Remdesivir for the treatment of COVID-19.

BACKGROUND

Remdesivir is an antiviral medicine approved for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19). This led to widespread implementation, although the available evidence remains inconsistent. This update aims to fill current knowledge gaps by identifying, describing, evaluating, and synthesising all evidence from randomised controlled trials (RCTs) on the effects of remdesivir on clinical outcomes in COVID-19.

OBJECTIVES

To assess the effects of remdesivir and standard care compared to standard care plus/minus placebo on clinical outcomes in patients treated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

SEARCH METHODS

We searched the Cochrane COVID-19 Study Register (which comprises the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, ClinicalTrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform, and medRxiv) as well as Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index) and WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies, without language restrictions. We conducted the searches on 31 May 2022.

SELECTION CRITERIA

We followed standard Cochrane methodology. We included RCTs evaluating remdesivir and standard care for the treatment of SARS-CoV-2 infection compared to standard care plus/minus placebo irrespective of disease severity, gender, ethnicity, or setting. We excluded studies that evaluated remdesivir for the treatment of other coronavirus diseases.

DATA COLLECTION AND ANALYSIS

We followed standard Cochrane methodology. To assess risk of bias in included studies, we used the Cochrane RoB 2 tool for RCTs. We rated the certainty of evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for outcomes that were reported according to our prioritised categories: all-cause mortality, in-hospital mortality, clinical improvement (being alive and ready for discharge up to day 28) or worsening (new need for invasive mechanical ventilation or death up to day 28), quality of life, serious adverse events, and adverse events (any grade). We differentiated between non-hospitalised individuals with asymptomatic SARS-CoV-2 infection or mild COVID-19 and hospitalised individuals with moderate to severe COVID-19.

MAIN RESULTS

We included nine RCTs with 11,218 participants diagnosed with SARS-CoV-2 infection and a mean age of 53.6 years, of whom 5982 participants were randomised to receive remdesivir. Most participants required low-flow oxygen at baseline. Studies were mainly conducted in high- and upper-middle-income countries. We identified two studies that are awaiting classification and five ongoing studies. Effects of remdesivir in hospitalised individuals with moderate to severe COVID-19 With moderate-certainty evidence, remdesivir probably makes little or no difference to all-cause mortality at up to day 28 (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.81 to 1.06; risk difference (RD) 8 fewer per 1000, 95% CI 21 fewer to 6 more; 4 studies, 7142 participants), day 60 (RR 0.85, 95% CI 0.69 to 1.05; RD 35 fewer per 1000, 95% CI 73 fewer to 12 more; 1 study, 1281 participants), or in-hospital mortality at up to day 150 (RR 0.93, 95% CI 0.84 to 1.03; RD 11 fewer per 1000, 95% CI 25 fewer to 5 more; 1 study, 8275 participants). Remdesivir probably increases the chance of clinical improvement at up to day 28 slightly (RR 1.11, 95% CI 1.06 to 1.17; RD 68 more per 1000, 95% CI 37 more to 105 more; 4 studies, 2514 participants; moderate-certainty evidence). It probably decreases the risk of clinical worsening within 28 days (hazard ratio (HR) 0.67, 95% CI 0.54 to 0.82; RD 135 fewer per 1000, 95% CI 198 fewer to 69 fewer; 2 studies, 1734 participants, moderate-certainty evidence). Remdesivir may make little or no difference to the rate of adverse events of any grade (RR 1.04, 95% CI 0.92 to 1.18; RD 23 more per 1000, 95% CI 46 fewer to 104 more; 4 studies, 2498 participants; low-certainty evidence), or serious adverse events (RR 0.84, 95% CI 0.65 to 1.07; RD 44 fewer per 1000, 95% CI 96 fewer to 19 more; 4 studies, 2498 participants; low-certainty evidence). We considered risk of bias to be low, with some concerns for mortality and clinical course. We had some concerns for safety outcomes because participants who had died did not contribute information. Without adjustment, this leads to an uncertain amount of missing values and the potential for bias due to missing data. Effects of remdesivir in non-hospitalised individuals with mild COVID-19 One of the nine RCTs was conducted in the outpatient setting and included symptomatic people with a risk of progression. No deaths occurred within the 28 days observation period. We are uncertain about clinical improvement due to very low-certainty evidence. Remdesivir probably decreases the risk of clinical worsening (hospitalisation) at up to day 28 (RR 0.28, 95% CI 0.11 to 0.75; RD 46 fewer per 1000, 95% CI 57 fewer to 16 fewer; 562 participants; moderate-certainty evidence). We did not find any data for quality of life. Remdesivir may decrease the rate of serious adverse events at up to 28 days (RR 0.27, 95% CI 0.10 to 0.70; RD 49 fewer per 1000, 95% CI 60 fewer to 20 fewer; 562 participants; low-certainty evidence), but it probably makes little or no difference to the risk of adverse events of any grade (RR 0.91, 95% CI 0.76 to 1.10; RD 42 fewer per 1000, 95% CI 111 fewer to 46 more; 562 participants; moderate-certainty evidence). We considered risk of bias to be low for mortality, clinical improvement, and safety outcomes. We identified a high risk of bias for clinical worsening.

AUTHORS' CONCLUSIONS: Based on the available evidence up to 31 May 2022, remdesivir probably has little or no effect on all-cause mortality or in-hospital mortality of individuals with moderate to severe COVID-19. The hospitalisation rate was reduced with remdesivir in one study including participants with mild to moderate COVID-19. It may be beneficial in the clinical course for both hospitalised and non-hospitalised patients, but certainty remains limited. The applicability of the evidence to current practice may be limited by the recruitment of participants from mostly unvaccinated populations exposed to early variants of the SARS-CoV-2 virus at the time the studies were undertaken.  Future studies should provide additional data on the efficacy and safety of remdesivir for defined core outcomes in COVID-19 research, especially for different population subgroups.