Journal of Primary Care Specialties

: 2022  |  Volume : 3  |  Issue : 1  |  Page : 3--7

Use of chloroquine and hydroxychloroquine in COVID-19 patients: A dilemma

Archana Bhatia1, Sandeep Kumar Bains2, Bansal Tajinder3, S Sandhu Kuldeep4, Jaideepa3,  
1 Department of Periodontology and Implantology, Dasmesh Institute of Research and Dental Sciences, Faridkot, Punjab, India
2 Department of Oral Medicine and Radiology, Dasmesh Institute of Research and Dental Sciences, Punjab, India
3 Department of Oral Medicine and Radiology, RR Dental College and Hospital, Udaipur, Rajasthan, India
4 Department of Conservative and Endodontics, RR Dental College and Hospital, Udaipur, Rajasthan, India

Correspondence Address:
Dr. Sandeep Kumar Bains
Department of Oral Medicine and Radiology, Dasmesh Institute of Research and Dental Sciences, Faridkot - 151 203, Punjab


The terror of coronavirus disease 2019 (COVID-19) is present universally. The number of cases is on rise. There is always debate about the use of chloroquine and hydroxychloroquine as a prophylaxis. Healthcare workers being the front-line soldiers need additional protection as compared to general population. This review article highlighted the mechanism of action of both drugs and their role in COVID-19 patients.

How to cite this article:
Bhatia A, Bains SK, Tajinder B, Kuldeep S S, Jaideepa. Use of chloroquine and hydroxychloroquine in COVID-19 patients: A dilemma.J Prim Care Spec 2022;3:3-7

How to cite this URL:
Bhatia A, Bains SK, Tajinder B, Kuldeep S S, Jaideepa. Use of chloroquine and hydroxychloroquine in COVID-19 patients: A dilemma. J Prim Care Spec [serial online] 2022 [cited 2023 Feb 4 ];3:3-7
Available from:

Full Text


In December 2019 in Wuhan city of China, there was sudden outburst of coronavirus disease 2019 (COVID-19) which extended over 90% of countries universally and became health emergency of international concern.[1] A novel coronavirus was affirmed as causative agent of COVID-19 by Chinese center for disease control and prevention on January 8, 2020.[2] The World Health Organization (WHO) on January 30, 2020, confirmed this outbreak as a public health disaster of international status with mortality rate to be 3.4%. Considering its spread all over the world, WHO in March 2020 declared it as pandemic disease.[3]


Coronaviruses are single-stranded RNA viruses, and the term novel is being used considering it to be new virus to already existing coronavirus family Coronaviridae. The term corona designates to crown shape of the proteins that coat them. This virus is highly infectious and its resemblance to coronavirus species seen in bats, and potentially pangolins have been confirmed in recent research thus it is found to be zoonotic in origin, i.e. animals to humans transmission.[4]

Severe acute respiratory syndrome coronavirus (SARS-CoV) was first recognized in year 2002, and the Middle-East respiratory syndrome coronavirus (MERS-CoV) was first acknowledged in year 2012. COVID-19 is now called as SARS-CoV-2.[5]


In India, as on 17 September 2020, 08:00 IST (GMT + 5:30), there are total cases of 51,18,253, of which, 83198 deaths reported [Table 1].[6] As reported by the WHO, Globally, as of 5:18 pm CEST, August 11, 2020, there have been 19,936,210 confirmed cases of COVID-19, including 732,499 deaths [Table 2].[7]{Table 1}{Table 2}

Globally, as of 10:53 am CEST, 17 September 2020, there have been 29,679,284 confirmed cases of COVID-19, including 936,521 deaths, reported to the WHO.

 Clinical Symptoms

Patient present with prodromal symptoms such as cold- or flu-like symptoms usually appears 2–4 days after a coronavirus infection. However, there can be variations in symptoms from person-to-person. The most common symptoms are high-grade fever, dry cough, shortness of breath or dyspnea, and fatigue or tiredness.[8] Some patients may experience myalgia or muscle pain, headache, sore throat, vomiting, and diarrhea. There can be diminished sense of smell (hyposmia) and abnormal taste sensation (dysguesia).[9] Computed tomographic scan shows ground-glass opacities, bilateral patchy shadows, and bilateral pneumonia in the chest. Severe patients may develop arrhythmia and shock which need ventilatory support.[10]


The management of positive cases is by supportive therapy only. Many clinical trials are being conducted worldwide but till date no vaccine has been invented. According to the Center of Disease control so far, there are no US Food and Drug Administration-approved drugs for the management of COVID-19 infected patients.[11] The treatment is focused on the prevention of infection by adhering to universal WHO recommended safety measures which includes proper handwashing with soap for at least 20 s, disinfection of frequently touched surfaces, maintaining physical distance of 3 meters or 6 feet, usage of mask and preventing social gathering.[12] Supportive care comprises the use of hydration, antipyretics, analgesics, and antitussives. Asymptomatic patients are advised to self-isolate for at least 7 days after a positive test result. Symptomatic positive COVID-19 patients are hospitalized where they remain under close observations for 21 days and are managed based on symptoms.[13] There oxygen level is maintained via high-flow oxygen or noninvasive positive pressure ventilators. In severe cases, patient may develop acute respiratory distress syndrome which requires intubation with mechanical ventilation in an intensive care unit setting.[14]

Many antiviral drugs such as remdesivir, favipiravir, chloroquine (CQ)/hydroxychloroquine (HCQ), convalescent plasma, interleukin-6 (IL-6) inhibitors, and lopinavir-ritonavir have been proposed in the treatment of COVID-19 time to time.[15] Their effectiveness is being assessed and they are under clinical trials.


CQ was first synthesized in 1934 and is the main drug for the prevention and treatment of malaria. They are routinely used in autoimmune conditions including systemic lupus erythematosus, porphyria cutanea tarda, rheumatoid arthritis, and Q fever and also act as immunomodulating agent.[16] Later on in year 1955, HCQ, a derivative of CQ became available in the market. It proved to be better with additional outcomes and less side effects.[17] They are lipophilic weak bases that quickly pass across cell membranes and gather in acidic organelles, such as lysosomes, Golgi, and endoplasmic reticulum. These drugs are active against Plasmodium parasites, the causative agent of malaria which acts by interacting with parasites DNA causing inhibition of the polymerization of heme.[18]

HCQ shows its anti-inflammatory properties by increasing the pH within intracellular vacuoles and endosomes, thus interferes with antigen processing in macrophages and antigen-presenting cells.[19] CQ/HCQ shows antibacterial, antiviral, and antifungal activities. It is found to be active against HIV, poliovirus, rabies virus, herpes simplex virus, and hepatitis B virus. CQ is available for oral administration in tablet form as CQ phosphate 500 mg and HCQ sulfate 200 mg. A maximum dose of 2000 CQ and HCQ are used in active malarial cases. The mean half-life of CQ is 22 days and for HCQ is 20–60 days. The peak plasma concentration of CQ found to be 30 min and that of HCQ is 3–4 h.[20]

Nausea, vomiting, and diarrhea are frequent side effects of these drugs. Arnaout et al.[21] assessed the use of CQ and observed nausea and abdominal cramps in 24% and diarrhea in 17% of breast cancer patients. Furst et al.[22] found GIT side effects with dose of 800 mg HCQ in patients of rheumatoid arthritis [Table 3].{Table 3}

 Mechanism of Action

The mechanism of action of HCQ/CQ against COVID-19 is still to be fully explained. CQ was first studied in SARS-CoV for the SARS coronavirus epidemic in year 2002–2003. There is 79% of genetic sequence similarity of SARS-CoV and SARS-CoV-2.[23]

 Hindrance of Cell Membrane Fusion

Various cellular proteases such as trypsin, elastase, and cathepsin L actively participate in cell membrane fusion of SARS-COV-2 by after causing endocytosis in the presence of triggering factors such as proteolytic activation.[24] CQ/HCQ may involve the interference of the endosome acidification process, which might inactivate lysosomal proteases, thus interfering with the fusion of virus and host membranes.[25]

 Inhibition of Receptor Recognition Process

SARS-COV-2 virus has its S protein which when enters in host body is broken down into two subunits such as S1 and S2. SARS-COV-2 attaches to the angiotensin-converting enzyme 2 receptors whereas S2 binds with cell membrane. CQ and HCQ may inhibit terminal glycosylation by preventing virus attachment to receptors.[26]

de Wilde et al.[27] assessed the efficacy of CQ against MERS-CoV and HCoV-229E in the human hepatoma cell line (Huh-7) and found that CQ was effective in hindering replication cycle of MERS-CoV. There was 3.0 μM concentration of CQ and 3.3 μM of HCQ. Study provided that the selectivity indexes of CQ were 19.4 and for HCQ were more than 15. It was found that addition of 16 μm of CQ 1 h before MERS-CoV infection decreased the production of virus by 1-log and with 32 μM concentrations of CQ by 2-logs. Cortegiani et al.[28] in their in vitro study evaluated the role of HCQ on Vero E6 cells infected with SARSCoV-2 found significant reduction in viral replication with an effective concentration 90 of 6.90 μM.

 Inhibition of T Cell Activation and Cytokine Production

CQ/HCQ prevents T cell activation and obstructs expression of CD154 on the surface of CD4 + T cells. They cause change in pH of endosomes, thus decrease cytokines production such as IL-1, IL-6, and tumor necrosis factor-α from T cells and B cells.[29] Huang et al.[30] and Chen et al.[31] in their studies have observed increased level of cytokines and pro-inflammatory factors such as IL-6 and IL-10 in SARS-CoV-2 patients, concluding that cytokine release syndrome is associated with disease severity.

 Alteration of Cell Signaling Pathway and Host Defense Mechanism

It is established that there is transmission of signals from the surface of cell to its nucleus such as SARS-CoV through mitogen-activated protein kinase (MAPK) pathway delivers.[32] HCQ could lead to the formation of cellular reactive oxygen species, which are necessary for activation of innate immunity. Thus, CQ/HCQ can both suppress the activation of p38 MAPK pathway and affect the host defense mechanism.[10]

Gao et al.[33] conducted a clinical study in >10 Chinese hospitals to assess the efficacy of CQ on pneumonia associated in COVID-19 positive patients. They recommended 500 mg of CQ per day for 10 days to their patients. They suggested that CQ is efficacious in treating pneumonia in COVID-19 positive patients because of its anti-viral and anti-inflammatory properties.

Yao et al.[15] in their vitro study evaluated pharmacological properties of CQ and HCQ on SARS-CoV-2 infected Vero cells. It was found that CQ was highly efficient in controlling 2019-nCoV infection. HCQ was more potent than CQ in inhibiting SARS-CoV-2 in vitro.

It is not very clear whether to consume or not to consume CQ or HCQ as a precautionary measure or to treat COVID-19 in malaria-endemic areas. It may have impact on local malaria prevalence. Subjects consuming CQ or HCQ by its own without medical consultation would become plasmodium asymptomatic carriers.[34] This may lead to decrease or inhibition of parasite count and mostly if CQ-sensitive strains supplants CQ-resistant strains. After stopping of drugs, there are chances that malaria would rebound itself because of deficiency of control measures. In addition, as CQ-resistant strains are still circulating, CQ intake could result in selection of resistant strains bearing mutations on some Plasmodium genes involved in drug resistance. Coppee et al.[35] assessed possible association between some Plasmodium genes and altered activity of other antimalarials such as artemisinin-based combination therapy. Author suggested that long use of CQ or HCQ may lead to emergence of malarial resistant strains. Singh et al.[36] in their meta-analysis of 3 studies on assessing the efficacy of HCQ on control as well as on COVID-19 subjects which focused on viral clearance measured by reverse transcriptase-polymerase chain reaction (RT-PCR) found no benefit on COVID-19 subjects. There were more deaths with the use of HCQ as compared to control. Authors found increase mortality rate with HCQ.[37]


CQ and HCQ are relatively cheap, readily available and have few side effects. There are few clinical trials that warned the use of CQ/HCQ in COVID-19 patients due to high mortality rates compared to control whereas other found good results too. There is insufficient evidence that strongly recommend these drugs in the management of COVID-19-positive patients. The present study has not sufficient data to support the use of CQ/HCQ in COVID-19 patients and increasing care should be taken about the application of CQ/HCQ in COVID-19.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Available from: [Last accessed on 2020 Mar 26].
2Available from: [Last accessed on 2020 Mar 26].
3Available from: [Last accessed on 2020 Apr 02].
4Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727-33.
5Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 2020;382:1199-207.
6Available from: [Last accessed 2020 Aug 11]
7Available from: [Last accessed 2020 Aug 11]
8Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708-20.
9Liu L, Lei X, Xiao X, Yang J, Li J, Ji M, et al. Epidemiological and Clinical Characteristics of Patients With Coronavirus Disease-2019 in Shiyan City, China. Front. Cell. Infect. Microbiol 2020;10:284. doi: 10.3389/fcimb.2020.00284.
10Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA 2020. [doi: 10.1001/jama. 2020.1585].
11Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: An old drug against today's diseases? Lancet Infect Dis 2003;3:722-7.
12Disposition of Non-Hospitalized Patients with COVID-19. Centers for Disease Control and Prevention. Available from: [Last accessed 2020 Apr 10].
13Return-to-Work Criteria for Healthcare Workers. Centers for Disease Control and Prevention. Available from: p-return-work.html. [Last accessed on 2020 Apr 13].
14Management of Patients with Confirmed 2019-NCoV. Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19). Centers for Disease Control and Prevention. Available from: [Last accessed on 2020 Apr 0].
15Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020;71:732-9.
16Tönnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy – A review of the literature. Immunopharmacol Immunotoxicol 2013;35:434-42.
17Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: From malaria to autoimmunity. Clin Rev Allergy Immunol 2012;42:145-53.
18Concordia Pharmaceuticals Inc. Plaquenil Hydroxychloroquine Sulfate Tablets, USP; 2017.
19Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum 1993;23:82-91.
20Ducharme J, Farinotti R. Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements. Clin Pharmacokinet 1996;31:257-74.
21Arnaout A, Robertson SJ, Pond GR, Lee H, Jeong A, Ianni L, et al. A randomized, double-blind, window of opportunity trial evaluating the effects of chloroquine in breast cancer patients. Breast Cancer Res Treat 2019;178:327-35.
22Furst DE, Lindsley H, Baethge B, Botstein GR, Caldwell J, Dietz F, et al. Dose-loading with hydroxychloroquine improves the rate of response in early, active rheumatoid arthritis: A randomized, double-blind six-week trial with eighteen-week extension. Arthritis Rheum 1999;42:357-65.
23Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020;395:565-74.
24Belouzard S, Millet JK, Licitra BN, Whittaker GR. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses 2012;4:1011-33.
25Al-Bari MA. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol Res Perspect 2017;5:e00293.
26Simmons G, Zmora P, Gierer S, Heurich A, Pöhlmann S. Proteolytic activation of the SARS-coronavirus spike protein: Cutting enzymes at the cutting edge of antiviral research. Antiviral Res 2013;100:605-14.
27de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother 2014;58:4875-84.
28Cortegiani A, Ingoglia G, Ippolito M. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care 2020. [doi: 10.1016/j.jcrc. 2020.03.005].
29Jang CH, Choi JH, Byun MS, Jue DM. Chloroquine inhibits production of TNF-alpha, IL-1beta and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes. Rheumatology (Oxford) 2006;45:703-10.
30Huang 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. Lancet 2020;395:497-506.
31Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020;395:507-13.
32Kopecky-Bromberg SA, Martinez-Sobrido L, Palese P. 7a protein of severe acute respiratory syndrome coronavirus inhibits cellular protein synthesis and activates p38 mitogen-activated protein kinase. J Virol 2006;80:785-93.
33Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020;14:72-3. doi: 10.5582/bst.2020.01047. Epub 2020 Feb 19. PMID: 32074550.
34Mvumbi DM, Bobanga TL, Melin P, De Mol P, Kayembe JM, Situakibanza HN, et al. High prevalence of Plasmodium falciparum infection in asymptomatic individuals from the Democratic Republic of the Congo. Malar Res Treat 2016;2016:5405802.
35Coppée R, Sabbagh A, Clain J. Structural and evolutionary analyses of the Plasmodium falciparum chloroquine resistance transporter. Sci Rep 2020;10:4842.
36Singh AK, Singh A, Singh R, Misra A. Hydroxychloroquine in patients with COVID-19: A systematic review and meta-analysis. Diabetes Metab Syndr 2020;14:589-96.
37Molina JM, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect 2020;50:384.