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Remdesivir

Last reviewed: October 12, 2021

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The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject.

 

Overview 

Remdesivir is an intravenous nucleotide prodrug of an adenosine analog that was initially developed during the 2013 Ebola epidemic (Weston, March 2020; Brown, September 2019). When converted to its active form (largely by plasma carboxylesterases; its further metabolism is largely mediated by hydrolases), remdesivir interferes with RNA polymerase and is thought to lead to premature termination of RNA transcription (Yang, September 2020). It is also able to evade viral exonuclease proofreading, which is an advantage, as the ability of the coronavirus detect and remove any incompatible nucleotides during its replication and transcription can block the efficacy of drugs that work by altering coronavirus nucleotide sequence.   

Early in the pandemic, remdesivir was found to have antiviral effects against SARS-CoV-2 in both in vitro studies and in vivo studies with rhesus macaques (Wang, February 2020; Williamson, June 2020). In May 2020, FDA approved an Emergency Use Authorization for remdesivir in adults and children hospitalized with severe COVID-19. FDA approval for use in hospitalized adults and children over age 12 followed in October 2020.   

Several large, randomized trials have been published on the use of remdesivir in patients with COVID-19. The largest so far, the ACTT-1 and SOLIDARITY trials, have found varying results:  

  • ACTT-1 showed a reduction in time to clinical improvement and, in subgroup analysis, a mortality benefit in patients requiring supplemental oxygen but not ventilation.   
  • Conversely, SOLIDARITY showed no mortality benefit with the use of remdesivir.   
  • Notably, the trials had different primary endpoints, and thus varied in design and what they were powered to examine.   
  • ACTT-1’s primary endpoint was time to clinical improvement — it was not powered for mortality.   
  • SOLIDARITY was powered for mortality, but was not designed to examine subgroups by time to clinical improvement or based on clinical status other than ventilated versus non-ventilated.   
  • A quarter of patients in ACTT-1 were ventilated upon enrollment, as opposed to 8% in SOLIDARITY. Approximately a quarter of patients in ACTT-1 received concomitant glucocorticoids, while nearly half did in SOLIDARITY. Time from symptom onset to randomization was examined in ACTT-1, but similar data was not available for SOLIDARITY. The majority of patients in ACTT-1 lived in North America, while the majority in SOLIDARITY lived in Asia, Africa or Latin America.   

Further clinical outcomes data on remdesivir are being collected in the large platform trial RECOVERY, and data is forthcoming. Inserm’s Phase 3 DisCoVeRy trial (conducted at 48 sites in Europe as an add-on to the WHO Solidarity trial) was stopped in January 2021 after a Data and Safety Monitoring Board review evaluated participants on remdesivir (200 mg IV on Day 1 followed by 100 mg IV thereafter for 9 more days)and on standard of care and found no evidence of efficacy in clinical outcomes or viral clearance at 15 or 29 days after initiation of remdesivir. However, looking at the subset of patients who were not on mechanical ventilation or ECMO at study entry, remdesivir did significantly delay progression to mechanical ventilation or death, which is in line with the findings of the ACTT-1 trial. There were important differences between the study populations in ACTT-1 and DisCoVeRy, that might partially explain the discrepant findings. Fewer ACTT-1 participants were on oxygen at baseline than DisCoVeRy participants (87% versus 99%) and fewer received steroids (23% versus 40%, respectively).   

More recently, there have been efforts to capture large-scale observational data on remdesivir outcomes. An observational analysis of a large real-world database (N= 28,855 remdesivir patients and 16,687 propensity-matched non-remdesivir patients) compared mortality between hospitalized COVID-19 patients who did and did not get remdesivir (Mozaffari, October 2021). During the study period (between August and November 2020), patients on remdesivir had a significantly lower risk of death at day 14 than patients not on remdesivir (for both those on low-flow and high-flow oxygen at baseline, aHR 0.76 [0.68-0.83]). A mortality difference was also seen on Day 28 (aHR 0.89 [0.82-0.96]. These findings accord with the ACTT-1 trial and trends seen in the Solidarity trial.   

Another retrospective observational study conducted at five hospitals in the Baltimore and Washington DC area (N=358 remdesivir; 1,957 controls) looked at whether remdesivir with or without corticosteroids hastened clinical improvement among hospitalized patients with confirmed COVID-19 (Garibaldi, March 2021).  This study used propensity-score matching to pair each remdesivir recipient with a patient who did not receive remdesivir, on the basis of age, severity of illness, sex and other clinical parameters, and examined a primary outcome of rate of clinical improvement (hospital discharge or decrease of two points on a clinical severity scale). The study found that remdesivir recipients had a faster time to clinical improvement than controls (median [IQR] of 5 days [4-8] versus 7 days [4-10], respectively). The mortality rate was 7.7% and 14% in the remdesivir and control groups, respectively (aHR non-significant at 0.70; 95% CI, 0.38-1.28). Furthermore, the study did not find an additive benefit in time to clinical improvement when corticosteroids were added to remdesivir. In terms of antiviral effect, an independent add-on randomized controlled study (N=185) to the WHO Solidarity trial, NOR-Solidarity, found that remdesivir did not affect viral clearance of SARS-CoV-2 among hospitalized people with COVID-19 (Barratt-Due, July 2021).    

A meta-analysis of four randomized trials of remdesivir (7,333 total patients across studies) found uncertain impact of remdesivir on death or progression to mechanical ventilation, with an OR for mortality with remdesivir of 0.9 (95% CI, 0.7-1.12) and for mechanical ventilation of 0.9 (95% CI, 0.76-1.03) as compared to placebo or usual care (Siemieniuk, July 2020). Subgroup analyses on patients with lesser degrees of illness were absent, which may have occluded a benefit in a certain subgroup (i.e., the subgroup shown to benefit in the ACTT-1 trial, those requiring low-flow supplemental oxygen).

 

Guidelines 

There is a lack of consensus among society and organizational guidelines on whether remdesivir should be used in the management of COVID-19, given the varying results in existing clinical trial data.  

IDSA guidelines recommend use of remdesivir among hospitalized patients with severe COVID-19 (defined as patients with SpO2 ≤94% on room air, or patients who require supplemental oxygen), but recommend against the routine use of remdesivir in patients with COVID-19 requiring mechanical ventilation or extracorporeal mechanical oxygenation.  

  • Among patients with severe COVID-19 on supplemental oxygen but not on mechanical ventilation or ECMO, IDSA suggests treatment with 5 days of remdesivir rather than 10 days of remdesivir.   
  • Among COVID-19 patients without the need for supplemental oxygen and with oxygen saturation >94% on room air, IDSA suggests against the routine use of remdesivir.    

National Institutes of Health guidelines recommend use of remdesivir in hospitalized COVID-19 patients requiring supplemental oxygen through nasal cannula.  

  • For patients who require oxygen through a high flow device or noninvasive ventilation, remdesivir plus dexamethasone may be used.   

World Health Organization guidelines conditionally recommend against remdesivir outside of clinical trials for COVID-19, regardless of disease severity.  

 

Key Literature 

In summary: Overall, there is conflicting data, but it appears based on randomized trials that remdesivir does not provide an overall mortality benefit to the aggregated group of patients hospitalized with COVID-19, but that it does reduce time to clinical improvement when given early in the course of illness and/or in patients with mild hypoxia but less severe disease. While observational trials are more vulnerable to confounding, there is some suggestion from large-scale comparative efficacy studies of observational cohorts that remdesivir may confer a modest mortality benefit.   

  

Repurposed antiviral drugs for COVID-19 — Interim WHO SOLIDARITY trial results (WHO Solidarity Trial Consortium, October 2020).

Overall, in this large multinational open-label non-placebo controlled randomized trial, remdesivir was not associated with reduced mortality compared to standard of care.  

Study population:  

  • 11,266 hospitalized adult patients with COVID-19, representing 405 hospitals and 30 countries. 
  • Patients were equally randomized between whichever study drugs were locally available and standard of care (open-label, local standard-of-care vs. remdesivir or hydroxychloroquine or interferon beta-1a or lopinavir/ritonavir).  
  • 2,750 patients were randomized to receive 10 days of remdesivir.   
  • Of those allocated remdesivir, 98.5% began treatment. The intent-to-treat (ITT) analysis included 2,743 remdesivir vs. 2,708 control.  
  • 35% of patients were younger than 50 years of age, 45% were between 50-69 years of age, and 19% were 70 years of age or older. 62% were male.  
  • 25% of patients had diabetes and 21% had heart disease.  
  • 63% of patients were on oxygen at entry, and 8% were ventilated upon study enrollment.  
  • 62% of patients were randomized between days 0-1 of hospitalization.  

Primary endpoint:  

  • In-hospital mortality of remdesivir vs. control.  
  • Secondary endpoints included ventilation and time to discharge. 

Key findings:  

  • Overall mortality was 11.8%.  
  • There was no difference in mortality between patients receiving standard of care and remdesivir (RR=0.95 (0.81-1.11, p=0.50; 301/2743 vs. 303/2708).  
  • There was no difference in initiation of ventilation or time to discharge between patients receiving standard of care and remdesivir.  
  • The proportion of individuals still hospitalized at day 7 for remdesivir vs. control were 69% vs. 59%.  
  • The use of other agents in the remdesivir group and controls were: corticosteroids (47.8% vs 47.6%, respectively); convalescent plasma (1.9% vs 2.1%, respectively); anti-IL-6 therapy (4.9% vs 5.3%, respectively); non-trial interferon (0.1% vs 0.9%, respectively); and non-trial antiviral (2.4% vs 5.6%, respectively).  

Limitations:  

  • Open-label design.  
  • Time from symptom onset to randomization was not included. If there was a delay between symptom onset and presenting for care, the benefit of remdesivir (an antiviral) may have been lost.  
  • Time to recovery in the remdesivir group may have been artificially extended due to a planned 10-day course. 
  • Subgroup analyses were not done other than in patients who were already ventilated upon study entry.  
  • The patient's provider could choose to deviate from protocol and stop/change therapy; further details have not been shared.
  • There were variable numbers of patients in the remdesivir and interferon arms, despite the trial being randomized. This could reflect different drugs being available at different sites, but the difference is not explained.
  • An intention to treat analysis was done for the primary endpoint, despite patients not necessarily receiving the drug they were initially randomized to. An analysis was not performed based on the drugs patients were actually randomized to.



Remdesivir for the Treatment of Covid-19 — Final Report (Beigel, October 2020). 

Overall, in this randomized-placebo controlled trial, remdesivir shortened time to recovery by 5 days and was safe. Patients who were randomized after 10 days of symptoms did not experience this effect. In subgroup analysis, remdesivir was associated with lower mortality in patients requiring supplemental oxygen but not ventilation.

Study population:    

  • 1,062 hospitalized adult patients (79.8% located in North America) with COVID-19. 
  • 541 patients were randomized to remdesivir and 52 to placebo.   
  • Median 6 days from symptom onset to starting remdesivir.    
  • The mean age of patients was 58.9 years; 64.4% were male.  
  • 53.3% of patients were white.  
  • 50.2% had hypertension, 44.8% had obesity, and 30.3% had diabetes.  
  • 15% of patients had mild-moderate disease, and 85% had severe disease.  
  • The median number of days between symptom onset and randomization was 9 (IQR 6-12).

Primary endpoint:    

  • Time to clinical recovery (defined as discharge from the hospital or hospitalization for infection control purposes only) during 28 days post enrollment, as measured by an eight-point ordinal scale. 
  • Secondary outcomes included clinical status at day 15 using the ordinal scale. 

Key findings:   

  • Patients who received remdesivir had a median recovery time of 10 days, as compared with 15 days among those who received placebo (RR for recovery, 1.29; p<0.001).  
  • Kaplan–Meier estimates of mortality by day 15 were 6.7% in the remdesivir group and 11.9% in the placebo group (hazard ratio, 0.55; 95% CI, 0.36 to 0.83).  
  • There was no difference in 28-day mortality between patients who received remdesivir (6.7%) or placebo by day 15 (11.4%; HR 0.73; 95% CI, 0.52 to 1.03).  
  • On subgroup analysis of patients at ordinal scale 5 (requiring supplemental oxygen but not ventilation), mortality in the remdesivir arm was 4%, versus 12.7% in the placebo arm (HR 0.30, 95% 0.14-0.64).  
  • The rate ratio for recovery was largest among patients with a baseline ordinal score of 5 (RR for recovery, 1.45; 95% CI, 1.18 to 1.79).  
  • Patients who underwent randomization during the first 10 days after symptom onset had a rate ratio for recovery of 1.37 (95% CI, 1.14 to 1.64), whereas patients who underwent randomization more than 10 days after the onset of symptoms had a rate ratio for recovery of 1.20 (95% CI, 0.94 to 1.52).  
  • Adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and 163 of the 516 patients who received placebo (31.6%).  
  • 35.6% of patients received hydroxychloroquine and 23% received a glucocorticoid.  

Limitations:    

  • The original primary endpoint was ordinal endpoint after 14 days, but this was changed to a time-to-recovery endpoint based on researchers’ realization that the clinical course of COVID-19 could be longer than initially thought.   
  • The trial was not powered for mortality.  
  • The clinical relevance of the ordinal scale is not clear.  
  • Patients generally received remdesivir around 9 days after symptom onset; this may have been too late to see a mortality benefit.

  

Effect of Remdesivir vs. Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial (Spinner, Aug 2020)

Overall, in this open-label randomized controlled trial, 5 days of remdesivir was associated with a higher odds of a better clinical status distribution than those receiving standard care. The clinical significance of this finding is unclear.

Study population:

  • 584 patients at 105 hospitals in the United States, Europe and Asia, hospitalized with moderate COVID-19 (defined as pulmonary infiltrates and room-air oxygen saturation >94%).
  • Patients were randomized to either a 5-day course of remdesivir, a 10-day course or standard of care.
  • The median age was 57 (IQR 46-66) and 227 (39%) subject were women.
  • 56% had cardiovascular disease, 42% had hypertension and 40% had diabetes.
  • Patients were enrolled if they had a positive SARS-CoV-2 PCR within 4 days of randomization.

Primary endpoint:

  • Day 11 clinical status based on a 7-point ordinal scale; category 1 was death, category 7 was discharged.

Key findings:

  • 533 (91%) of the participants completed the trial, including 76% of the 5-day remdesivir group and 38% of the 10-day group.
  • Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group.
  • On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; p = .02).
  • The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (p = .18 by Wilcoxon rank sum test).
  • There was no difference in 28-day all-cause mortality.

Limitations:

  • Open-label design, which could have led to selection bias
  • No virologic data was collected.
  • An important number of patients did not complete their assigned treatment duration, primarily due to hospital discharge; the occurred more frequently in the 10 day group, and could have affected the results.
  • The median duration of symptoms prior to randomization over a week in all groups. This could have affected the study results.
  • The initial endpoint was proportion of patients discharged by day 14; this was changed the day study enrollment began.
  • Other therapies used for SARS-CoV-2 as part of local standard of care were initially allowed.
  • The 10-day group actually received a median of 6 days of remdesivir; the effect of 5 days of treatment compared to 10 days of treatment is not adequately answered in this study.
  • All participants had moderate disease with low risk of mortality or clinical progression. It is unclear whether differences in outcomes would be observed by duration of remdesivir treatment with a population that was more ill.

 

SIMPLE-Severe Trial: Gilead-sponsored multinational, open-label trial of remdesivir in patients with severe COVID-19 (Goldman, May 2020).   

Overall, in hospitalized patients with COVID-19 who are not on mechanical ventilation or extracorporeal mechanical oxygenation, 5 days of remdesivir shows similar clinical benefit to 10 days. 

Study population:  

  • Patients in this study had either SpO2 ≤94% on room air or were receiving supplemental oxygen.   
  • 397 patients received remdesivir for 5 days; 197 received remdesivir for 10 days. 

Primary endpoint 

  • Clinical status at day 14.  

Key findings: 

  • After adjusting for imbalances in the baseline clinical status, the day 14 distribution in clinical status on the ordinal scale was similar in the 5-day and 10-day groups (p=0.14).   


 

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial (Wang, May 2020).   

Overall, in this under-powered study, remdesivir did not show a benefit in time to clinical improvement, 28-day mortality or rate of viral clearance in patients with severe COVID-19 compared to placebo.

Study population: 

  • 237 patients received IV remdesivir for 10 days; concomitant use of lopinavir/ritonavir, corticosteroids and interferons was permitted.   
  • The median time from symptom onset to starting remdesivir was 10 days.   

Primary endpoint 

  • Time to clinical improvement, defined as improvement on an ordinal scale or discharged alive from the hospital, whichever came first.  

Key findings: 

  • There was no difference in the time to clinical improvement between the groups (median 21 days vs. 23 days).   
  • For those who started remdesivir within 10 days of symptom onset, a faster time to clinical improvement was seen in the remdesivir arm (median 18 days vs. 23 days); this was not statistically significant.   
  • There was no mortality benefit at 28 days. 

Limitations: 

  • Due to under-enrollment, the trial was stopped early and was likely under-powered.     

 

Safety 

Although a full understanding of remdesivir’s safety profile remains incomplete, notable considerations include:   

Hepatotoxicity  

  • Remdesivir should not be used in combination with other hepatotoxic drugs, and clinicians should monitor hepatic function throughout treatment (FDA EUA, July 2020).    

Nephrotoxicity  

  • Clinicians should monitor kidney function of all patients on remdesivir, particularly those with pre-existing renal impairments and those receiving other nephrotoxins.    
  • Avoid use for patients with eGFR <30 ML/min or full-term neonates with SCr >1 mg/dL (FDA EUA, July 2020).  

Bradycardia  

  • There have been reports of bradycardia in patients receiving remdesivir, and an analysis of the WHO safety reports found an increased likelihood of bradycardia among remdesivir recipients, compared to other agents, with a reporting OR of 1.65 (95% CI, 1.23-2.22) (Touafchia, February 2021Barkas, February 2021Gubitosa, November 2020).  

   

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