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Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

Zhaowei Chen1, Jijia Hu1, Zongwei Zhang1, Shan Shan Jiang1, Shoumeng Han1, Dandan Yan1, Ruhong Zhuang1, Ben Hu2, Zhan Zhang1 •
Wuhan University1, Chinese Academy of Sciences2
30 Mar 2020-medRxiv (Cold Spring Harbor Laboratory Press)-
TL;DR: Among patients with COVID-19, the use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia.
Abstract: Aims Studies have indicated that chloroquine (CQ) shows antagonism against COVID-19 in vitro. However, evidence regarding its effects in patients is limited. This study aims to evaluate the efficacy of hydroxychloroquine (HCQ) in the treatment of patients with COVID-19. Main methods From February 4 to February 28, 2020, 62 patients suffering from COVID-19 were diagnosed and admitted to Renmin Hospital of Wuhan University. All participants were randomized in a parallel-group trial, 31 patients were assigned to receive an additional 5-day HCQ (400 mg/d) treatment, Time to clinical recovery (TTCR), clinical characteristics, and radiological results were assessed at baseline and 5 days after treatment to evaluate the effect of HCQ. Key findings For the 62 COVID-19 patients, 46.8% (29 of 62) were male and 53.2% (33 of 62) were female, the mean age was 44.7 (15.3) years. No difference in the age and sex distribution between the control group and the HCQ group. But for TTCR, the body temperature recovery time and the cough remission time were significantly shortened in the HCQ treatment group. Besides, a larger proportion of patients with improved pneumonia in the HCQ treatment group (80.6%, 25 of 31) compared with the control group (54.8%, 17 of 31). Notably, all 4 patients progressed to severe illness that occurred in the control group. However, there were 2 patients with mild adverse reactions in the HCQ treatment group. Significance Among patients with COVID-19, the use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia. Trial registration URL: https://www.clinicaltrials.gov/. The unique identifier: ChiCTR2000029559.

Summary (2 min read)

Jump to: [Introduction] – [(which was not certified by peer review)] – [Study design and participants] – [Statistical Analysis] – [Results] – [Discussion] and [Conclusion]

Introduction

  • Coronaviruses are enveloped positive-sense single-stranded RNA viruses belonging to the family Coronaviridae and are broadly distributed in humans and other vertebrates, eventually causing damage in digestive, respiratory and even multiple systems.
  • Sequencing analysis of throat swabs samples and electron microscope observations indicated a novel coronavirus, which was named SARS-CoV-2 (formerly known as 2019-nCoV) [2] .
  • Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has been confirmed to have obvious human-to-human characteristics [3, 4] .
  • For this, the U.S. Food and Drug Administration (FDA) has been working to investigate the use of CQ in COVID-19 [10] .

(which was not certified by peer review)

  • The copyright holder for this preprint this version posted April 10, 2020.
  • Interestingly, through a follow-up survey, the authors found that none of their 80 SLE patients who took long-term oral HCQ had been confirmed to have SARS-CoV-2 infection or appeared to have related symptoms.
  • The copyright holder for this preprint this version posted April 10, 2020.
  • Neither the research performers nor the patients were aware of the treatment assignments.
  • Experts and guides for COVID-19 in China have also recommended chloroquine phosphate superior to the treatment of SARS-CoV-2 infection [8, 9] .

Study design and participants

  • The clinical research protocol was reviewed and approved by the Ethics Committee in Renmin Hospital of Wuhan University (Wuhan, China).
  • All research procedures adhered to the tenets of the Declaration of Helsinki.
  • This trial for SARS-CoV-2 has already been registered in the Chinese Clinical Trial Registry , the unique identifier: 2000029559.
  • Informed consent was obtained from all patients.
  • Diagnosis and classification of COVID-19 were based on the criteria of the China National Health Commission.

Statistical Analysis

  • Data were described as the mean (standard deviation, SD), n (%), the t-test or χ² test was used to compare the differences between the two groups.
  • A two-sided p-value of less than 0.05 was considered statistically significant.
  • Statistical analyses were performed using Graphpad Prism, version 6.0.

Results

  • 62 patients were identified as having COVID-19 and enrolled in this study, none quit .
  • The copyright holder for this preprint this version posted April 10, 2020.
  • Patients were randomly assigned into two groups.
  • Compared with the control group [3.2 (1.3) days], the body temperature recovery time was significantly shortened in the HCQ treatment group [2.2 (0.4) days].

Discussion

  • CQ and its derivatives have been broadly used as immunomodulators in the treatment of systemic lupus erythematosus (SLE) and other rheumatism [12] .
  • As the pharmacological mechanism of CQ is further elucidated, its additional clinical applications, especially the antiviral activity, are also increasingly valued [13] .
  • Researchers have even reported both prophylactic and therapeutic advantages of CQ for SARS-CoV infection [17] is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

Conclusion

  • The potential of HCQ in the treatment of COVID-19 has been partially confirmed.
  • Large-scale clinical and basic Abbreviations: HCQ, hydroxychloroquine.

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Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial
Zhaowei Chen
1,
, Jijia Hu
1,
, Zongwei Zhang
1
, Shan Jiang
2
, Shoumeng Han
3
, Dandan Yan
4
, Ruhong
Zhuang
5
, Ben Hu
6
and Zhan Zhang
7,*
1
Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
2
Department of Dermatology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
3
Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, China.
4
Department of Pathology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
5
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
6
CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety
Mega-Science, Chinese Academy of Sciences, Wuhan 430060, China.
7
Department II of Respiratory Disease and Intensive Care, Renmin Hospital of Wuhan University,
Wuhan 430060, China.
Zhaowei Chen and Jijia Hu contributed equally to this work.
*
Corresponding author:
Zhan Zhang, Department II of Respiratory Disease and Intensive Care, Renmin Hospital of Wuhan
University, Wuhan 430060, China. Email: doctorzhang2003@163.com
Abstract
Aims: Studies have indicated that chloroquine (CQ) shows antagonism against COVID-19 in vitro.
However, evidence regarding its effects in patients is limited. This study aims to evaluate the efficacy
of hydroxychloroquine (HCQ) in the treatment of patients with COVID-19.
Main methods: From February 4 to February 28, 2020, 62 patients suffering from COVID-19 were
diagnosed and admitted to Renmin Hospital of Wuhan University. All participants were randomized in
a parallel-group trial, 31 patients were assigned to receive an additional 5-day HCQ (400 mg/d)
treatment, Time to clinical recovery (TTCR), clinical characteristics, and radiological results were
assessed at baseline and 5 days after treatment to evaluate the effect of HCQ.
Key findings: For the 62 COVID-19 patients, 46.8% (29 of 62) were male and 53.2% (33 of 62) were
female, the mean age was 44.7 (15.3) years. No difference in the age and sex distribution between the
control group and the HCQ group. But for TTCR, the body temperature recovery time and the cough
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 10, 2020. ; https://doi.org/10.1101/2020.03.22.20040758doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
remission time were significantly shortened in the HCQ treatment group. Besides, a larger proportion
of patients with improved pneumonia in the HCQ treatment group (80.6%, 25 of 31) compared with the
control group (54.8%, 17 of 31). Notably, all 4 patients progressed to severe illness that occurred in the
control group. However, there were 2 patients with mild adverse reactions in the HCQ treatment group.
Significance: Among patients with COVID-19, the use of HCQ could significantly shorten TTCR and
promote the absorption of pneumonia.
Significance: Among patients with COVID-19, the use of HCQ could significantly shorten TTCR and
promote the absorption of pneumonia.
Trial registration: URL: https://www.clinicaltrials.gov/. The unique identifier: ChiCTR2000029559.
Keywords: COVID-19; SARS-CoV-2; Pneumonia; Hydroxychloroquine
Running title: Efficacy of hydroxychloroquine in COVID-19.
Introduction
Coronaviruses are enveloped positive-sense single-stranded RNA viruses belonging to the family
Coronaviridae and are broadly distributed in humans and other vertebrates, eventually causing damage
in digestive, respiratory and even multiple systems. In December 2019, a series of pneumonia cases of
unknown etiology appeared in Wuhan, Hubei, China [1]. Sequencing analysis of throat swabs samples
and electron microscope observations indicated a novel coronavirus, which was named SARS-CoV-2
(formerly known as 2019-nCoV) [2]. Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2
has been confirmed to have obvious human-to-human characteristics [3,4]. As of March 20, 2020, more
than two hundred thousand confirmed cases have been identified globally, for a total of 8778 deaths
[5].
As the epidemic is spreading to many countries, COVID-19 poses a severe threat to global health
[6].
Therefore, it is urgent to develop effective drugs against COVID-19.
The recent publication of results showing the activity of chloroquine (CQ) against SARS-CoV-2 in
vitro
[7], some experts and researchers also have been recommended the efficacy of this antimalarial
drug in patients with COVID-19 [8,9]. For this, the U.S. Food and Drug Administration (FDA) has
been working to investigate the use of CQ in COVID-19 [10]. As a derivative of CQ,
hydroxychloroquine (HCQ) has similar therapeutic effects and fewer adverse effects. Based on its
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 10, 2020. ; https://doi.org/10.1101/2020.03.22.20040758doi: medRxiv preprint
characteristics of immunity regulation, antithrombotic activity, and inflammation improvement, HCQ
has been routinely used in the clinical treatment of systemic lupus erythematosus (SLE) [11]. However,
the efficacy of HCQ in COVID-19 remains unknown.
Interestingly, through a follow-up survey, we found that none of our 80 SLE patients who took
long-term oral HCQ had been confirmed to have SARS-CoV-2 infection or appeared to have related
symptoms. In addition, among the 178 patients diagnosed with COVID-19 pneumonia in our hospital,
none were receiving HCQ treatment before admission. All predicting the use of HCQ in SARS-CoV-2
infections. As one of the clinical research registration units in China, we aimed to investigate the
efficiency of HCQ in patients with COVID-19 in this study.
Materials and Methods
Study design and participants
The clinical research protocol was reviewed and approved by the Ethics Committee in Renmin
Hospital of Wuhan University (Wuhan, China). All research procedures adhered to the tenets of the
Declaration of Helsinki. This trial for SARS-CoV-2 has already been registered in the Chinese Clinical
Trial Registry (ChiCTR), the unique identifier: ChiCTR2000029559. Informed consent was obtained
from all patients.
From February 4, 2020, to
February 28, 2020, 142 patients with confirmed COVID-19 were admitted.
Diagnosis and classification of COVID-19 were based on the criteria of the China National Health
Commission. For this trial, the selection criteria: 1. Age
≥
18 years; 2. Laboratory (RT-PCR) positive of
SARS-CoV-2; 3. Chest CT with pneumonia; 4. SaO
2
/SPO
2
ratio > 93% or PaO
2
/FIO
2
ratio > 300
mmHg under the condition in the hospital room (mild illness); 5. Willing to receive a random
assignment to any designated treatment group and not participating in another study at the same time.
The exclusion criteria: 1. Severe and critical illness patients or participating in the trial does not meet
the patient's maximum benefit or does not meet any criteria for safe follow-up in the protocol after a
doctor’s evaluation; 2. Retinopathy and other retinal diseases; 3. Conduction block and other
arrhythmias; 4. Severe liver disease (e.g., Child-Pugh score
≥
C or AST> twice the upper limit); 5.
Pregnant or breastfeeding; 6. Severe renal failure [estimated glomerular filtration rate (eGFR)
≤
30
mL/min/1.73m
2
] or receiving renal replacement therapy; 7. Possibility of being transferred to another
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 10, 2020. ; https://doi.org/10.1101/2020.03.22.20040758doi: medRxiv preprint
hospital within 72 h; 8. Received any trial treatment for COVID-19 within 30 days before this research.
62 patients who met the trial criteria were randomly assigned in a to two groups, all received the
standard treatment (oxygen therapy, antiviral agents, antibacterial agents, and immunoglobulin, with or
without corticosteroids), patients in the HCQ treatment group received additional oral HCQ
(hydroxychloroquine sulfate tablets, Shanghai Pharma) 400 mg/d (200 mg/bid) between days 1 and 5
(Figure 1), patients in the control group with the standard treatment only. Randomization was
performed through a computer-generated list stratified by site. Treatments were assigned after
confirming the correctness of the admission criteria. Neither the research performers nor the patients
were aware of the treatment assignments.
Endpoints
5 days after enrollment or severe adverse reactions appeared was the observation endpoint. Changes in
time to clinical recovery (TTCR) and clinical characteristics of patients were evaluated after
administration. TTCR is defined as the return of body temperature and cough relief, maintained for
more than 72 h. Normalization and mitigation criteria included the following: a. Body temperature
≤
36.6 °C on the surface,
≤
37.2 °C under the armpit and mouth or
≤
37.8 °C in the rectum and tympanic
membrane; b. Cough from patients’ reports, slight or no cough was in the asymptomatic range. Body
temperature, cough check three times daily to calculate the average level. For radiological changes, the
chest CT results in one day before (Day 0) and one day after (Day 6) the study for evaluation.
Pulmonary recovery is defined as three levels: exacerbated, unchanged, and improved, moderately
improved when less than 50 % of pneumonia were absorbed, and more than 50 % means significantly
improved.
Statistical Analysis
Data were described as the mean (standard deviation, SD), n (%), the t-test or
χ
² test was used to
compare the differences between the two groups. A two-sided p-value of less than 0.05 was considered
statistically significant. Statistical analyses were performed using Graphpad Prism, version 6.0.
Results
62 patients were identified as having COVID-19 and enrolled in this study, none quit (Figure 1). As
shown in Table 1, For all patients, the age was 44.7 (15.3) years old, 46.8% (29 of 62) were male and
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 10, 2020. ; https://doi.org/10.1101/2020.03.22.20040758doi: medRxiv preprint
53.2% (33 of 62) were female. Patients were randomly assigned into two groups. There was no
significant difference in the age and sex distribution between the two groups of patients, but there are
significant differences in TTCR between the two groups. For fever, 17 patients in the control group and
22 patients in the HCQ treatment group had a fever in day 0. Compared with the control group [3.2 (1.3)
days], the body temperature recovery time was significantly shortened in the HCQ treatment group [2.2
(0.4) days]. For cough, 15 patients in the control group and 22 patients in the HCQ treatment group had
a cough in day 0, The cough remission time was significantly reduced in the HCQ treatment group.
Notably, a total of 4 of the 62 patients progressed to severe illness, all of which occurred in the control
group not receiving HCQ treatment. For adverse effects, it should be noted that there were two patients
with mild adverse reactions in the HCQ treatment group, one patient developed a rash, and one patient
experienced a headache, none severe side effects appeared among them.
To further explore the effect of HCQ on pneumonia, we compared and analyzed the chest CT of
patients on day 0 and day 6. In our study, pneumonia was improved in 67.7% (42/62) of patients, with
29.0% moderately absorbed and 38.7% significantly improved. Surprisingly, a larger proportion of
patients with improved pneumonia in the HCQ treatment group (80.6%, 25 of 31) compared with the
control group (54.8%, 17 of 31). Besides, 61.3% of patients in the HCQ treatment group had a
significant pneumonia absorption.
Discussion
CQ and its derivatives have been broadly used as immunomodulators in the treatment of systemic lupus
erythematosus (SLE) and other rheumatism [12]. As the pharmacological mechanism of CQ is further
elucidated, its additional clinical applications, especially the antiviral activity, are also increasingly
valued [13]. The efficiency of CQ has been proven in a variety of viruses, including human coronavirus
[[14], [15], [16]]. Researchers have even reported both prophylactic and therapeutic advantages of CQ
for SARS-CoV infection [17]. The severe acute respiratory syndrome caused by SARS-CoV-2 in
several patients is quite similar to SARS-CoV in 2002 and is currently seriously threatening global
health by triggering COVID-19. However, none specific drugs are available for the prevention or
treatment of COVID-19.
Recently, Wang et al. identified that CQ could effectively inhibit the replication and spread of
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted April 10, 2020. ; https://doi.org/10.1101/2020.03.22.20040758doi: medRxiv preprint
Citations
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Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19.

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Joshua Geleris, Yifei Sun1, Jonathan Platt1, Jason Zucker1, Matthew R. Baldwin1, George Hripcsak1, Angelena Labella, Daniel K. Manson, Christine J. Kubin1, R. Graham Barr, Magdalena E. Sobieszczyk1, Neil W. Schluger1 •
Columbia University1
07 May 2020-The New England Journal of Medicine
TL;DR: In this observational study involving patients with Covid-19 who had been admitted to the hospital, hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death.
Abstract: Background Hydroxychloroquine has been widely administered to patients with Covid-19 without robust evidence supporting its use. Methods We examined the association between hydroxychloroqu...

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Immunology of COVID-19: Current State of the Science.

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Icahn School of Medicine at Mount Sinai1, University of Würzburg2
16 Jun 2020-Immunity
TL;DR: The current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death are summarized.

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Journal Article•DOI•
Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State.

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Eli S. Rosenberg1, Elizabeth Dufort2, Tomoko Udo1, Larissa A. Wilberschied2, Jessica Kumar2, James M. Tesoriero2, Patti Weinberg, James N Kirkwood2, Alison Muse2, Jack DeHovitz1, Debra Blog2, Brad Hutton2, David R. Holtgrave1, Howard A. Zucker2 •
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23 Jun 2020-JAMA
TL;DR: Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality.
Abstract: Importance Hydroxychloroquine, with or without azithromycin, has been considered as a possible therapeutic agent for patients with coronavirus disease 2019 (COVID-19). However, there are limited data on efficacy and associated adverse events. Objective To describe the association between use of hydroxychloroquine, with or without azithromycin, and clinical outcomes among hospital inpatients diagnosed with COVID-19. Design, Setting, and Participants Retrospective multicenter cohort study of patients from a random sample of all admitted patients with laboratory-confirmed COVID-19 in 25 hospitals, representing 88.2% of patients with COVID-19 in the New York metropolitan region. Eligible patients were admitted for at least 24 hours between March 15 and 28, 2020. Medications, preexisting conditions, clinical measures on admission, outcomes, and adverse events were abstracted from medical records. The date of final follow-up was April 24, 2020. Exposures Receipt of both hydroxychloroquine and azithromycin, hydroxychloroquine alone, azithromycin alone, or neither. Main Outcomes and Measures Primary outcome was in-hospital mortality. Secondary outcomes were cardiac arrest and abnormal electrocardiogram findings (arrhythmia or QT prolongation). Results Among 1438 hospitalized patients with a diagnosis of COVID-19 (858 [59.7%] male, median age, 63 years), those receiving hydroxychloroquine, azithromycin, or both were more likely than those not receiving either drug to have diabetes, respiratory rate >22/min, abnormal chest imaging findings, O2saturation lower than 90%, and aspartate aminotransferase greater than 40 U/L. Overall in-hospital mortality was 20.3% (95% CI, 18.2%-22.4%). The probability of death for patients receiving hydroxychloroquine + azithromycin was 189/735 (25.7% [95% CI, 22.3%-28.9%]), hydroxychloroquine alone, 54/271 (19.9% [95% CI, 15.2%-24.7%]), azithromycin alone, 21/211 (10.0% [95% CI, 5.9%-14.0%]), and neither drug, 28/221 (12.7% [95% CI, 8.3%-17.1%]). In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving hydroxychloroquine + azithromycin (HR, 1.35 [95% CI, 0.76-2.40]), hydroxychloroquine alone (HR, 1.08 [95% CI, 0.63-1.85]), or azithromycin alone (HR, 0.56 [95% CI, 0.26-1.21]). In logistic models, compared with patients receiving neither drug cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95% CI, 1.12-4.05]), but not hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]) or azithromycin alone (adjusted OR, 0.64 [95% CI, 0.27-1.56]), . In adjusted logistic regression models, there were no significant differences in the relative likelihood of abnormal electrocardiogram findings. Conclusions and Relevance Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. However, the interpretation of these findings may be limited by the observational design.

966 citations

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Wuhan Jinyintan Hospital1, Shanghai Jiao Tong University2, Chinese Academy of Sciences3
30 Jan 2020-The Lancet
TL;DR: Characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia, and further investigation is needed to explore the applicability of the Mu LBSTA scores in predicting the risk of mortality in 2019-nCoV infection.

16,282 citations

"Efficacy of hydroxychloroquine in p..." refers background in this paper

  • ...Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has been confirmed to have obvious human-to-human characteristics [3,4]....

    [...]

Journal Article•DOI•
Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia.

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Qun Li1, Xuhua Guan1, Peng Wu2, Xiaoye Wang1, Lei Zhou1, Yeqing Tong1, Ruiqi Ren1, Kathy Leung2, Eric H. Y. Lau2, Jessica Y. Wong2, Xuesen Xing1, Nijuan Xiang1, Yang Wu1, Chao Li1, Chen Qi1, Dan Li1, Tian Liu1, Jing Zhao1, Man Liu1, Wenxiao Tu1, Chuding Chen1, Lianmei Jin1, Rui Yang1, Qi Wang1, Suhua Zhou1, Rui Wang1, Hui Liu1, Yingbo Luo1, Yuan Liu1, Ge Shao1, Huan Li1, Zhongfa Tao1, Yang Yang3, Yang Yang4, Zhiqiang Deng5, Boxi Liu5, Zhitao Ma5, Yanping Zhang1, Guoqing Shi1, Tommy Tsan-Yuk Lam2, Joseph T. Wu2, George F. Gao6, George F. Gao1, Benjamin J. Cowling2, Bo Yang5, Gabriel M. Leung2, Zijian Feng1 •
Chinese Center for Disease Control and Prevention1, University of Hong Kong2, Southern University of Science and Technology3, Shenzhen University4, Centers for Disease Control and Prevention5, Chinese Academy of Sciences6
29 Jan 2020-The New England Journal of Medicine
TL;DR: There is evidence that human-to-human transmission has occurred among close contacts since the middle of December 2019 and considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere.
Abstract: Background The initial cases of novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in December 2019 and January 2020. We analyzed data on the...

13,101 citations

"Efficacy of hydroxychloroquine in p..." refers background in this paper

  • ...Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has been confirmed to have obvious human-to-human characteristics [3,4]....

    [...]

Journal Article•DOI•
Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.

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Manli Wang1, Ruiyuan Cao, Leike Zhang1, Xing-Lou Yang1, Jia Liu1, Mingyue Xu1, Zhengli Shi1, Zhihong Hu1, Wu Zhong, Gengfu Xiao1 •
Chinese Academy of Sciences1
04 Feb 2020-Cell Research
TL;DR: This study evaluated the antiviral efficiency of five FAD-approved drugs including ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine and two well-known broad-spectrum antiviral drugs remdesivir and favipiravir against a clinical isolate of 2019-nCoV in vitro.
Abstract: Dear Editor, In December 2019, a novel pneumonia caused by a previously unknown pathogen emerged in Wuhan, a city of 11 million people in central China. The initial cases were linked to exposures in a seafood market in Wuhan. As of January 27, 2020, the Chinese authorities reported 2835 confirmed cases in mainland China, including 81 deaths. Additionally, 19 confirmed cases were identified in Hong Kong, Macao and Taiwan, and 39 imported cases were identified in Thailand, Japan, South Korea, United States, Vietnam, Singapore, Nepal, France, Australia and Canada. The pathogen was soon identified as a novel coronavirus (2019-nCoV), which is closely related to sever acute respiratory syndrome CoV (SARS-CoV). Currently, there is no specific treatment against the new virus. Therefore, identifying effective antiviral agents to combat the disease is urgently needed. An efficient approach to drug discovery is to test whether the existing antiviral drugs are effective in treating related viral infections. The 2019-nCoV belongs to Betacoronavirus which also contains SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV). Several drugs, such as ribavirin, interferon, lopinavir-ritonavir, corticosteroids, have been used in patients with SARS or MERS, although the efficacy of some drugs remains controversial. In this study, we evaluated the antiviral efficiency of five FAD-approved drugs including ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine and two well-known broad-spectrum antiviral drugs remdesivir (GS5734) and favipiravir (T-705) against a clinical isolate of 2019nCoV in vitro. Standard assays were carried out to measure the effects of these compounds on the cytotoxicity, virus yield and infection rates of 2019-nCoVs. Firstly, the cytotoxicity of the candidate compounds in Vero E6 cells (ATCC-1586) was determined by the CCK8 assay. Then, Vero E6 cells were infected with nCoV2019BetaCoV/Wuhan/WIV04/2019 at a multiplicity of infection (MOI) of 0.05 in the presence of varying concentrations of the test drugs. DMSO was used in the controls. Efficacies were evaluated by quantification of viral copy numbers in the cell supernatant via quantitative real-time RT-PCR (qRT-PCR) and confirmed with visualization of virus nucleoprotein (NP) expression through immunofluorescence microscopy at 48 h post infection (p.i.) (cytopathic effect was not obvious at this time point of infection). Among the seven tested drugs, high concentrations of three nucleoside analogs including ribavirin (half-maximal effective concentration (EC50)= 109.50 μM, halfcytotoxic concentration (CC50) > 400 μM, selectivity index (SI) > 3.65), penciclovir (EC50= 95.96 μM, CC50 > 400 μM, SI > 4.17) and favipiravir (EC50= 61.88 μM, CC50 > 400 μM, SI > 6.46) were required to reduce the viral infection (Fig. 1a and Supplementary information, Fig. S1). However, favipiravir has been shown to be 100% effective in protecting mice against Ebola virus challenge, although its EC50 value in Vero E6 cells was as high as 67 μM, suggesting further in vivo studies are recommended to evaluate this antiviral nucleoside. Nafamostat, a potent inhibitor of MERS-CoV, which prevents membrane fusion, was inhibitive against the 2019-nCoV infection (EC50= 22.50 μM, CC50 > 100 μM, SI > 4.44). Nitazoxanide, a commercial antiprotozoal agent with an antiviral potential against a broad range of viruses including human and animal coronaviruses, inhibited the 2019-nCoV at a low-micromolar concentration (EC50= 2.12 μM; CC50 > 35.53 μM; SI > 16.76). Further in vivo evaluation of this drug against 2019-nCoV infection is recommended. Notably, two compounds remdesivir (EC50= 0.77 μM; CC50 > 100 μM; SI > 129.87) and chloroquine (EC50= 1.13 μM; CC50 > 100 μM, SI > 88.50) potently blocked virus infection at low-micromolar concentration and showed high SI (Fig. 1a, b). Remdesivir has been recently recognized as a promising antiviral drug against a wide array of RNA viruses (including SARS/MERS-CoV) infection in cultured cells, mice and nonhuman primate (NHP) models. It is currently under clinical development for the treatment of Ebola virus infection. Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and results in pre-mature termination. Our time-ofaddition assay showed remdesivir functioned at a stage post virus entry (Fig. 1c, d), which is in agreement with its putative antiviral mechanism as a nucleotide analogue. Warren et al. showed that in NHP model, intravenous administration of 10mg/kg dose of remdesivir resulted in concomitant persistent levels of its active form in the blood (10 μM) and conferred 100% protection against Ebola virus infection. Our data showed that EC90 value of remdesivir against 2019-nCoV in Vero E6 cells was 1.76 μM, suggesting its working concentration is likely to be achieved in NHP. Our preliminary data (Supplementary information, Fig. S2) showed that remdesivir also inhibited virus infection efficiently in a human cell line (human liver cancer Huh-7 cells), which is sensitive to 2019-nCoV. Chloroquine, a widely-used anti-malarial and autoimmune disease drug, has recently been reported as a potential broadspectrum antiviral drug. Chloroquine is known to block virus infection by increasing endosomal pH required for virus/ cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. Our time-of-addition assay demonstrated that chloroquine functioned at both entry, and at postentry stages of the 2019-nCoV infection in Vero E6 cells (Fig. 1c, d). Besides its antiviral activity, chloroquine has an immune-modulating activity, which may synergistically enhance its antiviral effect in vivo. Chloroquine is widely distributed in the whole body, including lung, after oral administration. The EC90 value of chloroquine against the 2019-nCoV in Vero

5,660 citations

"Efficacy of hydroxychloroquine in p..." refers background in this paper

  • ...The recent publication of results showing the activity of chloroquine (CQ) against SARS-CoV-2 in vitro [7], some experts and researchers also have been recommended the efficacy of this antimalarial drug in patients with COVID-19 [8,9]....

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Journal Article•DOI•
A novel coronavirus outbreak of global health concern.

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Chen Wang, Peter Horby1, Frederick G. Hayden2, George F. Gao3•
University of Oxford1, University of Virginia2, Chinese Center for Disease Control and Prevention3
15 Feb 2020-The Lancet

5,446 citations

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Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.

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Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.

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Frequently Asked Questions (17)
Q1. What are the contributions mentioned in the paper "Efficacy of hydroxychloroquine in patients with covid-19: results of a randomized clinical trial" ?

This study aims to evaluate the efficacy of hydroxychloroquine ( HCQ ) in the treatment of patients with COVID-19. It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 

Based on itscharacteristics of immunity regulation, antithrombotic activity, and inflammation improvement, HCQ has been routinely used in the clinical treatment of systemic lupus erythematosus (SLE) [11]. 

As of March 20, 2020, more than two hundred thousand confirmed cases have been identified globally, for a total of 8778 deaths [5]. 

Other rare adverse reactions caused by HCQ include gastrointestinal reactions, cramps, liver dysfunction, itching, headache, dizziness, insomnia, peripheral neuropathy [13]. 

CQ and its derivatives have been broadly used as immunomodulators in the treatment of systemic lupus erythematosus (SLE) and other rheumatism [12]. 

Pulmonary recovery is defined as three levels: exacerbated, unchanged, and improved, moderately improved when less than 50 % of pneumonia were absorbed, and more than 50 % means significantly improved. 

The data in this study revealed that after 5 days of HCQ treatment, the symptoms of patients with COVID-19 were significantly relieved, manifesting as shorten in the recovery time for cough and fever. 

For adverse effects, it should be noted that there were two patients with mild adverse reactions in the HCQ treatment group, one patient developed a rash, and one patient experienced a headache, none severe side effects appeared among them. 

a total of 4 of the 62 patients progressed to severe illness, all of which occurred in the control group not receiving HCQ treatment. 

Although HCQ has proven to be effective, with advantages of inexpensive and easily accessible, its potential detrimental effects in viral diseases must also be taken seriously. 

Body temperature ≤ 36.6 °C on the surface, ≤ 37.2 °C under the armpit and mouth or ≤ 37.8 °C in the rectum and tympanic membrane; b. Cough from patients’ reports, slight or no cough was in the asymptomatic range. 

In the present study, the reduced risk of progression to severe illness in patients with HCQ treatment also explained the intervention effect of HCQ on the pathological process of the COVID-19. 

Sequencing analysis of throat swabs samples and electron microscope observations indicated a novel coronavirus, which was named SARS-CoV-2 (formerly known as 2019-nCoV) [2]. 

Statistical analyses were performed using Graphpad Prism, version 6.0.62 patients were identified as having COVID-19 and enrolled in this study, none quit (Figure 1). 

To assess the safety and effects of CQ in patients with COVID-19, the authors registered this trial in ChiCTR and chose HCQ (the sulfate and phosphate salts of CQ) as the intervention agent. 

Chest CT with pneumonia; 4. SaO2/SPO2 ratio > 93% or PaO2/FIO2 ratio > 300 mmHg under the condition in the hospital room (mild illness); 5. Willing to receive a random assignment to any designated treatment group and not participating in another study at the same time. 

This trial for SARS-CoV-2 has already been registered in the Chinese Clinical Trial Registry (ChiCTR), the unique identifier: ChiCTR2000029559.