

Table 4. Adverse Drug Reactions of Hydroxychloroquine Therapy

CommonAbdominal Pain. Anorexia. Nausea. Vomiting. Diarrhea. Headaches. Emotional Lability. Skin Reactions. Tinnitus. Dizziness. Vertigo. Alopecia. Hair Colour Changes.UncommonHypoglycaemia. Bone Marrow Disorders. Acute Hepatic Failure. Angioedema. Photosensitivity Reaction. Severe Cutaneous Adverse Reactions (Scars).CautionG6PD Deficiency (Haemolysis), Moderate to Severe Hepatic Impairment & Renal Impairment (Monitor Blood Levels), Alcoholism, Psoriasis (Severe Flare-up of Psoriasis). Pregnancy and Lactation (Crosses Placenta and secreted in Milk, however, regarded as generally safe to use).Major ToxicityAcute Use- Cardiotoxicity (Long QT Syndrome, Torsades De Pointes-TdP, Sudden cardiac deaths). Chronic Use-Retinopathy and Myopathy & Neuropathy.

Of all the adverse drug reactions, cardiac toxicity, of late, has gained paramount importance. These drugs are known to prolong the QTc interval (80, 81, 84). This is due to the drug-related block of the inward rectifier potassium ion channel (Kir2.1) (85). This impairs ventricular repolarization, broadens cardiac action potential, and hence the long QT interval. Drug-induced QT/QTc per se is asymptomatic. However, it can lead to Torsades de Pointes (TdP), a potentially lethal polymorphic ventricular tachycardia. Patients with TdP present with episodes of near syncope, syncope with or without convulsions, and sudden cardiac death. Ventricular tachycardia in TdP has a characteristic initiation sequence. It starts with early after depolarization (EAD), which fires a premature ventricular beat followed by a long pause. Next, a sinus beat with a longer QT interval occurs. The T wave of the sinus beat is interrupted by a ventricular premature beat that is the first beat of the polymorphic ventricular tachycardia.

Myopathy and, to a lesser extent, neuropathy are well-documented complications of therapy with CQ/HCQ and other antimalarial agents (82). CQ typically produces a vacuolar myopathy characterized by a progressive proximal weakness that resolves rapidly with discontinuation of the drug. Anti-malarial myopathy is an ill recognized entity and should be suspected if patients on CQ/HCQ show elevated muscle enzymes. Muscle biopsy for histological examination and ultrastructural studies confirms the diagnosis (86)

Retinopathy is the most dreaded complication with CQ/HCQ (83). Retinopathy is more commonly associated with CQ than HCQ. The drugs bind to the retinal pigment melanin and cause toxic retinal damage by disrupting lysosomal degradation in the retinal pigment epithelium. The disease causes bilateral paracentral visual field defects and depigmentation of the paracentral retinal pigment epithelium. Later there is progressive development of bull's eye maculopathy and paracentral scotoma, which may progress to severe visual loss. Factors that predispose to retinopathy include i. prolonged therapy (>5 yr.), ii. a dose of >5mg/kg actual body weight per day, iii. high cumulative dose (above 600-1000g), iv. Stage 3-5 chronic kidney disease, and v. comedication with Tamoxifen. Patients on long term CQ & HCQ therapy need regular screening as per protocol to detect retinal toxicity at an early stage. The drug should be stopped at the first sign of toxicity.

7. Drug Interactions

CQ and HCQ have major drug interactions and are clinically important. These are broadly classified into the following groups which include: i. drugs that cause QT prolongation and potentiate cardiotoxicity of CQ and HCQ; ii. drugs that inhibit cytochrome 450 enzymes and increase drug levels and toxicity of CQ and HCQ; iii. CQ and HCQ inhibit P-glycoprotein (P-gp), an energy dependant effluent transporter, and increase levels of drugs eliminated through P-gp. iv. CQ and HCQ complete with the metabolism of other drugs and increase their bioavailability. v. CQ and HCQ absorption may be affected by drugs that bind it in the gut or alter pH in the stomach (Table 5). The CQ/HCQ drug interaction includes several commonly prescribed drugs and clinicians need to aware of this. CQ & HCQ are generally safe in pregnancy. The drug crosses the placenta, however, there have been no adverse effects on the fetus. The drug is secreted in milk but causes no adverse effects on the neonate. Overall, these drugs are considered safe to use during pregnancy and breastfeeding (87). Besides, CQ & HCQ can cause hemolysis in patients with G6PD deficiency and such patients on drugs to need close monitoring.

Table 5. Chloroquine and Hydroxychloroquine Drug Interactions. Drugs that cause QT interval prolongation.

Macrolides (Erythromycin, Clarithromycin & Azithromycin)Have additive /synergistic effect on QT interval prolongation, increases chances of toxic arrhythmias, polymorphic ventricular fibrillation, and death.Quinolones (Ciprofloxacin & Levofloxacin)Anti-arrhythmic (Amiodarone & Sotalol)Antifungal (Ketoconazole & Fluconazole),Antidepressants (Amitriptyline and Dothiepin)Anti-emetics (Ondansetron, Granisetron and Dolasetron)Drugs that inhibit Cytochrome 450 enzyme.CimetidineIncreases CQ & HCQ levels and possible toxicity.Diltiazem and VerapamilFluoxetine (Prozac), Paroxetine (Paxil)Metronidazole (Flagyl)Drugs that are eliminated through the P-glycoprotein (P-gp) eliminator pathway (CQ and HCQ Inhibit of P-gp).DigoxinIncreases serum levels of digoxin and ciclosporin and needs close monitoring.CiclosporinDrugs that compete with the metabolism of CQ and HCQ.MetoprololIncreases bioavailability of metoprololTamoxifenIncreases chances of retinopathyMethotrexateReduces absorption of methotrexate and reduces methotrexate hepatotoxicityDrugs which reduce the absorption of CQ & HCQ either by binding or altering gastric pHAntacids, Kaolin and proton pump inhibitorsReduce absorption of CQ and HCQ; maintain 4 hr period between intake of 2 class of drugs.

Azithromycin, a macrolide has been known to cause prolongation of QT/QTc interval and a higher risk of cardiac deaths (88, 89). The FDA has issued a warning that azithromycin can lead to potentially fatal arrhythmias and advised to discourage the use of this antibiotic among patients with underlying heart disease and/or those with known electrolyte imbalance (90). So, concomitant use of CQ or HCQ and azithromycin, as has been done in French trial puts the patient's to a higher risk of cardiotoxicity and should be avoided (23, 59, (91). We believe if antibiotic/antibiotics are indicated in patients on CQ and/or HCQ, an alternative antibiotic with no cardiac effects and drug interaction can be chosen.

Other drugs used in managing COVID-19 patients may show drug interaction with CQ/HCQ (92). Lopinavir/ritonavir strongly inhibits CYP3A4 and has a large number of significant drug interaction concerns. Remdesivir in vitro studies appear to be a substrate for the drug-metabolizing enzymes CYP2C8, CYP2D6, and CYP3A4, as well as a substrate for organic anion transporting polypeptides 1B1 (OATP1B1) and P-glycoprotein (P-gp) transporters. The clinical relevance of these in vitro assessments has not been established, and whether remdesivir would be a clinically relevant victim or perpetrator of drug interactions is still unknown. Interleukin-6 Pathway Inhibitors such as tocilizumab, sarilumab, and siltuximab are being studied for their potentially beneficial ability to limit the cytokine response that may be seen in some patients with COVID-19. One unique drug interaction consideration with these drugs is their effect on drug metabolism.

8. Clinical Guidelines for Safe Use of HCQ in COVID-19

Although HCQ has had a substantial margin of safety (84, 93), its use in critically sick patients like COVID-19 has caused several instances of serious cardiac events and deaths (21). These events are likely to occur more often under 3 circumstances namely: - i. with higher doses of the drug (69), ii. concomitant use of azithromycin, which potentiates the effect on QT interval (64, 88), iii. in patients who have underlying co-morbid conditions which can predispose such patients to long QT interval and Torsades de Pointes (81, 84). A 21-point risk score based on ten parameters to predict QT interval prolongation has been developed and validated (94). Patients with low risk (≤ 6) have a 15% chance of long QT interval, which increases to 37% in moderate risk (7, 8, 9, 10) score and 73% in those with a high-risk score (≥11).

It is proposed that a stepwise action plan be followed up while HCQ is used in patients with COVID-19 (Table 6) (94, 95, 96). It takes in to account drug allergy and the possibility of underlying congenital long QT syndrome; both of which are an absolute contraindication to HCQ therapy. As HCQ has drug interaction with many commonly used drugs, these need to be identified and the non-essential drug should be stopped during HCQ therapy. Here, concomitant use of azithromycin is of great significance and if the 2 drugs are used together, patients need to be followed intensively for long QT syndrome. Next patients' risk score for QTc prolongation should be calculated and if the score is ≥11, chances of long QTc are substantial and the drug is contraindicated. It is recommended that all patients of COVID-19 who are potential candidates for HCQ therapy should have the determination of QTc interval. A QTc interval of ≥500 msec is a contraindication for HCQ therapy. While the patient is on the drug, determination of QTc by telemetry or interval ECG should be done and drug dosage altered or stopped as per protocol. Patients should have a correction of electrolyte imbalance and the use of loop diuretics should be monitored to reduce the chances of cardiotoxicity. In the case of TdP with stable tachycardia develops following HCQ, magnesium sulfate 1-2 G given IV over 15 min period is indicated. If patients do not respond, Isoproterenol 2-10 mcg/min infusion or pacing to a rate of 100-120 depolarizations/minute as required to suppress PVC, usually terminates TdP (94).

Table 6. Step-wise Actions to be Followed for Starting Subjects on Chloroquine or Hydroxychloroquine Purpose: To prevent long QTc interval, Torsades de pointes (TdP) causing polymorphic ventricular tachycardia and sudden cardiac deaths.

StepParticularsAction1Check: known drug allergy Congenital Long QT Syndrome (occurs in 1:7000)Drug contraindicated2Check drug interaction. Refer to table 4 for a list of drugs which have a drug interaction with CQ or HCQStop non-essential drugs which have a drug interaction3Check the risk score for QTc prolongation. Total score-21. Score ≤6 (risk low, chance 15%); 7-10 (risk moderate, chance 37%); ≥11 (risk high, chance 73%). Risks include age ≥68 yr.-1, Female gender-1, Concomitant loop diuretic-1, serum K+ ≤3.5 mEq/L-2, admission QTc ≥450 msec-2, Acute MI-2, sepsis-3, heart failure-3, one QTc prolonging drug-3, ≥2 QTc prolonging drugs-3 additional points i.e. 6.Drug contraindicated when risk is high (score ≥11).4Calculate baseline QTc. {QT interval-start of the Q wave to the end of the T wave; QTc = QT / √ RR, use an app to calculate QTc. Normal-≤430 msec (male)/≤450 msec (female)}(75).Drug contraindicated if baseline QTc ≥500 msec5Monitor: serum K+ & Mg+; Monitor the use of loop diuretics.Correct electrolyte imbalance6Plan: Interval ECG (12 hourly) or cardiac telemetry in sick patients. Interval ECG in ambulatory subjects.Reduce dose if QTc prolongs, stop the drug if QTc ≥500 msec.In case of Torsades de pointes: Stable tachycardia: Give magnesium sulfate 1 to 2 g IV x 15 min; not-responsive- Give Isoproterenol 2-10 mcg/min infusion or pacing to a rate of 100-120 depolarizations/minute as required to suppress PVC, usually terminates TdP-Tisdale JE, et al. Circ Cardiovasc Qual Outcomes. 2013; 6:479-487

9. The scenario as of today

The role of antimalarial drugs namely CQ & HCQ in management of COVID-19 patients is a dynamic phenomenon and will rapidly change as soon as the results of randomized drug trials are available. As of today, few facts are clear. CQ & HCQ have the potential to have an antiviral property based on the site of action. These drugs are immunomodulators and downregulate cytokine production. Both these actions can mitigate the effects of SARS-CoV-2 virus in target organs namely lungs, heart, liver, and gut. There is convincing evidence in vitro that both CQ & HCQ have strong antiviral properties. The million-dollar question is whether these in vitro studies shall transform into the clinical response (97, 98). This can only be proved or disproved once well designed randomized controlled trials are completed and their results evaluated. Till that time, we have to rely on the available trials. The second question which needs an answer is how safe is these drugs in a setting of COVID-19. Both CQ and HCQ have a narrow margin of safety. Thus, indiscriminate unsupervised use of these drugs as a prophylactic or therapeutic weapon can cause serious side effects mostly related to cardiotoxicity (99). We believe supervised use of CQ as a prophylactic agent in high-risk populations advocated by ICMR is a safe and appropriate step (57, 58). If the drug shows results, it shall be a huge weapon to block the transmission of the virus. If the results are otherwise, the results trial shall go a long way to take the right lesson on the use of antimalarials in COVID-19.

Author Contribution

All authors have contributed equally and all authors have read and accepted the final document before submission.

Declaration of Competing Interest

None

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