By Dr Abdul Malik Mohamed Thalha, Dr Yeong Yeh Lee, Dr Alwi Besari & Dr Sharifah Faridah Syed Omar
We are at the most unprecedented of times. The COVID-19 pandemic has been gaining momentum since the first report came from Wuhan, China in December 2019. As of 12 May 2020, 4,425,094 people have been infected with SARS-CoV-2 with deaths reaching 297,723.1 Doctors are desperately looking for an effective drug, and there have been a number of candidates on trial; one of them, remdesivir, is probably the most exciting of all. This is the drug developed for the Ebola epidemic in 2015, but it was found to be less effective in clinical trials than in in vitro studies. Is remdesivir the panacea for COVID-19? In this clinical opinion, we critically appraised the article published in NEJM on the compassionate use of remdesivir in severe COVID-19.
Remdesivir or GS-5734, is the monophosphoramidate prodrug of C-adenosine nucleoside analogue GS-441524, developed and marketed by Gilead Sciences (Foster City, USA). In contrast to the interest shown in COVID-19, little is known of remdesivir in human trials of Ebola virus other than case reports2 and ongoing multicentre phase-III randomised controlled trials (RCT)3 (Table 1). Overall, from in vitro studies, the compound seems to have a broad-spectrum anti-CoVs activity including SARS-CoV and MERS-CoV, the close cousins of SARS-CoV-2.4 For example, SARS-CoV has been shown to be inhibited effectively by remdesivir in the primary human airway epithelial cell cultures.5 Based on a recent study in the rhesus macaque, data has shown that remdesivir prevented clinical disease from MERS-CoV when administered 24h before.6 In addition, compared to controls, the macaque treated with remdesivir 12h after infection had less severe disease, lower viral loads in the lung and less lung damage.
The encouraging preclinical data seem to have translated into several small clinical studies, and larger multicentre RCTs are ongoing. Before RCTs, there have been approvals from Gilead Sciences for prescription of remdesivir on compassionate grounds in severe COVID-19 disease. Those with severe COVID-19 are most likely to have respiratory complications, increased need for respiratory support, intensive care and a higher rate of mortality. From the Wuhan experience,7 3.2% of patients with COVID-19 required mechanical ventilation, but recent data from New York reported a higher rate of 12.2%.8
In the New York report, out of those patients needing mechanical ventilation, about a quarter died and two-thirds remained in the hospital. This is where remdesivir benefits the most. Overall, over a median follow-up of 18 days, Grein et al.9 reported that 68% (36/53) on remdesivir needed less oxygen support including all patients on ambient air and 71% (5/7) who were receiving non-invasive oxygen support. More notable is that with remdesivir, 57% of those needing ventilation could be extubated and 75% stopped needing ECMO. The clinical improvement from remdesivir was translated into a greater hospital discharge rate of 47% (25/53), more days before mortality (interval between remdesivir initiation to death was 15 days) and a mortality rate of 13% (7/53).
The clinical benefits of remdesivir were better for those not receiving ventilation than those on ventilation (hazard ratio for improvement 0.33), and older age was the only determining factor for less clinical improvement despite being on remdesivir. On the other hand, the mortality benefits did not differ between those receiving invasive vs non-invasive ventilation; however, the risk of death was higher in the elderly (above 70-years old) and those with higher creatinine level at baseline.
The reported results are undoubtedly remarkable; however, several points or limitations need to be considered. Many have been described by the authors, including small sample size, limited duration of follow-up and the lack of a randomised control group. As with all open-label and uncontrolled studies, the remdesivir study is subjected to potential bias as it does not minimise the effect of knowledge of treatment allocation on reporting of key outcomes.10 In addition, it may be of concern that a sizeable number of patients’ data could not be analysed i.e. 13% of the cohort (including seven patients with no post-treatment data and one with a dosing error). Furthermore, some outcome data were omitted, for example in the patients labelled 1 to 4 and 11 to 18, where in spite improvement in oxygen support, the final outcome (discharge or death) was omitted. Similarly, the patients numbered 20, 24, 25, 29, 32–34 and 38 did not have their final outcome recorded. In all, these make up 37% (20/53) of ‘unavailable’ outcome data.
While on one hand there are no new safety events that we did not know about remdesivir, on the other hand, the reported 60% of adverse events, especially 23% elevation in liver enzymes and 23% of serious adverse events, should not be taken lightly. In addition, viral load data were not collected, information which would have helped the authors in correlating viral suppression with observed clinical and mortality benefits.
Also, the duration of remdesivir therapy was not entirely uniform across all patients, with only 19% (10/53) receiving 5–9 days of treatment and 6% (3/53) receiving less than 5 days’ treatment. More controversial is the initial draft that was leaked to the press which mentioned that remdesivir was ‘not associated with a difference in time to clinical improvement when compared to a standard of care as control’. The report in the press further stressed that 13.9% of the remdesivir patients had died compared to 12.8% of patients in the control arm.
As of 29 April 2020, preliminary results from the Adaptive COVID-19 Treatment Trial (ACTT) have been released.11 This multicentre, adaptive, randomised double-blind controlled trial of the safety and efficacy of remdesivir for the treatment of non-severe COVID-19 involving 800 subjects has shown ‘a clear-cut significant positive effect in diminishing time to recovery’ from 15 days to 11 days. However, the mortality rate of remdesivir vs placebo arm i.e. 8% vs 11% in placebo arm was not statistically significant. Being the larger study, the preliminary results provide additional clinical reason for use of remdesivir, especially in having benefit to non-severe COVID-19 patients. However, finer details of the trial need to be explored before clinicians are convinced, especially in the light of recent negative study results reported in The Lancet.12
As a conclusion, while the encouraging preclinical and open-label studies seem to suggest a clinical benefit from remdesivir in severe COVID-19, remdesivir is not a panacea. There are many clinical aspects of COVID-19 treatment that are poorly understood, e.g. cytokine storm, which are not covered in this study. It will be interesting to see the results of a RCT trial13 before the final judgement call on this compound can be made.
Read full opinion article here OR download full journal paper here:
1 worldometers. COVID-19 Coronavirus Pandemic 2020, 14 May 2020. https://www.worldometers.info/coronavirus/(link is external)(accessed 12/05/20).
2 Dörnemann J, Burzio C, Ronsse A et al. First Newborn Baby to Receive Experimental Therapies Survives Ebola Virus Disease. Journal Infect Dis 2017; 215: 171–4.
3 Mulangu S, Dodd LE, Davey RT et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. New Engl J Med 2019; 381: 2293–303.
4 Sheahan TP, Sims AC, Graham RL et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med 2017; 9: eaal3653.
5 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.
6 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 USA 2020; 117: 6771–6.
7 Meng L, Qiu H, Wan L et al. Intubation and Ventilation amid the COVID-19 Outbreak: Wuhan’s Experience. Anesthesiology 2020; 132: 1317–32.
8 Richardson S, Hirsch JS, Narasimhan M et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA 2020: e206775 [Epub ahead of print 22/04/20].
9 Grein J, Ohmagari N, Shin D et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med 2020: NEJMoa2007016 [Epub ahead of print 10/04/20].
10 Manja V, Lakshminrusimha S. Epidemiology and Clinical Research Design, Part 1: Study Types. Neoreviews 2014; 15: e558-e69.
11 National Institutes of Health: NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19 [Press release]. 2020 April 29. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-shows-r…(link is external) (accessed 12/05/20).
12 Wang Y, Zhang D, Du G et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020. 2020 Apr 29 doi: 10.1016/S0140-6736(20)31022-9.
13 U.S. national Library of Medicine. ClinicalTrials.gov. A trial of remdesivir in adults with severe COVID-19 2020 , April 15. https://clinicaltrials.gov/ct2/show/study/NCT04257656(l
Source: Thalha, A., Lee, Y., Besari, A. and Omar, S., 2020. Have we found the panacea to COVID-19 with remdesivir, an old but newly packaged drug?. Journal of the Royal College of Physicians of Edinburgh, 50(2), pp.159-161.
**All previous posts about COVID-19 here: https://sciencemediacentremalaysia.com/tag/covid-19/
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