What is the role of the antiviral drug remdesivir in the treatment of coronavirus disease 2019 (COVID-19)?

Updated: Aug 10, 2020
  • Author: David J Cennimo, MD, FAAP, FACP, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
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Answer

The broad-spectrum antiviral agent remdesivir (GS-5734; Gilead Sciences, Inc) is a nucleotide analog prodrug. On May 1, 2020, The US FDA issued EUA of remdesivir to allow emergency use of the agent for severe COVID-19 (confirmed or suspected) in hospitalized adults and children. [24, 25] A phase 1b trial of an inhaled nebulized version was initiated in late June 2020 to determine if remdesivir can be used on an outpatient basis and at earlier stages of disease. [162]

Remdesivir was studied in clinical trials for Ebola virus infections but showed limited benefit. [163] Remdesivir has been shown to inhibit replication of other human coronaviruses associated with high morbidity in tissue cultures, including severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. Efficacy in animal models has been demonstrated for SARS-CoV and MERS-CoV. [164]

Several phase 3 clinical trials are testing remdesivir for treatment of COVID-19 in the United States, South Korea, and China. Positive results were seen with remdesivir after use by the University of Washington in the first case of COVID-19 documented on US soil in January 2020. [165] The drug was prescribed under an open-label compassionate use protocol, but the US FDA has since moved to allow expanded access to remdesivir, permitting approved sites to prescribe the investigational product for multiple patients under protocol without requesting permission for each. [166] An adaptive randomized trial of remdesivir coordinated by the National Institute of Health (NCT04280705) was started first against placebo, but additional therapies can be added to the protocol as evidence emerges. The first experience with this study involved passengers of the Diamond Princess cruise ship in quarantine at the University of Nebraska Medical Center in February 2020 after returning to the United States from Japan following an on-board outbreak of COVID-19. [167] Trials of remdesivir for moderate and severe COVID-19 compared with standard of care and varying treatment durations are ongoing.

EUA of remdesivir was based on preliminary data analysis of the Adaptive COVID-19 Treatment Trial (ACTT) was announced April 29, 2020. The analysis included 1,063 hospitalized patients with advanced COVID-19 and lung involvement, showing that patients who received remdesivir recovered faster than similar patients who received placebo. Preliminary results indicate that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (P< 0.001). Specifically, the median time to recovery was 11 days in patients treated with remdesivir compared with 15 days in those who received placebo. Results also suggested a survival benefit by day 14, with a mortality rate of 7.1% in the remdesivir group, compared with 11.9% in the placebo group, but this was not statistically significant. [26]

The ACTT results differ from a smaller randomized trial conducted in China and published hours before the press release by the NIH. Results from this randomized, double-blind, placebo-controlled, multicenter trial (n = 237; 158 to remdesivir and 79 to placebo; 1 patient withdrew) found remdesivir was not associated with statistically significant clinical benefits, measured as time to clinical improvement, in adults hospitalized with severe COVID-19. Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less. The authors concluded that numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. [168]

A phase 3, randomized, open-label trial showed that remdesivir was associated with significantly greater recovery and reduced odds of death compared with standard of care in patients with severe COVID-19. The recovery rate at day 14 was higher in patients who received remdesivir (n = 312) compared with those who received standard of care (n = 818) (74.4% vs 59%; P< 0.001). The mortality rate at day 14 was also lower in the remdesivir group (7.6% vs 12.5%; P = 0.001). [169]

The open-label phase 3 SIMPLE trial (n = 397) in hospitalized patients with severe COVID-19 disease not requiring mechanical ventilation showed similar improvement in clinical status with the 5-day remdesivir regimen compared with the 10-day regimen on day 14 (OR: 0.75 [95% CI 0.51-1.12]). In this study, 65% of patients who received a 5-day course of remdesivir showed a clinical improvement of at least 2 points on the 7-point ordinal scale at day 14, compared with 54% of patients who received a 10-day course. After adjustment for imbalances in baseline clinical status, patients receiving a 10-day course of remdesivir had a distribution in clinical status at day 14 that was similar to that of patients receiving a 5-day course (P = 0.14). The study demonstrates the potential for some patients to be treated with a 5-day regimen, which could significantly expand the number of patients who could be treated with the current supply of remdesivir. The trial is continuing with an enrollment goal of 6,000 patients. [168]

Data presented at the virtual COVID-19 Conference in July 2020 included a comparative analysis of clinical recovery and mortality outcomes from the phase 3 SIMPLE trials versus a real-world cohort of patients with severe COVID-19 receiving standard of care. The analysis showed remdesivir was associated with a 62% reduction in the risk of mortality compared with standard of care. Subgroup analyses found these results were similar across different racial and ethnic groups. While these data are important, they require confirmation in prospective clinical trials. [170]

Similarly, the phase 3 SIMPLE II trial in patients with moderate COVID-19 disease showed that 5 days of remdesivir treatment was 65% more likely to yield clinical improvement at day 11 than standard of care (P = 0.18). These data show that early intervention with a 5-day treatment course can significantly improve outcomes. [171]

The first published report concerning remdesivir compassionate use described clinical improvement in 36 of 53 hospitalized patients (68%) with severe COVID-19. At baseline, 30 patients (57%) were receiving ventilation and 4 (8%) extracorporeal membrane oxygenation (ECMO). Measurement of efficacy requires randomized, placebo-controlled trials. [172]

Observations during compassionate use follow-up (median of 18 days) included the following:

  • Oxygen-support class improved in 36 patients (68%), including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated.
  • Twenty-five patients (47%) were discharged.
  • Seven patients (13%) died.
  • The mortality rate was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.

Additional data for compassionate use of remdesivir was released on July 10, 2020, and demonstrated that remdesivir treatment was associated with significantly improved clinical recovery and a 62% reduction in the risk of mortality compared with standard of care. Findings from the comparative analysis showed that 74.4% of remdesivir-treated patients recovered by day 14 versus 59% of patients receiving standard of care. The mortality rate in patients treated with remdesivir in the analysis was 7.6% at day 14 compared with 12.5% among patients not taking remdesivir (adjusted OR, 0.38; 95% CI, 0.22-0.68, P = 0.001). The analyses also found that 83% of pediatric patients (n = 77) and 92% of pregnant and postpartum women (n = 86) with a broad spectrum of COVID-19 severity recovered by day 28. [170]

An in vitro study showed that the antiviral activity of remdesivir plus interferon beta (IFNb) was superior to that of lopinavir/ritonavir (LPV/RTV; Kaletra, Aluvia; AbbVie Corporation). Prophylactic and therapeutic remdesivir improved pulmonary function and reduced lung viral loads and severe lung pathology in mice, whereas LPV/RTV-IFNb slightly reduced viral loads without affecting other disease parameters. Therapeutic LPV/RTV-IFNb improved pulmonary function but did not reduce virus replication or severe lung pathology. [173]

Remdesivir use in children

Remdesivir emergency use authorization includes pediatric dosing that was derived from pharmacokinetic data in healthy adults. Remdesivir has been available through compassionate use to children with severe COVID-19 since February 2020. A phase 2/3 trial (CARAVAN) of remdesivir was initiated in June 2020 to assess safety, tolerability, pharmacokinetics, and efficacy in children with moderate-to-severe COVID-19. CARAVAN is an open-label, single-arm study of remdesivir in children from birth to age 18 years. [174]

Data were presented on compassionate use of remdesivir in children at the virtual COVID-19 Conference held July 10-11, 2020. Results showed most of the 77 children with severe COVID-19 improved with remdesivir. Clinical recovery was observed in 80% of children on ventilators or ECMO and in 87% of those not on invasive oxygen support. [175]

For additional information, see Coronavirus Disease 2019 (COVID-19) in Children.

Remdesivir use in pregnant women

Data were presented at the virtual COVID-19 Conference held July 10-11, 2020, on compassionate use of remdesivir in 86 pregnant women (67 while pregnant and 19 on postpartum days 0-3). No new safety signals were observed. Results showed pregnant women had higher rates of recovery than nonpregnant adults treated with compassionate use remdesivir (92% vs 62%), likely owing to the younger age of pregnant women (median age, 33 years vs 64 years). [176]

Drug interactions with remdesivir

Coadministration of remdesivir is not recommended with chloroquine or hydroxychloroquine. Based on in vitro data, chloroquine demonstrated an antagonistic effect on the intracellular metabolic activation and antiviral activity of remdesivir. [25]


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