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\begin{document}

\title{Remdesivir: A critical review}



\author[1]{Zeinab Mohseni Afshar}%
\author[2]{Dariush Hosseinzadeh}%
\author[3]{Arefeh Babazadeh}%
\author[3]{Amirreza Allahgholipour}%
\author[4]{Terence Sio}%
\author[5]{Mark Sullman}%
\author[6]{Kristin Carson-Chahhoud}%
\author[3]{Rezvan Hosseinzadeh}%
\author[3]{Mohammad Barary}%
\author[3]{Soheil Ebrahimpour}%
\affil[1]{Kermanshah University of Medical Sciences}%
\affil[2]{Bogomolets National Medical University}%
\affil[3]{Babol University of Medical Science}%
\affil[4]{Mayo Clinic Arizona}%
\affil[5]{University of Nicosia}%
\affil[6]{University of South Australia}%


\vspace{-1em}



  
  \date{June 13, 2024}


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\selectlanguage{english}
\begin{abstract}
Remdesivir has appeared to be the most effective medication against the
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
and is broadly administered to the coronavirus disease 2019 (COVID-19)
patients around the world. Remdesivir is an RNA polymerase inhibitor
with a broad spectrum of antiviral activities against RNA viruses in
in-vitro and in-vivo models of SARS-CoV, the Middle East respiratory
syndrome (MERS), and SARS-CoV-2. Remdesivir is the first Food and Drug
Administration (FDA) approved anti-SARS-CoV-2 treatment for adult and
pediatric patients and has been used intravenously for patients
requiring hospitalization for COVID-19. However, questions have been
raised about the value of remdesivir in treating COVID-19, and governing
bodies worldwide have been hesitant to approve this medication.
Nevertheless, in the context of the public health emergency and the
urgent need for effective treatments for patients with COVID-19,
remdesivir has been approved by several authorities worldwide. Here, we
discuss characteristics and applications of remdesivir, and various
challenging studies with different outcomes about its efficacy are also
reviewed.%
\end{abstract}%



\sloppy


\textbf{Remdesivir: A critical review}

\textbf{Running title:} A critical review on remdesivir

Zeinab Mohseni Afshar\textsuperscript{1}, Dariush
Hosseinzadeh\textsuperscript{2}, Arefeh Babazadeh\textsuperscript{3},
Amirreza Allahgholipour\textsuperscript{4}, Terence T.
Sio\textsuperscript{5}, Mark J. M. Sullman\textsuperscript{6, 7},
Kristin Carson-Chahhoud\textsuperscript{8}, Rezvan
Hosseinzadeh\textsuperscript{9}, Mohammad Barary\textsuperscript{9, 10},
Soheil Ebrahimpour\textsuperscript{3, *}

\begin{enumerate}
\tightlist
\item
  Clinical Research Development Center, Imam Reza Hospital, Kermanshah
  University of Medical Sciences, Kermanshah, Iran.
\item
  Student of O.~O. Bogomolets National Medical University, Kyiv, Ukraine
\item
  Infectious Diseases and Tropical Medicine Research Center, Health
  Research Institute, Babol University of Medical Sciences, Babol, Iran
\item
  Student Research Committee, School of Nursing and Midwifery, Shahid
  Beheshti University of Medical Sciences, Tehran, Iran
\item
  Department of Radiation Oncology, Mayo Clinic, Phoenix, Arizona, USA
\item
  Department of Social Sciences, University of Nicosia, Nicosia, Cyprus
\item
  Department of Life and Health Sciences, University of Nicosia,
  Nicosia, Cyprus
\item
  Australian Centre for Precision Health, University of South Australia,
  Adelaide, Australia
\item
  Student Research Committee, Babol University of Medical Sciences,
  Babol, Iran
\item
  Students' Scientific Research Center (SSRC), Tehran University of
  Medical Sciences, Tehran, Iran
\end{enumerate}

\textbf{Correspondence:} Soheil Ebrahimpour, Infectious Diseases and
Tropical Medicine Research Center, Health Research Institute, Babol
University of Medical Sciences, Babol, Iran. Tel: +989111149309, Fax:
+981132207918, Email: drsoheil1503@yahoo.com

\textbf{Acknowledgments}

The authors would like to thank the clinical research development center
of Imam Reza Hospital, Kermanshah University of Medical Sciences, for
their kind support\textbf{.}

\textbf{Data Availability Statement}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

\textbf{Conflict of interest disclosure}

TTS reports that he provides strategic and scientific recommendations as
a member of the Advisory Board and speaker for Novocure, Inc. and also
as a member of the Advisory Board to Galera Therapeutics, which are not
in any way associated with the content or disease site as presented in
this manuscript. All other authors have no relevant financial interests
to be declared.

\textbf{Author Contributions}

\begin{itemize}
\tightlist
\item
  \textbf{ZMA:} Data collection and writing the manuscript.
\item
  \textbf{DH:} Data collection and writing the manuscript.
\item
  \textbf{AB:} Data collection and writing the manuscript.
\item
  \textbf{AA:} Data collection and writing the manuscript.
\item
  \textbf{TTS:} Contributed substantial revisions to the manuscript's
  content.
\item
  \textbf{MJMS:} Contributed substantial revisions to the manuscript's
  content.
\item
  \textbf{KCC:} Helped with manuscript writing and contributed
  substantial revisions to the manuscript's content.
\item
  \textbf{RH:} Data collection and helped with manuscript writing.
\item
  \textbf{MB:} Data collection, helped with manuscript writing, and
  contributed substantial revisions to the manuscript's content.
\item
  \textbf{SE:} Design of the research study and supervision.
\end{itemize}

\textbf{Abstract}

Remdesivir has appeared to be the most effective medication against the
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
and is broadly administered to the coronavirus disease 2019 (COVID-19)
patients around the world. Remdesivir is an RNA polymerase inhibitor
with a broad spectrum of antiviral activities against RNA viruses
in\emph{in-vitro} and \emph{in-vivo} models of SARS-CoV, the Middle East
respiratory syndrome (MERS), and SARS-CoV-2. Remdesivir is the first
Food and Drug Administration (FDA) approved anti-SARS-CoV-2 treatment
for adult and pediatric patients and has been used intravenously for
patients requiring hospitalization for COVID-19. However, questions have
been raised about the value of remdesivir in treating COVID-19, and
governing bodies worldwide have been hesitant to approve this
medication. Nevertheless, in the context of the public health emergency
and the urgent need for effective treatments for patients with COVID-19,
remdesivir has been approved by several authorities worldwide. Here, we
discuss characteristics and applications of remdesivir, and various
challenging studies with different outcomes about its efficacy are also
reviewed.

\textbf{Keywords:} SARS-CoV-2; COVID-19; Remdesivir; Antiviral

\textbf{Introduction}

COVID-19 is now prevalent over a whole country. The remdesivir, an
antiviral drug, is becoming a 'molecule of expectancy' for this
disease's behavior. USFDA gave emergency approval to this drug for the
treatment of COVID-19 {[}1{]}. In this article, we tried to show the
probable molecular mechanism of remdesivir to prevent the RNA synthesis
of SARS-CoV-2. Up to now, remdesivir has appeared to be the most
effective medication against the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) infection and is broadly administered to the
coronavirus disease 2019 (COVID-19) patients around the world {[}2{]}.

Remdesivir or GS-5734 is a broad-spectrum antiviral medication
nucleoside analog against several single-stranded RNA viruses, including
SARS-CoV-2 {[}3{]}. It was the first FDA-approved drug for clinical use
in SARS-CoV-2 infection {[}4{]}. Recently, controversies have emerged in
the remdesivir trials and its efficacy in reducing COVID-19-related
morbidity and mortality. In this article, characteristics and
applications of remdesivir are briefly reviewed, and various challenging
studies with different outcomes about its efficacy are discussed.

\textbf{Mechanism of action and indications}

Remdesivir is an adenosine analog with broad-spectrum antiviral activity
against RNA viruses, such as filoviruses, paramyxoviruses,
pneumoviruses, and coronaviruses. It inhibits viral replication by
causing a delayed chain termination of RNA synthesis {[}5-7{]},
inhibiting SARS-CoV-2 in human airway epithelial cells (Figure 1)
{[}8{]}. The~active metabolite~of remdesivir interferes with the action
of viral~RNA-dependent RNA polymerase~and evades~proofreading~by
viral~exoribonuclease~(Exon), causing a decrease in viral RNA production
{[}9, 10{]}. The active configuration of remdesivir takes action as a
nucleoside analog and prevents the RNA-dependent RNA polymerase (RdRp)
of coronaviruses, including SARS-CoV-2. The RdRp incorporates Remdesivir
into the growing RNA product and permits the addition of three more
nucleotides before RNA synthesis stalls {[}11{]}. In COVID-19, RdRp
contains subunits nsp7, nsp8, and nsp12 under physiological conditions,
but the functional RdRp complex can be reassembled in vitro, similar to
MERS-CoV (Middle East Respiratory Syndrome coronavirus), containing only
nsp8 and nsp12 subunits {[}12{]}. When using nucleotide analogs
inclusive of remdesivir, the opportunity of everlasting accumulation of
the mutation must be considered. Cleavage of analogs via way of means of
the 3`5'-exonuclease (ExoN) hobby of the replication complicated
mediated in SARS-CoV-2 via way of means of the nsp14 subunit may be
problematic {[}12{]}.

Remdesivir enters the cells earlier than being cleaved to monophosphate
shape through carboxylesterase 1 or cathepsin A. It is then
phosphorylated through a kinase of unknown beginning to shape the lively
triphosphate to shape remdesivir triphosphate (RDVTP or GS443902)
{[}3{]}. Before the COVID-19 pandemic, the primary utilization of
remdesivir had been for Ebola and Nipah viruses {[}5, 13{]}.
Nevertheless, with the onset of the current pandemic, remdesivir has
been introduced as a valuable medication with promising effects and good
safety profiles {[}9{]}.

\textbf{Dosing, timing, and route of administration}

Remdesivir should be administered intravenously with a loading dose of
200 mg diluted in normal saline (0.9\%) or 5\% dextrose given over 60
minutes on day 1, followed by 100 mg once daily for adults and children
weighing [?] 40 kg {[}14{]}. For pediatrics weighing 3.5-40 kg, a loading
dose of 5 mg/kg of body weight on the first day, followed by a
maintenance dose of 2.5 mg/kg, is recommended {[}15{]}. The recommended
duration for remdesivir therapy is 5-10 days {[}16{]}. If administered
in an appropriate stage, it can significantly decrease the mortality of
the patients with COVID-19 {[}17{]}. The best time to start remdesivir
treatment is 10 days from the disease onset, preferably in the first 3
days, before developing host hyperinflammatory response {[}18-21{]}.
However, due to the possible protracted viral shedding of SARS-CoV-2 in
some patients, even late administration of remdesivir is suggested
{[}22, 23{]}.

Trials have shown that remdesivir can be the most beneficial in
hospitalized patients with severe but non-critical forms of SARS-CoV-2
infection, who have not been admitted yet to the intensive care unit
(ICU) or undergone mechanical ventilation {[}24{]}. Therefore, patients
who already have signs of respiratory failure are not ideal for
receiving this drug {[}22{]}. Furthermore, some studies have shown that
early remdesivir treatment could also be considered in hospitalized
patients with moderate COVID-19 with no need for supplemental oxygen
therapy {[}19{]}. At the beginning of the pandemic, remdesivir was
recommended for a duration of up to 10 days in selected patients.
Nevertheless, soon it was demonstrated that there is no significant
difference between a 5-day and a 10-day course of this medication, even
in severe COVID-19 patients. One explanation of such a finding is that a
shorter treatment duration may cause fewer adverse drug reactions {[}25,
26{]}. Nonetheless, despite its rapid onset of action and the ability to
suppress viral replication, some authorities have suggested that
remdesivir may not be able to eradicate SARS-CoV-2 in immunosuppressed
patients, especially those on T cell-or B cell-depleting therapies or
other immunosuppressing agents. Hence, demonstrating the necessitation
of a longer duration of therapy in these individuals {[}27, 28{]}.

\textbf{Adverse drug reactions}

\textbf{Hepatotoxicity}

The maximum scientific research the use of remdesivir confirmed no
extensive affiliation among remedy and hepatotoxicity, however in a few
smaller research, remdesivir can motive improved ALT / AST levels.
Therefore, liver feature exams for remdesivir have to be cautiously
monitored and stated in the in-depth care unit if there are records of
liver disease {[}29{]}. In a few cases, increased aminotransferases
following remdesivir initiation in three COVID-19 patients {[}30{]}.
According to a study on compassionate-use remdesivir against COVID-19,
23\% of the patients reported increased hepatic enzymes, and thus, two
of them were discontinued remdesivir prematurely {[}31{]}. Together,
monitoring liver function tests (LFTs) in these patients is warranted.

\textbf{Gastrointestinal symptoms}

There were three COVID-19 patients treated with remdesivir, of which two
of them manifested with nausea, and one suffered from gastroparesis
after the treatment initiation {[}30{]}. Based on a study in China, a
higher proportion of remdesivir recipients than placebo recipients had
dosing prematurely stopped because of anorexia, nausea, and vomiting
{[}32{]}.

\textbf{Respiratory toxicity}

In an in vitro experiment, remdesivir became proven to inhibit
TGF\selectlanguage{greek}β\selectlanguage{english}1-brought on activation of lung fibroblasts and dose-dependently
decreased TGF\selectlanguage{greek}β\selectlanguage{english}1-brought on mesenchymal metastasis in the alveolar
epithelium. Our consequences imply that remdesivir can proactively
alleviate the severity of pulmonary fibrosis and offer hints for
stopping pulmonary fibrosis in sufferers with COVID-19 {[}33{]}. Based
on the findings from a study in China, more patients in the remdesivir
group than the placebo group suffered from respiratory failure or acute
respiratory distress syndrome (10\% versus 8\%), and therefore,
discontinued the study drug (5\% versus 1\%) {[}32{]}.

\textbf{Cardiovascular toxicity}

The cardiotoxicity of remdesivir is because of its binding to human
mitochondrial RNA polymerase. Remdesivir, on the alternative hand,
prolongs the period of the electrical discipline ability via lowering
Na\textsuperscript{+} top amplitude and dose-structured spontaneous
pulsation rate, which might also additionally result in QT prolongation
and torsades du point {[}34{]}. One case of hypotension was reported to
be potentially related to remdesivir in a study on experimental
therapies against Ebola {[}35{]}. Although relatively rare,
hypersensitivity reactions, including infusion-related reactions and
anaphylaxis, have been observed after remdesivir administration {[}36{]}

\textbf{Nephrotoxicity}

The renal toxicity of remdesivir is due to distinct mechanisms. First,
remdesivir triphosphate itself has a low cap potential for mitochondrial
toxicity because it motives mitochondrial damage in renal tubular
epithelial cells and weakly inhibits mammalian DNA and RNA polymerase
{[}37{]}. Acute kidney failure (AKI) has been reported after the
initiation of remdesivir {[}32{]}. Thus, monitoring renal function
biomarkers is mandated in these patients.

\textbf{Pregnancy risks}

While it is not recommended to use in pregnant women, remdesivir could
be administered in special cases after carefully weighing the pros and
cons of the treatment. Based on previous reports of its use against
Ebola, remdesivir appears safe in human pregnancies. However, the safety
of remdesivir in this special group of patients needs to be further
evaluated by clinical trials on pregnant women of COVID-19 {[}35{]}.

\textbf{Interactions}

In the type of steroids, drugs like dexamethasone and betamethasone
induce cytochrome P450 enzymes (CYP3A4) and thus will rapidly eliminate
remdesivir {[}38{]}.

Doctors need to be careful about this interaction. Rifampicin,
rifabutin, and rifapentine strongly induce the CYP3A4 enzyme. These
medications are used in the treatment of tuberculosis and leprosy.
Remdesivir has no known interactions with any bronchodilators and
beta-blockers, and antivirals, including oseltamivir {[}39{]}.

Up to now, no significant drug-drug interactions between remdesivir and
other medications have been reported. Nonetheless, it is recommended not
to start remdesivir concomitantly with vasopressors, primarily as those
already on vasopressors are more likely to suffer from end-organ
failure, making remdesivir therapy not beneficial for them. Another
relative contraindication for this drug is the concomitant use of
chloroquine (CQ)/hydroxychloroquine (HCQ) due to these drugs'
antagonistic effect on antiviral activity remdesivir. There are also
trials showing that CYP450 inducers, such as rifampicin, carbamazepine,
and phenytoin, may decrease remdesivir serum levels {[}40, 41{]}. On the
other hand, due to the increased risk of hepatic impairment with
remdesivir therapy, concomitant use of other hepatotoxic agents is
discouraged {[}42{]}.

\textbf{Safety}

Fortunately, remdesivir has proved to have an excellent safety profile
for nearly all population groups. Moreover, having shown
no\emph{in-vitro} and \emph{in-vivo} genotoxicity, remdesivir seems to
be safe in pregnancy. However, close monitoring of LFTs is required
because of potential hepatitis after remdesivir injection and its
overlap with other causes of LFTs impairment during pregnancy. Besides,
its use in nursing women is also safe. Being predominantly eliminated by
the kidneys, remdesivir should be used cautiously in patients with
creatinine clearance \textless{} 30 mL/min. However, the short duration
of treatment makes it feasible to be used even in lower estimated
glomerular filtration rates (eGFRs) {[}43{]}, to the point that even it
has been reported that in some trials, remdesivir was well tolerated by
patients with end-stage kidney disease (ESRD) {[}44{]}. Moreover,
although it seems that remdesivir should not be administrated for
individuals with chronic liver diseases, such as chronic hepatitis,
there have been case reports showing no difference in the
pharmacokinetics of this drug in severe cirrhotic and non-cirrhotic
patients {[}45{]}. Nonetheless, further studies are needed to validate
the safety, efficacy, and required dose adjustment of remdesivir in
COVID-19 patients with underlying chronic hepatic disorders. At present,
it is recommended not to administer remdesivir for patients with
baseline serum transaminases levels exceeding five times the upper limit
of normal (ULN) since this medication per se can increase both alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) {[}46{]}.
Thus, if ALT increases \textgreater{} 5 \selectlanguage{ngerman}× ULN, and evidence of liver
inflammation or elevating levels of conjugated bilirubin, alkaline
phosphatase (ALP), or international normalized ratio (INR) is observed
during remdesivir therapy, it should be promptly discontinued until ALT
falls below 5 × ULN {[}47{]}. Nonetheless, If necessary, remdesivir
could be safely given in patients with increased baseline LFTs {[}48{]},
in which close monitoring of LFTs is needed to prevent further liver
damage.

Increasing evidence has witnessed that COVID-19 is implicated in
injuries of multiple organs, including lung, liver, gastrointestinal
tract, heart, and kidney. Hence, distinguishing the underlying causes of
adverse events during remdesivir treatment is complex. Moreover, the
latest safety data from Grein et al.'s study on compassionate-use
remdesivir which reported adverse events in 60\% of the patients, and
the RCT in China, which reported adverse events in 66\% of remdesivir
recipients versus 64\% of placebo recipients, might be limited by the
inclusion criteria, finite sample size and follow-up duration. Since the
experience of remdesivir application in the newly emerging COVID-19 is
still limited, adverse drug effects need to be paid much attention
{[}49-51{]}.

\textbf{Efficacy and controversies}

Several trials have been performed on the efficacy and benefits of
remdesivir added to other agents in managing SARS-CoV-2-infected
patients. Preliminary studies had highlighted the additive efficacy of
remdesivir plus inhaled steroids in hypoxic COVID-19 patients {[}52{]}.
However, it was later understood that systemic corticosteroids attain
the most beneficial effect with or without remdesivir or any other
antiviral agent {[}53, 54{]}. In addition, co-administration of
remdesivir and dexamethasone has decreased the mortality rate and
mechanical ventilation requirement in moderate-to-severe COVID-19
patients {[}55{]}. More recent trials have concluded that human
monoclonal antibodies (mAb), such as baricitinib, a selective Janus
kinase (JAK) 1 and 2 inhibitors, plus remdesivir, can be more effective
than remdesivir alone in decreasing the time-to-recovery and clinical
improvement, especially in patients needing supplemental oxygen therapy
{[}56{]}. This beneficial effect may be due to alleviating immune
response and inhibiting the hyperinflammatory phase by baricitinib.
{[}57{]}.

For remdesivir itself, there have been contradictory results reported by
different trials. For example, some reported the absence of a
statistically significant clinical benefit in reducing the
time-to-improvement {[}18{]}. Moreover, some authorities even believe
that remdesivir treatment neither can improve survival nor shorten
hospitalization {[}58{]}. Whereas, results of other studies, including
those performed by the World Health Organization (WHO), were different,
revealing remdesivir as a beneficial agent in shortening the recovery
time in hospitalized COVID-19 patients while having no impact on
mortality rate {[}20, 22, 59, 60{]}. Accordingly, the lack of efficacy
in reducing the overall mortality rate was recommended against
remdesivir treatment {[}61{]}. Interestingly, most of the trials
concluding the lack of efficacy of remdesivir had been carried out on
the Asian population, highlighting that the Asian patients may show
poorer outcomes after remdesivir therapy {[}62{]}. On the other hand,
there have been trials acknowledging the positive role of remdesivir in
decreasing the mortality rate of these patients {[}19, 63-65{]}. For
this reason, other guidelines, except the WHO guideline, still recommend
remdesivir, particularly in the early stages of the disease {[}66{]}. In
general, while the patients requiring supplemental oxygen therapy may
benefit the most from remdesivir, its application in those in need of
high-flow oxygenation, noninvasive ventilation (NIV), or mechanical
ventilation may not be helpful {[}20{]}.

Hence, remdesivir administration has become quite challenging due to the
disparities mentioned above. It is noteworthy that some have concluded
that a 5-day course of remdesivir treatment, rather than a 10-day one,
induced a relatively better outcome than standard care, despite having
no significant difference {[}67{]}. It should be noted that these
disparities may be the result of the heterogenicity of populations and
study protocol in different clinical trials. Moreover, underlying
disorders predisposing patients to more severe infection should also be
considered another reason for the lack of favorable response and poor
outcomes in some individuals {[}68{]}. Furthermore, the positive effect
of concomitant corticosteroid administration in many hospitalized
patients should also be considered before interpreting the favorable
efficacy of remdesivir, leading to the overestimation of outcome
improvement rates {[}69{]}.

\textbf{Conclusion}

As discussed above, remdesivir is efficacious in COVID-19 patients,
especially non-severe cases. Remdesivir has been used in many countries
as an emergency medication for patients with COVID-19, and several
patients showed better clinical outcomes. Also, this medication has
little interaction with other medications, making it an ideal candidate
for administration in these patients. Moreover, close monitoring of
liver function tests (LFTs) and estimated glomerular filtration rate
(eGFR) is mandated in patients undergoing remdesivir therapy, as
hepatotoxicity and renal damage have been reported in such patients.
Overall, as indicated in different guidelines worldwide, remdesivir
could be a drug of choice in non-severe SARS-CoV-2-infected patients.

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\textbf{Figure legends}

\textbf{Figure 1. The function of Remdesivir in the treatment of
COVID-19 patients.} The SARS-CoV-2 virus can enter host cells and
activate the immune system through ACE2 and TMPRSS2 receptors. In
patients with COVID-19, after entering the body, the virus translates
its genome through the ribosome and produces RdRp. After administration,
remdesivir (GS-5734) is activated, forming GS-441524, which in turn
binds to RdRp and prevents virus RNA replication.
\textbf{Abbreviation:}ACE2, Angiotensin-converting enzyme 2; TMPRSS2,
Transmembrane Serine Protease 2; RdRp, RNA-dependent RNA polymerase.\selectlanguage{english}
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