By Betty Tran, MD, MSc

Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago

Dr. Tran reports no financial relationships relevant to this field of study.

SYNOPSIS: In this group of patients hospitalized with severe COVID-19, the majority of whom required invasive ventilation, 68% had clinical improvement after treatment with remdesivir on a compassionate-use basis.

SOURCE: Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe COVID-19. N Engl J Med 2020; April 10. doi: 10.1056/NEJMoa2007016. [Epub ahead of print].

The severe acute respiratory coronavirus 2 (SARS-CoV-2) and the disease it causes, COVID-19, have overwhelmed health systems globally, with more than 3 million confirmed cases and 230,000 deaths as of this writing.1 In severe cases requiring admission to the intensive care unit (ICU) or invasive ventilation, mortality rates upward of 60% to 70% have been reported.2-3 Currently, there is no proven effective therapy, and management has largely consisted of supportive care, including various forms of oxygen support. Ongoing trials using antiretrovirals, anti-inflammatory agents, and convalescent plasma are ongoing.

Remdesivir is a prodrug of a nucleotide analogue that inhibits viral ribonucleic acid (RNA) polymerases. Gilead Sciences sponsored early compassionate use of remdesivir for hospitalized COVID-19 patients beginning Jan. 25, 2020. Criteria included oxygen saturation 94% or lower while breathing room air or on oxygen support, a creatinine clearance above 30 mL/minute, serum transaminases less than five times the upper limit of normal, and patients taking no other investigational agents for COVID-19. Planned treatment consisted of a 10-day course of remdesivir, with a loading dose of 200 mg intravenously (IV) on day 1, followed by 100 mg daily for nine days. Follow-up was continued through at least 28 days after beginning treatment or until discharge or death.

In total, 61 patients received at least one dose of remdesivir, although eight patients were excluded because of missing baseline information or an erroneous start date, leaving 53 patients for analysis. Seventy-five percent of these received the full 10-day treatment. Patients from the United States, Europe, and Canada comprised the bulk of the cohort. The median age was 64 years (interquartile range [IQR] 48-71), 75% were male, and at baseline 34 patients (64%) received invasive ventilation (30 on mechanical ventilation, and four received extracorporeal membrane oxygenation [ECMO]). The median duration of symptoms before initiation of remdesivir treatment was 12 days (IQR 9-15).

Over a median of 18 days (IQR 13-23) after receiving remdesivir, 36 of 53 patients (68%) improved regarding oxygen support, including 17 of 30 patients (57%) receiving invasive mechanical ventilation who were extubated and three of four patients (75%) on ECMO who stopped receiving it. As of the last follow-up, 25 of 53 patients (47%) had been discharged (24% of those who received invasive ventilation, 89% of those receiving noninvasive ventilation support). Overall mortality in the cohort was 13%. Adverse events, most commonly increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension, occurred in 60% of patients, with 23% of patients experiencing serious adverse events (e.g., multi-organ dysfunction, septic shock).

COMMENTARY

This preliminary report describing the clinical outcomes seen in a small group of patients hospitalized for severe COVID-19 disease treated with remdesivir is encouraging, although interpretation is difficult, primarily given the lack of a randomized control group. Remdesivir has broad-spectrum activity against a variety of virus families, has in vitro activity against SARS-CoV-2, and previously has been shown to have a favorable safety profile. It is unclear whether the listed adverse events from this report were actually a result of remdesivir, since these issues have been reported as part of the disease spectrum of COVID-19.

After this report was published, a randomized, double-blind, placebo-controlled multicenter trial out of Hubei, China, found no statistically significant benefits for remdesivir, although there was a trend toward faster time to clinical improvement among those who received it.4 A few points are noteworthy, however. First, patients enrolled in this study were allowed to receive lopinavir-ritonavir, steroids, and interferons concomitantly. Second, the study stopped enrolling early, with a subsequent reduction in statistical power from 80% to 58%. Third, the patient population in the Hubei study had fewer patients on higher oxygen support (i.e., high-flow nasal cannula, noninvasive or invasive mechanical ventilation, ECMO): 18% of the remdesivir group, 13% of the placebo group.

In contrast, it was announced recently that a preliminary analysis of a National Institute of Allergy and Infectious Diseases clinical trial found that COVID-19 patients treated with remdesivir had a 31% faster recovery time compared to placebo (P < 0.001), with a median time to recovery of 11 vs. 15 days.5 Furthermore, a survival benefit was suggested, with a mortality rate of 8.0% for the remdesivir group vs. 11.6% for the placebo group (P = 0.059).5 It is also important to note that regardless of these mixed findings, remdesivir has not been shown to be curative or preventive. As we await more formal details from these trial results, we should continue the type of ICU level care that has resulted in clinically meaningful outcomes for critically ill patients after decades of research, namely the A2F bundle (Assessing/preventing/managing pain, both spontaneous awakening and breathing trials, choice of analgesia/sedation, delirium assessment/prevention/management, early mobility/exercise, and family engagement).6

REFERENCES

  1. World Health Organization. Coronavirus disease (COVID-19) pandemic. https://www.who.int/emergencies/diseases/novel-coronavirus-2019
  2. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020; Feb. 24. doi: 10.1001/jama.2020.2648. [Epub ahead of print].
  3. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020; March 13. doi: 10.1001/jamainternmed.2020.0994. [Epub ahead of print].
  4. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: A randomized, double-blind, placebo-controlled, multicenter trial. Lancet 2020; April 29. doi: 10.1016/S0140-6736(20)31022-9.
  5. National Institute of Allergy and Infectious Diseases. NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19. April 29, 2020. https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-COVID-19
  6. Pun BT, Balas MC, Barnes-Daly MA, et al. Caring for critically ill patients with the ABCDEF bundle: Results of the ICU Liberation Collaborative in over 15,000 adults. Crit Care Med 2019;47:3-14.