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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 11  |  Issue : 2  |  Page : 65-70

The role of hydroxychloroquine in COVID-19: Where do we stand?


1 Department of Diabetology, Dr. Mohan’s Diabetes Specialities Centre, Chennai, Tamil Nadu, India; Department of Diabetology, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India
2 Department of Diabetology, Dr. Mohan’s Diabetes Specialities Centre, Chennai, Tamil Nadu, India

Date of Submission12-May-2020
Date of Acceptance21-May-2020
Date of Web Publication24-Jun-2020

Correspondence Address:
Dr. Ranjit Mohan Anjana
Department of Diabetology, Madras Diabetes Research Foundation and Department of Diabetology, Dr. Mohan’s Diabetes Specialities Centre, 4, Conran Smith Road, Gopalapuram, Chennai 600086, Tamil Nadu.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JOD.JOD_33_20

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  Abstract 

Hydroxychloroquine (HCQ) is a drug, which has long been used in the treatment of malaria, rheumatoid arthritis, systemic lupus erythematosus, and Sjogren’s syndrome. Recently with the COVID-19 pandemic hitting the world, there have been studies suggesting that hydroxychloroquine may be useful both in the prevention and the treatment of COVID-19, although the evidence so far has been conflicting. This article reviews the available evidence for the use of hydroxychloroquine in COVID-19 and also mentions some of the ongoing trials in this field.

Keywords: Coronavirus disease 2019, hydroxychloroquine, treatment


How to cite this article:
Anjana RM, Sastry NG, Ramuu M, Gupta PK, Shalini J, Srivastava BK, Kocherlakota CM, Nandan TS, Praveen G, Nair J, Philips R, Mohan V, Unnikrishnan R. The role of hydroxychloroquine in COVID-19: Where do we stand?. J Diabetol 2020;11:65-70

How to cite this URL:
Anjana RM, Sastry NG, Ramuu M, Gupta PK, Shalini J, Srivastava BK, Kocherlakota CM, Nandan TS, Praveen G, Nair J, Philips R, Mohan V, Unnikrishnan R. The role of hydroxychloroquine in COVID-19: Where do we stand?. J Diabetol [serial online] 2020 [cited 2020 Sep 20];11:65-70. Available from: http://www.journalofdiabetology.org/text.asp?2020/11/2/65/287608




  Introduction Top


Chloroquine is a drug that has been used for the treatment of malaria for nearly a century now, and its hydroxyl (OH) congener, hydroxychloroquine (HCQ) has been approved for autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and Sjogren’s syndrome. Incidentally, HCQ has been found to be effective against the novel coronavirus or severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) (in vitro and some in vivo data). The syndrome caused by SARS CoV-2, coronavirus disease–2019 (COVID-19) is a fast growing pandemic, and there have been more than 275,000 deaths so far across the globe. With no vaccine or specific anti-coronaviral drug in sight in the near horizon, people are desperately clutching at straws. Against this backdrop, it would be useful to evaluate the evidence in favor of, or against, the use of HCQ in patients with moderate to severe COVID-19. Moreover, in those at high risk (e.g., asymptomatic healthcare workers or household contacts of suspected or confirmed cases), it has been suggested that HCQ may be used prophylactically.


  Evidence for Hydroxychloroquine in COVID-19 Patients Top


Chloroquine and HCQ have been found to be effective against SARS-CoV-2 in Chinese patients with COVID-19. An early clinical trial, conducted in Chinese patients with COVID-19, showed that chloroquine had a significant effect, both in terms of clinical outcome and viral clearance, when compared to control groups. Chinese experts recommended that patients diagnosed as mild, moderate, and severe cases of COVID-19 pneumonia and without contraindications to chloroquine, be treated with 500 mg chloroquine twice a day for 10 days. HCQ (an analog of chloroquine) has been shown to have anti-SARS-CoV activity in vitro. The clinical safety profile of HCQ is better than that of chloroquine (during long-term use), thereby allowing higher daily dose, and there are fewer concerns about drug–drug interactions.[1]

Hence it was decided by French physicians[2] to evaluate the role of HCQ on respiratory viral loads. Confirmed patients with COVID-19 (n = 36) were included in a single-arm protocol in the first half of March 2020, to receive 600 mg of HCQ daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on the clinical presentation, azithromycin (AZ) was added to the treatment. Untreated patients and patients refusing the protocol were included as controls. Presence and absence of virus at Day 6 post-inclusion was considered the end point. Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms, and eight had lower respiratory tract infection symptoms. Twenty cases were treated with HCQ in this study, and they showed a significant reduction of the viral carriage at Day 6 post-inclusion compared to controls. When AZ was added to HCQ, it was found to be significantly more efficient for virus elimination. Despite the small sample size, this survey showed that HCQ treatment is significantly associated with viral load reduction or disappearance in patients with COVID-19, and that its effect was reinforced by AZ.[1]

However, a study from the United States of 84 patients with COVID-19 by the New York School of Medicine found that patients who were treated with a combination of HCQ and AZ had a very high risk of cardiac arrhythmias due to QT interval prolongation.[3],[4]

Recently, a Chinese team published results of a study, which showed that chloroquine and HCQ inhibit SARS-CoV-2 in vitro with HCQ and found it to be more potent than chloroquine.[5] The preliminary results of this study also suggested a synergistic effect of the combination of HCQ and AZ. AZ has been shown to be active in vitro against Zika and Ebola viruses and to prevent severe respiratory tract infections when administrated to patients with viral infection. The speculated potential risk of severe QT interval prolongation induced by the association of the two drugs has not been established yet but should definitely be considered. Further studies on this combination are needed, as such combination may both act as an antiviral therapy against SARS-CoV-2 and prevent bacterial superinfections.[1]

In view of recent studies and discussion on chloroquine and HCQ, a recent paper by Singh et al.[6] aimed to review existing literature and relevant websites regarding these drugs and COVID-19, adverse effects related to drugs, and related guidelines. The authors systematically searched the PubMed database up till March 21, 2020, and retrieved all the articles published on chloroquine and HCQ and COVID-19. Two small human studies have been conducted with both these drugs in COVID-19, and have shown significant improvement in some parameters in patients with COVID-19. Considering minimal risk on use, long experience of use in other diseases, cost-effectiveness, and easy availability across India, the authors proposed that both these drugs are worthy of fast track clinical trial for treatment, and may be carefully considered for clinical use as experimental drugs. As HCQ has been approved for treatment of diabetes in India, it should be further researched in diabetes and COVID-19.


  Mechanisms of Action of Hydroxychloroquine Top


It is being increasingly evident that the antiviral and anti-inflammatory activities of chloroquine may have a role in the treatment of patients with novel COVID-19. Chloroquine increases endosomal pH and interferes with the glycosylation of cellular receptor of SARS-CoV, and thereby it has the potential to block viral infection. In addition, chloroquine also inhibits the quinone reductase-2, which is involved in sialic acid biosynthesis (an acidic monosaccharide of cell transmembrane proteins required for ligand recognition) that makes this drug a broad antiviral agent. Moreover, chloroquine changes the pH of lysosomes, and likely inhibits cathepsin that leads to the formation of the autophagosome, which cleaves SARS-CoV-2 spike protein.[6]

Furthermore, chloroquine through the inhibition of MAP-kinase interferes with SARS-CoV-2 molecular cross talk, besides altering the virion assembly and budding, and interferes with the proteolytic processing of the M protein. Previous experimental studies have also shown that chloroquine has potent anti-SARS-CoV-1 effects in vitro, primarily attributable to a deficit in the glycosylation receptors at the virus cell surface, so that it cannot bind to the angiotensin-converting enzyme 2 (ACE2) expressed in lung, heart, kidney, and intestine. As SARS-CoV-2 uses the similar surface receptor ACE2, it is believed that chloroquine can also interfere with ACE2 receptor glycosylation, thus preventing SARS-CoV-2 attachment to the target cells. Chinese researchers who studied the effect of chloroquine in vitro (using Vero E6 cell line infected by SARS-CoV-2) found chloroquine to be highly effective in reducing viral replication and that it can be easily achievable with standard dosing due to its favorable penetration in tissues including the lung.[6]

As the structure and mechanism of action of chloroquine and HCQ are similar with the exception of an additional hydroxyl moiety in one terminal in HCQ, both act as weak bases that can change the pH of acidic intracellular organelles, including endosomes/lysosomes, essential for the membrane fusion. It is believed that both the agents could be effective tools against SARS-CoV-1 and SARS-CoV-2.

However, an important question that still remains is whether HCQ has a similar effect on SARS-CoV-2 infection. As of February 23, 2020, seven clinical trial entries for using HCQ to treat COVID-19 were found in the Chinese Clinical Trial Registry (http://www.chictr.org.cn). Some data show HCQ effectively inhibited both the entry, transport, and the post-entry stages of SARS-CoV-2, similar to chloroquine, and one study found HCQ to be a more potent agent than chloroquine in inhibiting SARS-CoV-2 in vitro.[7]

An additional issue to be considered in severely sick patients is cytokine storm associated with disease severity of SARS-CoV-2. Clinical investigation found that high concentration of cytokines were detected in the plasma of critically ill patients infected with SARS-CoV-2, suggesting that cytokine storm was associated with disease severity.[8] The significant decrease in the production of pro-inflammatory markers and cytokines with HCQ has made this agent a successful disease-modifying anti-inflammatory agent in the treatment of various autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, and Sjogren’s syndrome. Therefore, in patients with COVID-19, HCQ may also contribute in attenuating the inflammatory response.

A new HCQ treatment study was recently released by Professor Didier Raoult at IHU Méditerranée Infection, Marseille, France.[9] A cohort of 1061 patients with COVID-19, treated for at least 3 days with the HCQ-AZ combination and a follow-up of at least 9 days was investigated. No cardiac toxicity was observed. A good clinical outcome and virological cure was obtained in 973 patients within 10 days (91.7%). A poor outcome was observed for 46 patients (4.3%); 10 were transferred to intensive care units, 5 patients died (0.47%) (7495 years old), and 31 required 10 days of hospitalization or more. The authors concluded that the HCQ-AZ combination, when started immediately after diagnosis, is a safe and efficient treatment for COVID-19, with a mortality rate of 0.5%, in the elderly patients. It avoids worsening and also clears virus persistence and contagiosity in most cases.[9]


  Precautions while Using Hydroxychloroquine in COVID-19 Top


Expectedly, some precautions will be needed while using both these drugs that include frequent monitoring of hematological parameters (red blood cell, white blood cell, and platelet counts), measurement of serum electrolytes, blood glucose (because of hypoglycemic potential of HCQ), and hepatic as well as renal functions. As both these drugs have the potential to prolong QT interval, routine electrocardiography (ECG) is essential before starting these drugs. Coadministration of other drugs known to prolong the QT interval (such as anti-arrhythmic, antidepressants, antipsychotics, antihistaminics, teneligliptin, ondansetron, and moxifloxacin) must be avoided.[6]

Moreover, addition of AZ to HCQ as done in the French trial by Gautret et al.[2] may increase the risk of QT prolongation. ECG needs to be performed daily if corrected QT interval (QTc) is 450–500 msec. In addition, hypoglycemia must be looked for in patients with diabetes, especially with concurrent use of chloroquine or HCQ and lopinavir or ritonavir. Chloroquine and HCQ should not be used concurrently with lopinavir or ritonavir and remdesivir due to anticipated QTc prolongation. Finally, pharmacovigilance on visual and mental disturbance is also closely required.[6]

Although there are sporadic case reports of chloroquine-induced cardiomyopathy and reversible heart failure in the literature, many studies and large meta-analysis conducted in patients with rheumatoid arthritis pointed to a reduced cardiovascular risk with both these compounds. Nevertheless, as both chloroquine and HCQ have the potential to prolong QTc, a baseline ECG should be done in patients with established cardiovascular disease. All clinicians using these drugs must be aware of the contraindications to both these compounds: hypersensitivity to these agents, retinopathy, porphyria, epilepsy, preexisting maculopathy, glucose 6 phosphatase (G6PD) deficiency, recent myocardial infarction, and QTc >500 msec.


  What Are the Recommendations by Indian Council of Medical Research? Top


The Indian Council of Medical Research (ICMR) has published revised guidelines on the management of patients with COVID-19 where they have mentioned that based on data from uncontrolled clinical trials, certain drugs may be considered for off-label treatment of patients with severe COVID-19 infections, who are admitted in the intensive care unit (ICU) (not for children, pregnant, and lactating women): HCQ 400 mg twice a day on day 1, followed by 200 mg twice a day for days 2–5, and AZ 500 mg once a day for 5 days. The drugs need to be administered under close medical supervision, and the corrected QT interval needs to be monitored for prolongation. Pharmacovigilance is a must. They have also gone on to recommend HCQ as prophylaxis for asymptomatic healthcare workers and asymptomatic household contacts who are treating or caring for patients with suspected or laboratory-confirmed COVID-19, which is as follows (not for children <15 years of age)—For healthcare workers: HCQ 400 mg bid on day 1 and then 400 mg once a day once a week for the next 7 weeks, with meals; for household contacts of laboratory-confirmed cases: HCQ 400 mg bid on day 1 and then 400 mg once tablet a week for the next 3 weeks, with meals.[10]


  American College of Cardiology Recommendations on Monitoring QTc Interval Prolongation Top


On March 29, 2020, the American College of Cardiology (ACC) came out with recommendations on how to monitor for ventricular arrhythmias that may occur with concomitant use of HCQ and AZ in patients with COVID-19.[11] The ACC mentioned that although only a small proportion of patients with QTc prolongation have malignant ventricular arrhythmias such as torsades de pointes (TdP), drug-associated QT prolongation is associated with increased arrhythmic and non-arrhythmic mortality, and it therefore continues to be an important metric of drug safety. Data show inhibition of the inwardly rectifying potassium channel (iKr) and resultant mild QT prolongation associated with both agents. They further state that the safety of QT prolonging medications may be maximized by close monitoring and optimization of these factors. A risk score has been derived and validated by Tisdale et al.[12] for the prediction of drug-associated QT prolongation among cardiac-care-unit-hospitalized patients [Table 1].
Table 1: Risk score for drug-associated QTc prolongation[11],[12]

Click here to view


A Tisdale score of ≤6 predicts low risk, 7–10 medium risk, and ≥11 high risk of drug-associated QT prolongation [Table 2].
Table 2: Risk levels for drug-associated QT prolongation[11],[12]

Click here to view


In conclusion, there is emerging data to show that HCQ can efficiently inhibit SARS-CoV-2 infection in vitro. In combination with its anti-inflammatory function, it has been predicted that the drug has a good potential to combat the disease. This possibility awaits confirmation by clinical trials. Although HCQ is less toxic than CQ, prolonged and overdose usage can still cause poisoning. We need carefully designed clinical trials to look at the efficacy and safety of HCQ in COVID-19.

Following are the suggested monitoring of QTc interval for inpatient use[11],[12]:

Baseline

  • a. Discontinue and avoid all other noncritical QT prolonging agents.


  • b. Assess a baseline ECG, renal function, hepatic function, serum potassium, and serum magnesium.


  • c. When possible, have an experienced cardiologist or electrophysiologist measure QTc [Table 3], and seek specialist input in the setting of acute renal or hepatic failure.
Table 3: QTc formulas; consider using Fridericia or Framingham correction, especially for heart rates over 90 bpm[11],[12]

Click here to view


Relative contraindications (subject to modification based on potential benefits of therapy)

  • a. History of long QT syndrome, or


  • b. Baseline QTc > 500 msec (or >530–550 msec in patients with QRS duration >120 msec)


Ongoing monitoring, dose adjustment, and drug discontinuation

  • a. Place on telemetry before the start of therapy.


  • b. Monitor and optimize serum potassium daily.


  • c. Acquire an ECG 2–3h after the second dose of HCQ, and daily thereafter.


  • d. If QTc increases by >60 msec or absolute QTc >500msec (or >530–550 msec if QRS >120 msec), discontinue AZ (if used) and/or reduce dose of HCQ and repeat ECG daily.


  • e. If QTc remains increased >60 msec and/or absolute QTc >500 msec (or >530–550 msec, if QRS >120 msec), reevaluate the risk/benefit of ongoing therapy, consider consultation with an electrophysiologist and consider discontinuation of HCQ.


Recently, the Indian Heart Rhythm Society has also published guidelines on the cardiovascular safety of HCQ[13] [Figure 1].
Figure 1: Hydroxychloroquine therapy according to cardiovascular risk.
HCQ = hydroxychloroquine, QTc = corrected QT interval[13]


Click here to view



  Conclusion Top


To conclude, HCQ may not be the panacea for COVID-19 that people think it will be. On the contrary, one does not really know at this point in time as one needs unequivocal randomized controlled clinical trial data to be able to answer this question definitively. Even as this article is being written, World Health Organization (WHO) has planned an international (>70 countries) trial called “Solidarity” to help find an effective treatment for COVID-19. The “Solidarity” trial will compare four treatment options against the standard of care, to assess their relative effectiveness against COVID-19, namely remdesivir, lopinavir–ritonavir, interferon β-1a, and chloroquine/HCQ. In the future, it is hoped that we will have more definite guidance on the expanding role of HCQ in preventing or treating COVID-19-like disorders.


  Addendum Top


Since this article was first written, there have been certain important developments pertaining to the use of HCQs in COVID-19 which are summarised below.

  1. In a case control study conducted by the Indian Council of Medical Research (ICMR), HCQs was found to prevent SARS-CoV2 infection in 80% of health care workers who were given the drug for prophylaxis.[14]


  2. A multinational registry study of more than 96000 hospitalised patients with COVID-19 from 671 hospitals across 6 continents showed that use of HCQs with or without a macrolide was not associated with clinical benefit, and on the contrary, was associated with reduced survival and increased risk of cardiac arrhythmias.[15] However, doubts regarding the veracity of the primary data sources have led to the above article being retracted by the journal at the request of the authors themselves.[16]


  3. Most recently, the Chief Investigators of the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial have released a statement to the effect that there is no beneficial effect of HCQ on hospitalised patients with COVID-19 and that they are therefore stopping enrolment of patients into the HCQ arm of this study.[17]


Acknowledgement

We wish to thank Dr. Viraj Suvarna from Eris Lifesciences for his help with this article.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Rathi S, Ish P, Kalantri A, Kalantri S. Hydroxychloroquine prophylaxis for COVID-19 contacts in India. Lancet Infect Dis 2020. [Epub ahead of print].  Back to cited text no. 1
    
2.
Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agents2020: [Published online ahead of print, 2020 Mar 20].  Back to cited text no. 2
    
3.
Saleh M, Gabriels J, Chang D, Kim BS, Mansoor A, Mahmood E, et al. The effect of chloroquine, hydroxychloroquine and azithromycin on the corrected QT interval in patients with SARS-CoV-2 infection. Circ Arrhythm Electrophysiol 2020. [Published online ahead of print, 2020 Apr 29].  Back to cited text no. 3
    
4.
Chorin E, Dai M, Shulman E, Wadhwani L, Bar-Cohen R, Barbhaiya C, et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nat Med2020. [Published 2020 Apr 24].  Back to cited text no. 4
    
5.
Pastick KA, Okafor EC, Wang F, Lofgren SM, Skipper CP, Nicol MR, et al. Review: Hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19). Open Forum Infectious Diseases 2020;7:1-9.  Back to cited text no. 5
    
6.
Singh AK, Singh A, Shaikh A, Singh R, Misra A. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes Metab Syndr 2020;14:241-6.  Back to cited text no. 6
    
7.
Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-cov-2 infection in vitro. Cell Discov 2020;6:16.  Back to cited text no. 7
    
8.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China [published correction appears in Lancet, 2020 Jan 30].Lancet 2020;395:497‐506.  Back to cited text no. 8
    
9.
Professor Didier Raoult releases the results of a new hydroxychloroquine treatment study on 1061 patients. Available from: http://covexit.com/professor-didier-raoult-releases-the-results-of-a-new-hydroxychloroquine-treatment-study-on-1061-patients/. [Last accessed on 2020 Apr 10].  Back to cited text no. 9
    
10.
ICMR revised guidelines on management of COVID-19. March 31,2020. Available from: https://icmr.nic.in/ [Last accessed on 2020 Apr 10].  Back to cited text no. 10
    
11.
American College of Cardiology. Ventricular arrhythmia risk due to hydroxychloroquine-azithromycin treatment for COVID-19. Available from: https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19. [Last accessed on 2020 Apr 10].  Back to cited text no. 11
    
12.
Tisdale JE, Jaynes HA, Kingery JR, Mourad NA, Trujillo TN, Overholser BR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes 2013;6:479-87.  Back to cited text no. 12
    
13.
Kapoor A, Pandurangi U, Arora V, Gupta A, Jaswal A, Nabar A, et al. Cardiovascular risks of hydroxychloroquine in treatment and prophylaxis of COVID-19 patients: A scientific statement from the Indian Heart Rhythm Society. Indian Pacing Electrophysiol J2020;20:117–20.  Back to cited text no. 13
    
14.
Chatterjee P, Anand T, Singh KJ, Rasaily R, Singh R, Das S, et al. Healthcare workers and SARS-CoV-2 infection in India: a case-control investigation in the time of COVID-19. Indian J Med Res2020; DOI: 10.4103/ijmr.IJMR_2234_20.  Back to cited text no. 14
    
15.
Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet 2020(Published online May 22). 10.1016/S0140-6736(20)31180-6.  Back to cited text no. 15
    
16.
Mehra MR, Ruschitzka F, Patel AN. Retraction: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet 2020 (Published online June 05). 10.1016/S0140-6736(20)31324-6.   Back to cited text no. 16
    
17.
Horby P and Landray M, Chief Investigators of the RECOVERY Trial. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19. A statement from the Chief Investigators of the Randomised Evaluation of COVID-19. Available from https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19 [Accessed on 5 June 2020]  Back to cited text no. 17
    


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