key: cord-333999-k92fmnq7
authors: Yang, Chih-Jen; Wei, Yu-Jui; Chang, Hus-Liang; Chang, Pi-Yu; Tsai, Chung-Chen; Chen, Yen-Hsu; Hsueh, Po-Ren
title: Remdesivir Use in the Coronavirus Disease 2019 Pandemic: A Mini-Review
date: 2020-10-05
journal: J Microbiol Immunol Infect
DOI: 10.1016/j.jmii.2020.09.002
sha: 
doc_id: 333999
cord_uid: k92fmnq7

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative viral pathogen of coronavirus disease 2019 (COVID-19), appears to have various clinical presentations and may result in severe respiratory failure. The global SARS-CoV-2-associated viral pneumonia pandemic was first reported in December 2019 in China. Based on known pharmacological mechanisms, many therapeutic drugs have been repurposed to target SARS-CoV-2. Among these drugs, remdesivir appears to be the currently most promising according to several clinical trials and reports of compassionate use. In this mini-review, we summarize the current evidence on the efficacy and challenges of remdesivir for the treatment of coronavirus disease 2019 (COVID-19).

Coronaviruses are non-segmented, enveloped, positive-sense, and single-stranded RNA viruses that commonly exist in mammals 1 . Human and animal coronaviruses comprise four genera, named α, β, γ, and δ. β-Coronaviruses include those that cause Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), and coronavirus disease 2019 (COVID-19) 1, 2 . Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with pulmonary and parabronchial epithelial cells to enter through the epithelial cell membrane 3 . The virus primarily spreads through saliva droplets or discharge from the nose of an infected individual after coughing or sneezing and is the causative pathogen of COVID-19 3 , which appears to have a spectrum of clinical presentations that ranges from asymptomatic to severe respiratory failure [4] [5] [6] [7] . SARS-CoV-2 caused an outbreak of novel pathogenic viral pneumonia in December 2019, which subsequently became a global pandemic 7, 8 . Several preventive strategies were then implemented by governments worldwide in an attempt to control the spread of the virus, including but not limited to the shutting of air and sea borders, case identification and tracking, quarantining individuals with suspected infections, travel restrictions, big data integration, and facemask policies [9] [10] [11] [12] . Furthermore, many drugs have been proposed to control and treat COVID-19 13-15 . J o u r n a l P r e -p r o o f SARS-CoV-2 enters cells through direct interactions between the viral S protein and the cellular receptor angiotensin-converting enzyme 2 16, 17 . After entering a cell, the virus releases its genome, which is translated into viral replicase polyproteins and cleaved into functional proteins by proteases. Viral genome replication is mediated by the viral replication complex, which includes RNA-dependent RNA polymerase (RdRp) 18 . Viral nucleocapsids are assembled from the packaged viral genomes and translated to form viral structural proteins, which are then released by exocytosis [19] [20] [21] [22] .

Based on the currently understood mechanisms, many therapeutic drugs are being investigated and developed to fight SARS-CoV-2 during the current COVID-19 pandemic. Several ongoing clinical trials are testing the efficacy of single and combination treatments 23, 24 . Many different drugs are under evaluation 25 , including antiviral nucleotide analogs such as remdesivir [26] [27] [28] [29] [30] , antiviral nucleoside analogs such as favipiravir 31 and ribavirin 32 , protease inhibitors such as lopinavir/ritonavir 33 , antimalarials such as chloroquine and hydroxychloroquine alone 34 or combined with azithromycin 35, 36 , biologics such as tocilizumab 37 , corticosteroids 38, 39 , colchicine 40 , nonsteroidal anti-inflammatory drugs such as indomethacin 41, 42 , and convalescent plasma 43 . These candidate drugs are listed in Table 1. J o u r n a l P r e -p r o o f Based on several clinical trials and reports on its compassionate use, remdesivir is considered by many to be the most promising drug for the treatment of COVID-19 [44] [45] [46] . Remdesivir (GS-5734) is a prodrug of an adenosine analog, and its triphosphate form can be used as a substrate for many viral RdRp complexes 47, 48 . It has been reported to inhibit viral RNA synthesis by a specific mechanism of delayed chain termination for MERS-CoV, SARS-CoV, and SARS-CoV-2 49 [26] [27] [28] 30 .

In the current study, a PubMed search using a combination of the keywords "COVID-19" "SARS-CoV-2" and "remdesivir" was performed. We included all studies J o u r n a l P r e -p r o o f written in English. The initial literature search identified 39 articles, which included three large-scale randomized clinical trials. Some compassionate-use experiences were also included in this review.

Remdesivir was developed by a collaboration among Gilead Science, the U.S. Centers 

Gilead Science had provided more than 1,000 doses of remdesivir for compassionate use worldwide by the end of May 2020, and this was first used in China. All compassionate-use treatments and clinical trials involved the administration of remdesivir at a 200-mg loading dose on the first day, with a 100-mg maintenance dose for 9 subsequent days 26, 28, 30, 59, 60 ; this regime is identical to that utilized in the previous Ebola trial 61 , which appears to be the model for all subsequent trials involving remdesivir. 62 . On the patient's seventh day of hospitalization and following clinical deterioration, the patient was administered intravenous remdesivir through the compassionate-use access scheme; no adverse events were observed on infusion.

The patient received the first dose of remdesivir on hospital day 7 when they developed severe pneumonia that could not be treated successfully using the broad-spectrum antibiotics vancomycin and cefepime. The patient recovered on hospital day 8 and no longer required supplemental oxygen.

In a case series of 28 patients with severe COVID-19 in Seattle, USA, 14 eventually died and 7 received remdesivir through compassionate-use access; however, the outcomes of these patients were not reported 59 . Clinically, the process of obtaining remdesivir for compassionate use is both challenging and time-consuming. For optimal results, remdesivir should be administered as soon as possible, although late administration may also be effective to treat SARS-CoV-2 63 .

Canada, and 9 were in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) showed an improvement in oxygen-support class, including 17 of the 30 patients (57%) receiving mechanical ventilation, who were extubated. A total of 25 patients (47%) were discharged and 7 patients (13%) died; the mortality rate was 18% (6 of 34) among patients who received invasive ventilation and 5% (1 of 19) among those who did not receive invasive ventilation.

Four randomized control trials have been published to date. First, to evaluate the efficacy and safety of remdesivir in patients with COVID-19, a randomized, placebo-controlled, double-blind, multicenter, phase 3 clinical trial was launched on February 5, 2020, in China 30, 60 . Eligible patients were adults admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Randomization was performed J o u r n a l P r e -p r o o f less from symptom onset to enrolment, an oxygen saturation of 94% or less breathing room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia were enrolled.

Patients were permitted the concomitant use of lopinavir-ritonavir, interferon, and corticosteroids. The study concluded that the use of remdesivir was not associated with a significant difference in the time to clinical improvement (hazard ratio, 1. There was no significant difference in clinical status on day 11 between the 10-day remdesivir and standard care groups 70 . All of these large-scale remdesivir trials are summarized in Table 2 .

A lyophilized formulation of remdesivir was evaluated in a phase 1 trial for potential future use in clinical trials owing to its storage stability in resource-limited J o u r n a l P r e -p r o o f settings. All adverse events were grade 1 or 2 in severity 60 . Clinically, common adverse drug reactions (ADRs) noted during the compassionate use of remdesivir in patients with COVID-19 reported by Grein et al. included increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension 28 . Four patients (8%) discontinued remdesivir treatment prematurely, one due to a worsening of preexisting renal failure, one because of multiple organ failure, and two because of elevated aminotransferases, one of whom had a maculopapular rash.

In a trial conducted by Wang et al. 30 in Wuhan, China, adverse events were reported in 66% of patients in the remdesivir group and 64% in the control group.

The most common adverse events in the remdesivir group were constipation, hypoalbuminemia, hypokalemia, anemia, thrombocytopenia, and increased total bilirubin. The incidence of serious adverse events was 18% in the remdesivir group and 26% in the control group. In the trial led by Beigel et al. 26 , serious adverse events occurred in 21.1% of the remdesivir group and 27.0% of the placebo group. The most common adverse events were anemia and decreased hemoglobin (7.9% and 9.0% in the remdesivir and placebo groups, respectively). Overall, the incidence of adverse events was not significantly different between the remdesivir and placebo groups. Table 1 . Current candidate drugs for the treatment of COVID-19 Table 2 . Published studies of remdesivir treatment for COVID-19 as of August 2020 J o u r n a l P r e -p r o o f 30 Beigel et al. 26 Grein et al. 28 Goldman et al. 27 Spinner et al 70 Enrolled 

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