key: cord-0829142-vf2zuafv
authors: Shrestha, Dhan Bahadur; Budhathoki, Pravash; Syed, Nawazish-i-Husain; Rawal, Era; Raut, Sumit; Khadka, Sitaram
title: Remdesivir: A potential game-changer or just a myth? A systematic review and meta-analysis()
date: 2020-10-26
journal: Life Sci
DOI: 10.1016/j.lfs.2020.118663
sha: 344966aee4c01c958e8c234a09d60053fde79f9d
doc_id: 829142
cord_uid: vf2zuafv

AIMS: COVID-19 outbreak has created a public health catastrophe all over the world. Here, we have aimed to conduct a systematic review and meta-analysis on remdesivir use for COVID-19. MAIN METHODS: We searched Pubmed, Scopus, Embase, and preprint sites and identified ten studies for qualitative and four studies for quantitative analysis using PRISMA guidelines. The quantitative synthesis was performed using fixed and random effect models in RevMan 5.4. Heterogeneity was assessed using the I-squared (I(2)) test. KEY FINDINGS: Comparing 10-day remdesivir group with placebo or standard of care (SOC) group, remdesivir reduced 14 days mortality (OR 0.61, CI 0.41–0.91), need for mechanical ventilation (OR 0.73, CI 0.54–0.97), and severe adverse effects (OR 0.69, 95% CI 0.54 to 0.88). Clinical improvement on day 28 (OR 1.59, CI 1.06–2.39), day 14 clinical recovery (OR 1.48, CI 1.19–1.84), and day 14 discharge rate (OR 1.41, CI 1.15–1.73) were better among remdesivir group. Earlier clinical improvement (MD −2.51, CI −4.16 to −0.85); and clinical recovery (MD −4.69, CI −5.11 to −4.28) were seen among the remdesivir group. Longer course (10 days) of remdesivir showed a higher discharge rate at day 14 (OR 2.11, CI 1.50–2.97), but there were significantly higher rates of serious adverse effects, and drug discontinuation than the 5-day course. SIGNIFICANCE: Remdesivir showed a better 14 days mortality profile, clinical recovery, and discharge rate. Overall clinical improvement and clinical recovery were earlier among the remdesivir group. 10-day remdesivir showed more adverse outcome than 5-day course with no significant benefits.

Corona Virus Disease -19 outbreak which was first seen in the Hubei province of China in late December of 2019 has become a widespread pandemic. The infection is caused by a new strain of coronavirus which was later named as Severe Acute Respiratory Syndrome -Coronavirus 2 (SARS- CoV 2) . The virus has spread all over the globe and created a public health catastrophe meanwhile dragging several countries into economic crises. The symptoms of infection range from mild viral illness symptoms including sore throat, headache, cough, fever to severe symptoms of pneumonia, and ARDS. As of August 28, 2020, 24 million cases have been confirmed and more than 800,000 deaths have been recorded due to COVID-19 [1] . However, a lack of standardized treatment makes the situation even more frightful. Remdesivir is being used as one of the repurposed drugs in combating the illness all around the world.

Remdesivir, a nucleotide analog prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2 [2] . . Subsequent evaluation by numerous virology laboratories demonstrated the ability of remdesivir to inhibit coronavirus replication, including SARS-CoV-2 [3] . As a nucleoside analog, remdesivir acts as an RNA dependent RNA polymerase (RdRp) inhibitor, targeting the viral genome replication process. The RdRp is the protein complex coronaviruses use to replicate their RNA-based genomes. After the host metabolizes remdesivir into active NTP, the metabolite competes with adenosine triphosphate (ATP: the natural nucleotide normally used in this process) for incorporation into the nascent RNA strand. In addition, the drug is believed to outpace the proofreading property Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was used for our systematic review [7] .

We included the studies focusing on mortality rate, clinical improvement and recovery, discharge rate, adverse effects, mechanical ventilation, and respiratory support, mean difference of clinical improvement as well recovery among patients taking remdesivir compared to the patients receiving standard of care alone. Also, we included studies comparing a longer regimen and a shorter regimen of remdesivir comparing the above outcomes.

We included studies including patients diagnosed with COVID-19 who received remdesivir in addition to the standard of care (SOC) or only receiving standard of care or placebo with comparison made with the remdesivir group.

Our treatment arm consists of patients taking remdesivir along with the SOC while the control arm consists of patients receiving SOC or placebo.

For our quantitative analysis, mortality, clinical improvement and recovery, discharge rate, mechanical ventilation, and respiratory support, adverse effects, mean difference of clinical J o u r n a l P r e -p r o o f improvement as well recovery and treatment outcome at day 14 and day 28 among the treatment and control group that occurred during treatment were outcomes of interest.

We compared mortality, clinical improvement, and recovery, discharge rate, mechanical ventilation, and respiratory support, adverse effects, mean difference of clinical improvement as well recovery and treatment outcome at day 14, and day 28 between treatment and control arms. Also, we compared the longer regimen and shorter regimen of remdesivir for the above outcomes.

Pubmed, PubMed Central, Embase, Scopus, and preprint servers like medRxiv and bioRxiv were accessed by our reviewers (PB and DBS) who independently searched and evaluated the quality of the studies till August 25, 2020. We filtered the studies using Covidence and extracted data for quantitative and qualitative synthesis. Any potential conflict was solved taking the final opinion of another reviewer (SK). Another reviewer (ER) assessed the risk of bias and cross-checked all the selected studies.

We have documented the detailed search strategy in Supplementary file no. 1.

We extracted the data for quantitative synthesis through Covidence and did the analysis using RevMan 5.4. Assessment of heterogeneity was done using the I-squared (I 2 ) test. We used a random/fixed effect for the pooling of selected studies. J o u r n a l P r e -p r o o f

We have included Randomized Control Trials (RCTs), prospective, and retrospective observational studies in which the patients received remdesivir for the treatment of COVID-19 in the qualitative analysis. For the quantitative analysis, we included only RCTs with a treatment arm and a control arm. We excluded studies in which remdesivir was used for treatment among the pediatric age group, pregnant women, patients with Acquired Immunodeficiency Syndrome (AIDS), end-stage liver disease, and cancer in the entire study population. We excluded meta-analysis, reviews, protocols, in-silico studies, Artificial

Intelligence-based simulation studies, and the studies in which the outcome was not properly defined among the patients treated with remdesivir.

We evaluated the quality of studies thoroughly and also took into account only the outcomes that were of our interest. 

The I-squared (I 2 ) test was used for the assessment of heterogeneity. We interpreted the Isquared (I 2 ) test done based on the Cochrane Handbook for Systematic Reviews of J o u r n a l P r e -p r o o f

Interventions as follows [15] :i) 0% to 40%: might not be important ii) 30% to 60%: may represent moderate heterogeneity iii) 50% to 90%: may represent substantial heterogeneity iv) 75% to 100%: considerable heterogeneity.

The importance of the observed value of I 2 depends on (i) magnitude and direction of effects and (ii) strength of evidence for heterogeneity (e.g. P-value from the chi-squared test, or a confidence interval for I 2 )."

Reporting bias was checked by prefixed reporting of the outcome.

Statistical analysis was performed using RevMan 5.4 software. Risk Ratio (RR)/ Odds Ratio (OR) was used for outcome estimation whenever appropriate with 95% Confidence Interval (CI). The fixed/random-effects model was used according to heterogeneities. We analyzed the mean differences among the two groups for the duration of clinical improvement and recovery using the median, sample size, and interquartile range whenever the means and standard deviations were not provided in the study [16] .

We used the random effect model, in cases of heterogeneity.

J o u r n a l P r e -p r o o f

We did not run sensitivity analysis being there were only three RCTs comparing remdesivir with SOC and two only comparing shorter and longer regimens of remdesivir. Also, there is low-moderate heterogeneity in most fields of our analysis so sensitivity analysis was not used.

We identified a total of 5573 studies after electronic database searching. We removed 600

duplicates 

Overall four RCTs are included in the quantitative synthesis.

We have compared outcomes of randomized studies with 10 days of remdesivir versus placebo or standard of care (SOC) and also longer course (10 days) of remdesivir with shorter one (5 days). Mortality rate, clinical improvement (≥2-point improvement in the ordinal score), clinical recovery (an improvement from a baseline score of 2 to 5 to a score of 6 or 7 or from a baseline score of 6 to a score of 7 in the ordinal score), and discharge rate were our primary outcome variables. Development of adverse effects (severe, overall, and grade ≥3 adverse events), invasive and non-invasive mechanical ventilation requirement, and mean J o u r n a l P r e -p r o o f duration of clinical recovery and improvement were our secondary outcome variables between remdesivir versus placebo or standard of care (SOC) and shorter (5 days) versus longer (10 days) use of remdesivir. Among the included studies meta-analysis, we found there is lowhigh heterogeneity, may be due to different study design, biological variability among studies, and risk of bias among studies that could not be omitted fully.

The meta-analysis of odds ratios (OR) for remdesivir compared with placebo or SOC using fixed effect model among three randomized studies showed that remdesivir reduces 14 days mortality (OR 0.61, 95% CI 0.41 to 0.91; participants = 1688; studies = 3; I 2 = 0%).

Meanwhile, there is no significant difference between two groups for 28 days mortality (OR 1.02, 95% CI 0.50 to 2.06; participants = 629; studies = 2; I 2 = 0%) (Fig. 3) . 1.00 to 2.08; participants = 629; studies = 2; I 2 = 0%; Day 28; OR 1.59, 95% CI 1.06 to 2.39; participants = 629; studies = 2; I 2 = 0%) (Fig. 4) . Similarly, there is clinically significant clinical recovery in day 14 among remdesivir groups compared to placebo or SOC (OR 1.48, 95% CI 1.19 to 1.84; participants = 1452; studies = 2; I 2 = 0%) (Fig. 5) . The meta-analysis of three randomized controlled trials showed that the odds of having severe adverse effects is less among remdesivir group (OR 0.69, 95% CI 0.54 to 0.88; participants = 1688; studies = 3; I 2 = 0%) though odds for the development of overall adverse effect (OR 1.10, 95% CI 0.70 to 1.72; participants = 1688; studies = 3; I 2 = 74%) and grade ≥3 adverse event (OR 0.85, 95% CI 0.52 to 1.38; participants = 629; studies = 2; I 2 = 32%) among two groups is statistically insignificant (Fig. 7) .It is also important to note that the discontinuation of the drug(due to adverse effects in patients) is not significant among the groups. (OR 1.26, 95% CI 0.50 to 3.19) (Supplementary file 3. Fig. 1 ).

Journal Pre-proof Based on our meta-analysis, the need for mechanical ventilation and respiratory support at day 14 was significantly less with remdesivir, which was also supported with subgroup analysis among IMV and ECMO receiving patients, whereas among NIMV and high-flow oxygen receiving patients it was of no significance. Also, the 10 days course of the drug showed the increased requirement of ECMO and IMV in contrast to the 5 days drug course. Piscoya et al.

study showed no significant decrease in the requirement of invasive ventilation with remdesivir (RR 0.57, 95% CI 0.23 to 1.42) [21] .

In present meta-analysis, remdesivir showed a statistically significant reduction in 14-day mortality, speedy clinical improvement/ recovery leading to discharge, less requirement of the ventilator with a lesser degree of severe adverse events compared with placebo or SOC.

Many other drugs were repurposed like remdesivir as candidate treatment options for COVID- 

There is no uniformity in findings of the various randomized controlled with conflicting outcomes in terms of clinical improvement following treatment with remdesivir. Although we have included four RCTs, they have several limitations, and also, the presence of heterogeneity among studies. Also, non-uniform treatment options lead to some difficulties comparing them. The biases among the included studies in our meta-analysis were due to lack of complete follow-up, early reporting, and additional use of several therapeutic agents as supportive care. These all lead to some discrepancy in the study results and uncertainty on findings regarding the result of remdesivir use. Safety and efficacy of remdesivir in COVID-19 patients is still dubious. Henceforth, we believe that these findings should be supported by undergoing large scale double-blinded RCTs to increase the confidence of remdesivir use in COVID-19.

The preliminary evidence shows patients receiving remdesivir had lesser 14 days mortality, improved clinical recovery and discharge rates. The clinical improvement and recovery were reported to be earlier in patients receiving remdesivir. Shorter course is preferred over longer because 10-day remdesivir showed more adverse outcome than 5-day course with no significant benefits. However, the current evidences are drawn from limited studies and mostly open-label studies with small sample size impose some limitation. Despite early promise, further ongoing large-scale trials results should be awaited to make a full decision.

But there is significantly higher rates of serious adverse effects

16; participants = 781; studies = 2; I 2 = 0%), and drug discontinuation due to medication intolerance (OR 2.74, 95% CI 1.06 to 7.07, participants = 781, studies = 2, I 2 = 0%) among longer (10 days) course than shorter (5 days) treatment group. Also IMV or ECMO requirement is higher among longer (10 days) course group

73 to 2.72, participants = 781, studies = 2, I 2 = 0%), clinical improvement at 14 days (OR 0.79, 95% CI 0.58 to 1.07, participants = 781, studies = 2, I 2 = 48%), clinical recovery (OR 0.75, 95% CI 0.55 to 1.02, participants = 781, studies = 2, I 2 = 31%), overall adverse effects (OR 1.26, 95% CI 0.93 to 1.69, participants = 781, studies = 2, I 2 = 0%), and NIMV or high flow oxygen requirement

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