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REVIEW
Chloroquine and Hydroxychloroquine for the
Prevention and Treatment of COVID-19:
A Fiction, Hope or Hype? An Updated Review
Sultan AM Saghir,
1
Naif A AlGabri,
2,3
Mahmoud M Alagawany,
4
Youssef A
Attia,
5,6
Salem R Alyileili,
7
Shaaban S
Elnesr,
8
Manal E Sha,
9
Omar YA Al-
shargi,
10
Nader Al-balagi,
11
Abdullah S
Alwajeeh,
12
Omar SA Alsalahi,
13
Amlan K
Patra,
14
Asmaa F Khafaga,
15
Ahmed
Negida,
16,17
Ahmed Noreldin,
18
Wesam Al-Amarat,
19
Amer A
Almaiman,
20
Khaled A El-Tarabily,
21,22
Mohamed E Abd El-Hack
4
1
Department of Medical Analysis, Princess Aisha Bint Al-
Hussein College of Nursing and Medical Sciences, Al-
Hussein Bin Talal University, Ma’an, 71111, Jordan;
2
Pathology Department, Faculty of Veterinary Medicine,
Thamar University, Dhamar, Yemen;
3
Laboratory of
Regional Djibouti Livestock Quarantine, Abu Yasar
International Est. 1999, Djibouti, Djibouti;
4
Department
of Poultry, Faculty of Agriculture, Zagazig University,
Zagazig, 44511, Egypt;
5
Department of Agriculture,
Faculty of Environmental Sciences, King Abdulaziz
University, Jeddah, 21589, Kingdom of Saudi Arabia;
6
Department of Animal and Poultry Production, Faculty
of Agriculture, Damanhour University, Damanhour,
Egypt;
7
Department of Integrative Agriculture, College of
Food and Agriculture, United Arab Emirates University,
Al-Ain, 15551, United Arab Emirates;
8
Department of
Poultry Production, Faculty of Agriculture, Fayoum
University, Fayoum, 63514, Egypt;
9
Department of
Biological Sciences, Zoology, King Abdulaziz University,
Jeddah, 21589, Kingdom of Saudi Arabia;
10
Department
of Pharmacology, College of Pharmacy, Riyadh Elm
University, Riyadh, Kingdom of Saudi Arabia;
11
Ministry of
Health, Riyadh, Kingdom of Saudi Arabia;
12
Anti-
DopingLab, Doha, Qatar;
13
Department of Medical
Laboratories, Faculty of Medicine and Health Sciences,
Hodeidah University, Al Hodaidah, Yemen;
14
Department
of Animal Nutrition, West Bengal University of Animal
and Fishery Sciences, Belgachia, Kolkata, India;
15
Department of Pathology, Faculty of Veterinary
Medicine, Alexandria University, Edna, 22758, Egypt;
16
School of Pharmacy and Biomedical Sciences, University
of Portsmouth, Portsmouth, UK;
17
Zagazig University
Hospitals, Faculty of Medicine, Zagazig University, Zagazig,
Egypt;
18
Histology and Cytology Department, Faculty of
Veterinary Medicine, Damanhour University, Damanhour,
22511, Egypt;
19
Department of Medical Support, Al-
Karak University College, Al-Balqa’ Applied University,
Salt, Jordan;
20
Department of Applied Medical Sciences,
Community College of Uniazah, Qassim University,
Buraydah, 51431, Kingdom of Saudi Arabia;
21
Department of Biology, College of Science, United Arab
Emirates University, Al-Ain, 15551, United Arab Emirates;
22
Biosecurity and One Health Research Centre, Harry
Butler Institute, Murdoch University, Murdoch, Western
Australia, 6150, Australia
Abstract: In December 2019, the novel coronavirus disease pandemic (COVID-19) that
began in China had infected so far more than 109,217,366 million individuals worldwide and
accounted for more than 2,413,912 fatalities. With the dawn of this novel coronavirus
(SARS-CoV-2), there was a requirement to select potential therapies that might effectively
kill the virus, accelerate the recovery, or decrease the case fatality rate. Besides the currently
available antiviral medications for human immunodeciency virus (HIV) and hepatitis
C virus (HCV), the chloroquine/hydroxychloroquine (CQ/HCQ) regimen with or without
azithromycin has been repurposed in China and was recommended by the National Health
Commission, China in mid-February 2020. By this time, the selection of this regimen was
based on its efcacy against the previous SARS-CoV-1 virus and its potential to inhibit viral
replication of the SARS-CoV-2 in vitro. There was a shortage of robust clinical proof about
the effectiveness of this regimen against the novel SARS-CoV-2. Therefore, extensive
research effort has been made by several researchers worldwide to investigate whether this
regimen is safe and effective for the management of COVID-19. In this review, we provided
a comprehensive overview of the CQ/HCQ regimen, summarizing data from in vitro studies
and clinical trials for the protection against or the treatment of SARS-CoV-2. Despite the
initial promising results from the in vitro studies and the widespread use of CQ/HCQ in
clinical settings during the 1st wave of COVID-19, current data from well-designed rando-
mized controlled trials showed no evidence of benet from CQ/HCQ supplementation for the
treatment or prophylaxis against SARS-CoV-2 infection. Particularly, the two largest rando-
mized controlled trials to date (RECOVERY and WHO SOLIDARITY trials), both con-
rmed that CQ/HCQ regimen does not provide any clinical benet for COVID-19 patients.
Therefore, we do not recommend the use of this regimen in COVID-19 patients outside the
context of clinical trials.
Keywords: antiviral drugs, chloroquine, COVID-19, drug safety, hydroxychloroquine,
SARS-CoV-2, treatments
Introduction
Coronavirus disease-2019 (COVID-19) is a disease pandemic caused by a new
strain of coronavirus called severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2).
1
Formerly, this disease was referred to as ‘2019 novel coronavirus’
or “2019-nCoV.” The virus name (SARS-CoV-2) was chosen because the virus is
genetically related to the coronavirus responsible for the SARS outbreak of 2003.
1
While related, the two viruses are different.
1
The spread of SARS-CoV-2 began in
Wuhan, China, by the end of December 2019.
2
As of February 17, 2020, the
Correspondence: Youssef A Attia; Khaled A El-Tarabily
Email yaattia@kau.edu.sa; ktarabily@uaeu.ac.ae
Therapeutics and Clinical Risk Management 2021:17 371–387 371
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php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the
work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For
permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
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COVID-19 pandemic has swept the world and infected
more than 109,217,366 million individuals worldwide
and accounted for more than 2,413,912 fatalities.
2
The initial case fatality rate of this virus was estimated
to be 2% but ranged in some countries from 4 to 9%. After
adjustment for asymptomatic cases, this virus’s actual
fatality rate was estimated to be around 1%. The major
challenge of COVID-19 is the rapid transmission of the
virus and the substantial proportion of asymptomatic indi-
viduals who accounted for 40-50% of transmission.
3
Extensive efforts are being made to ght this virus,
including both pharmacological and non-pharmacological
interventions. In the search for potential pharmacologic
agents that might be useful to protect against the virus
and/or treat COVID-19 patients, clinicians have reposi-
tioned chloroquine (CQ) and hydroxychloroquine (HCQ)
as a treatment regimen.
3
The rationale for selecting this
regimen in the early months of the pandemic was the
following: (1) This regimen has been previously utilized
for the cure against SARS-CoV-1 with documented suc-
cess, and (2) recent in vitro experiments in China showed
that these agents could inhibit viral replication in vitro.
3
Since then, this regimen has divided the world with one
extreme trolling it as “game changer in medicine” while
other touting it as ‘useless and dangerous’. Therefore, in
the present article, we provide a comprehensive review of
the use of CQ/HCQ regimen with or without azithromycin,
illustrating the structure, mechanism of action, side effects
and drug interactions, and experimental studies data, and
data of clinical trials.
Structure of the SARS-CoV-2 Virus
Coronaviruses are spherical with an average diameter of
80-120 nm. They possess a number of club-shaped (17-20
nm) glycoproteins spikes projecting from the surface of
the viral envelope.
4
The virus particle contains ve major
structural proteins, which are glycoprotein spikes (S), an
envelope protein (E), matrix protein (M), and nucleocapsid
(N) protein.
4
The glycoprotein spikes mediate virus’s
attachment to different host cell receptors, depending
upon the receptor-binding domain (RBD). On attachment
to the host cell receptor, the glycoprotein spikes S protein
cleavages into two subunits, namely, N-terminal S1 and
C-terminal S2 subunit regions by the host proteases
enzyme.
4
S1 subunit contains a signal peptide and
a RBD. Meanwhile, S2 subunit contains conserved fusion
peptide (FP), heptad repeat (HR) peptides, transmembrane
domain (TM), and a cytoplasmic domain.
4
The S1 subunit of SARS-CoV-2 showed 70% identity
to Beta coronavirus’s S1 subunits (SARS-CoV-1) isolated
from human and bats.
5
Human angiotensin-converting
enzyme 2 (hACE2) acts as the key receptor to infect the
human cells.
5
The S2 subunit plays an important role in
mediating the virus fusion and entry into the host cell, in
which heptad repeat 1 and 2 (HR1, HR2) can interact with
six helical bundles, thereby bringing the viral and cellular
membrane in close proximity for fusion.
5
The ACE2-binding afnity of RBD in S1 subunit of
SARS-CoV-2 is 10 to 20-fold higher, which might con-
tribute to the higher infectivity and transmissibility of
SARS-CoV-2 compared to SARS-CoV-1.
5
The
M glycoprotein is pre–glycosylated M polypeptides with
a size range of 25–30 kDa (221–262 amino acids) and
gives shape to the virus envelope.
5
Envelope protein (E) is
a small polypeptide with a size range of 8.4–12 kDa (76-
109 amino acids) and is the integral membrane protein.
4,5
Chemical Compositions and Sources of
CQ and HCQ
CQ and HCQ have similar chemical structures and cellular
mechanisms of action.
3
CQ is administered as a phosphate
salt, whereas HCQ is administered as a sulfate. Both drugs
are absorbed in the upper intestinal tract.
6
The CQ is
produced by systematic modication of quinine, which is
a plant alkaloid and quinoline containing compound.
7
Hans Andersag discovered CQ in 1934 at the Bayer
laboratory and named it “Resochin”. It became available
in clinical practice in 1947 and quickly became the drug of
choice for the treatment of malaria.
7
CQ, 7-chloro-4-(4-diethylamino-1-methylbutylamino)-
quinoline is made by reacting 4-diethylamino-1-methylbuty-
lamine with 4, 7-dichloroquinoline at 180°C.
8
Each of the
two components involved in CQ synthesis can be prepared in
several ways (Figure 1). In 1946, HCQ sulfate was synthe-
sized as a derivative of CQ by incorporating a hydroxyl
group into CQ, and they both share comparable mechanisms
of action as weak bases and immuno-modulators.
3
It was proved that CQ is two to three times as toxic in
animals as HCQ.
9
More interestingly, HCQ, compared with
CQ, is vastly available to cure auto-immune diseases like
rheumatoid arthritis and systemic lupus erythematosus.
10
Mechanism of Action of CQ and HCQ
Both CQ and HCQ are weak bases that increase the pH of
acidic intracellular organelles like lysosomes/endosomes
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that require low pH for maturation and function.
11
CQ
showed elevation in pH of lysosomes from nearly 4.5 to
6.5 at 100 μM. However, the effect of HCQ on pH values
of lysosomes/endosomes is not known due to the lack of
studies in this regard.
3
Moreover, CQ was found to cause changes in the glyco-
sylation of ACE2 spike protein and receptor that ultimately
inhibits the entry step and the post-entry phase of SARS-CoV
-2.
12
HCQ in the time-of-addition experiment showed its
ability to exert the same mechanism (Figure 2).
In addition to the previously known mechanism,
a novel mechanism of action for CQ and HCQ on
COVID-19 was discovered in 2020 by Fantini et al
13
as
it is known that SARS-CoV-2 starts its replication by
attaching to the spike (S) viral protein of respiratory
cells.
13
The S protein utilizes sialic acids and ACE-2
receptor connected to host cell surface gangliosides for
entry. The study showed that CQ (or its more active
derivative, HCQ) has a high afnity for binding to gang-
liosides and sialic acids.
13
The study also distinguished a novel ganglioside-
binding domain (111–158) at the tip of the N-terminal
domain of the SARS-CoV-2 S protein. It is expected that
this domain can ease attachment with the ACE-2 receptor
and enhance contact of the virus to lipid rafts.
13
Side Effects of the CQ/HCQ Treatment
High doses of CQ were found to cause severe side effects,
but it was reported that CQ in a prescribed dose exerts
relatively few adverse effects.
14
Ocular adverse effects
such as long and subtle symptoms of reduced visual acuity,
diplopia, retinal toxicity, and bilateral loss of vision were
found to be the most severe side effects caused by high
doses of CQ.
15
A high dosage of CQ also causes critical
psychiatric issues such as hallucinations, paranoia, and
suicidal ideations.
16
Injecting CQ intramuscularly has
shown to cause potentially life-threatening hypotension.
17
Other adverse effects include pruritus, photosensitivity,
seizures, paranoia, hallucinations, and retinopathy charac-
terized by the inability to focus on near and far objects
18
(Figure 3). HCQ has a more solubility and less toxic
metabolites compared with CQ. Hence, it has fewer
adverse effects and is relatively safer.
19
For these reasons,
HCQ is often preferred over CQ where possible.
18
Hydroxychloroquine
Chloroquine
37.1.1.1 37.1.1.2 37.1.1.3
Figure 1 Chemical composition of chloroquine and hydroxychloroquine.
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Cautions and Contraindications
Patients receiving CQ or/and HCQ must be monitored
for their haematological parameters (RBC, WBC, and
platelet counts), blood glucose (hypoglycemic risk of
HCQ), serum electrolytes, renal as well as hepatic
functions.
20
Electrocardiography (ECG) is essential
before starting therapy with these medications and the
concomitant use of these drugs with other drugs known
to extend the corrected QT (QTc) interval of the heart
(like antihistamines, anti-depressants, anti-arrhythmic,
anti-psychotics, moxioxacin, teneligliptin, and ondan-
setron) should be averted.
21
The addendum of HCQ to
azithromycin, as reported by Gautret et al
22
in the
French trial, may elevate QTc extension.
23
If QTc is
450–500 msec, it is recommended to do daily ECG.
CQ and HCQ must not be utilized simultaneously with
ritonavir/lopinavir and remdisivir for expected QTc
extension. Additionally, hypoglycaemia should be
observed in diabetes patients, particularly with conco-
mitant usage of CQ/HCQ and ritonavir/lopinavir.
23
Pharmacovigilance on the mental and visual disorder is
also carefully wanted (Figure 4).
Despite case reports of reversible heart failure and CQ-
induced cardiomyopathy in the literature, large meta-
analysis and numerous investigations carried out in
patients having rheumatoid arthritis conrmed a lowered
cardiovascular hazard with both drugs; nonetheless,
a baseline ECG must be completed in patients with certain
cardiovascular disease.
24
Every clinician utilizing these
drugs should realize contraindications to both compounds;
porphyria, pre-existing maculopathy, retinopathy, glucose-
6-phosphate dehydrogenase deciency, epilepsy, recent
myocardial infarction, hypersensitivity to these agents,
and QTc>500 msec.
20
There is no evidence that CQ and
HCQ are contraindicated in lactating and pregnant
women.
25
It is worth noticing that CQ and HCQ interact with
various drugs; many lead to QT prolongation and might
lead to serious cardiac events and death. As mentioned
earlier, this includes patients who take the CQ/HCQ
Figure 2 The possible mode of action of chloroquine and hydroxychloroquine versus SARS-CoV-2 infection: (1) interference with the terminal glycosylation of cellular
receptor angiotensin-converting enzyme 2 (ACE-2) leads to obstructing virus-receptor attachment; (2) increasing the pH of acidic cellular organelles lead to prevention of
endocytosis with adverse inuences on post-translational modication of recently synthesized viral RNA and virion transport; (3) blocking of viral protein synthesis and
virion assembly.
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regimen with azithromycin. Such patients require close
cardiac monitoring as long as they are on the CQ/HCQ
regimen.
23
Besides, CQ/HCQ might decrease blood
glucose; therefore, these drugs can be used with caution
in patients with diabetes mellitus. A recent study showed
that using these drugs during the pandemic contributed to
Ocular adverse effects
Reduced visual acuity
Diplopia
Retinal toxicity
Bilateral loss of vision
Psychiatric issues
Hallucinations
Paranoia
suicidal ideations
Intramuscular injection
Potentially life-
threatening hypotension
Pruritus and
photosensitivity
Figure 3 The possible side effects of chloroquine and hydroxychloroquine.
There is no evidence that
CQ HCQ are contraindicated
in lactating and pregnant
women
Reversible heart failure
cardiomyopathy was
noted in some patients
(baseline ECG should be
done in patients with
established cardiovascular
disease)
Pharmacovigilance on
visual and mental
disturbance is closely
required.
ECG is essential before
starting therapy and daily
ECG if QTc is 450–500
msec.
Hypoglycemia must be
looked for in patients with
diabetes
Patients must be
monitored for:
•Hematological
parameters (RBC, WBC,
and platelet counts)
•Blood glucose
(hypoglycemic risk of
HCQ)
•Serum electrolytes
•Renal and hepatic
functions
CQ and HCQ are
contraindicated in patients
suffered:
•Porphyria
•Pre-existing maculopathy
•Retinopathy
•G6pd deficiency
•Epilepsy
•Recent myocardial
infarction
•Hypersensitivity to these
agents
Avoided the concomitant
use of some drugs such
as:
•Anti-histamines
•Anti-depressants
•Anti-arrhythmic
•Anti-psychotics
•Moxifloxacin
•Teneligliptin
•Ondansetron
•Azithromycin
•Lopinavir/Ritonavir
•Remdisivir
Figure 4 Cautions and contraindications during treatment with chloroquine (CQ) and hydroxychloroquine (HCQ).
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hypoglycaemic events.
26
A summary of the common drug
and disease interactions of CQ and HCQ are shown in
(Table 1).
Methods of Selecting Studies for This
Review
We searched PubMed, SCOPUS, and Web of Science until
December 31, 2020, using the keywords “(chloroquine OR
hydroxychloroquine) and (COVID-19 OR SARS-CoV-2
OR 2019-nCOV)”. Studies were screened for eligibility
for this review. Studies meeting the following conditions
were reviewed (1) study design: experimental animal stu-
dies and prospective clinical trials, (2) study drug: chlor-
oquine and hydroxychloroquine, (3) outcomes: viral
inhibition in experimental studies and mortality or time
to recovery in clinical trials. Studies that do not satisfy
these criteria were excluded from the review. Eligible
studies were presented in tables and narratively discussed
in the text.
Experimental Studies
The continuous and rapid spread of the COVID-19
pandemic has led to extensive ongoing efforts
worldwide to develop effective and safe therapy. CQ
and HCQ in COVID-19 are among the drugs being
tested, which were reported on February 4, 2020, to
suppress SARS-CoV-2 in vitro. There is considerable
in vitro evidence that CQ and HCQ are efcient in
preventing SARS-CoV-2 vigour. Liu et al
3
detected
that both drugs have a 50% cytotoxic concentration
(CC50). However, the 50% maximum efcient concen-
tration was lower for CQ than HCQ (EC50 – the dose at
which viral RNA elevation is suppressed by 50%)
regardless of the multiplicity of infection (MOI – the
ratio of virions to host cells).
3
Wang et al
27
found that CQ has in vitro antiviral vigour
with an EC50 of 1.13 μM and CC50 >100 μM at an MOI
of 0.05 and shown that the eclecticism for SARS-CoV-2 is
high compared with that for host cells. The study also
showed that CQ at a concentration of 0.36 mg/L decreased
viral load by 50% in vitro using Vero E6 cells.
27
Yao et al
28
also proved the activity of CQ versus
SARS-CoV-2 and detected that CQ was less potent than
HCQ in vitro versus SARS-CoV-2 (EC50 of 5.47 μM and
0.72 μM, respectively, MOI = 0.01). Based on physiologi-
cally based pharmacokinetic (PBPK) model results, oral
HCQ sulfate with a supplying dose of 400 mg twice a day
then 200 mg twice a day as a maintenance dose for four
days is advised for SARS-CoV-2 infection, and it is three
times more potent than CQ phosphate when given 500 mg
twice per day for ve days in advance.
28
Clinical Trials on CQ/HCQ Regimen for
the Protection Against SARS-CoV-2
Infection
Although preclinical evidence suggests that CQ and HCQ
can inhibit viral replication and might prevent COVID-19,
the current evidence does not support their prophylaxis
efcacy against SARS-CoV-2 infection.
27
Expert opinions advised using the CQ/HCQ regimen
for prophylaxis against SARS-CoV-2 infection, particu-
larly between healthcare laborers who are at higher hazard
of infection.
29,30
However, this opinion was refuted by
data from a well-designed randomized controlled trial on
821 participants. Participants were allocated to be admini-
strated with either HCQ or placebo within four days after
exposure. The happening of novel symptoms compatible
with COVID-19 did not vary markedly among the two
groups (11.8% versus 14.3%; P=0.35).
31
Table 1 The Commonest Drug Interactions and Disease
Interactions of the Chloroquine (CQ) and Hydroxychloroquine
(HCQ) Regimen
CQ HCQ
Drug
interactions
●Hydroxyzine
●Azithromycin
●Ciprooxacin
●Duloxetine
●HCQ
●Levetiracetam
●Pregabalin
●Meoquine
●Primaquine
●Albuterol
●Amitriptyline
●Calcium/Vitamin D
●Duloxetine
●Leunomide
●Albuterol
●Tramadol
Disease
interactions
●Oculotoxicity
●Porphyria
●Arrhythmias
●Bone marrow suppression
●Ototoxicity
●Seizures
●Glucose-6-PD deciency
●Hepatotoxicity
●Myasthenia gravis
●Psoriasis
●Oculotoxicity
●Porphyria
●Arrhythmias
●Bone marrow suppression
●Ototoxicity
●Seizures
●Glucose-6-PD deciency
●Hepatotoxicity
●Myasthenia gravis
●Psoriasis
●Diabetes
●Heart disease
●Renal impairment
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Clinical Experiments on CQ/HCQ
Regimen for the Therapy of COVID-19
Recent literature has suggested that CQ/HCQ drugs could
be used as antiviral drugs to cure COVID-19 infections.
24
In addition, Iyer et al
32
stipulated that the CQ can block
the quinone reductase-2, a fundamental agent needed for
the sialic acid biosynthesis that SARS-CoV-2 utilizes it
as the receptor moieties. A recent small clinical study by
Gautret et al
22
reported that positive SARS-CoV-2 in
nasopharyngeal secretions signicantly decreased on day
six after inclusion in HCQ-treated COVID-19 patients
against patients who received supportive care only.
22
The
CQ elevates pH in host cell lysosomes and passively
affects virus–receptor linking and intervenes with the gly-
cosylation of SARS-CoV-2 receptors. Additionally, it
showed a hopeful antiviral inuence versus SARS-CoV-2
in vitro and limited the course of the disease and enhanced
COVID-19-pneumonia patients.
33
The rst evidence of CQ effectiveness in COVID-19
came from China in February 2020 by the Chinese
government.
34
These data reported that CQ phosphate
was given to over 100 patients in China and reduced the
duration of illness and signicantly improved pneumonia
infection and lung imaging. There were no adverse events
reported. It seems that combining data from various in-
progress trials using a variety of study designs released
such ndings. A study by Gautret et al
22
in France on
March 17, 2020, considered as the rst clinical trial, was
conducted as an open-label non-randomized controlled
experiment.
22
The trial included patients who suffered
from SARS-CoV-2 among which 22 of the 36 patients
included in the study had symptoms in the upper respira-
tory tract, eight had symptoms in the lower respiratory
tract, while six patients were asymptomatic.
22
The experi-
mental group (22 patients) was treated with HCQ 200 mg
three times per day for ten days, whereas the control group
was treated with ordinary care.
22
Azithromycin was also
prescribed for six patients of the treatment group to pre-
vent bacterial superinfection. In this trial, SARS-CoV-2
carriage at day 6 was the primary outcome which was
examined by testing nasopharyngeal swabs utilizing PCR
of SARS-CoV-2 RNA.
22
The experiment’s outcomes revealed that the experi-
mental group was markedly tested negative for the virus
than patients in the control group (70% vs. 12.5% virolo-
gically cured, P<0.001) on day 6. Furthermore, the results
of HCQ and azithromycin combination were astonishing
as all patients treated with this combination were negative
on day 6. The study proved the efciency of HCQ and the
possible synergistic inuence of its combination with azi-
thromycin needs further declaration, as suggested by
Gautret et al.
22
Despite this trial’s favourable outcomes, severe limita-
tions have made its results questionable.
35
First, there was
recruitment for an additional six patients but were
excluded, and no intention-to-treat analysis was performed
due to many reasons that have led to the failure of follow-
ing-up these patients.
35,36
Secondly, the researchers added
that the sample size was not enough to achieve 85%
power, which required recruiting 48 patients for the
required power to be achieved. The overstatement of
inuence sizes and false-positive outcomes can be
expected from the underpowered trial with a sample size
of 36 patients.
37
On the sixth day, the researchers reported
that a patient showed negative for the virus but revealed
positive on the eighth day, which raised a concern about
a trial lacking for long-term and medium follow-up data
since the primary outcome is viral PCR status at day 6.
37
This incidence indicates that long-term data of CQ/HCQ
effectiveness in the therapy of COVID-19 is necessary.
Finally, the trial’s allocation bias cannot be denied where
there was no randomization for patients to the control and
treatment groups.
37
Another pilot study published on March 25, 2020, by
Chen et al
38
who evaluated the safety and efcacy of HCQ
in the management of patients with COVID-19. A sum of
30 patients diagnosed with COVID-19 was recruited and
randomly allocated (1:1) into the treatment and control
groups. The test group treated with oral CQ sulfate
(400 mg one time a day for ve days) based on conven-
tional treatment, while the control group received tradi-
tional treatment.
38
The principal outcome was the negative
change rate of COVID-19 nucleic acid in respiratory phar-
yngeal swab on the seventh day. On day 7, the test group’s
throat swabs showed negative COVID-19 nucleic acid in
13 patients (86.7%), with one case progressed to severe
during the treatment.
38
In comparison to the treatment
group, 14 (93.3%) subjects in the control group (P>0.05)
also tested negative. The average period between virus
nucleic acid negative maintenance and patients’ hospitali-
zation in the test and control groups was 4 (1–9) days and
2 (1-4) days, respectively (U=83.5, P>0.05).
38
In terms of
safety, abnormal liver function and transient diarrhea in the
experimental and the control groups subjects were noticed
in 4 (26.7%) and 3 (20%) cases, respectively (P>0.05).
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The small sample size in this study has made a general
conclusion that the prediction of typical COVID-19
patients is perfect.
38
Following that, an extensive argument was raised
against Gautret et al
22
study by Kim et al.
39
It was reported
that there was a rush in judgment of the study due to the
pressing requirement for efcient therapy for SARS-CoV
-2. The clinical trial’s limitations were discussed, such as
using an invalidated replacement endpoint, deciency of
blinding or randomization, and including the small sample
size. Another study highlighted methodological aws that
were considered to impact the validity of the ndings.
40
Despite the limitations in the rst clinical trial, its
promising results ended up advising the usage of CQ/
HCQ in the management of COVID-19 ofcially by
guidelines. The National Health Commission published
the recommendation of treatment COVID-19 by CQ,
China, published in mid-February 2020, indicating that
500 mg CQ phosphate (equivalent to 300 mg CQ) twice
per day for ten days is recommended for patients with
COVID-19.
41
On March 17, 2020, other recommendations
published by the L. Spallanzani National Institute for
Infectious Disease in Italy, in which the combination of
CQ (500 mg CQ per day) or HCQ (200-500 mg HCQ per
day) with a different antiviral drug is indicated for
COVID-19.
42
A pharmacokinetic study in France aimed to optimize
HCQ dosing in the intensive care unit (ICU) of COVID-19
patients was carried out by Perinel et al.
43
The study
recruited 13 patients in ICU who were treated by HCQ
at a dose of 200 mg twice per day. The mean age of
patients was 68 years, 31% with moderate or severe
renal failure, and 46% were obese.
43
The study demon-
strated that the dosing regimen of 200 mg thrice a day is
inappropriate to reach a supposed target blood level of 1–
2 mg/L in this population. According to data from patients
with rheumatoid arthritis and the 161 blood levels regis-
tered, the proposed dosing regimen delivers a dose of
800 mg once per day on the rst day, then 200 mg twice
per day for seven days.
43
The efcacy of combining azithromycin and HCQ was
also evaluated by an uncontrolled non-comparative obser-
vational study carried out by Gautret et al
22
in 80 patients
diagnosed with a relatively mild infection of COVID-19.
Six days were set as the minimum follow-up period. There
was a clinically marked amelioration in all patients, except
for one patient aged 86 years who died, and another
patient (74-year-old) was still in the ICU. The viral load
of nasopharyngeal samples rapidly decreased. Of these
samples, 83% of the patients were tested negative on the
seventh day, while on the eight’s day, 93% were
negative.
22
On day 5 of the treatment, respiratory samples’
viral cultures were found negative in 97.5% of the
patients.
22
Therefore, patients were quickly got out of the
infectious disease unit with ve days as an average length
of stay. Although the number of patients was just 80 and
the severity of the illness was mild, the study reected an
excellent picture of the combination of azithromycin and
HCQ.
22
Regarding the optimal dose of HCQ in COVID-19
patients, Garcia-Cremades et al
44
tested the safe and effec-
tive dosage of HCQ for COVID-19 treatment. It was
predicted that doses of over 400 mg twice a day of HCQ
for ≥5 days reduced viral loads quickly, shortening the
treatment course, decreasing the number of patients with
detectable SARS-CoV-2 infection.
44
In contrast, increas-
ing the dose of HCQ to over 600 mg twice a day has more
probability of prolonging QTc intervals.
44
In recent study
from Belgium, Catteau et al
45
have shown that the low
dose HCQ monotherapy has reduced mortality rate com-
pared with the non-HCQ treated patients.
45
A study from South Korea by Lee et al
46
investigated
the effectiveness of post-exposure prophylaxis after
a signicant exposure of COVID-19 in a long-term care
hospital using HCQ (400 mg orally daily till the end of 14
days of quarantine) in 211 persons containing 22 health-
care workers and 189 patients, with negative PCR checks
for COVID-19.
46
After completing the post-exposure pro-
phylaxis period by 184 patients and 21 care-workers with-
out any severe effects, all PCR tests were negative at the
ending of the 14 days of quarantine.
46
The shortage of
control groups in the study and having other 29 hospital
staff who tested negative after the 14 days of quarantine
although they did not receive post-exposure prophylaxis
(Although being classied low-risk exposure) are consid-
ered essential limitations in the study.
46
In a study high-
lighted COVID-19 and immunomodulation in
inammatory bowel diseases (IBD), Neurath
47
mentioned
that there is a possibility for drug–drug interactions
between HCQ or IBD therapies. The risk of interaction is
potentially increased by combination of medication with
HCQ and iniximab/adalimumab for nerve harm.
47
However, there is no evidence to discontinue IBD-
specic medications in COVID-19 patients cured with
such drugs. The favourable effect of HCQ and azithromy-
cin combination on the clinical results and viral loads of
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patients infected with COVID-19 has led to implementing
the regimen by clinicians worldwide.
48
On the other hand,
both drugs have been independently revealed to inuence
the electrical system of the heart, causing QT-interval
elongation, drug-induced torsades de pointes, and drug-
stimulated sudden cardiac death.
48
In this context, an American study carried out by
Chorin et al
49
examined the QT-interval in 84 patients
with COVID-19 cured with a combination of HCQ
(400 mg daily on day one, then 200 mg daily from day 2
to 5) and azithromycin (500 mg per day for ve days).
After 4.3 ± 1.7 days as an average time for exposure to
HCQ/azithromycin, ECG was followed up.
49
It was found
that the QTc markedly extended. In a group of nine (11%)
of those patients, there was a severe prolongation of the
QTc to >500 ms, which is a marker of a high danger of
sudden cardiac death caused by malignant arrhythmia.
49
Out of the group of nine patients, ve patients had
a normal QTc. It was suggested that regular evaluation
for QTc must be implemented by patients with COVID-19
who are cured with a combination of HCQ/azithromycin
combination, especially those who have comorbidities or/
and with other QT-prolonging medications.
49
A randomized clinical experiment by Borba et al
50
from Brazil compared the effect of high doses (600 mg
twice per day for ten days) against small doses (450 mg
twice a day on day one and OD for four days) of CQ
diphosphate as adjunctive therapy for 81 adult patients
treated with SARS-CoV-2 infection.
50
Forty patients
received low doses, while 41 received high doses. In the
small dose group, 15.0% (6 out of 40) of patients died
on day 13 days compared with 39% of the high-dose group
(16 of the 41 patients). Regarding safety, 4 of 36 patients
(11.1%) receiving low-dose experienced prolongation of
QTc interval compared with 7 of 37 (18.9%) patients
receiving the high-dose.
50
Besides, ventricular tachycardia
was developed in 2 patients (2.7%) in the high-dose group.
As a result of these ndings, the trial was stopped. It was
inferred that the high dosage of CQ must not be advised
for adversely ill patients with COVID-19.
50
Patients with systemic lupus erythematosus (SLE) were
a population of interest for Mathian et al.
51
SARS-CoV-2
represents a source of concern for the management of
patients with SLE. In patients with SLE, the use of immu-
nosuppressive drugs, the intrinsic perturbations of the
immune response, and the potential presence of organ
damage associated with their disease make those patients
at higher risk of severe infections. Currently, and as a part
of SLE treatment, HCQ is a standard long-term drug for
SLE.
52
HCQ also has antiviral activity in COVID-19, and its
therapeutic or even prophylactic activity for COVID-19
was proved by preliminary clinical trials. Mathian et al
51
examined the clinical observations of COVID-19 in
a series of 17 patients with SLE receiving long-term treat-
ment of HCQ (median of 7.5 years) and with obesity and
chronic kidney disease as comorbidities.
51
Although this
study gave an initial clinical view of the infection course
in patients with SLE cured with HCQ, it did not conclude
the severity and incidence rate of COVID-19 in SLE.
Moreover, it was also shown that HCQ does not protect
against COVID-19, at least its negative practice, in
patients with SLE.
51
On the other hand, strong evidence from a well-
designed randomized controlled trial (RCT) does not
advocate the usage of CQ/HCQ regimens in COVID-19
patients. Data from the UK’s recovery trial, the world’s
largest COVID-19 clinical trial to date, by Horby and
Landray
53
showed that HCQ did not reduce the 28-day
mortality rate among COVID-19 patients compared to the
standard of care.
53
While these outcomes were questioned
by several experts owing to the relatively higher loading
dose.
On the rst day of the study (2400 mg in 24 hours),
similar ndings were reached by the WHO’s solidarity
trial in several countries worldwide. On June 5, 2020, the
WHO announced that based on an interim analysis of the
trial data, HCQ did not reduce the mortality compared to
the standard of care.
54
The characteristics of the in vitro
studies on SARS-CoV-2 and clinical trials studying the
efcacy of CQ and HCQ in COVID-19 patients are illu-
strated in Table 2.
Past Experiences, Current Situations, and
Future Directions
Based on the review of the existing literature, the CQ/
HCQ regimen gained worldwide attention. It showed
a promise in the preclinical experiments and some clinical
studies during the early months of the pandemic.
Nonetheless, the usage of the CQ/HCQ regimen in treating
COVID-19 has been challenged by the recent data from
well-designed RCTs. The CQ and HCQ are widely used
for the rst-line of treatment against the malarial parasite
in most endemic Asia and African countries.
63
Besides
malaria treatment, CQ is utilized in rheumatoid arthritis,
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Table 2 Characteristics of the in vitro Investigations on SARS-CoV-2 and Clinical Trials Studying the Efcacy of Chloroquine and
Hydroxychloroquine in COVID-19 Patients
Reference
and Country
Population
(n Patients)
Intervention and Comparison
Groups
Primary Outcomes
China
28
in vitro study with SARS-CoV-2-infected
Vero cells
Infected Vero cells were treated with CQ
or HCQ at 0.032, 0.16, 0.80, 4, 20, or
100 μM for 24 or 48 h.
●CQ and HCQ decreased viral replication
in a concentration-dependent manner.
●EC
50
values for CQ were 23.90 and 5.47
μM at 24 and 48 h, respectively.
●EC
50
values for HCQ were 6.14 and
0.72 μM at 24 and 48 h, respectively.
China
28
in vitro study with Vero cells Vero cells were pre-treated CQ or HCQ
at 0.032, 0.16, 0.80, 4, 20, or 100 μM for
two h and were then infected with SARS-
CoV-2 and incubated for 24 or 48 h.
●HCQ showed a higher in vitro antiviral
inuence in comparison with CQ.
●The EC
50
values for CQ were greater
than 100 and 18.01 μM at 24 and 48 h,
respectively.
●EC
50
values for HCQ were 6.25 and
5.85 μM at 24 and 48 h, respectively.
China
3
in vitro study with African green monkey
kidney VeroE6 cells
SARS-CoV-2 infected cells at four
different multiplicities of infection (MOI)
and treated with CQ or HCQ up to 50
μM for 48 h
●CC
50
values of CQ and HCQ were 273
and 250 μM, respectively, which are not
signicantly different.
●At all MOI (0.01, 0.02, 0.2, and 0.8), EC
50
for HCQ (4.51, 4.06, 17.31, and 12.96
μM) was higher than that of CQ (2.71,
3.81, 7.14, and 7.36 μM).
●Statistically, the variations in EC
50
values
were signicant at MOI of 0.01 (P < 0.05)
and 0.2 (P < 0.001).
China
27
in vitro study with Vero E6 cells. Cells were infected with SARS-CoV-2 at
MOI of 0.05 in the presence of different
concentrations of CQ, penciclovir,
ribavirin, nafamostat, nitazoxanide,
remdesivir, favipiravir and chloroquine.
●EC
50
, SI index, and CC
50
values for CQ
were 1.13 μM, >100 μM, and 88.5.
●These values were higher for for ribavirin
(EC
50
= 110 μM, CC
50
> 400 μM, and SI >
3.65), penciclovir (EC
50
= 96.0 μM, CC
50
> 400 μM, SI > 4.17) and favipiravir (EC
50
= 61.9 μM, CC
50
> 400 μM, SI > 6.46),
nafamostat (EC
50
= 22.50 μM, CC
50
> 100
μM, SI > 4.44), and was comparable to
nitazoxanide (EC
50
= 2.12 μM; CC
50
>
35.53 μM; SI > 16.76) and remdesivir
(EC
50
= 0.77 μM; CC
50
> 100 μM; SI >
129.87) for EC
50
.
France
22
Age >12 years and positive for SARS-
CoV-2. Patients with HCQ or CQ allergy
were excluded or had another
recognized contraindication to cure with
the drug. Pregnant and breastfeeding
patients were excluded.
Oral HCQ 200 mg TD × ten days (n=20).
Symptomatic treatment and AZT (n = 6;
500 mg/d on day 1 then 250 mg/d for
next 4 days) with HCQ.
Patients (n=16) who rejected the cure or
had relegation criteria, served as
controls.
●Control patients were younger than HCQ-
treated patients (37.3 years vs 51.2 years).
●At sixth day post-inclusion, 70% of HCQ-
cured patients were negative compared
with 12.5% in the control group (p= 0.001).
●At day six post-inclusion, 100% of patients
treated with combination of HCQ and AZT
were negative compared with 57.1% in
patients cured with HCQ only, and 12.5% in
the control group (p<0.001).
(Continued)
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Table 2 (Continued).
Reference
and Country
Population
(n Patients)
Intervention and Comparison
Groups
Primary Outcomes
China
38
Conrmed COVID-19 patients. Thirty
patients were randomly grouped into
treatment and control groups.
Oral HCQ sulfate 400 mg OD × 5 days
(n=15).
No HCQ was provided to Patients
(n=15).
●On day 7, the number of negative sam-
ples did not differ (13 (86.7%) cases in
the HCQ group versus 14 (93.3%) cases
in the control group; P>0.05)
●The period from hospitalization to nega-
tive result of virus nucleic acid did not
differ (4±1.9 days in HCQ versus 2±1.4
days in the control group; P>0.05).
●The time for body temperature normaliza-
tion was comparable (1±0.2 day I HCQ
group versus 1±0.3 days in the control
group).
●Radiological progress was noted on CT
images in 7 cases (46.7%) of the control
group and 5 cases (33.3%) of the HCQ
group, and all patients revealed ameli-
oration in follow-up examinations.
●Three cases (20%) of the control group
and four cases (26.7%) of the HCQ
group had abnormal liver function and
transient diarrhoea (P>0.05).
South Korea
46
COVID-19 exposed individuals (211
containing 22 careworkers and 189
patients) with negative PCR tests for
COVID-19 in a long-term care hospital in
Korea. Four patients and one coworker
were not nally completed.
COVID-19 exposed individuals were
administered HCQ at 400 mg OD x 14
days during the quarantine.
No control groups.
●At the ending of two weeks of quarantine,
all follow-up PCR tests were negative.
●A sum of 32 individuals (15.6%) men-
tioned one or more symptoms through
post-exposure prophylaxis.
●The most common symptoms were skin
rash (4.3%), loose stool or diarrhoea
(9%), bradycardia (0.95%), and gastroin-
testinal upset (0.95%). Post-exposure
prophylaxis was stopped in 5 patients
(2.7%) because of the requirement for
fasting (1), bradycardia (2), and gastro-
intestinal upset (2).
Netherlands
55
Patients (n = 95) were aged 18 years or
older and suspected of having COVID-19
disease.
CQ was a loading dose of 600 mg
followed by 300 mg BD (starting 12
h after the loading dose), for the next
four days
●CQ treatment in patients with COVID-19
markedly extended the QTc interval by
34–35 ms; 23% of the patients had a QTc
interval exceeding 500 ms. Statistically
marked inuences were detected on QRS
interval (mean difference 6 ms), PR inter-
val (mean difference 8 ms), and heart rate
(mean difference –10 bpm).
(Continued)
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Table 2 (Continued).
Reference
and Country
Population
(n Patients)
Intervention and Comparison
Groups
Primary Outcomes
Netherlands
23
A retrospective investigation of 251
patients having COVID-19.
HCQ was orally administrated at 400 mg
BD for one day (loading dose) then
200 mg BD for four days. AZT was orally
administrated for ve days at a dose of
500 mg OD.
●The QTc interval extended from
a baseline of 439 ± 29 ms to a maximum
value of 473 ± 36 ms (P < .001), which
happen on day 4.1 ± 2 of treatment.
●Extreme novel QTc interval extension to
>500 ms revealed in 23% of the patients.
●One patient showed polymorphic ventri-
cular tachycardia.
USA
56
A retrospective investigation of 1376
patients having COVID-19.
HCQ (n = 811) was provided at 600 mg
BD on day 1, followed by 400 mg/d for 4
next days.
Control group patients were less
adversely ill at baseline than those with
HCQ-treated patients (n = 565; the ratio
of the partial pressure of arterial oxygen
to the fraction of inspired oxygen, 223 vs
360).
●HCQ use was not accompanied with
a markedly lower or higher hazard of
death or intubation (hazard ratio, 1.04;
95% CI, 0.82 to 1.32).
USA
57
A retrospective investigation of 368
patients diagnosed with COVID-19.
HCQ (n = 97) alone and HCQ + AZT (n
= 113) in combination.
In the control group (n = 158), no HCQ
was provided.
●The hazard of death from any reason
was elevated in the HCQ group
(adjusted hazard ratio, 2.61; 95% CI, 1.10
to 6.17; P=0.03).
●The risk of death was similar in the
HCQ+AZ group (adjusted hazard ratio,
1.14; 95% CI, 0.56 to 2.32; P=0.72).
●The hazard of ventilation was compar-
able in the HCQ group (adjusted
hazard ratio, 1.43; 95% CI, 0.53 to 3.79;
P=0.48) and the HC+AZ group (adjusted
hazard ratio, 0.43; 95% CI, 0.16 to 1.12;
P=0.09).
France
58
A retrospective investigation of 181
patients having COVID-19 and requiring
oxygen ≥ 2 L/min.
HCQ (n = 84) 600 mg/d for 7 day
In control (n = 97), no HCQ was
provided.
●20.2% of the patients in the HCQ group
were died within seven days or moved
to the ICU vs 22.1% in the no–HCQ
group (16 vs 21 events, the relative
hazard of 0.91, 95% CI 0.47-1.80) in the
HCQ group.
●The death of 2.8% of the patients was
within seven days vs 4.6% in the no–
HCQ group (three vs four events, the
relative risk of 0.61, 95% CI 0.13–2.89).
●27.4% in the HCQ group versus 24.1% in
control group patients developed acute
respiratory distress syndrome within
seven days (24 vs 23 events, relative risk
of 1.14, 95% CI 0.65-2.00).
●8 patients receiving HCQ (9.5%)
revealed electrocardiogram modica-
tions requesting HCQ stop.
(Continued)
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Table 2 (Continued).
Reference
and Country
Population
(n Patients)
Intervention and Comparison
Groups
Primary Outcomes
USA
59
A retrospective investigation of 181
patients having COVID-19.
HCQ at 200–600 mg OD/BD (n = 271)
alone;
HCQ + AZT (n = 735) in combination;
AZT 200–500 mg once/OD/BD (n =
211), and no drug (n =221)
●The death of patients treating with AZT
alone, 21/211 (10.0% (95% CI, 5.9%-
14.0%)), HCQ + AZT was 189/735
(25.7% (95% CI, 22.3%-28.9%)), HCQ
alone, 54/271 (19.9% (95% CI, 15.2%-
24.7%)), and neither drug, 28/221 (12.7%
(95% CI, 8.3%–17.1%)).
●Co marked variations in mortality for
patients receiving HCQ + AZT (hazard
ratio of 1.35 (95% CI, 0.76–2.40)), HCQ
alone (hazard ratio of 1.08 (95% CI, 0.-
63–1.85)), or AZT alone (hazard ratio of
0.56 (95% CI, 0.26–1.21)) in comparison
with patients administrating neither
drug.
●Cardiac arrest was markedly higher in
patients receiving HCQ + AZT
(adjusted OR, 2.13 (95% CI, 1.12–4.05)),
but not HCQ alone (adjusted OR, 1.91
(95% CI, 0.96–3.81)) or AZT alone
(adjusted OR, 0.64 (95% CI, 0.27-1.56))
compared with patients receiving neither
drug.
China
60
A retrospective investigation of 181
patients having COVID–19 and treated
with HCQ.
HCQ 400 mg/d (200 mg BD) for 7–10
days (n = 48).
In the control group (n = 520), no HCQ
was provided.
●Mortalities reduced in HCQ group
(18.8% (9/48) versus 45.8% (238/520) in
control group (p<0.001)).
●The time of hospitalization before
patient death was 15 (10–21) days for
the HCQ group versus 8 (4–14) days for
control groups (p<0.05).
●The level of inammatory cytokine IL–6
markedly decreased from 22.2 (8.3–-
118.9) pg/mL to 5.2 (3.0-23.4) pg/ml
(p<0.05) in the HCQ group, but there is
no alteration in the control group.
Recovery trial
UK
61
An ongoing randomized controlled trial
of more than 11,000 COVID-19 patients
to date
HCQ(200 mg tablet containing 155 mg
base equivalent) received a loading dose
of four tablets (800 mg) at zero and six
hours, then two tablets (400 mg) starting
at twelve hours after the initial dose and
then every twelve hours for the next nine
days or until discharge.
●28-day mortality was 26.8% and 25% in
the HCQ and standard of care groups.
●HCQ treatment was markedly accompa-
nied with an elevated length of hospital
stay and elevated hazard of developing to
death.
Solidarity
trial
54
An ongoing randomized controlled trial
of more than 5,000 COVID-19 patients
to date
HCQ
Standard of care
●Not Available; Details were not
published.
(Continued)
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systemic and discoid lupus erythematosus, sarcoidosis,
scleroderma, pemphigus porphyria cutanea tarda.
63
Despite drugs’ adverse effects on humans, such as cardiac,
retinal, and neuromuscular toxicities, their benets out-
weigh the toxicity effects.
64,65
The CQ and HCQ have
also been tested to treat various diseases such as human
immunodeciency diseases, Q fever, whipple disease, and
fungal infection.
65,66
These drugs have several
other benecial properties, including anti-inammatory,
immuno-modulating, anti-infective, anti-thrombotic, and
anti-tumoral properties.
65
Due to these multifaceted effects of CQ and HCQ,
including antiviral properties, these drugs have been exten-
sively investigated against the SARS-COV-2 virus and
COVID-19 patients, and the outcomes widely varied.
Indeed, few in vitro investigations have revealed antiviral
inuences against SARS-COV-2.
3,27,28
The results are pre-
liminary based on the small clinical trials and usually
cofounding with pre-existing comorbidities, age, and
severity of disease.
51
The prophylaxis use of CQ and HCQ did not show any
clinical efcacy in randomized controlled trials. In most
cases, there is a lack of randomized control trials with long-
term supervision of the patients and their contacts to explore
the efcacy of CQ/HCQ for postexposure prophylaxis.
Many times, its toxicity, particularly cardiac toxicities, out-
weighed its benets, unlike the treatment of malarial infec-
tion. A recent meta-analysis of 12 studies showed no
evidence of clinical benet from CQ/HCQ administration
in COVID-19 patients.
35
Other limitations of this regimen
were (1) the potential interaction with azithromycin and
several other medications leading to QT prolongation and
possible cardiovascular side effects and (2) the hypoglyce-
mia if not adequately monitored in diabetic patients. While
close monitoring might optimize is regimen’s safety, the
safety prole does not make it suitable for a pandemic
situation. With several cases overwhelming the healthcare
systems, it becomes unpractical to screen all patients for the
potential interactions in the clinical setting. Future direc-
tions in the CQ/HCQ drugs might include improved drug
delivery either by inhalation
67
or transcatheter delivery
through the bronchial artery.
68
The randomized and controlled WHO Solidarity
69
trial
did not nd an effectiveness of HCQ in reducing mortality
rate (risk ratio of 1.19; P = 0.23) among the hospitalized
COVID-19 patients. Based on lack of benets of using
HCQ, WHO
54
and National Institute of Health had
stopped trial for hospitalized COVID patients.
61
A recent
randomized controlled trial by Horby et al
61
in the UK
comprising 4716 COVID-19 patients showed that admin-
istration of HCQ had no benets in decreasing death rate
(rate ratio of 1.09; P = 0.15).
Moreover, a recent meta-analysis based on 28 rando-
mized trial containing 10.012 COVID-19 patients treated
with HCQ, 307 patients with CQ and 63 patients with both
CQ and HCQ in which WHO Solidarity
69
and
RECOVERY
61
included that HCQ treatment was asso-
ciated with increased (risk ratio of 1.11; P = 0.02) mortal-
ity rate, whereas CQ did not show (risk ratio of 1.77; P =
0.21) any benet in reducing mortality rate.
70
Finally,
according to new data from two large RCTs (Recovery
and Solidarity), the United States Food and Drug
Administration (FDA) revoked the CQ/HCQ regimen’s
emergency usage authorization in COVID-19 patients.
Table 2 (Continued).
Reference
and Country
Population
(n Patients)
Intervention and Comparison
Groups
Primary Outcomes
US and
Canada
62
An internet-based randomized controlled
trial in non-hospitalized patients in the US
and Canada
HCQ(800 mg once, followed by 600 mg
in 6 to 8 hours, then 600 mg daily for 4
more days)
Placebo
●Symptom severity did not signicantly
differ over 14 days (−0.27 points (95%
CI, −0.61 to 0.07 points); P=0.117).
●At 14 days, 24% of the participants
receiving HCQ had ongoing symptoms
compared with 30% receiving placebo
(P=0.21).
●Medication adverse effects occurred in
43% of HCQ group compared to 22%
in the placebo group (P < 0.001).
Abbreviations: HCQ, hydroxychloroquine; CQ, chloroquine; OD, one a day; BD, twice a day; TD, thrice a day; CI, condence interval; EC50, Half maximal effective
concentration; CC50, 50% cytotoxic concentration. SI, selectivity index.
http://doi.org/10.2147/TCRM.S301817
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The drugs are currently used for clinical trial purposes
only.
21
Furthermore, we searched clinicaltrials.gov for
clinical trials on COVID-19 using the keywords: “chlor-
oquine OR hydroxychloroquine”. Then, we ltered the
records to identify the “ongoing studies only”. The search
retrieved 97 ongoing studies; the summary of the 97
ongoing studies and their characteristics are provided in
the Supplementary Table S1.
Conclusion and Recommendations
Based on the initial early experimental data of CQ and HCQ
for treatment of SARS-CoV-2, the regimen received an
emergency usage authorization from the FDA for COVID-
19 on March 28, 2020. However, the two largest RCTs data
to date showed no clinical advantage of HCQ treatment in
COVID-19 patients. As a result, the FDA revoked the emer-
gency use authorization of this regimen. In terms of prophy-
laxis, one RCT showed no evidence of post-exposure
prevention from COVID-19. Despite the initial promising
ndings in the in vitro studies and the widespread use of CQ/
HCQ in clinical settings during the 1
st
wave of COVID-19,
current data from well-designed randomized controlled trials
showed no evidence of benet from CQ/HCQ supplementa-
tion for the treatment or prophylaxis against SARS-CoV-2
infection. Particularly, the two largest randomized controlled
trials to date (RECOVERY
61
and WHO SOLIDARITY
69
),
both conrmed that CQ/HCQ regimen does not provide any
clinical benet for COVID-19 patients. Therefore, we do not
recommend the use of this regimen in COVID-19 patients
outside the context of clinical trials.
Data Sharing Statement
This review article is based on the published available
literature.
Author Contributions
All authors (S.S., N.A., M.A., Y.A., S.A., S.S.E., M.S., O.
A., N.A., A.A., O.A., A.K.P., A.K., A.N., A.N., W.A-A.,
A.A.A., K.A.E.-T. and M. A.E.-H.) have made
a signicant contribution to this review article. They all
equally shared in the conception, study design, execution,
acquisition of data, analysis and interpretation. S.S., N.A.,
M.A., Y.A., S.A., S.S.E., K.A.E.-T, and M.A.E.-H. have
drafted the manuscript. M.S., O.A., N.A., A.A., O.A., A.K.
P., A.K., A.N., A.N., W.A-A., A.A.A., K.A.E.-T. have
substantially revised and critically reviewed the article.
All authors have agreed on the submission to this journal
and agreed on all versions of the article before submission
or during revisions. All authors agreed to take responsi-
bility and be accountable for the contents of this article.
Funding
No funding.
Disclosure
The authors report no conicts of interest for this work and
declare that the research was conducted in the absence of
any commercial or nancial relationships that could be
construed as a potential conict of interest.
References
1. WHO. Naming the coronavirus disease (COVID-19) and the virus
that causes it. 2020a. Available from: https://www.who.int/emergen
cies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-
coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it.
Accessed April 9, 2021
2. WHO. Coronavirus disease (COVID-19) Weekly Epidemiological
Update. 2020b; 1–22. Available from: https://www.who.int/docs/
default-source/coronaviruse/situation-reports/20200831-weekly-epi-
update-3.pdf?sfvrsn=d7032a2a_4. Accessed April 9, 2021.
3. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic deriva-
tive of chloroquine, is effective in inhibiting SARS-CoV-2 infection
in vitro. Cell Discov. 2020;6:16. doi:10.1038/s41421-020-0156-0
4. Chan JF, Kok KH, Zhu Z, et al.. Genomic characterization of the
2019 novel human-pathogenic coronavirus isolated from a patient
with atypical pneumonia after visiting Wuhan. Emerg Microbes
Infect. 2020;9:221–236. doi:10.1080/22221751.2020.1719902
5. Chen J. Pathogenicity and transmissibility of 2019-nCoV. A quick
overview and comparison with other emerging viruses. Microbes
Infect. 2020;22:69–71. doi:10.1016/j.micinf.2020.01.004
6. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychlor-
oquine and chloroquine: implications for rheumatology. Nat Rev
Rheumatol. 2020;16:155–166. doi:10.1038/s41584-020-0372-x
7. Andersag H. Antimalariamittel aus der Gruppe halogensubstituierter
Chinolinverbindungen [Antimalarials from the group of halogen-sub-
stituted quinoline compounds]. Chem Ber. 1948;81:499–
507. German. doi:10.1002/cber.19480810607
8. Drake NL, Creech HJ, Garman JA, et al. Synthetic antimalarials. The
preparation of certain 4-aminoquinolines. J Am Chem Soc.
1946;68:1208–1213. doi:10.1021/ja01211a021
9. McChesney EW. Animal toxicity and pharmacokinetics of hydroxy-
chloroquine sulfate. Am J Med. 1983;75:11–18. doi:10.1016/0002-
9343(83)91265-2
10. Colson P, Rolain J-M, Lagier J-C, et al. Chloroquine and hydroxy-
chloroquine as available weapons to ght COVID-19. Int J Antimicrob
Agents. 2020;55:105932. doi:10.1016/j.ijantimicag.2020.105932
11. Kumar R, Srivastava JK, Singh R, et al.. Available compounds with
therapeutic potential against Covid-19: antimicrobial therapies, sup-
portive care, and probable vaccines. Front Pharmacol.
2020;6:582025. doi:10.3389/fphar.2020.582025
12. Chen L, Chen H, Dong S, et al. The effects of chloroquine and
hydroxychloroquine on ACE2-related coronavirus pathology and
the cardiovascular system: an evidence-based review. Function.
2020a;1:zqaa012. doi:10.1093/function/zqaa012
13. Fantini J, Di Scala C, Chahinian H, Yahi N. Structural and molecular
modelling studies reveal a new mechanism of action of chloroquine and
hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob
Agents. 2020;55:105960. doi:10.1016/j.ijantimicag.2020.105960
Therapeutics and Clinical Risk Management 2021:17 http://doi.org/10.2147/TCRM.S301817
DovePress
385
Dovepress Saghir et al
Therapeutics and Clinical Risk Management downloaded from https://www.dovepress.com/ by 37.17.194.124 on 30-Apr-2021
For personal use only.
Powered by TCPDF (www.tcpdf.org) 1 / 1
14. Goel P, Gerriets V. Chloroquine. In: StatPearls [Internet]. Treasure
Island (FL): StatPearls Publishing; 2020. Available from https://www.
ncbi.nlm.nih.gov/books/NBK551512/. Accessed April 9, 2021.
15. Braga CBE, Martins AC, Cayotopa ADE, et al. Side effects of
chloroquine and primaquine and symptom reduction in malaria ende-
mic area (Mâncio lima, Acre, Brazil). Interdiscip Perspect Infect Dis.
2020;2015:346853. doi:10.1155/2015/346853
16. Kumar R, Sharma A, Srivastava JK, Siddiqui MH, Uddin MS,
Aleya L. Hydroxychloroquine in COVID-19: therapeutic promises,
current status, and environmental implications. Environ Sci Pollut
Res Int. 2021;15:1–14. doi:10.1007/s11356-020-12200-1
17. White NJ. Cardiotoxicity of antimalarial drugs. Lancet Infect Dis.
1998;7:549–558. doi:10.1016/S1473-3099(07)70187-1
18. Juurlink DN. Safety considerations with chloroquine, hydroxychlor-
oquine and azithromycin in the management of SARS-CoV-2
infection. CMAJ. 2020;192:E450–E453. doi:10.1503/cmaj.200528
19. Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines
against coronavirus disease 2019 (COVID-19): chloroquine or
hydroxychloroquine. Int J Antimicrob Agents. 2020;55:105945.
doi:10.1016/j.ijantimicag.2020.105945
20. 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 Clin Res Rev. 2020;14:241–246. doi:10.1016/j.dsx.2020.03.011
21. FDA, USA. ARALEN®. Chloroquine phosphate, USP. US FDA, for
malaria and extraintestinal amebiasis. 2020; 1–8. Reference ID:
3402523
22. Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and azi-
thromycin as a treatment of COVID-19: results of an open-label
non-randomized clinical trial. Int J Antimicrob Agents. 2020;
56:105949. doi:10.1016/j.ijantimicag.2020.105949
23. Chorin E, Wadhwani L, Magnani S, et al. QT interval prolongation
and torsade de pointes in patients with COVID-19 treated with
hydroxychloroquine/azithromycin. Heart Rhythm. 2020a;17:142
5–1433. doi:10.1016/j.hrthm.2020.05.014
24. Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S.
A systematic review on the efcacy and safety of chloroquine for
the treatment of COVID-19. J Crit Care. 2020;57:279–283. doi:10.
1016/j.jcrc.2020.03.005
25. Dashraath P, Wong JL, Lim MX, et al. Coronavirus disease 2019
(COVID-19) pandemic and pregnancy. Am J Obstet Gynecol.
2020;6:521–531. doi:10.1016/j.ajog.2020.03.021
26. Shah K, Tiwaskar M, Chawla P, et al. Hypoglycemia at the time of
COVID-19 pandemic. Diabetes Metab Syndr Clin Res Rev.
2020;14:1143–1146. doi:10.1016/j.dsx.2020.07.003
27. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effec-
tively inhibit the recently emerged novel coronavirus (2019-nCoV) in
vitro. Cell Res. 2020;30:269–271. doi:10.1038/s41422-020-0282-0
28. Yao X, Ye F, Zhang M, 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;71:723–739. doi:10.1093/cid/ciaa237
29. Cohen MS. Hydroxychloroquine for the prevention of Covid-19-
searching for evidence. N Engl J Med. 2020;383:585–586.
doi:10.1056/NEJMe2020388
30. Tilangi P, Desai D, Khan A, Soneja M. Hydroxychloroquine prophy-
laxis for high-risk COVID-19 contacts in India: a prudent approach.
Lancet Infect Dis. 2020;20:1119–1120. doi:10.1016/S1473-3099(20)
30430-8
31. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial
of hydroxychloroquine as postexposure prophylaxis for Covid-19.
N Engl J Med. 2020;383:517–525. doi:10.1056/NEJMoa2016638
32. Iyer M, Jayaramayya K, Subramaniam MD, et al. COVID-19: an
update on diagnostic and therapeutic approaches. BMB Rep.
2020;53:191–205. doi:10.5483/BMBRep.2020.53.4.080
33. Jian G, Jun L, Xu S, et al. Anti-inammatory and immunoregulatory
effects of total glucosides of Yupingfeng powder. Chin Med J (Engl).
2009;122:1636–1641. doi:10.3760/cma.j.issn.0366-6999.2009.14.007
34. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has
shown apparent efcacy in treatment of COVID-19 associated pneu-
monia in clinical studies. Biosci Trends. 2020;14:72–73. doi:10.5582/
bst.2020.01047
35. Ullah W, Abdullah MH, Roomi S, et al. Safety and efcacy of
hydroxychloroquine in COVID-19: a systematic review and
meta-analysis. J Clin Med Res. 2020;12:483–491. doi:10.14740/
jocmr4233
36. Ranganathan P, Pramesh C, Aggarwal R. Common pitfalls in statis-
tical analysis: intention-to-treat versus per-protocol analysis. Perspect
Clin Res. 2016;7:144–146. doi:10.4103/2229-3485.184823
37. Dumas-Mallet E, Button KS, Boraud T, Gonon F, Munafo MR. Low
statistical power in biomedical science: a review of three human
research domains. R Soc Open Sci. 2017;4:160254. doi:10.1098/
rsos.160254
38. Chen J, Liu D, Liu L, et al. A pilot study of hydroxychloroquine in
treatment of patients with moderate COVID-19. J. Zhejiang. Univ.
(Medical Sci.). 2020b;49:215–219. doi:10.3785/j.issn.1008-9292.20
20.03.03
39. Kim AHJ, Sparks JA, Liew JW, et al. A rush to judgment? Rapid
reporting and dissemination of results and its consequences regarding
the use of hydroxychloroquine for COVID-19. Ann Intern Med.
2020;172:819–821. doi:10.7326/m20-1223
40. Dahly D, Gates S, Morris T. Statistical review of hydroxychloroquine
and azithromycin as a treatment of COVID-19: results of an
open-label non-randomized clinical trial. 2020. doi:10.5281/
zenodo.3724167
41. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease
2019 (COVID-19). Drug Discov Ther. 2020;14:58–60. doi:10.5582/
ddt.2020.01012
42. Nicastri E, Petrosillo N, Bartoli T, et al. National institute for the
infectious diseases “L. Spallanzani” IRCCS. Recommendations for
COVID-19 clinical management. Infect Dis Rep. 2020;12:8543.
doi:10.4081/idr.2020.8543
43. Perinel S, Launay M, Botelho-Nevers E, et al. Towards optimization
of hydroxychloroquine dosing in intensive care unit COVID-19
Patients. Clin Infect Dis. 2020;7:ciaa394. doi:10.1093/cid/ciaa394
44. Garcia-Cremades M, Solans BP, Hughes E, et al. Optimizing hydro-
xychloroquine dosing for patients with COVID-19: an integrative
modeling approach for effective drug repurposing. Clin Pharmacol
Ther. 2020;108:253–263. doi:10.1002/cpt.1856
45. Catteau L, Dauby N, Montourcy M, et al. Low-dose hydroxychlor-
oquine therapy and mortality in hospitalised patients with
COVID-19: a nationwide observational study of 8075 participants.
Int J Antimicrob Agents. 2020;4:106144. doi:10.1016/j.ijantimicag.
2020.106144
46. Lee SH, Son H, Peck KR. Can post-exposure prophylaxis for
COVID-19 be considered as an outbreak response strategy in
long-term care hospitals?. Int J Antimicrob Agents. 2020;55:105988.
doi:10.1016/j.ijantimicag.2020.105988
47. Neurath MF. COVID-19 and immunomodulation in IBD. Gut.
2020;69:1335–1342. doi:10.1136/gutjnl-2020-321269
48. Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use asso-
ciated with QT prolongation and refractory ventricular arrhythmia.
Clin Toxicol. 2006;44:173–175. doi:10.1080/15563650500514558
49. Chorin E, Dai M, Shulman E, et al. The QT interval in patients with
COVID-19 treated with hydroxychloroquine and azithromycin. Nat
Med. 2020b;26:808–809. doi:10.1038/s41591-020-0888-2
50. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses
of chloroquine diphosphate as adjunctive therapy for patients hospi-
talized with severe acute respiratory syndrome Coronavirus 2
(SARS-CoV-2) infection. A randomized clinical trial. JAMA Netw
Open. 2020;3:e208857. doi:10.1001/jamanetworkopen.2020.8857
http://doi.org/10.2147/TCRM.S301817
DovePress
Therapeutics and Clinical Risk Management 2021:17
386
Saghir et al Dovepress
Therapeutics and Clinical Risk Management downloaded from https://www.dovepress.com/ by 37.17.194.124 on 30-Apr-2021
For personal use only.
Powered by TCPDF (www.tcpdf.org) 1 / 1
51. Mathian A, Mahevas M, Rohmer J, et al. Clinical course of corona-
virus disease 2019 (COVID-19) in a series of 17 patients with
systemic lupus erythematosus under long-term treatment with
hydroxychloroquine. Ann Rheum Dis. 2020;79:837–839. doi:10.11
36/annrheumdis-2020-217566
52. Savarino A, Boelaert JR, Cassone A, et al. Effects of chloroquine on
viral infections: an old drug against today’s diseases?. Lancet Infect
Dis. 2003;3:722–727. doi:10.1016/S1473-3099(03)00806-5
53. Horby P, Landray M No clinical benet from use of hydroxychlor-
oquine in hospitalised patients with COVID-19. 2020. Available
from: https://www.ox.ac.uk/news/2020-06-05-no-clinical-benet-use-
hydroxychloroquine-hospitalised-patients-covid-19guidance/naming-
the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it
54. WHO. WHO discontinues hydroxychloroquine and lopinavir/ritona-
vir treatment arms for COVID-19. 2020c. Available from: www.who.
int/news-room/detail/04-07-2020-who-discontinues-
hydroxychloroquine-and-lopinavir-ritonavir-treatment-arms-for-
covid-19
55. Van-den Broek MPH, Möhlmann JE, Abeln BGS, Liebregts M, Van-
dijk VF, Van-de Grade EM. Chloroquine-induced QTc prolongation
in COVID-19 patients. Neth Heart J. 2020;28:406–409. doi:10.1007/
s12471-020-01429-7
56. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychlor-
oquine in hospitalized patients with Covid-19. N Engl J Med.
2020;382:2411–2418. doi:10.1056/NEJMoa2012410
57. Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxy-
chloroquine usage in United States veterans hospitalized with
Covid-19. Med. 2020;1:114–127. doi:10.1016/j.medj.2020.06.001
58. Mahevas M, Tran VT, Roumier M, et al. No evidence of clinical
efcacy of hydroxychloroquine in patients hospitalized for
COVID-19 infection with oxygen requirement: results of a study
using routinely collected data to emulate a target trial. BJM.
2020;369:m1844. doi:10.1101/2020.04.10.20060699
59. Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment
with hydroxychloroquine or azithromycin with in-hospital mortality
in patients with COVID-19 in New York state. JAMA.
2020;323:2493–2502. doi:10.1001/jama.2020.8630
60. Yu B, Wang DW, Li C. Hydroxychloroquine application is associated
with a decreased mortality in critically ill patients with COVID-19.
MedRxiv. 2020;20073379. doi:10.1101/2020.04.27.20073379
61. Horby P, Mafham M, Linsell L, et al. Effect of hydroxychloroquine
in hospitalized patients with Covid-19. N Engl J Med.
2020;383:2030–2040. doi:10.1056/NEJMoa2022926
62. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in
nonhospitalized adults with early COVID-19. Ann Intern Med.
2020;173:623–631. doi:10.7326/M20-4207
63. Mushtaque M. Reemergence of chloroquine (CQ) analogs as
multi-targeting antimalarial agents: a review. Eur J Med Chem.
2015;90:280–295. doi:10.1016/j.ejmech.2014.11.022
64. Taylor WRJ, White NJ. Antimalarial drug toxicity. Drug Saf.
2004;27:25–61. doi:10.2165/00002018-200427010-00003
65. Plantone D, Koudriavtseva T. Current and future use of chloroquine
and hydroxychloroquine in infectious, immune, neoplastic, and neu-
rological diseases: a mini-review. Clin Drug Investig. 2018;38:
653–671. doi:10.1007/s40261-018-0656-y
66. Bonam SR, Muller S, Bayry J, Klionsky DJ. Autophagy as an emer-
ging target for COVID-19: lessons from an old friend, chloroquine.
Autophagy. 2020;16:2260–2266. doi:10.1080/15548627.2020.177
9467
67. Tai TT, Wu TJ, Wu HD, et al. A strategy to treat COVID-19 disease
with targeted delivery of inhalable liposomal hydroxychloroquine: a
non-clinical pharmacokinetic study. Clin Transl Sci. 2020;14
(1):132–136. doi:10.1101/2020.07.09.196618
68. Zaitoun MMA, Basha MAA, Elmokadem AH. Transcatheter drug
delivery through bronchial artery for COVID-19: is it ction or could
it come true?. Eur Radiol Exp. 2020;4:42. doi:10.1186/s41747-020-
00171-4
69. Pan H, Peto R, AbdoolKarim Q, et al. Repurposed antiviral drugs for
COVID-19; interim WHO solidarity trial results. N Engl J Med.
2021;384:497–511. doi:10.1056/NEJMoa2023184
70. Axfors C, Schmitt AM, Janiaud P, et al.. Mortality outcomes with
hydroxychloroquine and chloroquine in COVID-19: an international
collaborative meta-analysis of randomized trials. MedRxiv.
2020:20194571. doi:10.1101/2020.09.16.20194571.
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