Is there evidence to support initiation of remdesivir after 7 days in hospitalized patients with severe COVID-19?

Introduction
An antiviral with in vitro activity against a range of ribonucleic acid (RNA) viruses including filorviruses, paramyxoviruses, pneumoviruses, arenaviruses, and coronaviruses, remdesivir has been shown to inhibit the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in primary human airway epithelial cells.1 In clinical studies of coronavirus disease 2019 (COVID-19) in humans, remdesivir use has resulted in clinical improvement, shortened recovery time, and reduced oxygen requirements. According to the prescribing information, remdesivir is indicated in hospitalized and non-hospitalized adult and pediatric patients (≥1.5 kg) with mild to moderate to disease at high-risk for COVID-19 progression.2 Labeling states that remdesivir should be initiated within 7 days of symptom onset when given in non-hospitalized patients and after diagnosis of symptomatic COVID-19 in hospitalized patients. A 3-day treatment duration is recommended in non-hospitalized patients, while a 5-day course is recommended in hospitalized patients not requiring extra-corporeal membrane oxygenation (ECMO) or mechanical ventilation (MV), with the option to extend for an additional 5 days in the absence of clinical improvement. In patients requiring ECMO or MV, labeling recommends a treatment duration of 10 days.

The severity of SARS-CoV-2 infection can be classified as mild to moderate at increased risk for progression, severe, and critical disease.3,4 Mild to moderate infection is defined as oxygen saturation (SpO2) ≥94% on room air without a need for supplemental oxygen, while severe COVID-19 is defined as SpO2<94% on room air or requiring supplemental oxygen.3 In patients that are critically ill, respiratory failure, septic shock, or multiple organ dysfunction are present, and involve more intensive management methods.4

Guidelines
Treatment guidelines for COVID-19 include recommendations on the initiation and duration of treatment with remdesivir and other therapies based on the patient’s clinical status and risk for disease progression, among other factors.3,4 In February 2024, the National Institutes of Health (NIH) guideline released their final update of the COVID-19 treatment guidelines, while the Infectious Diseases Society of America (IDSA) continues to update their guidelines. Both guidelines recommend the initiation of remdesivir in mild to moderate disease within 7 days of symptom onset; whether a treatment benefit could potentially extend to patients when initiated later, particularly in hospitalized patients after 7 days of symptom onset with severe disease, is not currently addressed in guidelines.

Table 1. COVID-19 Remdesivir Guideline Recommendations3,4
IDSANIH
Mild to moderate infectionIf high risk for progression, initiation within 7 days of symptom onset recommended in hospitalized and non-hospitalized patients

Conditional recommendation; low certainty evidence		If high risk for progression, initiation within 7 days of symptom onset recommended in non-hospitalized patients

Moderate recommendation, moderate quality evidence
Hospitalized patients not requiring supplemental O2No recommendation givenRecommended in immunocompromised and other high-risk patients

Moderate recommendation, moderate quality evidence (for immunocomprised patients) and expert opinion (for other high-risk patients)
Severe infectionRemdesivir treatment recommended over no antiviral treatment

Conditional recommendation; moderate quality evidence		No recommendation given
COVID-19 infection requiring supplemental O2In patients not on MV or ECMO, 5-day treatment duration suggested over 10-day duration

Conditional recommendation; low certainty evidence		Recommended with dexamethasone in most hospitalized patients

Moderate recommendation; moderate quality evidence
COVID-19 infection requiring invasive ventilation and/or ECMORoutine initiation of remdesivir is suggested against

Conditional recommendation; very low certainty evidence		No recommendation given
Abbreviations: COVID-19= coronavirus disease 2019; ECMO=extracorporeal membrane oxygenation; IDSA=Infectious Diseases Society of America; MV=mechanical ventilation; NIH=National Institutes of Health; O2=oxygen.

Literature Summary
Of the studies with a significant impact on recommendations for remdesivir in the NIH COVID-19 guidelines, ACTT-1 and DisCoVeRy included patients with severe disease and reported on late versus early remdesivir initiation.4-6 In ACTT-1, a double-blind, randomized controlled trial (RCT) of patients with severe COVID-19, hospitalized patients with laboratory-confirmed SARS-CoV-2 infection with pulmonary infiltrates, SpO2 ≤94% on room air or need for supplemental oxygen, high-flow nasal cannula (HFNC), oxygen, non-invasive ventilation (NIV), MV or ECMO were randomized to either 10 days of remdesivir or placebo therapy.5 Patients were randomized to therapy a median of 9 days (interquartile [IQR] 6−12 days) from symptom onset. The majority of patients (55%) had at least 2 coexisting conditions, 26% had 1 coexisting condition, and 23% were receiving corticosteroids during the study. The primary outcome of time to clinical recovery was 10 days in the remdesivir arm versus 15 days in the placebo arm (rate ratio [RR], 1.29; 95% confidence interval [CI], 1.12 to 1.49). A prespecified subgroup analyses found that in patients who initiated remdesivir within ≤10 days of symptom onset (RR, 1.37; 95% CI, 1.14 to 1.64) were more likely to have a shorter time to recovery on remdesivir compared to those who initiated treatment >10 days after symptom onset (RR, 1.20; 95% CI, 0.94 to 1.52).

In DisCoVeRy, an open-label (OL) RCT in patients with moderate to severe COVID-19, hospitalized patients with laboratory-confirmed SARS-CoV-2 infection, rales or crackles on examination and SpO2 ≤94% on room air, a need for supplemental oxygen, high-flow nasal cannula (HFNC), non-invasive ventilation (NIV), or MV were randomized 1:1:1:1 to either standard of care (SOC) plus 10 days of remdesivir, SOC plus lopinavir-ritonavir, SOC plus lopinavir-ritonavir plus interferon beta-1a, SOC plus hydroxychloroquine, or SOC only.6 Patients were randomized to therapy a median of 9 days from symptom onset. The majority of patients (61%) had moderate COVID-19 and 39% had severe disease. Seventy-four percent of patients had ≥1 coexisting condition and 40% received corticosteroids during the study.

The distribution of the primary outcome of clinical status at day 15 was assessed using a World Health Organization (WHO) ordinal scale across 7 categories, which reported the percentage of patients 1) not hospitalized with no limitations on activities (15% of patients on remdesivir versus 18% on control), 2) not hospitalized with limitations on activities (31% on remdesivir versus 18% on control), 3) hospitalized, not requiring supplemental O2 (12% on remdesivir versus 7% on control), 4) hospitalized, requiring supplemental O2 (18% on remdesivir versus 16% on control), 5) hospitalized, on NIV or HFNC (4% on remdesivir versus 3% on control), 6) hospitalized, on MV or ECMO (15% on remdesivir versus 19% on control), 7) who died (5% on remdesivir versus 6% on control).6 The effect measure of the 7-point ordinal scale found no overall difference between remdesvir and control arms of the study (odds ratio [OR], 0.98; 95% CI, 0.77 to 1.25). In a prespecified subgroup analysis of the primary outcome that compared duration of symptoms prior to randomization, there was still no benefit with remdesivir when assessed in patients that initiated therapy within ≤7 days (OR, 1.14; 95% CI, 0.75 to 1.75), 8 to 14 days (OR, 1.01; 95% CI, 0.73 to 1.39), or >14 days (OR, 0.44; 95% CI, 0.18 to 1.77) of symptom onset.

Since the last NIH guideline update in February 2024, a retrospective study was published investigating the impact of initiating remdesivir in patients with an early symptom onset (<7 days) versus late symptom onset (≥7 days) on all-cause mortality.7 The chart review analyzed data from hospitalized patients from May 1, 2020 to July 31, 2020 from 10 facilities that received at least 1 dose of remdesivir. Patients were stratified based on their duration of symptoms (< 7 days versus ≥7 days) at the time of remdesivir initiation. Baseline characteristics were similar between the 2 groups. The primary outcome of in-hospital all-cause mortality was shown to be similar between patients with a symptom onset of <7 days (34.9%) compared to ≥7 days (31%; p=0.57) at the time of remdesivir initiation. There were also no statistically significant differences between symptom groups for the secondary outcomes of total length of stay, time to discharge, oxygen requirements, or number of ventilator days.

Table 2. Studies Analyzing Remdesivir Initiation and Symptom Duration5-7
Study DesignSubjectsInterventionsResultsConclusions
Flannery et al 20247

Retrospective chart review		N=217 patients with confirmed SARS-CoV-2 infectionPatients were included who received ≥1 dose of RDV and stratified based on symptom onset (< 7 days versus ≥7 days)
  • Hospital all-cause mortality was not significantly different between patients with an early symptom onset (<7 days) versus late symptom onset (≥7 days)
  • Secondary outcomes of total length of stay, time to discharge, oxygen requirements, and number of ventilator days were similar between groups
  • No difference in in-hospital, all-cause mortality when RDV initiated within <7 days of symptom onset versus ≥7 days
Ader et al 20226

OL RCT

DisCoVeRy		N=857 patients with confirmed SARS-CoV-2 infection, illness of any duration, SpO2 ≤94% on room air, supplemental O2, HFNC, NIV, or MVSOC plus RDV 200 mg IV on day 1, followed by 100 mg IV once daily for 9 days plus SOC (n=429)

SOC plus lopinavir-ritonavir (n=150)

SOC plus lopinavir-ritonavir plus interferon beta-1a (n=150)

SOC plus hydroxychloroquine (n=151)

SOC alone (n=152)
  • No difference in clinical status based on WHO 7-point ordinal scale between treatment arms at 15 days (OR, 0.98; 95% CI, 0.77 to 1.25)
  • Prespecified subgroup analysis based on symptom duration found no difference in clinical status between treatment arms
  • No clinical status benefit with RDV regardless of prior symptom duration
Beigel et al 20205

DB, PC, RCT

ACTT-1		N=1062 patients with confirmed SARS-CoV-2 infection and ≥1 of the following: Pulmonary infiltrates, SpO2 ≤94% on room air, supplemental O2, HFNC, NIV, MV, or ECMORDV 200 mg IV on day 1, followed by 100 mg IV once daily for 9 days (n=541)

PB for 10 days (n=521)
  • Time to clinical recovery: 10 days with RDV versus 15 days with placebo (RR, 1.29; 95% CI, 1.12 to 1.49)
  • Significant benefit for time to recovery observed in patients randomized within ≤10 days of symptom onset requiring supplemental oxygen (RR, 1.37; 95% CI, 1.14 to 1.64), but not in those who initiated after >10 days (RR, 1.20; 95% CI, 0.94 to 1.52)
  • Time to clinical recovery reduced in patients with severe COVID-19
  • Benefit was most apparent in hospitalized patients randomized within ≤10 days of symptom onset requiring supplemental oxygen
Abbreviations: CI=confidence interval; COVID-19= coronavirus disease 2019; DB=double-blind; ECMO=extracorporeal membrane oxygenation; HFNC=high-flow nasal cannula; IV=intravenous; MV=mechanical ventilation; NIV=noninvasive ventilation; OL=open-label; OR=odds ratio; PB=placebo; PC=placebo controlled; RCT=randomized controlled trial; RDV=remdesivir; RR=rate ratio; SARS-CoV-2= severe acute respiratory syndrome coronavirus; SpO2= oxygen saturation; SOC=standard of care; WHO=World Health Organization.

Conclusion
In summary, higher quality evidence from the ACTT-1 and DisCoVeRy RCTs are conflicting on whether late initiation of remdesivir may provide benefit in hospitalized patients with COVID-19. The ACTT-1 trial demonstrated a shorter time to recovery in patients randomized to treatment within ≤10 days of symptom onset who required supplemental oxygen, while the DisCoVeRy trial found no overall clinical benefit with remdesivir versus control; subgroup analysis also indicated there was no clinical benefit based on the duration of symptoms prior to randomization. More recent lower-quality data from a retrospective chart review also demonstrated no difference for the outcome of in-hospital all-cause mortality with early versus late initiation of remdesivir. These mixed findings make it difficult to draw conclusions about the efficacy of late initiation of remdesivir. Further confirmatory clinical trials are still needed to elucidate whether late initiation of remdesivir may be associated with clinical improvement in severe COVID-19 infection.

References

  1. Taha HR, Keewan N, Slati F, et al. Remdesivir: A closer look at its effect in COVID-19 pandemic. Pharmacology. 2021;106(9-10):462-468. doi:10.1159/000518440
  2. Veklury [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2024.
  3. Infectious Diseases Society of America (IDSA) Guidelines on the Treatment and Management of Patients with COVID-19. IDSA. Updated August 12, 2024. Accessed January 20, 2025. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
  4. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines Panel. COVID-19 Treatment Guidelines. National Institutes of Health. Updated February 29, 2024. Accessed January 20, 2025. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines
  5. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 – Final report. N Engl J Med. 2020;383(19):1813-1826. doi:10.1056/NEJMoa2007764.
  6. Ader F, Bouscambert-Duchamp M, Hites M, et al. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial. Lancet Infect Dis. 2022;22(2):209-221. doi:10.1016/S1473-3099(21)00485-0
  7. Flannery A, Knecht A, Sundaresh K. Evaluation of the efficacy of remdesivir for the treatment of coronavirus disease 2019. HCA Healthc J Med. 2024;5(2):67-73. doi:10.36518/2689-0216.1406

Prepared by:
Christie Denton, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

February 2025

The information presented is current as January 8, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.