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 International Journal of Antimicrobial Agents 57 (2021) 106216

Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents

journal homepage: www.elsevier.com/locate/ijantimicag

Safety and efficacy of artemisinin-piperaquine for treatment of

COVID-19: an open-label, non-randomised and controlled trial
Guoming Li a,†, Mei Yuan c,†, Haihong Li c, Changsheng Deng b, Qi Wang b, Yexiao Tang b,
Hongying Zhang a, Weisheng Yu b, Qin Xu a, Yuanyuan Zou b, Yueming Yuan a, Jiawen Guo a,
Chunming Jin c, Xiangdong Guan d,∗, Fengjie Xie c,∗, Jianping Song a,b,∗
a
Institute of Science and Technology Park, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China
b
Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
c
Department of Intensive Medicine, Hongqi Hospital affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang, People’s Republic of China
d
Department of Surgical Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China

a r t i c l e i n f o a b s t r a c t

Article history: Background: There are no effective therapies for patients with coronavirus disease-2019 (COVID-19).
Received 13 August 2020
Accepted 24 October 2020 Methods: Forty-one patients with confirmed COVID-19 were enrolled in the study and divided into two
groups: artemisinin-piperaquine (AP) (n = 23) and control (n = 18). The primary outcome were the time
taken to reach undetectable levels of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and
Keywords:
the percentage of participants with undetectable SARS-CoV-2 on days 7, 10, 14, and 28. The computed
Artemisinin
tomography (CT) imaging changes within 10 days, corrected QT interval changes, adverse events, and
Piperaquine
COVID-19 abnormal laboratory parameters were the secondary outcomes.
Antimalarial Results: The mean time to reach undetectable viral RNA (mean ± standard deviation) was 10.6 ± 1.1
SARS-CoV-2 days (95% confidence interval [CI] 8.4–12.8) for the AP group and 19.3 ± 2.1 days (95% CI 15.1–23.5) for
the control group. The percentages of patients with undetectable viral RNA on days 7, 10, 14, 21, and 28
were 26.1%, 43.5%, 78.3%, 100%, and 100%, respectively, in the AP group and 5.6%, 16.7%, 44.4%, 55.6%,
and 72.2%, respectively, in the control group. The CT imaging within 10 days post-treatment showed no
significant between-group differences (P > 0.05). Both groups had mild adverse events.
Conclusions: In patients with mild-to-moderate COVID-19, the time to reach undetectable SARS-CoV-2
was significantly shorter in the AP group than that in the control group. However, physicians should
consider QT interval changes before using AP.
© 2020 The Author(s). Published by Elsevier Ltd.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

1. Introduction firmed deaths worldwide by 23 April 2020. The cumulative num-

ber of confirmed cases exceeded 12 million and deaths exceeded
Coronavirus disease 2019 (COVID-19) is an infectious disease 540 0 0 0 By 09 July 2020 [1].
caused by severe acute respiratory syndrome coronavirus 2 (SARS- Several studies have reported the incubation periods in COVID-
CoV-2). There were 2.55 million confirmed cases and 179 0 0 0 con- 19 to be 3–7 days from the first contact [2,3]. According to China’s
Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Trial
Seventh Edition), COVID-19 patients are usually categorised into
∗
Corresponding authors at: Institute of Science and Technology Park, Guangzhou mild, moderate, severe, and critical, based on their symptoms. A
University of Chinese Medicine, Guangzhou 510405, Guangdong, People’s Republic large number of clinical trials for potential COVID-19 drugs are
of China (Jianping Song); Department of Surgical Intensive Care Unit, The First Af-
underway. Although various treatments – such as antiviral ther-
filiated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Repub-
lic of China (Xiangdong Guan); Department of Intensive Medicine, Hongqi Hospital apy, cell therapy, immunotherapy, and Chinese herbal medicine –
affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang, People’s Re- have shown variable efficacy, no drugs or biologics had been ap-
public of China(Fengjie Xie). proved by the FDA for the treatment of COVID-19 at the time of
E-mail addresses: [email protected] (X. Guan), [email protected] (F. Xie), writing this article [4]. Antivirals such as lopinavir and ritonavir
[email protected] (J. Song).
†
have not shown better antiviral efficacy than standard treatment
Contributed equally and shared joint first authorship.

https://doi.org/10.1016/j.ijantimicag.2020.106216
0924-8579/© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
G. Li, M. Yuan, H. Li et al. International Journal of Antimicrobial Agents 57 (2021) 106216

[5]. The use of the antimalarials chloroquine and hydroxychloro- metabolic diseases; 4) allergy to 4-aminoquinolines; 5) blood sys-
quine is controversial. A few clinical trials have shown that hy- tem diseases; 6) arrhythmia or chronic heart disease; 7) retinal
droxychloroquine has failed to treat COVID-19 [6]. The National In- disease or hearing loss; and 8) mental illnesses or skin diseases
stitute of Health has advised discontinuing the clinical trials in- (including rash, dermatitis, psoriasis).
volving hydroxychloroquine because, although harmless, this drug The COVID-19 patients were categorised according to China’s
is reported to be ineffective [7]. However, studies from China have Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Trial
demonstrated the efficacy and safety of chloroquine in Chinese pa- Seventh Edition) as follows:
tients with COVID-19 [8]. A study from France reported that hy- Mild: mild clinical symptoms with no pneumonia manifestation
droxychloroquine significantly reduced the viral load in patients on CT imaging; Moderate: symptoms such as fever, cough, and res-
with COVID-19, and demonstrated synergistic interactions with piratory symptoms, and pneumonia manifestation on CT imaging.
azithromycin [9]. Researchers are optimistic that a vaccine will
help to lessen this epidemic; however, the development cycle of 2.3. Treatment
a vaccine is long and time-consuming [10,11].
Besides fast-tracking the development of COVID-19-specific AP group: AP (ARTEPHARM Co., Ltd.) was used as an antiviral
treatments, other treatment strategies should also be tested. One and symptomatic treatment. AP was orally administrated with a
such treatment strategy involves the use of drugs that are already loading dose of two tablets (artemisinin 125 mg and piperaquine
in use for different indications – an approach known as drug re- 750 mg) for the first day and followed by a maintenance dose of
purposing. Artemisinin and piperaquine (AP) is a new-generation one tablet/day (artemisinin 62.5 mg and piperaquine 375 mg) for
artemisinin combination therapy (ACT) based antimalarials. The the next six days. The total dose was eight tablets in seven days.
first-line antimalarial drug artemisinin and its derivatives are not Control group: Hydroxychloroquine/Arbidol, according to
only potent antimalarials but also possess considerable antiviral China’s Novel Coronavirus Pneumonia Diagnosis and Treatment Plan
properties [12,13,14]. Artemisinin is reported to reduce the prolif- (Trial Seventh Edition), was mainly used as an antiviral and symp-
eration of the hepatitis B virus [15], hepatitis C virus [16,17], and tomatic treatment. Hydroxychloroquine sulfate (Shanghai Zhongxi
human immunodeficiency virus [18,19]. Piperaquine is a bisquino- Pharmaceutical Co., Ltd.) was orally administered as a loading dose
line antimalarial drug, similar to chloroquine. Piperaquine was first of 800 mg/day for the first three days, followed by a maintenance
synthesised in China in the 1960s and has been widely used in dose of 400 mg daily for the next five days. Arbidol hydrochloride
China and other countries ever since. Chloroquine is not only well- (CSPC Ouyi Pharmaceutical Co., Ltd.) was orally administrated 600
tolerated but also has similar potency against Plasmodium falci- mg/day for eight days, divided into three doses daily.
parum and Plasmodium vivax [20]. Chloroquine is reported to treat When drug doses were completed, positive patients continued
Middle-east respiratory syndrome and atypical respiratory syn- to receive symptomatic treatment, and met the discharge condi-
drome (SARS) [21]. Moreover, in vitro experiments have shown tions when two consecutive tests for nucleic acid became negative.
that chloroquine has an inhibitory effect on SARS-CoV-2 [22]. AP is All the patient were quarantined for 14-day observation after dis-
a fourth-generation ACT, which plays an essential role in the pre- charge. The quarantine restriction was lifted if the tests remained
vention and treatment of malaria. If AP also treats COVID-19, many negative.
countries will benefit, especially the developing countries affected
by malaria. 2.4. Assessment

2. Methods Critical inspection indicators: upper respiratory tract specimens

were obtained daily from each patient, and RT-PCR for SARS-CoV-
2.1. Study design 2 was conducted in the local Center for Disease Control and Pre-
vention or the hospital. The RT-PCR test kits (BioGerm) [23] could
The study was approved by the ethical committee of Hongqi detect the ORF1ab/N gene for SARS-CoV-2 nucleic acid and the ref-
Hospital affiliated to Mudanjiang Medical University (registration erence mean Ct value for detecting the genes was 38. For the FAM
number: 202014). The trial protocol and application documents channel, the HEX/VIC channel, and the ROX channel of RT-PCR, if
were submitted to the China Clinical Trial Registration Center for the Ct value of the two channels was ≤ 38, the result was positive,
online registration (registration number: ChiCTR20 0 0 033049). Ini- otherwise it was negative. The epidemiological characteristics, clin-
tially, this trial was an open-label, randomised, parallel-group, con- ical symptoms, signs, and adverse events were recorded with case
trolled trial intended to compare the efficacy and safety of AP report forms. The clinical features, laboratory findings, and chest
tablets in comparison with hydroxychloroquine to treat patients CT scan data were recorded on case report forms and the hospi-
with mild-to-moderate COVID-19. Due to the rapid control of this tal case report system. The patients who were negative for SARS-
pandemic in China, the number of patients failed to meet the CoV-2 RNA two consecutive times were placed in quarantine for 14
trial requirements. Therefore, the trial was modified to a controlled days.
clinical trial and conducted during the same period. Patients with The conclusion was drawn by the professional imaging doctors
confirmed SARS-CoV-2 infection were divided into two groups. Pa- who compared the before and after images. The main analysis cri-
tients in the first group were treated with AP tablets and those teria were the number of affected lobes, presence of ground-glass
in the second group acted as controls and received hydroxychloro- nodules, patchy/punctate ground-glass opacities, patchy consolida-
quine/Arbidol as antiviral and symptomatic treatments. tion, fibrous stripes, and irregular solid nodules on each CT image
[24].
2.2. Patients ‘The time to undetectable viral RNA’ was defined as the time
between the first dose of drug administration and the time when
Inclusion criteria were: 1) age ≥ 18 years; 2) confirmed SARS- the RT-PCR for SARS-CoV-2 was negative for the first time. The rate
CoV-2 infection in upper respiratory tract specimens by real-time of patients to undetected SARS-CoV-2 by RT-PCR at days 7, 10, 14,
reverse-transcriptase-polymerase-chain-reaction (RT-PCR); 3) sig- 21, and 28 during drug administration, CT images results within
nature on the informed consent form. 10 days, abnormal laboratory index and adverse events were com-
Exclusion criteria were: 1) age < 18 years; 2) pregnancy; 3) pared between the two treatments. To assess the safety of AP, ECG
severe malignancy, heart/liver/kidney disease or poorly controlled (Japanese photoelectric electrocardiograph ECG-1250C six-channel

2
G. Li, M. Yuan, H. Li et al. International Journal of Antimicrobial Agents 57 (2021) 106216

and carrimycin might have certain effects on COVID-19 patients;

however, there was no significant statistical difference between the
two groups (P > 0.05). Herbal medicine was used for symptomatic
treatment in this study and the results showed that there was a
significant between-group difference (P = 0.030 ).

3.2. Overall time to achieve undetectable levels of SARS-CoV-2 RNA

The average time to achieve undetectable SARS-CoV-2 RNA in

the AP group was significantly less than that in the control group
(AP: 10.6 ± 1.1 days (95% CI 8.4–12.8), control: 19.3 ± 2.1 days
(95% CI 15.1-23.5)) (P = 0.001 ) (Figure 2). The percentages of the
patients to achieve undetectable SARS-CoV-2 at days 7, 10, 14, 21,
and 28 during drug administration in the AP group were 26.1%,
43.5%, 78.3%, 100%, and 100%, respectively, while that in the con-
trol group were 5.6%, 16.7%, 44.4%, 55.6%, and 72.2%, respectively
(Table 3). Analysis of these data indicated that the elimination rate
of SARS-CoV-2 RNA in the AP group was significantly higher than
Figure 1. Study flowchart.
that in the control group (RD = 0.28; 95% CI 0.07–0.49) (Figure 3).
The length of hospital stay for the AP group was 13.3 ± 4.8 days
and 21.3 ± 9.1 days for the control group (Table 3). Non of the pa-
automatic analysis of 12 leads) was used to monitor the QT change
tients progressed to the severe form of COVID-19.
before and 3–8 days after treatment in the AP group. Bazett’s for-
mula corrected the QTc algorithm:
 
QTc = QT/ RR∧ 0.5 , and RR = 60/Heart Rate. 3.3. CT imaging

Before treatment, the lungs of 82.6% (19/23) of the patients

2.5. Statistical analysis
in the AP group and 83.3% (15/18) of the patients in the control
group had visible inflammation. The CT imaging changes of the pa-
Qualitative indicators were described by percentage or compo-
tients were analysed within the next 10 days. Improvements in CT
sition ratio for descriptive statistical analysis; the mean and stan-
imaging were detected in 36.8% (7/19) of the AP group patients
dard deviation described the quantitative indicators. For qualitative
and 46.7% (7/15) of the control group patients. A total of 21.1%
data, the χ 2 , Fisher’s exact probability method and the Wilcoxon
(4/19) and 6.7% (1/15) of the patients in the AP and control groups,
rank-sum test were used. The quantitative data conformed to the
respectively, had no significant change. Exacerbations occurred in
normal distribution with the t-test and did not conform to the
10.5% (2/19) of the AP group patients and 13.3% (2/15) of the con-
normal distribution with the Wilcoxon rank-sum test for the two
trol group patients. A total of 31.6% (6/19) of the AP group pa-
groups. The hypothesis test uses a two-sided test uniformly. A P-
tients and 33.3% (5/15) of the control group patients were not re-
value < 0.05 is considered statistically significant. The overall neg-
examined within 10 days (Table 4).
ative conversion probability was estimated by analysing the time
taken by the patient to reach undetectable viral RNA levels. The
Kaplan-Meier method was used for this and the findings were 3.4. Safety analysis
compared with a log-rank test. SPSS19.0 was used to perform sta-
tistical analyses. The adverse reactions in both the groups were mild and dis-
appeared quickly after treatment. Three (13%) patients in the AP
3. Results group and three (17%) patients in the control group encountered
adverse reactions. The adverse reactions in the AP group patients
3.1. Baseline information of participants included nausea, muscle aches and fatigue, while that in the con-
trol group patients included nausea, rash and itching . In the AP
Of 25 patients accepted in the AP group, 23 (92%) completed group, three patients had alanine aminotransferase (ALT) levels
the treatment and were included in the final analysis. Similarly, of > 80 U/L and one patient had aspartate aminotransferase (AST)
22 control group patients, 18 (82%) completed the treatment and levels > 60 U/L post-treatment. In the control group, two patients
were included in the final analysis (Figure 1). The demographic had ALT levels > 80 U/L and one patient had AST levels > 60 U/L
baseline data and clinical characteristics of the patients were sum- post-treatment.
marised in Table 1. The average age of the AP group and control In 17 patients in the AP group, the ECG results indicated that
group patients was 42.7 years and 45.8 years, respectively. A total the average QTc interval value was 411.94 ms before treatment and
of 82.6% of the patients in the AP group and 88.9% of the patients 433.59 ms 3–8 days post-treatment. The average prolongation was
in the control group were diagnosed with moderate COVID-19, and 21.65 ms (95% CI 3.58–39.71 ms) after treatment. Twelve patients
the rest were mild COVID-19 patients. Patients in the two groups (70.59%) with varying degrees of prolongation: six (35.29%) with
were relatively balanced in terms of clinical features, and the lab- mild prolongation (< 30 ms), four (23.53%) with moderate prolon-
oratory indicators also showed no significant difference (P > 0.05). gation (30–60 ms), and two (11.76%) with severe prolongation (>
As there was no treatment to prove that the virus has a specific 60 ms). Furthermore, the paired sample t-test showed significant
effect, based on ethical requirements, other drugs may interfere between-group differences (P < 0.05) (Figure 4).
with the antiviral effect that has been clinically used, as shown in AP treatment did not cause TdP or other arrhythmias in the pa-
the list shown in Table 2. The enumeration of other antiviral drugs tients. The patients with prolonged QT intervals returned to normal
was based on facts and might affect the inevitable factors in evalu- after the treatment was discontinued. ECG changes for the control
ating the efficacy. Interferon α -1b, ribavirin, lopinavir, oseltamivir, group patients were not collected and recorded.

3
G. Li, M. Yuan, H. Li et al. International Journal of Antimicrobial Agents 57 (2021) 106216

Table 1
Baseline demographic and clinical characteristics of the patients.

Characteristicsa AP (n = 23) Control (n = 18) P-value

Age (years) 42.7 ± 11.8 45.8 ± 16.3 0.472

Males (%) 9 (39.1) 6 (33.3) 0.754
Disease severity (%)
Mild 4 (22.2) 2 (1.1) 0.679
Moderate 19 (82.6) 16 (88.9) 0.679
Coexisting conditions (%)
Hypertension 5 6 0.489
Diabetes 3 4 0.679
others 5 5 1.000
Vital signals
Body temperature (°C) 36.6 ± 0.5 36.8 ± 0.7 0.321
Respiratory rate (breaths/min) 19.3 ± 2.0 18.8 ± 1.7 0.345
Pulse (beats/min) 89.7 ± 17.0 87.5 ± 14.5 0.658
Systolic blood pressure (mmHg) 136.5 ± 20.6 143.7 ± 25.0 0.319
Diastolic blood pressure (mmHg) 88.1 ± 17.1 91.5 ± 12.2 0.460
Symptoms
Dyspnoea 0 1 0.439
Dysgeusia 0 1 0.439
Fever 3 7 0.075
Cough 6 8 0.322
Sputum production 3 4 0.679
Fatigue 0 1 0.439
Pharyngalgia 1 3 0.303
Pharyngoxerosis 3 1 0.618
Chest tightness 0 3 0.077
Dizziness 1 0 1.000
Muscular soreness 2 2 1.000
Insomnia 3 1 0.618
Nasal congestion 0 2 0.187
Diarrhoea 0 2 0.187
Laboratory parameters
Alanine aminotransferase (U/L) 24.48 ± 14.00 28.83 ± 21.31 0.436
Aspartate aminotransferase (U/L) 19.39 ± 5.17 20.78 ± 7.38 0.484
Lactate dehydrogenase (U/L) 171.43 ± 41.71 179.94 ± 40.66b 0.523
White cell count (× 10^9/L) 6.41 ± 1.71 5.99 ± 1.84 0.457
Neutrophil count (× 10^9/L) 3.87 ± 1.39 3.97 ± 1.38 0.825
Lymphocyte count (× 10^9/L) 1.97 ± 0.60 1.84 ± 0.81 0.555
Haematocrit 0.42 ± 0.04 0.39 ± 0.05 0.014
Platelet count (× 10^9/L) 262.00 ± 81.31 264.89 ± 83.67 0.912
Total bilirubin (μmol/L) 16.91 ± 6.69 13.12 ± 4.95 0.052
Urea (mmol/L) 3.96 ± 0.73 3.77 ± 1.37 0.601
Creatinine (μmol/L) 58.75 ± 10.09 54.27 ± 12.76b 0.612
Uric acid (μmol/L) 331.17 ± 87.98 278.06 ± 95.72 0.072
Creatine kinase (μmol/L) 72.22 ± 42.71 54.50 ± 33.29 0.241
Myoglobin (ng/mL) 31.29 ± 10.85 36.58 ± 11.95 0.146
Troponin 1 (μg/L) 0.63 ± 0.18 0.53 ± 0.22 0.111

Abbreviations: AP, artemisinin-piperaquine; control, hydroxychloroquine/Arbidol.

a
± values are means ± SD.
b
Lactate dehydrogenase and creatinine with 5.6% (1/18) missing data.

Table 2 share the research data to help in meeting the urgent treatment
Other antiviral treatments for the two groups.
needs.
Treatments N (%) AP (n = 23) Control (n = 18) P-value In AP treatment, artemisinin is reported to have a fast and com-
Interferon α -1b 12 (52.2) 6(33.3) 0.343 plete oral absorption, widespread distribution, rapid excretion, and
Hydroxychloroquine 0 (0) 5 (27.8) 0.011 a short half-life (1.93 hours) [25]. However, piperaquine has a long
Arbidol 0 (0) 15 (83.3) < 0.001 half-life (11.7 days) and a slow elimination rate [26]. Continuous
Carrimycin 0 (0) 3 (16.7) 0.077 administration of AP might result in toxicity and cause QT pro-
Oseltamivir 2 (8.7) 0 (0) 0.495
longation [27]. Therefore, after the first dose of two tablets was
Ribavirin 7 (30.4) 2 (11.1) 0.254
Lopinavir 2 (8.7) 0 (0) 0.495 administered, one tablet a day was chosen to minimise the side
Lianhua Qingwen capsules 18 (78.3) 12 (66.7) 0.489 effects and maximise the efficacy of artemisinin.
Herbal 23 (100) 14 (77.8) 0.030 Treatment of COVID-19 patients with herbal medicine such as
Abbreviations: AP, artemisinin-piperaquine; control, hydroxychloro- Lianhua Qingwen and Huoxiang Zhengqi significantly alleviates the
quine/Arbidol. patient’s symptoms and improves prognosis without having seri-
ous adverse reactions, but has not been found to significantly con-
tribute to viral assay findings [28,29,30]. Based on this, the focus of
4. Discussion this study was that AP could significantly shorten the time to reach
undetectable SARS-CoV-2. Due to the use of herbal medicine and
Although this study has various limitations, including that of other symptomatic treatment measures, no further analysis and in-
insufficient sample size and trial design, it was decided to publicly ferences were made on the improvement of clinical symptoms.

4
G. Li, M. Yuan, H. Li et al. International Journal of Antimicrobial Agents 57 (2021) 106216

Figure 2. Kaplan-Meier curves for the time taken to achieve undetectable viral RNA levels in different treatment groups.

Figure 3. Overall time taken to achieve undetectable viral RNA levels in different treatment groups.

Table 3
The time to undetectable viral RNA in patients.

AP (n = 23) Control (n = 18) P-value

Time to undetectable viral RNA in days (Mean ± SD) 10.6 ± 1.1 19.3 ± 2.1 < 0.005
Patients with undetectable viral RNA, N (%)
Day 7 6 (26.1) 1 (5.6) 0.112
Day 10 10 (43.5) 3 (16.7) 0.095
Day 14 18 (78.3) 8 (44.4) 0.049
Day 21 23 (100.0) 10 (55.6) < 0.005
Day 28 23 (100.0) 13 (72.2) 0.011
Duration of hospitalisation (days, mean ± SD) 13.3 ± 4.8 21.3 ± 9.1 < 0.005

Abbreviations: AP, artemisinin-piperaquine; control, hydroxychloroquine/Arbidol.

COVID-19 spreads from human to human through droplets, con- similar effect on lung improvement as the control group. As there
taminated hands or surfaces. SARS-CoV-2 has an incubation time are no effective antiviral drugs, it is recommended that AP be used
of 2–14 days. The spread index of this virus, as estimated by most as eight tablets in seven days for patients with mild-to-moderate
studies, is between 2.24 and 3.58, which is slightly higher than COVID-19. For regions lacking medical facilities, AP is also recom-
SARS [31]. COVID-19 can quickly progress from mild to severe [32]. mended during isolation and quarantine periods, if the condition
Traditional public health measures – including isolation, quaran- of the patient worsens. For the patients with suspected close con-
tine, social distancing, and community containment – are effective tacts of COVID-19, AP is recommended (eight tablets within seven
in curbing this pandemic [33]. days) as a precautionary treatment.
This study found that AP shortens the time the virus remains in SARS-CoV-2 directly infects endothelium and causes immune
the body. CT imaging results within 10 days of taking AP showed a cell recruitment that results in extensive endothelial dysfunction

5
G. Li, M. Yuan, H. Li et al. International Journal of Antimicrobial Agents 57 (2021) 106216

Table 4
Computed tomography imaging changes in patients.

After (≤ 10 days)
Group/casesBefore Improved No significant change Exacerbation No review

AP 19 7 4 2 6
Control 15 7 1 2 5

Abbreviations: AP, artemisinin-piperaquine; control, hydroxychloroquine/Arbidol.

a
AP group: four cases had no significant inflammatory reaction; control group: two
cases had no significant inflammatory reaction, and one case had unrecorded.
χ test by Fisher’s exact probability method showed that P = 0.669, no significant
b 2

between-group difference.

cial Project (2018ZX09303008) and Bureau of Traditional Chinese

Medicine Project of Guangdong Province, China (No. [2019]43).
Competing Interests: The funding agencies had no role in study
design, data collection, and analyses, decision to publish, or prepa-
ration of the manuscript
Ethical Approval: Hongqi Hospital affiliated with Mudan-
jiang Medical University (Registration Number: 202014) and
China Clinical Trial Registration Center (Registration Number:
ChiCTR20 0 0 033049).
Author contributions: G. Li and M. Yuan contributed equally to
this study. X. Guan, F. Xie, C. Deng, and J. Song designed, organised
and directed the trial. X. Guan, F. Xie, M. Yuan, H. Li, and C. Jin
carried out the fieldwork. G. Li, H. Li, M. Yuan, Q. Wang, X. Tang,
Figure 4. Electrocardiogram monitoring of the corrected QT interval change in the
H. Zhang Y. Zou, Y. Yuan, J. Guo, and W. Yu collected and analysed
artemisinin-piperaquine group.
∗
Paired sample t-test showed significant differences in the artemisinin-piperaquine the data. G. Li, Q. Xu, C. Deng, and J. Song wrote and revised the
(AP) group between before treatment and 3–8 days after treatment (P = 0.011 ). manuscript. All authors read and approved the final manuscript.

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