REVIEW

Perspectives on the Early Quality of Evidence Guidingthe Therapeutic Management of SARS-CoV-2:A Systematic Literature Review

Kaushik Subramanian . Anuradha Nalli . Vinitha Senthil .

Saurabh Jain . Aravind Nayak . Amit Bhat

Received: June 30, 2020 / Published online: August 18, 2020� Springer Healthcare Ltd., part of Springer Nature 2020

ABSTRACT

Background: The severe acute respiratory syn-drome coronavirus 2 (SARS-CoV-2) outbreak is aserious health concern. Repurposing of existingdrugs indicated for other conditions seems to bethe first choice for immediate therapeuticmanagement. The quality of early evidencefavoring the different treatment options needsto be apprised for informed decision-making.Methods: In this systematic literature review,we apprised the quality of available evidence fordifferent therapeutic options and also the basisfor different treatment guidelines. To include allstudies that are in different stages of publica-tion, we also included studies from the preprintservers BioRxiv and MedRxiv and publishedstudies from PubMed.

Results: We retrieved 5621 articles and inclu-ded 22 studies for the systematic review. Basedon our study, chloroquine/hydroxychloro-quine, either alone or in combination withazithromycin, remdesivir, corticosteroids, con-valescent sera, ritonavir/lopinavir, tocilizumaband arbidol were evaluated as therapeuticoptions. The data from different study designsreveal contradictory findings except for conva-lescent sera for which the evidence available isonly from case series. Based on this early evi-dence, various national guidelines recommendremdesivir, convalescent sera, corticosteroidsand hydroxychloroquine in different subsets ofpatients.Conclusion: Establishing consensus withrespect to the end points to be assessed for res-piratory viruses may enhance the quality ofevidence in case of future pandemics. The sys-tematic review highlighted the lacuna andmethodologic deficiency in early clinical evi-dence and included an update on differenttherapeutic management guidelines. Furtherclinical evidence from the ongoing trials maylead to evolution of treatment guidelines withthe addition of more therapeutic options.

Keywords: Clinical cure; Evidence; Infectiousdisease; SARS-CoV-2; Treatment options;Virological cure

Digital Features To view digital features for this articlego to https://doi.org/10.6084/m9.figshare.12722258.

K. Subramanian � A. Nalli � V. Senthil � S. Jain �A. NayakIndegene Pvt Ltd, Bengaluru, India

A. Bhat (&)Indegene Lifesystems Consulting (Shanghai) Co.Ltd, Shanghai, Chinae-mail: amit.bhat@indegene.com

Adv Ther (2020) 37:4107–4131

https://doi.org/10.1007/s12325-020-01460-5

Key Summary Points

The quality of early evidence favoring thedifferent treatment options needs to beapprised for informed decision-making.

We performed a comprehensivesystematic literature search and appraisalof early clinical evidence for thetherapeutic management of SARS-CoV-2infection.

An overview on the difference inrecommendations and the evidence basefor arriving at the recommendations byvarious guidelines have been provided.

The insights from quality of early evidencewill also assist in mounting a betterresponse to future pandemics.

INTRODUCTION

The severe acute respiratory syndrome coron-avirus 2 (SARS-CoV-2) outbreak, which startedas a cluster of pneumonia cases in Wuhan,China, in December 2019 was declared a pan-demic by the World Health Organization(WHO) on March 11, 2020 [1]. As per the datafrom the WHO, as of May 31, 2020, it hadinfected 5.9 million people globally, withapproximately 3,67,000 people succumbing tothe infection [2]. After isolation and sequenceanalysis, the causative virus was grouped intothe coronavirus (CoV) family, consisting of RNAviruses that had already caused three differentoutbreaks of pneumonia in the last 2 decades.The severe acute respiratory syndrome (SARS)that broke out in 2003 was caused by SARS-CoV,whereas the Middle East respiratory syndrome(MERS) that broke out in 2012 was caused bythe MERS-CoV [3]. The viral etiologic agent wasnamed SARS-CoV-2 by the international viralclassification commission, and the disease wasofficially named COVID-19 by the WHO [4].

Clinical observation with SARS-CoV-2revealed mild illness in a majority of the

patients and severe lung injury or multiorganfailure in approximately 5% of the patients,with a case fatality ratio of 1.4% [5]. Thepathologic findings in severely or critically illpatients revealed manifestations of shock andsepsis, which is hypothesized to be caused bythe virus-induced ‘‘cytokine storm’’ [6]. Thelevels of proinflammatory cytokines andchemokines, including tumor necrosis factor(TNF)-a, interleukin (IL)-1b, IL-6, granulocyte-colony-stimulating factor, interferon-gamma-induced protein-10, monocyte chemoattractantprotein-1 and macrophage inflammatory pro-teins 1-a, were reported to be elevated fromearly clinical observations, substantiating the‘‘cytokine storm’’ hypothesis. In cases with mildinfection, the resident macrophages in the lunginitiate an inflammatory response culminatingin the successful containment of the replicationof SARS-CoV-2. However, in patients with sev-ere COVID-19 infection, the pathologic findingsrevealed the impairment of the epithelial-en-dothelial barrier, leading to a large exudate intothe alveolar cavity [6]. The disruption of theendothelial lining initiates a vicious cycle oftissue damage because of the inflammatoryresponse facilitated by the accumulation ofregional macrophages, neutrophils and lym-phocytes, resulting in a ‘‘cytokine storm.’’ Apartfrom the epithelial cells, virus multiplication inlung capillary endothelial cells has also beenreported, which may lead to exudation ofplasma in the alveolar cavity leading tomicrovascular dysfunction. Abnormal coagula-tion leading to disseminated intravascularcoagulation has also been reported in themajority of fatal cases suggesting coagulopathydue to viral sepsis as a possible terminal clinicalmanifestation. The suggested reasons for coag-ulopathy in COVID-19 patients include but arenot limited to viral sepsis, cytokine storm andmulti-organ failure [4, 7]. The incidence ofvenous thromboembolism is also reported to behigh in COVID-19 patients treated in theintensive care unit (ICU), and hence multipletreatment guidelines recommend prophylactictreatment for venous thromboembolism tominimize fatal outcomes [8].

Elderly patients and patients with comor-bidities are more susceptible to severe COVID-

4108 Adv Ther (2020) 37:4107–4131

19 infection [9]. The current case fatality rate ofCOVID-19 is lower than during the 1918 influ-enza pandemic but higher than during the 1957influenza pandemic [10]. However, among therecent outbreaks of CoV infections (SARS-CoVand MERV), SARS-CoV-2 was found to be muchmore adoptable to different geographic loca-tions with a higher propensity for person-to-person transfer [11].

The typical response to a pandemic involvesboth short- and long-term plans tominimize thecase fatality rate and reduce the response time forfuture pandemics [11]. The current strategies forreducing fatality mainly involve symptomaticmanagement and therapeutic interventions [4].The choices available for therapeutic manage-ment weremainly based on immunemodulatorsacting on inflammatory tissue damage andantiviral drugs. Although immune modulatorscan minimize the inflammatory effects, theymay suppress the innate immune responses,leading to delay in viral clearance [11]. Antiviraldrugs that were proven to be effective in thetreatment of RNA virus infection are currentlybeing explored as possible treatment options.However, in the era of evidence-based medicine,the response to a pandemic typically involvesrepurposing existing drugs targeting specificsteps in the pathogenesis. The early evidencebase for the successful treatment of COVID-19may provide insights into mounting a responseto future pandemics. Furthermore, the gaps anddrawbacks in the early evidencemay also provideinsights into mounting appropriate responseswith respect to the generation of clinical evi-dence in case of future pandemics. Unlike previ-ous pandemics, the current one is in the era ofevidence-based medicine wherein the responsesby various national and international nodalorganizationswill be based only on the quality ofevidence. Furthermore, unlike other therapyareas, in case of pandemics, the treatmentguidelines may undergo rapid paradigm shifts asthe clinical evidence landscape gains maturitywith respect to treatment options and end pointsfor assessing efficacy. Hence, in this presentstudy, we evaluated the quality of early clinicalevidence currently guiding the treatment strate-gies for COVID-19 and the therapeutic recom-mendations of different treatment guidelines.

We also provided a perspective on the quality ofearly evidence and its probable utility for futureresponses to pandemics.

METHODS

This systematic literature review aimed toanswer the following questions: What are thedifferent pharmacologic interventions used inthe therapeutic management of patients withCOVID-19 infection? What is the quality of theevidence on which the different pharmacologicinterventions currently practiced in clinicalsettings for the therapeutic management ofCOVID-19 are based? Which drug/pharmaco-logic interventions used for the therapeuticmanagement of patients with COVID-19 havesufficient evidence to support their use in clin-ical practice?

Data Sources and Searches

To ensure the retrieval of all relevant studies, wesearched PubMed with a broad key word‘‘COVID-19.’’ We also included COVID-19 stud-ies in preprint servers, such as MedRxiv andBioRxiv (https://connect.biorxiv.org/relate/content/181). Duplicate studies were removed,and a consolidated Excel sheet was prepared forscreening. Any study evaluating a therapeuticdrug in in vivo or in vitromodelwas considered arelevant evidence base and graded based on thehierarchyof an evidence-based pyramid into pre-clinical, case report, case series, cross-sectional,retrospective cohort, prospective cohort, ran-domized controlled trials (RCTs), meta-analysisand systematic reviews. This systematic literaturereview was registered in Prospero(CRD42020180148). This article is based on pre-viously conducted studies and does not containany studies with human participants or animalsperformed by any of the authors.

Study Selection

The systematic review yielded a total of 4027articles from PubMed and 1591 articles frompreprint servers (Fig. 1). Primary screening with

Adv Ther (2020) 37:4107–4131 4109

the title and abstract revealed a total of 569relevant articles. On the basis of the full-textscreening, a total of 22 studies (Table 1) were

included for the evidence synthesis. The studiesincluded for appraisal ranged from case reportsto RCTs.

Fig. 1 PRISMA study selection flowchart

4110 Adv Ther (2020) 37:4107–4131

Data Extraction and Quality Assessment

The evidence was categorized as very low, low,moderate and strong as per the Grading ofRecommendations Assessment, Developmentand Evaluation (GRADE) evidence profile(Table 2). As per the GRADE system, evidencefrom RCTs was considered to be strong evi-dence, which is down-rated if there are seriouslimitations, imprecision, inconsistency, indi-rectness or publication bias. Observationalstudies are rated as low quality and up-rated ifthe magnitude of the effect is large, has mini-mal confounders and there is a dose-dependenteffect [12].

Data Synthesis and Analysis

The evidence base was individually rated fordifferent end points within a single study.Studies synthesizing the previous evidence basealong with the expert opinions were also con-sidered as an evidence base. The efficacy endpoints considered in pre-clinical studies inclu-ded reduction in viral copy numbers evaluatedby real-time polymerase chain reaction (RT-polymerase chain reaction [PCR]) and lack ofviral nucleoprotein assessed by immunofluo-rescence. However, in case of clinical studies,the various end points of efficacy assessed wereeither clinical cure (time to body temperaturenormalization, duration of cough, death orclinical worsening of disease) or virologic cure(negative RT-PCR).

RESULTS

Pharmacologic Interventions

Based on the systematic review of publishedevidence, the different pharmacologic inter-ventions explored for the therapeutic manage-ment of patients with COVID-19 werechloroquine/hydroxychloroquine, remdesivir,arbidol, lopinavir, ritonavir, glucocorticoids,immune modulators, immunoglobulin/plasmatherapy, tissue plasminogen activator, recom-binant erythropoietin, tocilizumab, baricitinib,

ivermectin, tetracyclines, statins, homohar-ringtonine and metronidazole. All the drugsthat have been explored as therapeutic optionswere previously used for the treatment of otherclinical conditions. Hence, the evidence basedoes not follow the conventional pre-clinical-early clinical (phases I and II) phase III studies.On the contrary, the drugs are repurposed, andhence the main aims of later-stage clinical trialsare to reposition the drug for COVID-19 (repo-sitioning clinical trials) [13].

Chloroquine and Hydroxychloroquine

Chloroquine is a 9-aminoquinoline, which is aweak base and facilitates an antimicrobial effectby increasing the pH of acidic vesicles. It hasbeen safely used for the treatment of malaria,amoebiasis and autoimmune diseases [14]. Thefirst evidence of its activity against CoV wasprovided by Vincent et al. in Vero E6 cellsagainst SARS-CoV. They confirmed the pro-phylactic effect of chloroquine in Vero E6 cellsthat were pretreated with 10 lM of chloroquine,which reduced the infectivity by 100% com-pared with the control. Similarly, the additionof 0.1–1 lM of chloroquine after infectionreduced the infection by 50%, suggesting theprobable therapeutic effect of chloroquine inSARS-CoV infection [14]. The anti-SARS-CoV-2activity of chloroquine was assessed by Wanget al. in the Vero E6 cell line. The time-of-ad-dition assay suggested a probable role ofchloroquine at the entry and post-entry stagesof SARS-CoV-2 infection. The effective concen-tration (EC90) was found to be 6.90 lM, which isclinically achievable with the administration of500-mg chloroquine [15]. In pharmacokineticmodeling studies, hydroxychloroquine, whichis an analog of chloroquine, was found to bemore potent than chloroquine with a bettersafety profile [16].

The first clinical evidence of efficacy wasreported by Gautret et al. from a cohort ofFrench patients who were treated with 600 mgof hydroxychloroquine. The study included 42patients (26 patients treated with hydroxy-chloroquine and 16 patients in the controlgroup) who were confirmed to be positive for

Adv Ther (2020) 37:4107–4131 4111

Table

1Earlyclinicalevidence

forthetreatm

entof

SARS-CoV

-2

S. no.

Stud

yname

Stud

ytype

Intervention

(n)

Dose

Con

trol

grou

p(n)

Dose

Outcome/

endpo

ints

Con

clusion

1Gautret

etal.

[17]

Prospectivecohort

study

Hydroxychloroquinealone

orin

combination

with

azithrom

ycin

(26)

600-mghydroxychloroquine

daily

and500-mg

azithrom

ycin

onday1

followed

by250mgfordays

2–5

Supportive

care

(16)

–Virologic

cure

Favorstreatm

entwith

azithrom

ycin

2Chenetal.[21]

Prospectively

rand

omized

study

Hydroxychloroquine(15)

400-mghydroxychloroquine

for

5days

plus

conventional

treatm

ent

Conventional

supportive

treatm

ent

(15)

–Virologic

cure

Nosignificant

difference

inthe

ratesof

virologiccure

3Zhaow

eiChen

etal.[18]

Randomized

controlledstudy

Hydroxychloroquine(31)

400-mghydroxychloroquine

for

5days

Standard

supportive

care

(31)

–Virologicand

clinical

outcom

es

Treatmentwith

hydroxychloroquine

significantlyim

proved

virologiccure

andalleviation

ofclinicalsymptom

s

4Molinaet

al.

[22]

Single-arm

,prospective,

cohortstudy

Hydroxychloroquineand

azithrom

ycin

(11)

600-mghydroxychloroquine

daily

for10

daysand500-mg

azithrom

ycin

onday1

followed

by250mgfordays

2–5

–Virologic

cure

Novirologiccurein

majorityof

thepatients

5Chorinet

al.

[20]

Single-arm

study

Hydroxychloroquine(84)

–Safety

Hydroxychloroquineextend

edtheQTinterval,increasing

therisk

ofarrythmia

6Millionet

al.

[19]

Single-arm

,retrospective,

cohortstudy

Hydroxychloroquineand

azithrom

ycin

(1061)

200mg3times

adayfor

10days

and500-mg

azithrom

ycin

onday1

followed

by250mgfordays

2–5

–Virologicand

clinical

cure

Highratesof

virologiccure

and

clinicalalleviationof

symptom

swereobserved

inpatients

7Magognoli

etal.[23]

Retrospective,

propensity-

score-matched

cohort

Hydroxychloroquineand

azithrom

ycin

(210)

Not

available

Supportive

care

(158)

–Death

and

ratesof

ventilation

Low

erratesof

deathin

the

controlgroup

Similarratesof

ventilation

intheintervention

andcontrol

groups

8Tanget

al.[24]

Randomized

controlledstudy

Hydroxychloroquineplus

standard

ofcare

(75)

1200

mgdaily

for3days

followed

by800mgdaily

Standard

ofcare

alone(75)

–Virologic

cure

Virologiccureratesweresimilar

inboth

theintervention

and

controlgroups

after28

days

oftreatm

ent

4112 Adv Ther (2020) 37:4107–4131

Table

1continued

S. no.

Stud

yname

Stud

ytype

Intervention

(n)

Dose

Con

trol

grou

p(n)

Dose

Outcome/

endpo

ints

Con

clusion

9Holshue

etal.

[28]

Casereport

Rem

desivir(1)

Not

available

––

Virologic

cure

Reduction

inviralload

observed;response

might

bedueto

immun

ityor

supportive

care

10Grein

etal.

[29]

Single-arm

,prospective

cohort

Rem

desivir(61)

200mgon

day1and100mg

fordays

2–9

––

Clin

icalcure

68%of

thepatientsexperienced

clinicalim

provem

entof

symptom

s

11Wanget

al.

[30]

Randomized

controlledtrial

Rem

desivir(158)

200mgon

day1and100mg

fordays

2–9

Supportive

care

(79)

-Clin

icalcure

Nosignificant

difference

inthe

timeto

clinicalim

provem

ent

amongthegroups

12Zha

etal.[34]

Prospectivecohort

Corticosteroid(11)

40-m

gmethylpredn

isoloneonce

daily

ortwiceaday

Supportive

care

(20)

–Clin

icalcure

Nosignificant

improvem

entin

patientstreatedwith

corticosteroids

13Wanget

al.

[36]

Prospectivecohort

Early,low

-dose,

corticosteroids(26)

1–2mg/kg/day

for5–

7days

Supportive

care

(20)

Clin

icalcure

Significant

improvem

entin

patientstreatedwith

corticosteroids

14Luet

al.[37]

Retrospective

cohort

Adjuvantcorticosteroid

(151)

hydrocortisone-equivalent

dosage

range:100–

800mg/d

Supportive

care

(93)

–Clin

icalcure

Nosignificant

difference

among

thetreatm

entgroups

15Shen

etal.[38]

Caseseries

Convalescentplasma(5)

[1:1000

endpointdilution

titer

–Virologicand

clinical

cure

Resolutionof

clinicalsymptom

sandreductionin

viralload

16Duanetal.[39]

Caseseries

Convalescentplasma(10)

[1:640neutralizingantibody

titer

–Virologicand

clinical

cure

Resolutionof

clinicalsymptom

sandreductionin

viralload

17Young

etal.

[40]

Casereport

Convalescentplasma(2)

Opticaldensityof

IgG

of0.586

dividedinto

2dosesat

12-h

interval

–Virologicand

clinical

cure

Resolutionof

clinicalsymptom

sandreductionin

viralload

18Zhu

etal.[44]

RCT

Arbidol

(16)

0.2-garbidol3times

aday

Lopinavir/

ritonavir

(34)

400mg/100mgof

lopinavir/ritonavir

twiceadayforaweek

Virologic

cure

Arbidolissuperior

incaseswith

mild-to-moderateSA

RS-

CoV

infection

19Liet

al.[45]

RCT

Arbidol

andlopinavir/

ritonavir(69)

200-mglopinavirand50-m

grotinavirtwiceadayor

200mgarbidol3

timesaday

Noantiviral

drug

(17)

–Virologic

cure

Nosignificant

difference

among

thetreatm

entgroups

Adv Ther (2020) 37:4107–4131 4113

SARS-CoV-2 by RT-PCR. Of the 20 patientstreated with hydroxychloroquine available forefficacy assessment, 14 (70%) patients experi-enced virologic cure after 6 days of treatment,whereas only 2 (12.5%) patients in the controlgroup were negative for SARS-CoV-2 after 6 daysof treatment. A subgroup of patients in thehydroxychloroquine group was also treatedwith azithromycin (6 patients), and all of themexperienced virologic cure, suggesting a betterefficacy for hydroxychloroquine in combina-tion with azithromycin than hydroxychloro-quine alone (100% vs. 57%, respectively) [17].

The first evidence of the efficacy of hydrox-ychloroquine from an RCT was publishedrecently in the preprint server MedRxiv. Thestudy recruited 62 patients positive for SARS-CoV-2 and randomly divided them into the test(hydroxychloroquine) and control (placebo)groups. Comparison of radiologic findingsrevealed that 61.3% of the patients in thehydroxychloroquine group showed significantimprovement, whereas only 16.1% of those inthe control group had significant improvement.The body temperature recovery time was alsosignificantly reduced in the hydroxychloro-quine group (2.2 [0.4] days) compared with thecontrol group (3.2 [1.3] days). Similarly, coughremission time was also significantly reduced inthe hydroxychloroquine group [18].

The efficacy of hydroxychloroquine in com-bination with azithromycin was also reported ina retrospective study involving French patients.A total of 1061 SARS-CoV-2-positive patientstreated with hydroxychloroquine (200 mg 3times a day) in combination with azithromycinwere included in the study (500 mg on day 1followed by 250 mg daily for the next 4 days).Virologic cure and clinical outcomes wereassessed. Approximately 92% of the patientsexperienced virologic cure (viral culture and RT-PCR), and 95% of the patients reported allevia-tion of clinical symptoms. Multivariate analysisrevealed older age (odds ratio [OR] 1.11, 95%confidence interval [CI] 1.07–1.15), selectivebeta-blocking agents (OR 4.16, 95% CI1.19–14.55), angiotensin II receptor blockers(OR 18.40, 95% CI 6.28–53.90) and mediumand high national Early Warning Score (NEWS;OR 9.48, 95% CI 3.25–27.66; OR = 10.05, 95%T

able

1continued

S. no.

Stud

yname

Stud

ytype

Intervention

(n)

Dose

Con

trol

grou

p(n)

Dose

Outcome/

endpo

ints

Con

clusion

20Yeet

al.[43]

Prospectivecohort

Lopinavir/ritonavirplus

adjuvant

treatm

ent(42)

80-m

glopinavirand20-m

gritonavir

Adjuvant

treatm

ent

alone(5)

–Clin

icalcure

Treatmentwithlopinavir/

ritonavirledto

norm

alizationof

body

temperature

21Xuet

al.[41]

Prospectivecohort

Tocilizumab

(20)

400–

800mg

––

Clin

icalcure

Allthepatientsexperienced

norm

alizationof

body

temperature

andwerevery

lowstableafter1dayof

treatm

ent

22Lun

aet

al.[42]

Casereport

Tocilizumab

(1)

8mg/kg

–Clin

icalcure

Patient’s

SpO

2im

proved

from

80to

97%

andthepatient

was

apyrexic

4114 Adv Ther (2020) 37:4107–4131

Table

2GRADEevidence

profile

Outcome

Certainty

assessment

No.

ofpatients

Effect

Certainty

Stud

yID

Stud

ydesign

Riskof

bias

Inconsistency

Indirectness

Imprecision

Other

considerations

Intervention

Com

parator

Relative(95%

CI)

Absolute

(95%

CI)

Mortality

Chenet

al.

[21]

RCT

Serious

Not

serious

Not

serious

Veryserious

None

0/15

0/15

–Verylow

Failure

ofvirologic

clearance

Chenet

al.

[21]

RCT

Serious

Not

serious

Serious

Veryserious

None

2/15

1/15

RR2.0(0.2–2

0)Verylow

Clin

ical

improvem

ent

Zhaow

eiChenet

al.

[18]

RCT

Serious

Not

serious

Serious

Serious

None

25/31

17/31

RR1.47

(1.02–

2.11)

Verylow

Virologiccure

Gautret

etal.

[17]

Prospective

cohort

Very serious

Serious

Not

serious

Serious

None

70%

12.5%

RR16.33

(2.8–9

5.26)

Verylow

Virologiccure

Molinaet

al.

[22]

Single-arm

study

Very serious

Serious

Serious

Serious

None

2/11

––

–Verylow

Mortality

Molinaet

al.

[22]

Single-arm

study

Very serious

Serious

Serious

Serious

None

1/11

––

–Verylow

QT

interval

Chorinet

al.

[20]

Single-arm

study

Very serious

Serious

Serious

Serious

None

11%

––

–Verylow

Mortality

Millionet

al.

[19]

Single-arm

,retrospective,

cohortstudy

Very serious

Serious

Serious

Not

serious

None

8/1061

––

–Verylow

Virologiccure

Millionet

al.

[19]

Single-arm

,retrospective,

cohortstudy

Very serious

Serious

Serious

Not

serious

None

973/1061

––

–Verylow

Mortality

Magognoli

etal.[23]

Retrospective,

propensity-

score-

matched

cohort

Very serious

Not

serious

Not

serious

Not

serious

None

51/210

18/158

RR2.49

(1.39–

4.47)

–Verylow

Rates

ofventilation

Magognoli

etal.[23]

Retrospective,

propensity-

score-

matched

cohort

Very serious

Not

serious

Serious

Not

serious

None

21/210

22/158

RR0.69

(0.36–

1.29)

–Verylow

Adv Ther (2020) 37:4107–4131 4115

Table

2continued

Outcome

Certainty

assessment

No.

ofpatients

Effect

Certainty

Stud

yID

Stud

ydesign

Riskof

bias

Inconsistency

Indirectness

Imprecision

Other

considerations

Intervention

Com

parator

Relative(95%

CI)

Absolute

(95%

CI)

Virologiccure

Tanget

al.

[24]

Randomized

controlled

study

Very serious

Serious

Serious

Not

serious

None

64/75

61/75

RR1.33

(0.56–

3.16)

–Verylow

Clin

icalcure

Holshue

etal.

[28]

Casereport

Very serious

Not

serious

Not

serious

Veryserious

None

1/1

––

–Verylow

Extubationof

mechanical

ventilation

Grein

etal.

[29]

Single-arm

,prospective

cohort

17/30

Verylow

Mortality

Grein

etal.

[29]

Single-arm

,prospective

cohort

Very serious

Serious

Serious

Serious

None

7/61

––

–Verylow

Body temperature

Wanget

al.

[36]

Prospective

cohort

Very serious

Serious

Serious

Serious

None

2.06

±0.28

5.29

±0.70

––

Verylow

Mortality

Luet

al.[37]

Retrospective

cohort

Very serious

Serious

Serious

Serious

None

12/31

5/31

RR3.2

(0.98–

10.89)

–Verylow

Body temperature

norm

alization

Shen

etal.

[38]

Caseseries

Not serious

Not

serious

Veryserious

Not

serious

None

4/5

––

–Verylow

Virologiccure

Shen

etal.

[38]

Caseseries

Not serious

Not

serious

Veryserious

Not

serious

5/5

––

–Verylow

Clin

icalcure

Duanet

al.

[39]

Caseseries

Not serious

Not

serious

Veryserious

Not

serious

10/10

––

–Verylow

Absorptionof

pulmonary

lesions

Duanet

al.

[39]

Caseseries

Not serious

Not

serious

Veryserious

Not

serious

10/10

––

–Verylow

Virologiccure

Young

etal.

[40]

Caseseries

Not serious

Not

serious

Veryserious

Not

serious

2/2/

––

–Verylow

Virologiccure

Zhu

etal.[44]

RCT

Serious

Not

serious

Not

serious

Not

serious

16/16

19/34

RR26.23

(1.45–

472.69)

–Verylow

Virologiccure

Liet

al.[45]

RCT

Serious

Not

serious

Serious

Serious

25/69

7/17

RR0.81

(0.27–

2.39)

–Verylow

4116 Adv Ther (2020) 37:4107–4131

CI 3.16–32.02, respectively) were significantlyassociated with poor clinical outcome. Cardiactoxicity was not reported in the study [19].Although cardiac toxicity was not reported inany of the studies, a study by Chorin et al.reported an extension of the QT interval inSARS-CoV-2-positive patients treated withhydroxychloroquine, suggesting a risk ofarrhythmia [20].

Despite the positive results favoring theusage of hydroxychloroquine with and withoutazithromycin in SARS-CoV-2-positive patients,a prospectively randomized study by Chen et al.reported a lack of significantly different viro-logic cure rates in patients treated withhydroxychloroquine compared with placebo.Other clinical end points such as time to bodytemperature normalization was also similaramong the groups [21]. In another prospectivesingle-arm study conducted by Molina et al., 11consecutive SARS-CoV-2-positive patients trea-ted with hydroxychloroquine were followed upfor the assessment of virologic and clinicaloutcomes. After 6 days of treatment, 80% of thepatients remained virologically positive forSARS-CoV-2 by qualitative PCR, which was incontrast to the earlier studies [17, 21]. This wasfurther reiterated in a recent study with apropensity-score-matched cohort of patientstreated with either hydroxychloroquine aloneor in combination with azithromycin or pla-cebo. The rates of death were lower in thosetreated with placebo (11.4%) compared withthose treated with hydroxychloroquine alone(27.8%) and those treated with hydroxychloro-quine and azithromycin (22.1%). The risk ofmechanical ventilation was similar in all thegroups. Virologic cure and improvement inclinical outcomes were not assessed in thisstudy [23].

In a recent RCT, the efficacy of hydroxy-chloroquine was compared with standard ofcare. The study recruited 150 patients con-firmed to be positive for SARS-CoV-2 and ran-domly treated with hydroxychloroquine plusstandard of care (75 patients) and standard ofcare alone (75 patients). The primary end pointwas virologic cure after 28 days of treatment.Virologic cure probability by 28 days inhydroxychloroquine plus standard of care wasT

able

2continued

Outcome

Certainty

assessment

No.

ofpatients

Effect

Certainty

Stud

yID

Stud

ydesign

Riskof

bias

Inconsistency

Indirectness

Imprecision

Other

considerations

Intervention

Com

parator

Relative(95%

CI)

Absolute

(95%

CI)

Daysto

norm

alization

ofbody

temperature

Yeet

al.[43]

Prospective

cohort

Very serious

Not

serious

Serious

Not

serious

4.8±

1.94

7.3±

1.53

––

Verylow

Body temperature

norm

alization

Xuet

al.[41]

Prospective

cohort

Very serious

Not

serious

Serious

Not

serious

20/20

––

–Verylow

Virologiccure

Lun

aet

al.

[42]

Casereport

Very serious

Veryserious

Not

serious

Not

serious

1/1

––

–Verylow

RRrelative

risk

Adv Ther (2020) 37:4107–4131 4117

85.4% (95% confidence interval [CI]73.8–93.8%), which was similar to that in thestandard of care alone group (81.3%; 95% CI71.2–89.6%) [24]. A summary of the availableevidence for hydroxychloroquine is provided inTable 1.

Currently available early clinical evidenceprovides contradictory findings on the efficacyof hydroxychloroquine in SARS-CoV-2-positivepatients. There are currently 125 clinical trialsregistered in the WHO International ClinicalTrials Registry Platform (ICTRP; https://clinicaltrials.gov/ct2/who_table) and 192 stud-ies registered in clinicaltrials.gov. The results ofthe ongoing studies will provide conclusiveevidence on the efficacy of hydroxychloroquinein the treatment of SARS-CoV-2.

Remdesivir

Remdesivir is a nucleoside analog with provenactivity against RNA viruses causing lethalhemorrhagic fever (Nipah and Ebola). It is anRNA-dependent RNA polymerase inhibitorcapable of inhibiting multiple CoVs [25]. In amouse SARS virus experimental model, theadministration of remdesivir 1 day after theinfection reduced the virus titer in the lungs.Similar findings were also observed with a rhe-sus monkey model of MERV-CoV [25–27]. Thepre-clinical efficacy of remdesivir was confirmedin in vitro studies with Vero E6 cell lines [15].

The probable therapeutic effect of remdesivirin a patient with SARS-CoV-2 was initiallyreported in a case report wherein remdesivir wasused on compassionate grounds. Althoughvirologic improvement and clinical cure wereobserved in the patient, remdesivir was usedonly on the 6th day of admission, and thecontinuous viral load testing revealed that areduction in viral load had begun before theadministration of the drug. Hence, the observedclinical effect might be due to immunity andsupportive treatment [28]. A larger prospectivecohort of patients treated with remdesivir oncompassionate grounds was recently reportedby Grein et al. [29]. Of the 61 patients whoreceived at least one dose of remdesivir, 53patients were available for follow-up. After a

median follow-up of 18 days, 36 patients (68%)had an improvement in oxygen-support class,including 17 of 30 patients (57%) receivingmechanical ventilation. A total of 25 patients(47%) were discharged, and 7 patients (13%)died with a mortality of 18% (6 of 34) amongpatients receiving invasive ventilation and 5%(1 of 19) among those not receiving invasiveventilation [29].

The efficacy of remdesivir was recently eval-uated in an RCT involving Chinese patientscompared with placebo. The study enrolled 237patients (158 to remdesivir and 79 to placebo)and evaluated the clinical improvement up today 28. The results of the study revealed a lackof significant difference in time to clinicalimprovement in patients treated with remde-sivir compared with placebo (hazard ratio, 1.23[95% CI 0.87–1.75]). In patients with symptomsfor B 10 days, remdesivir showed better efficacy(hazard ratio (HR), 1.52 [95% CI 0.95–2.43]),albeit without statistical significance [30].

The early clinical evidence for the efficacy ofremdesivir is inconclusive with only marginalefficacy. But owing to the differences in the endpoints considered in the studies, the precise roleof remdesivir may require larger studies withthe assessment of both virologic and clinicaloutcomes. At present, there are 22 trials regis-tered in clinicaltrials.gov and 13 studies regis-tered in the WHO-ICTRP.

Corticosteroids

Corticosteroids are immune modulators thatsuppress the inflammatory response, therebyminimizing tissue damage. The early observa-tional evidence for the effective use of corti-costeroids stems from the lower prevalence ofSARS-CoV-2 infection in patients with chronicrespiratory disease, suggesting a role for thedrugs given for chronic respiratory disease inreducing the prevalence of SARS-CoV-2 infec-tions in such patients [31]. The early pre-clinicalevidence provided by Matsuyama et al. reportedeffective antiviral activity of ciclesonide ininhibiting the replication of SARS-CoV-2 inepithelial cell lines with an effective concen-tration of 6.3 lM [32]. Despite the anti-

4118 Adv Ther (2020) 37:4107–4131

inflammatory effect provided by corticos-teroids, they also cause immune suppression,delaying viral clearance [33].

A recent prospective cohort study conductedby Zha et al. recruited 31 SARS-CoV-2-positivepatients treated with corticosteroids (11patients) or supportive care. The study found nostatistically significant association betweentreatment with corticosteroids and virus clear-ance time (HR 1.26; 95% CI 0.58–2.74), hospitallength of stay (HR 0.77; 95% CI 0.33–1.78) orduration of symptoms (HR 0.86; 95% CI0.40–1.83) [34]. A recent meta-analysis alsosuggested a higher relative risk for mortality andlonger length of stay in patients with SARS-CoVand MERS-CoV treated with corticosteroids[35].

In a retrospective cohort study conducted byWang et al., 46 SARS-CoV-2-positive patientstreated with either corticosteroids [25] or sup-portive care [19] were analyzed for clinical out-comes. The mean duration for bodytemperature back to the normal range was sig-nificantly shorter in patients treated with cor-ticosteroids compared with those without theadministration of corticosteroids (2.06 ± 0.28vs. 5.29 ± 0.70; P = 0.010). The patients inclu-ded in the study had severe pneumonia andwere treated early with a low dose of corticos-teroid, suggesting a favorable effect of early,low-dose treatment [36]. On the contrary,another observational study conducted by Luet al. reported a limited effect of adjuvanttreatment with corticosteroids in critically illpatients [37].

The early clinical evidence for the treatmentwith corticosteroids remains inconclusive.There are 72 RCTs currently under progress toevaluate the efficacy of different corticosteroidsat different stages of SARS-CoV-2 infection(clinicaltrials.gov).

Immunotherapy with ConvalescentPlasma/Sera

The early evidence of the efficacy of convales-cent plasma/sera was provided by two case ser-ies from China. In the first study, five criticallyill patients with acute respiratory distress

syndrome (ARDS) were administered convales-cent plasma/sera containing neutralizing IgGantibody at a titer of[ 1:1000 that had beenobtained from five patients previously recov-ered from SARS-CoV-2. All the patients were onmechanical ventilation at the time of treatmentand previously treated with antiviral agents andmethylprednisolone. After the treatment withconvalescent plasm/sera, body temperaturenormalized after 3 days in four of the fivepatients, and viral loads also became negativeafter 12 days of treatment. ARDS was resolved infour patients after 12 days of treatment, andthree patients were discharged [38]. In anotherprospective case series, ten patients were treatedwith convalescent plasma/sera with a neutral-izing antibody titer of[ 1:640. The radiologicexamination revealed the resolution of lunglesions after 7 days and virologic cure in sevenpatients [39]. These findings were also substan-tiated by a case report of two elderly patientstreated with convalescent plasma/sera fromSouth Korea. Both the patients had been previ-ously treated with hydroxychloroquine andlopinavir/ritonavir. Both the patients experi-enced virologic cure after 3 days of treatmentwith convalescent plasma/sera. The resolutionof lung lesions was also observed along withalleviation of other clinical symptoms [40].Although the evidence base for immunotherapywith convalescence plasma/sera is supported byonly weak quality evidence, it holds promise forfuture management strategies.

Tocilizumab

Previous studies on MERV-CoV and SARS-CoV-1have revealed the release of a plethora ofcytokines, including IL-6, which was also con-firmed in SARS-CoV-2 infection [41]. Hence,tocilizumab, which is a monoclonal antibodytargeting IL-6, was explored as a treatmentoption in the treatment of cases with severeSARS-CoV-2 infection. The earliest evidence ofits efficacy was provided from a case series by Xuet al. The study included 21 patients (17 severeand 4 critical) who were treated with tocilizu-mab. Irrespective of the disease severity, all thepatients experienced normalization of body

Adv Ther (2020) 37:4107–4131 4119

temperature 1 day after the treatment withtocilizumab. The oxygen saturation (SpO2)levels were also improved significantly, andone-third of patients on ventilator support wereput on a noninvasive ventilator a day after thetreatment. The percentage of lymphocytes andC-reactive proteins also returned to normal inmost patients after 5 days of treatment [41].

In a subsequent case report, tocilizumab wasalso used successfully for treating a patient withsickle cell anemia [42]. The patient was hospi-talized and, on day 1, developed symptoms ofSARS-CoV-2 infection, including fever (38.5 �C)and SpO2 dropping to 91% with crackles atpulmonary auscultation. The patient was trea-ted with antibiotics and hydroxychloroquine ata dosage of 200 mg orally every 8 h while theresults of RT-PCR were awaited. The patient wastreated with 1 pulse of intravenous tocilizumabat a dosage of 8 mg/kg on day 2 after the dete-rioration of symptoms and had a positive resultin RT-PCR for SARS-CoV-2 infection. Thepatient experienced clinical cure with animprovement in SpO2 and was discharged onday 5 [42]. The confounding effect of earlyhydroxychloroquine treatment cannot be ruledout as a possible cause of early clinical cure inthis patient. Further clinical studies are requiredto substantiate the utility of tocilizumab in thetreatment of SARS-CoV-2 patients.

Other Antiviral Drugs

Among the antiviral drugs, lopinavir, ritonavirand arbidol were explored in clinical studiesinvolving SARS-CoV-positive patients. In aprospective cohort study conducted by Ye et al.,47 patients treated with either lopinavir/riton-avir or adjuvant treatment were analyzed forefficacy outcomes. The study reported favorableoutcomes with respect to lowering body tem-perature in patients treated with lopinavir/ri-tonavir compared with adjuvant treatmentalone [43].

In a recent RCT, 50 patients with laboratory-confirmed COVID-19 were treated either withlopinavir/ritonavir (34 cases) or arbidol (16cases). All the patients had mild-to-moderateSARS-CoV-2 infection without ARDS. The

reduction in viral load was the primary endpoint. After 14 days of treatment, virologic curewas observed in all the patients treated witharbidol, but 15 (44.1%) patients treated withlopinavir/ritonavir still had detectable viralload. The study concluded the superior effect ofarbidol over lopinavir/ritonavir in the treat-ment of cases with mild-to-moderate SARS-CoVinfection [44]. In another RCT, 86 patients withmild-to-moderate SARS-CoV-2 infection wererandomly assigned to the lopinavir/ritonavirgroup [33] or the arbidol group [34] or the noantiviral drug group [16] [16]. The primary endpoint was virologic cure. The study reportedsimilar rates and duration of virologic cure in allthree groups, suggesting lack of clinical efficacyof antiviral drugs in the treatment of cases withmild-to-moderate SARS-CoV-2 infection [45].

Early Evidence and Treatment Guidelines

The treatment guidelines provided by differentnodal governmental agencies are evidence-based and are subject to change based on theavailability of newer evidence. They also takeinto account the local availability of drugs andevidence from studies done in specific geogra-phies [46]. Considering the evidence-basednature of treatment guidelines and their impli-cations for patient care, we have included thedifferent treatment guidelines and have alsosummarized the changes they have gonethrough mainly because of the evolution of theclinical evidence landscape. Early treatmentguidelines were limited by their methodologicrestrictions arising from the lack of qualityclinical evidence.

Despite the poor quality of early evidence,multiple treatment options were recommendedby different nodal agencies. WHO had pub-lished guidance document for the therapeuticmanagement of COVID-19 patients in March2020, which was updated in May 2020. Theearly treatment guideline released in March didnot recommend any pharmacologic interven-tion except symptomatic management ofCOVID-19 patients [47]. As per the recentguideline document from WHO, chloroquine/hydroxychloroquine, lopinavir/ritonavir,

4120 Adv Ther (2020) 37:4107–4131

remdesivir, unifenovir, favipiravir, tocilizumaband plasma therapy are recommended only inthe context of clinical trials and glucocorticoidsare recommended in any treatment setting [48].Among the treatment options, hydroxychloro-quine and chloroquine were provided emer-gency use authorization by the Food and DrugAdministration (FDA) for the treatment ofCOVID-19 patients based on early evidence.However, based on the subsequent clinical evi-dence the early use authorizations provided forchloroquine and hydroxychloroquine wererevoked as the adverse events outweighed thepotential benefits [49]. Similarly, remdesivir wasalso given emergency use authorization by theFDA [50].

As per the National Institutes of Health(NIH) guidelines, chloroquine and hydroxy-chloroquine (with and without azithromycin)are not recommended for the treatment ofCOVID-19 patients except in clinical trial set-ting. With respect to remdesivir, the NIHguidelines recommends its use in hospitalizedpatients, and it should be used on priority totreat patients requiring supplemental oxygen.Furthermore, lopinavir and ritonavir were alsonot recommended for routine use in COVID-19patients except in the context of clinical trials.The evidence base for convalescent plasma/serais also not sufficient to recommend in favor ofor against their use in the treatment of COVID-19 patients. Based on the recently publishedRECOVERY trial, NIH recommends the usage ofdexamethasone in patients who either requiresupplemental oxygen or are on mechanicalventilation [51].

As per the updated guidelines from theInfectious Diseases Society of America, hydrox-ychloroquine, chloroquine and azithromycinare recommended only in the setting of a clin-ical trial with a conditional recommendationwith low certainty evidence. Similarly, lopina-vir/ritonavir, convalescent sera and tocilizumabare also recommended only in the context ofclinical trials, whereas corticosteroids are rec-ommended only for severe COVID-19 patientsin routine hospital settings. Corticosteroids arenot recommended for the treatment of patientswith mild-to-moderate SARS-CoV-2. Remdesiviris also recommended for treatment in patients

with severe COVID-19 routine hospital settings[52].

The treatment guidelines released by theChinese National Health Commission have alsoundergone extensive evidence-based changes,and the recent 7th edition was published inMarch 2020. It recommended the use of a-in-terferon atomization inhalation (5 million unitsper time for adults in sterile injection water,twice a day) and lopinavir/ritonavir orally, twocapsules each time twice a day, based on weakevidence. It also recommended 40–80 mg/daymethylprednisolone based on weak evidenceand tocilizumab, convalescent plasma/seratherapy and glucocorticoids were also recom-mended for treatment [53].

The Directorate of Health Services, Govern-ment of India, had released multiple updatedguideline documents pertaining to differentaspects of COVID-19 including therapeuticmanagement. As per the early managementguidelines released in March, off-label use ofhydroxychloroquine and azithromycin wererecommended without any mention aboutspecific target patient groups [54]. Hydroxy-chloroquine was also recommended as chemo-prophylaxis in high-risk healthcare workers andasymptomatic first-degree contacts as per anadvisory released in March 2020. This recom-mendation was based on pre-clinical data, andthe advisory was updated in May 2020 provid-ing observational evidence on the lower inci-dence of COVID-19 in healthcare workers whowere on prophylactic treatment with hydroxy-chloroquine [55]. As per the recent evidence-based guidelines released in July, off-label use ofhydroxychloroquine should be used after dis-cussing the potential implications with patientsand should be used in an early stage of disease.The available evidence is not sufficient to rec-ommend against the use of hydroxychloro-quine. Remdesivir was provided emergency useauthorization and may be used in patientsrequiring supplemental oxygen. Convalescentplasma/sera could be considered in patientswith progressive requirement for supplementaloxygen depending on the availability (4 to13 ml/kg, usually 200 ml single dose givenslowly over not less than 2 h). The guidelinesalso recommend off-label use of tocilizumab in

Adv Ther (2020) 37:4107–4131 4121

mechanically ventilated patients. Unlike otherguidelines, both the early and recent Indianguidelines recommend the use of glucocorti-coids including dexamethasone in patients withprogressive deterioration of oxygenation indi-cators [56].

Apart from the above guidelines, multiplenational guidelines have been released by theaffected countries based on available evidence,consensus and local availability. AccordinglyRussian guidelines recommend lopinavir/riton-avir, recombinant interferon and ribavirin inmoderate-to-severe infections; French guideli-nes recommend lopinavir/ritonavir andhydroxychloroquine; Dutch guidelines recom-mend chloroquine, lopinavir/ritonavir and acombination of chloroquine with remdesivirand lopinavir/ritonavir in severe disease [57].The evidence base for most of these recom-mendations is not strong, and most of theseguidelines did not grade the evidence based onthe GRADE rating.

Recent Evidence

Apart from the early clinical evidence, two RCTsevaluating dexamethasone and remdesivir werepublished recently, after our literature searchtime period. But we have included the trials asthey also constitute an evidence base for recenttherapeutic management guidelines. Since mostof the early studies did not use all-cause mor-tality as a composite end point, the RECOVERYtrial utilized all-cause mortality to evaluate theefficacy of dexamethasone, a glucocorticoid,compared to standard of care. Glucocorticoidsare not recommended by multiple therapeuticmanagement guidelines owing to lack of evi-dence and the profound immunosuppressiveeffects [57]. The RECOVERY trial randomized atotal of 6425 patients to receive either dexam-ethasone (n = 2104) or standard of care(n = 4321). The rates of all-cause mortality weresignificantly lower in the dexamethasone armcompared to standard of care (22.9 vs. 25.7; rateratio: 0.83; P\ 0.0001). The study recruitedpatients with different baseline severity levels,and a prespecified subgroup analysis revealedsignificant reduction in all-cause mortality only

in patients requiring respiratory support atrandomization. This is in line with the anti-in-flammatory activity of dexamethasone, whichmight be pronounced and beneficial only dur-ing specific stages of the disease. In early-stageSARS-CoV 2-positive patients, dexamethasonemight alter the natural disease course [58].

Recently, the preliminary results of theAdaptive Covid-19 Treatment Trial (ACTT-1)that evaluated the efficacy of remdesivir in thetreatment of SARS-CoV was published. The trialrandomized 1063 patients to receive eitherremdesivir (n = 541) or placebo (n = 522) andevaluated the time to recovery with an eight-stage ordinal scale based on the clinical condi-tion at randomization. The overall rate ratio forrecovery after adjusting for baseline ordinalscores was found to significantly favor remde-sivir with an effect estimate of 1.31(P\0.0001). Across different ordinal score cat-egories, a significant recovery rate ratio wasobserved only for patients with an ordinal scoreof 5 (hospitalized, requiring any supplementaloxygen). The HR for mortality was also signifi-cantly favoring the remdesivir group only forpatients with an ordinal score of 5 (HR 0.22,95% CI 0.08, 0.58). However, in the overallpopulation, there was no significant reductionin mortality in the remdesivir arm (HR 0.70;95% CI 0.47, 1.04) [59].

Perspectives on Early Clinical Evidence

The normal workflow in the development oftreatment options for any indication involvespre-clinical to early clinical to late stage clinicaltrials. However, the normal workflow is ham-pered in case of pandemics. Based on the earlyevidence, the therapeutic options available weredrugs attenuating either the immunologicresponse (anti-inflammatory drugs) or the viralload (antiviral agents). Since the pathogenesisof SARS-CoV-2 involves mainly inflammatoryresponses, the most promising drugs are anti-inflammatory drugs. The inflammatoryresponse is also related to the viral load, whichmakes the selection of the ideal end point dif-ficult. From the early evidence and from thetrials in the pipeline, the most common end

4122 Adv Ther (2020) 37:4107–4131

Table

3Treatmentrecommendation

from

differentguidelines

andan

update

onCOVID

-19vaccines

Guidelin

eDrugs

recommended

Con

text

Con

traind

ications

WHO,M

ay,2

020

Chloroquine/hydroxychloroquine,lopinavir/

ritonavir,remdesivir,un

ifenovir,favipiravir,

tocilizum

abandplasmatherapy

Onlyin

thecontextof

RCTs

Nospecific

recommendation

becauseof

lack

of

evidence

Glucocorticoids

Inroutinesettings

COVID

-19TreatmentGuidelin

esPanel,National

Instituteof

Health

,updated,July,2020

Rem

desivir

Hospitalized

patients

Nospecific

recommendation

becauseof

lack

of

evidence

Dexam

ethasone

Patientsrequiring

supplementaloxygen

Lopinavir/ritonavir

Onlyin

thecontextof

RCTs

Guidelin

esfortreatm

entandmanagem

entof

patients

withCOVID

-19,

Infectious

DiseasesSocietyof

America,updatedJune,2

020

Hydroxychloroquine/chloroquine/azithrom

ycin

Onlyin

thecontextof

RCTs

Nospecific

recommendation

becauseof

lack

of

evidence

Lopinavir/ritonavir

Onlyin

thecontextof

RCTs

Convalescentsera

Onlyin

thecontextof

RCTs

Tocilizumab

Onlyin

thecontextof

RCTs

Corticosteroids

PatientswithSevere

COVID

-19,

only

Chinesenationalhealth

commission,7th

edition,March,

2020

a-Interferon

atom

izationinhalation

Based

onseverity

Nospecific

recommendation

becauseof

lack

of

evidence

Lopinavir/ritonavir

Methylpredn

isolon

e

Adv Ther (2020) 37:4107–4131 4123

Table

3continued

Guidelin

eDrugs

recommended

Con

text

Con

traind

ications

Revised

Guidelin

eson

Clin

icalManagem

entof

COVID

-

19,Ind

ianNationalGuidelin

e,July,2

020

Corticosteroids

includingdexamethasone

Patientswith

progressive

deteriorationof

lung

function

Earlypregnancyshould

beterm

inated

Rem

desivir

Patientsrequiring

supplementaloxygen

Convalescentplasma/sera

Patientswith

progressive

requirem

entof

oxygen

Tocilizumab

Mechanically

ventilated

patients

Current

status

ofCOVID

-19vaccines

Vaccine

cand

idate

Spon

sor

Trial

phase

Inactivatedvaccine

Wuhan

Instituteof

BiologicalProducts;China

National

PharmaceuticalGroup

(Sinopharm

)

Phase3

CoronaV

acSinovac

Phase3

Bacillus

Calmette-G

uerin

(BCG)live-attenu

ated

vaccine

Universityof

Melbourne

andMurdoch

Children’sResearch

Institute;Radboud

UniversityMedicalCenter;Faustm

an

Lab

atMassachusettsGeneralHospital

Phase2/3

AZD1222

The

Universityof

Oxford;

AstraZeneca;IQ

VIA

Phase2/3

mRNA-1273

Moderna

Phase2

Ad5-nCoV

CanSinoBiologics

Phase2

Adjuvantrecombinant

vaccinecand

idate

Anh

uiZhifeiLongcom

Biopharmaceutical,Instituteof

Microbiologyof

theChinese

Academyof

Sciences

Phase2

4124 Adv Ther (2020) 37:4107–4131

Table

3continued

Current

status

ofCOVID

-19vaccines

Vaccine

cand

idate

Spon

sor

Trial

phase

BNT162

Pfizer,BioNTech

Phase1/2

BBIBP-CorV

BeijingInstituteof

BiologicalProducts;China

National

PharmaceuticalGroup

(Sinopharm

)

Phase1/2

GX-19

Genexine

Phase1/2

Gam

-COVID

-Vac

Gam

aleyaResearchInstitute,Acellena

Contract

DrugResearchandDevelopment

Phase1/2

Self-am

plifyingRNA

vaccine

ImperialCollege

London

Phase1/2

LUNAR-COV19

ArcturusTherapeuticsandDuke-NUSMedicalSchool

Phase1/2

ZyC

oV-D

Zydus

Cadila

Phase1/2

INO-4800

Inovio

Pharmaceuticals

Phase1

mRNA-based

vaccine

CureV

acPh

ase1

SCB-2019

GlaxoSm

ithK

line,Sanofi,

CloverBiopharmaceuticals,

Dynavax

andXiamen

Innovax

Phase1

COVAX-19

VaxinePtyLtd

Phase1

NVX-CoV

2373

Novavax

Phase1

Plant-basedadjutant

COVID

-19vaccinecand

idate

Medicago;

GSK

;Dynavax

Phase1

Molecular

clam

pvaccine

CSL

;The

Universityof

Queensland

Phase1

Covaxin

BharatBiotech;NationalInstituteof

Virology

Phase1

bacT

RL-Spike

Symvivo

Pre-clinical

PittCoV

acc

UPM

C/U

niversityof

Pittsburgh

School

ofMedicine

Pre-clinical

Measlesvector

vaccine

Universityof

Pittsburgh’sCenterforVaccine

Research

Pre-clinical

Ii-Key

peptideCOVID

-19vaccine

Generex

Biotechnology

Pre-clinical

Recom

binant

vaccine

Vaxart

Pre-clinical

Adv Ther (2020) 37:4107–4131 4125

Table

3continued

Current

status

ofCOVID

-19vaccines

Vaccine

cand

idate

Spon

sor

Trial

phase

LineaDNA

TakisBiotech

Pre-clinical

Ad26.COV2-S

John

son&

John

son

Pre-clinical

AdC

OVID

Altimmun

ePre-clinical

T-COVID

TM

Altimmun

ePre-clinical

Proteinsubunitvaccine

Universityof

Saskatchew

anVaccine

andInfectious

Disease

Organization-InternationalVaccine

Centre

Pre-clinical

Recom

binant

vesicularstom

atitis

virus(rVSV

)vaccine

Merck;IAVI

Pre-clinical

Adenovirus-basedvaccine

Immun

ityBio;NantKwest

Pre-clinical

AAVCOVID

MassachusettsEye

andEar;Massachusetts

GeneralHospital;Universityof

Penn

sylvania

Pre-clinical

Recom

binant

vaccine

Sanofi,

Translate

Bio

Pre-clinical

HaloV

axVoltron

Therapeutics,Inc.;HothTherapeutics,Inc

Pre-clinical

mRNA-based

vaccine

Chulalongkorn

University’sCenterof

Excellencein

Vaccine

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points assessed were a 6- or a 7-point ordinalscale outcome that defines clinical benefit basedon the baseline clinical condition till the end ofthe study or death, whichever is earlier.Depending on the study, a 2- or 3-pointdecrease in the selected ordinal scale was con-sidered a marker of clinical efficacy. However,overall mortality might be the ideal compositeend point that represents clinical benefit in apandemic outbreak. On the contrary, overallmortality might not take into account the ini-tial patient status, thereby confounding theresults. In the prevailing scenario, ordinal-scaleend points as a marker of clinical improvementand virologic cure might be robust indicators ofclinical improvement, but a consensus on theordinal scale with respect to patients with dif-ferent severities of diseases might help inselecting the optimum therapeutic manage-ment strategy based on clinical evidence [60].

A case in point is the issue with the real-world evidence on the efficacy of hydroxy-chloroquine [61]. This was a multi-nationalregistry-based study, which was among theearliest evidence in support of hydroxychloro-quine for the treatment of SARS-CoV-2. How-ever, subsequent clinical trials providedcontradictory results that led to the questioningof the results of the study and subsequentjournal retraction. In our systematic literaturereview, this study was also considered as thiswas early clinical evidence. The availability ofpreprint servers also plays a huge role in dis-semination of early-stage evidence, which is amilieu never faced in the past. Although thisleads to faster dissemination, it can also lead topropagation of junk science. We have alsoincluded evidence from preprint servers tomake a comprehensive appraisal of early-stageevidence. Subsequent to the retraction of theLancet study on hydroxychloroquine, theFrench study published in the preprint serverMedRxiv was also withdrawn. Unlike the jour-nal retractions, preprint retractions do notrequire substantial explanation of the reasonsfor retraction. This further complicates thequality of early evidence [62].

Future Recommendations

The early-stage evidence available does notprovide convincing support in favor of oragainst a particular therapeutic regimen. This ismainly because of the heterogeneity withrespect to the patients, pathogen variants andend points. Considering the fact that the lastfew pandemics were caused by respiratoryviruses, drafting a consensus on the mostappropriate end point will help in improvingthe quality of evidence in future pandemics.Furthermore, despite the availability of RCTs,they were of low quality because of the inherentbias (no data on blinding) and imprecision.Since the field of evidence-based medicine is adynamically evolving field, future studies,especially studies of importance in dealing withmedical emergencies, should be appropriatelydesigned to provide reliable and timely evi-dence. Although the availability of preprintservers facilitates faster dissemination of data,the non-peer-reviewed nature of content needsto be interpreted with caution.

Vaccines hold great promise for the man-agement and control of COVID 19. Currently,42 vaccine candidates are under clinical devel-opment sponsored by academic, industry andgovernmental agencies. Out of 42 candidatevaccines, 24 vaccine candidates are in phase 1–3clinical development (Table 3) [63].

CONCLUSION

The current evidence base available for differenttreatment options provides ambiguous resultsmainly because of the study designs and the endpoints assessed. This is also reflected in the dif-ferent national treatment guidelines that werebased on relatively weak evidence. The system-atic review highlighted the lacuna andmethodologic deficiency in early clinical evi-dence and an update on different therapeuticmanagement guidelines. The results of theongoing clinical studies and well-designed real-world studies will improve the evidence baseand may lead to further evolution of treatmentguidelines with the addition of more therapeu-tic options. Furthermore, a consensus on the

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appropriate end points for efficacy in differentcategories of patient may also improve thequality of evidence in case of future pandemicsof respiratory viruses.

ACKNOWLEDGEMENTS

Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle. The Rapid Service Fee was funded by theIndegene Pvt Ltd.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Kaushik Subramanian, Anu-radha Nalli, Vinitha Senthil, Saurabh Jain, Ara-vind Nayak and Amit Bhat are employees ofIndegene Pvt Ltd.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

REFERENCES

1. Coronavirus Disease (COVID-19)—events as theyhappen [Internet]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen. Cited 14 May 2020.

2. WHO. Coronavirus disease (COVID-19) SituationReport— 114 [Internet]. Available from: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200513-covid-19-sitrep-114.pdf?sfvrsn=17ebbbe_4. May 2020.

3. Ye Z-W, Jin D-Y. Diagnosis, treatment, control andprevention of SARS-CoV-2 and coronavirus disease2019: back to the future. Sheng Wu Gong ChengXue Bao. 2020;36:571–92.

4. Li X, Geng M, Peng Y, Meng L, Lu S. Molecularimmune pathogenesis and diagnosis of COVID-19.J Pharm Anal. 2020;10:102–8.

5. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al.Clinical characteristics of coronavirus disease 2019in China. N Engl J Med. 2020;382:1708–20.

6. Li H, Liu L, Zhang D, Xu J, Dai H, Tang N, et al.SARS-CoV-2 and viral sepsis: observations andhypotheses. The Lancet. 2020;395:1517–20.

7. Liu J, Li S, Liu J, Liang B, Wang X, Wang H, et al.Longitudinal characteristics of lymphocyte respon-ses and cytokine profiles in the peripheral blood ofSARS-CoV-2 infected patients. medRxiv. 2020;2020.02.16.20023671.

8. Middeldorp S, Coppens M, Haaps TF van, FoppenM, Vlaar AP, Muller MCA, et al. Incidence of venousthromboembolism in hospitalized patients withCOVID-19. Journal of Thrombosis and Haemostasis[Internet]. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14888. Cited 24 Jul2020.

9. Nikolich-Zugich J, Knox KS, Rios CT, Natt B, Bhat-tacharya D, Fain MJ. SARS-CoV-2 and COVID-19 inolder adults: what we may expect regardingpathogenesis, immune responses, and outcomes.GeroScience. 2020;1–10.

10. Team TNCPERE. The Epidemiological characteris-tics of an outbreak of 2019 novel Coronavirus dis-eases (COVID-19)—China, 2020. CCDCW.2019;2020(2):113–22.

11. Gates B. Responding to Covid-19—a once-in-a-century pandemic? N Engl J Med. 2020;382:1677–9.

12. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G,Brozek J, et al. GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findingstables. J Clin Epidemiol. 2011;64:383–94.

13. Rosa SGV, Santos WC. Clinical trials on drug repo-sitioning for COVID-19 treatment. Rev PanamSalud Publica [Internet]. 2020;44. Available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105280/. Cited 17 May 2020.

14. Vincent MJ, Bergeron E, Benjannet S, Erickson BR,Rollin PE, Ksiazek TG, et al. Chloroquine is a potentinhibitor of SARS coronavirus infection and spread.Virol J. 2005;2:69.

15. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al.Remdesivir and chloroquine effectively inhibit therecently emerged novel coronavirus (2019-nCoV)in vitro. Cell Res. 2020;30:269–71.

4128 Adv Ther (2020) 37:4107–4131

16. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al.In vitro antiviral activity and projection of opti-mized dosing design of hydroxychloroquine for thetreatment of severe acute respiratory syndromeCoronavirus 2 (SARS-CoV-2). Clin Infect Dis [In-ternet]. Available from: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa237/5801998. Cited 17 May 2020

17. Gautret P, Lagier J-C, Parola P, Hoang VT, MeddebL, Mailhe M, et al. Hydroxychloroquine and azi-thromycin as a treatment of COVID-19: results ofan open-label non-randomized clinical trial. Int JAntimicrob Agents. 2020;105949.

18. Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al.Efficacy of hydroxychloroquine in patients withCOVID-19: results of a randomized clinical trial.medRxiv. 2020;2020.03.22.20040758.

19. Million M, Lagier J-C, Gautret P, Colson P, FournierP-E, Amrane S, et al. Early treatment of COVID-19patients with hydroxychloroquine and azi-thromycin: a retrospective analysis of 1061 cases inMarseille, France. Travel Med Infect Dis2020;101738.

20. Chorin E, Dai M, Shulman E, Wadhwani L, CohenRB, Barbhaiya C, et al. The QT interval in patientswith SARS-CoV-2 infection treated with Hydroxy-chloroquine/Azithromycin. medRxiv. 2020;2020.04.02.20047050.

21. Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, et al. A pilotstudy of hydroxychloroquine in treatment 1129 ofpatients with common coronavirus disease-19(COVID-19) [Internet]. Epistemonikos. Availablefrom: https://www.epistemonikos.org/en/documents/30d0f2552ff5342fbfcd1b09e9bac66d1325b467

22. Molina JM, Delaugerre C, Le Goff J, Mela-Lima B,Ponscarme D, Goldwirt L, et al. No evidence ofrapid antiviral clearance or clinical benefit with thecombination of hydroxychloroquine and azi-thromycin in patients with severe COVID-19infection. Med Mal Infect [Internet]. 2020; Avail-able from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195369/. Cited 17 May 2020

23. Magagnoli J, Narendran S, Pereira F, Cummings T,Hardin JW, Sutton SS, et al. Outcomes of hydroxy-chloroquine usage in United States veterans hospi-talized with Covid-19. medRxiv. 2020;2020.04.16.20065920.

24. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W,et al. Hydroxychloroquine in patients mainly withmild to moderate COVID-19: an open-label, ran-domized, controlled trial. medRxiv. 2020;2020.04.10.20060558.

25. Cao Y, Deng Q, Dai S. Remdesivir for severe acuterespiratory syndrome coronavirus 2 causingCOVID-19: An evaluation of the evidence. TravelMed Infect Dis [Internet]. 2020; Available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151266/. Cited 17 May 2020.

26. de Wit E, Feldmann F, Cronin J, Jordan R, OkumuraA, Thomas T, et al. Prophylactic and therapeuticremdesivir (GS-5734) treatment in the rhesusmacaque model of MERS-CoV infection. PNAS.2020;117:6771–6.

27. Sheahan TP, Sims AC, Leist SR, Schafer A, Won J,Brown AJ, et al. Comparative therapeutic efficacy ofremdesivir and combination lopinavir, ritonavir,and interferon beta against MERS-CoV. Nat Com-mun. 2020;11:222.

28. Holshue ML, DeBolt C, Lindquist S, Lofy KH,Wiesman J, Bruce H, et al. First case of 2019 novelcoronavirus in the United States. N Engl J Med.2020;382:929–36.

29. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E,Castagna A, et al. Compassionate Use of Remdesivirfor Patients with Severe Covid-19. N Engl J Med.2020.

30. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al.Remdesivir in adults with severe COVID-19: a ran-domised, double-blind, placebo-controlled, multi-centre trial. The Lancet. 2020;395:1569–78.

31. Halpin DMG, Faner R, Sibila O, Badia JR, Agusti A.Do chronic respiratory diseases or their treatmentaffect the risk of SARS-CoV-2 infection? LancetRespir Med. 2020;8:436–8.

32. Matsuyama S, Kawase M, Nao N, Shirato K, Ujike M,Kamitani W, et al. The inhaled corticosteroidciclesonide blocks coronavirus RNA replication bytargeting viral NSP15. bioRxiv. 2020;2020.03.11.987016.

33. Russell B, Moss C, Rigg A, Van Hemelrijck M.COVID-19 and treatment with NSAIDs and corti-costeroids: should we be limiting their use in theclinical setting? Ecancermedicalscience [Internet].2020;14. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105332/. Cited 17 May2020.

34. Zha L, Li S, Pan L, Tefsen B, Li Y, French N, et al.Corticosteroid treatment of patients with coron-avirus disease 2019 (COVID-19). Med J Aust.2020;212:416–20.

35. Yang Z, Liu J, Zhou Y, Zhao X, Zhao Q, Liu J. Theeffect of corticosteroid treatment on patients withcoronavirus infection: a systematic review andmeta-analysis. J Infect [Internet]. 2020; Available

Adv Ther (2020) 37:4107–4131 4129

from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195158/. Cited 17 May 2020.

36. Wang Y, Jiang W, He Q, Wang C, Wang B, Zhou P,et al. Early, low-dose and short-term application ofcorticosteroid treatment in patients with severeCOVID-19 pneumonia: single-center experiencefrom Wuhan, China. medRxiv. 2020;2020.03.06.20032342.

37. Lu X, Chen T, Wang Y, Wang J, Zhang B, Li Y, et al.Adjuvant corticosteroid therapy for critically illpatients with COVID-19. medRxiv. 2020;2020.04.07.20056390.

38. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al.Treatment of 5 critically ill patients with COVID-19with convalescent plasma. JAMA. 2020;323:1582–9.

39. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al.Effectiveness of convalescent plasma therapy insevere COVID-19 patients. Proc Natl Acad Sci USA.2020;117:9490–6.

40. Ahn JY, Sohn Y, Lee SH, Cho Y, Hyun JH, Baek YJ,et al. Use of Convalescent Plasma Therapy in TwoCOVID-19 Patients with Acute Respiratory DistressSyndrome in Korea. J Korean Med Sci [Internet].2020;35. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152526/. Cited 18 May2020.

41. Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al.Effective treatment of severe COVID-19 patientswith tocilizumab. PNAS. 2020;117:10970–5.

42. Luna GD, Habibi A, Deux J-F, Colard M, d’Oren-giani A-LPH d’Alexandry, Schlemmer F, et al. Rapidand severe Covid-19 pneumonia with severe acutechest syndrome in a sickle cell patient successfullytreated with tocilizumab. American Journal ofHematology [Internet]. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/ajh.25833. Cited 21 May 2020.

43. Ye X-T, Luo Y-L, Xia S-C, Sun Q-F, Ding J-G, Zhou Y,et al. Clinical efficacy of lopinavir/ritonavir in thetreatment of Coronavirus disease 2019. Eur RevMed Pharmacol Sci. 2020;24:3390–6.

44. Zhu Z, Lu Z, Xu T, Chen C, Yang G, Zha T, et al.Arbidol monotherapy is superior to lopinavir/ri-tonavir in treating COVID-19. J Infect [Internet].2020; Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195393/. Cited 18 May2020

45. Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y, et al. Anexploratory randomized controlled study on theefficacy and safety of lopinavir/ritonavir or arbidoltreating adult patients hospitalized with

mild/moderate COVID-19 (ELACOI). medRxiv.2020;2020.03.19.20038984.

46. Institute of Medicine (US) Committee on Standardsfor Developing Trustworthy Clinical PracticeGuidelines. Clinical Practice Guidelines We CanTrust [Internet]. Graham R, Mancher M, MillerWolman D, Greenfield S, Steinberg E, editors.Washington (DC): National Academies Press (US);2011;Available from: https://www.ncbi.nlm.nih.gov/books/NBK209539/. Cited 24 Jul 2020.

47. Clinical management of severe acute respiratoryinfection (SARI) when COVID-19 disease is sus-pected [Internet]. WHO; 2020. Available from:https://apps.who.int/iris/handle/10665/331446.Cited 24 Jul 2020.

48. Clinical management of COVID-19, interim guid-ance [Internet]. 2020. Available from: https://www.who.int/publications/i/item/clinical-management-of-covid-19

49. Commissioner O of the. Emergency Use Autho-rization. FDA [Internet]. 2020 []; Available from:https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-frame-work/emergency-use-authorization. Cited 24 Jul2020.

50. Commissioner O of the. Coronavirus (COVID-19)Update: FDA Issues Emergency Use Authorizationfor Potential COVID-19 Treatment [Internet]. FDA.2020. Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment. Cited 24 Jul 2020.

51. COVID-19 Treatment Guidelines Panel. Coron-avirus Disease 2019 (COVID-19) Treatment Guide-lines. [Internet]. National Institutes of Health.Available from: https://www.covid19treatmentguidelines.nih.gov/. Cited Jul2020

52. Infectious Diseases Society of America Guidelineson the Treatment and Management of Patients withCOVID-19 [Internet]. Available from: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/. Cited Apr2020.

53. Jin Y-H, Cai L, Cheng Z-S, Cheng H, Deng T, FanY-P, et al. A rapid advice guideline for the diagnosisand treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). MilMed Res. 2020;7:4.

54. Revised Guidelines on Clinical Management ofCOVID—19 [Internet]. Available from: https://www.mohfw.gov.in/pdf/RevisedNationalClinical

4130 Adv Ther (2020) 37:4107–4131

ManagementGuidelineforCOVID1931032020.pdf.Cited Mar 2020.

55. Directorate General of Health Services. Revisedadvisory on the use of Hydroxychloroquine (HCQ)as prophylaxis for COVID-19 infection [Internet].Available from: https://www.mohfw.gov.in/pdf/RevisedadvisoryontheuseofhydroxychloroquineasprophylaxisforSARSCOVID19infection.pdf. Cited May 2020.

56. Directorate General of Health Services. RevisedGuidelines on Clinical Management of COVID—19[Internet]. Available from: https://www.mo-hfw.gov.in/. Cited Mar 2020.

57. Dagens A, Sigfrid L, Cai E, Lipworth S, Cheng V,Harris E, et al. Scope, quality, and inclusivity ofclinical guidelines produced early in the covid-19pandemic: rapid review. BMJ [Internet]. 2020;369.Available from: https://www.bmj.com/content/369/bmj.m1936. Cited 24 Jul 2020.

58. RECOVERY Collaborative Group, Horby P, Lim WS,Emberson JR, Mafham M, Bell JL, et al. Dexam-ethasone in hospitalized patients with Covid-19—preliminary report. N Engl J Med 2020.

59. Beigel JH, Tomashek KM, Dodd LE, Mehta AK,Zingman BS, Kalil AC, et al. Remdesivir for thetreatment of Covid-19—preliminary report. N EnglJ Med 2020.

60. Desai A, Gyawali B. Endpoints used in phase IIIrandomized controlled trials of treatment optionsfor COVID-19. EClinicalMedicine. 2020;23:100403.

61. Mehra MR, Desai SS, Ruschitzka F, Patel AN.RETRACTED: Hydroxychloroquine or chloroquinewith or without a macrolide for treatment ofCOVID-19: a multinational registry analysis. Lan-cet. 2020.

62. Oransky AI. French hydroxychloroquine-COVID-19study withdrawn [Internet]. Retraction Watch.2020. Available from: https://retractionwatch.com/2020/05/21/french-hydroxychloroquine-covid-19-study-withdrawn. Cited 30 Jun 2020.

63. COVID-19 vaccine tracker [Internet]. Availablefrom: https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker.Cited 25 Jul 2020.

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