Grein et al., New England Journal of Medicine, April 2020

Whilst old age alone is the single most important risk factor for COVID-19, older patients and those with pre-existing respiratory or cardiovascular conditions are at the greatest risk for severe complications2-3. In the absence of a proven effective therapy, current management consists of supportive care, including invasive and non-invasive oxygen support and treatment with antibiotics4-5. As an unprecedent approach, many patients have received off-label or compassionate-use therapies such as anti-retrovirals, anti-parasitic agents, anti-inflammatory compounds, and convalescent plasma (plasmapheresis)6-9.

Remdesivir is a prodrug of a nucleotide analogue that is intracellularly metabolized to an analogue of adenosine triphosphate that inhibits viral RNA polymerases. Remdesivir has broad spectrum activity against members of several virus families, including filoviruses (e.g., Ebola) and coronaviruses (e.g., SARS-CoV and Middle East respiratory syndrome coronavirus [MERSCoV]) and has shown prophylactic and therapeutic efficacy in nonclinical models of these coronaviruses10-13. In vitro testing has also shown that remdesivir has activity against SARS-CoV-2. Remdesivir appears to have a favorable clinical safety profile, as reported on the basis of experience in approximately 500 persons, including healthy volunteers and patients treated for acute Ebola virus infection14-15.

In a recent paper, Grein and colleagues report outcomes in a cohort of patients hospitalized for severe COVID-19 who were treated with remdesivir on a compassionate-use basis. In all cases, SARS-CoV-2 infection was confirmed by means of RT-PCR and those on treatment had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. The patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. The paper report data from patients who received remdesivir during the period of January 25 to March 7, 2020.

Although 61 patients received at least one dose of remdesivir, data from 8 individuals could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were on mechanical ventilation and 4 (8%) on extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients on invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. A total of 32 patients (60%) reported adverse events, of which the common ones were increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension. In general, adverse events were more common in patients receiving invasive ventilation. A total of 12 patients (23%) had serious adverse events, of which the most common ones were multiple organ-dysfunction syndrome, septic shock, acute kidney injury, and hypotension, and were restricted to patients on invasive ventilation at baseline. Four patients (8%) discontinued remdesivir treatment prematurely: one because of worsening of pre-existing renal failure, one because of multiple organ failure, and two because of elevated aminotransferases, including one patient with a maculopapular rash. Given the nature of this compassionate-use program, data on a limited number of laboratory measures were collected, including median serum ALT, AST, and creatinine fluctuated during follow-up.

This preliminary report is the first to demonstrate efficacy in a small cohort of patients who were severely ill with COVID-19 and treated with remdesivir. It is expected that additional data from ongoing randomized, controlled trials will add to the evidence on the safety and efficacy of remdesivir for COVID-19. Specifically, improvement in oxygen-support status was observed in 68% of patients, and overall mortality was 13% over a median follow-up of 18 days. In a recent randomized, controlled trial of lopinavir–ritonavir in patients hospitalized for COVID-19, the 28-day mortality was 22%6. It is important to note that only 1 of 199 patients in that trial was on invasive ventilation at baseline. In case series and cohort studies, largely from China, mortality rates of 17 to 78% have been reported in severe cases, defined by the need for admission to an intensive care unit, invasive ventilation, or both16-21. For example, among 201 patients hospitalized in Wuhan, China, mortality was 22% overall and 66% (44 of 67) among patients receiving invasive mechanical ventilation. By way of comparison, the 13% mortality observed in this remdesivir compassionate-use cohort is noteworthy, considering the severity of disease in this patient population.

Nevertheless, the patients enrolled in this compassionate-treatment program are not directly comparable to those studied in the other reports. For example, 64% of remdesivir-treated patients were receiving invasive ventilation at baseline, including 8% who were receiving ECMO, and mortality in this subgroup was 18% (as compared with 5.3% in patients receiving non-invasive oxygen support), and the majority (75%) of patients were male, over 60 years of age, with coexisting conditions. It should be stressed that the compassionate-use program did not collect viral load data to confirm the antiviral effects of remdesivir or any association between baseline viral load and viral suppression and clinical response. Moreover, the duration of remdesivir therapy was not entirely uniform in the study, largely because clinical improvement enabled discharge from the hospital. The effectiveness of a shorter duration of therapy (5 days as compared with 10 days), which would allow the treatment of more patients during the pandemic, is being assessed in ongoing randomized trials of this therapy. No new safety signals were detected during short-term remdesivir therapy in this compassionate-use cohort. Nonclinical toxicology studies have shown renal abnormalities, but no clear evidence of nephrotoxicity due to remdesivir therapy was observed.

As reported in studies in healthy volunteers and patients infected with the Ebola virus, mild-to-moderate elevations in ALT, AST, or both were observed in this cohort of patients with severe COVID-1914-15. However, considering the frequency of liver dysfunction in patients with COVID-19, attribution of hepatotoxicity to either remdesivir or the underlying disease is challenging22. Nevertheless, the safety and side-effect profile of remdesivir in patients with COVID-19 require proper assessment in placebo-controlled trials. Interpretation of the results of this study is limited by the small size of the cohort, the relatively short duration of follow-up, potential missing data owing to the nature of the program, the lack of information on 8 of the patients initially treated, and the lack of a randomized control group. Although the latter precludes definitive conclusions, comparisons with contemporaneous cohorts from the literature, in whom general care is expected to be consistent with that in the present cohort, suggest that remdesivir may have clinical benefit in patients with severe COVID-19. Nevertheless, other factors may have contributed to differences in outcomes, including the type of supportive care (e.g., concomitant medications or variations in ventilatory practices) and differences in institutional treatment protocols and guidelines for hospitalization. Moreover, the use of invasive ventilation as a proxy for disease severity may be influenced by the availability of ventilators in a given location. The findings from these uncontrolled data will be no doubt informed by the ongoing randomized, placebo-controlled trials of remdesivir therapy for COVID-19.


This article is intended for medical professionals.

Read also:

An Evidence-based Perspective into Treatment options for COVID-19
Effectiveness of convalescent plasma therapy in severe COVID-19 patients

References:
1. Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, et al. Clinical, laboratory and imaging features of COVID-19: a systematic review and metaanalysis. Travel Med Infect Dis 2020 March 13 (Epub ahead of print).
2. Weiss P, Murdoch DR. Clinical course and mortality risk of severe COVID-19. Lancet 2020;395:1014-5.
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 (Epub ahead of print).
4. Onder G, Rezza G, Brusaferro S. Casefatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA 2020 March 23 (Epub ahead of print).
5. Poston JT, Patel BK, Davis AM. Management of critically ill adults with COVID-19. JAMA 2020 March 26 (Epub ahead of print).
6. Cao B, Wang Y, Wen D, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2001282.
7. Shen C, Wang Z, Zhao F, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA 2020 March 27 (Epub ahead of print).
8. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res 2020 March 5 (Epub ahead of print). 1
9. Baden LR, Rubin EJ. Covid-19 — the search for effective therapy. N Engl J Med. DOI: 10.1056/NEJMe2005477. 1
10. de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A 2020;117:6771-6.
11. Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med 2017;9(396):eaal3653.
12. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERSCoV. Nat Commun 2020;11:222.
13. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019- nCoV) in vitro. Cell Res 2020;30:269-71.
14. Mulangu S, Dodd LE, Davey RT Jr, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med 2019;381:2293-303.
15. European Medicines Agency. Summary on compassionate use: Remdesivir Gilead. April 3, 2020 (https://www.ema .europa.eu/en/documents/other/summary -compassionate-use-remdesivir-gilead_en .pdf).
16. Arentz M, Yim E, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State. JAMA 2020 March 19 (Epub ahead of print).
17. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020 February 7 (Epub ahead of print). 2
18. 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 February 24 (Epub ahead of print).
19. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-62.
20. Bhatraju PK, Ghassemieh BJ, Nichols M, et al. Covid-19 in critically ill patients in the Seattle region — case series. N Engl J Med. DOI: 10.1056/NEJMoa2004500.
21. ICNARC report on COVID-19 in critical care. London: Intensive Care National Audit & Research Centre, March 27, 2020 (https://www.icnarc.org/DataServices /Attachments/Download/b5f59585-5870 -ea11-9124-00505601089b).
22. Zhang C, Shi L, Wang FS. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol 2020 March 4 (Epub ahead of print). Copyright © 2020 Massachusetts Medical Society


Prepared by:
Dr Reshma Ramracheya
Research Scientist & University Research Lecturer at the University of Oxford
Senior Research Fellow at Wolfson College, University of Oxford
Reshma.ramracheya@ocdem.ox.ac.uk