Palabras clave: COVID-19, Coronavirus disease, Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2 Coronavirus Infections, Systematic Review, Remdesivir, Antivirals

Introduction

COVID-19 is an infection caused by the SARS-CoV-2 coronavirus[1]. It was first identified in Wuhan, China, on 31 December 2019[2]; seven months later, more than fifteen million cases of contagion had been identified across 188 countries[3]. On 11 March 2020, the WHO characterized the COVID-19 outbreak as a pandemic[1].

While the majority of cases result in mild symptoms, some might progress to pneumonia, acute respiratory distress syndrome, and death[4],[5],[6]. The case fatality rate reported across countries, settings and age groups is highly variable, but it ranges from about 0.5% to 10%[7]. In hospitalized patients, it has been reported to be higher than 10% in some centers[8].

One of the strategies underway to identify effective interventions for COVID-19 is repurposing drugs that have been used for the treatment of other diseases. Remdesivir is among these investigational medications. It is a directly acting antiviral agent, initially developed for the treatment of Ebola virus during the 2014 outbreak in Western Africa[9]. Remdesivir displays antiviral activity against many RNA viruses, including SARS-CoV-2, in both in vitro[10] and animal studies[11].

Following the publication of the ACTT-1, a trial conducted by the National Institute of Allergy and Infectious Diseases (NIAID), the US Food and Drug Administration issued an emergency use authorization of remdesivir for the treatment of COVID-19[12].

However, the results of ACTT-1 were questioned immediately, particularly for the decision to stop it early for benefit[13]. On the other hand, the decision of the United States government to buy virtually all stocks of the drug generated an urgent need for independent, transparent information about the effects of remdesivir on COVID-19.

Using innovative and agile processes, taking advantage of technological tools, and resorting to the collective effort of several research groups, this living systematic review aims to provide a timely, rigorous and continuously updated summary of the evidence available on the effects of remdesivir in patients with COVID-19.

Methods

This manuscript complies with the 'Preferred Reporting Items for Systematic reviews and Meta-Analyses' (PRISMA) guidelines for reporting systematic reviews and meta-analyses[14] (see Appendix 1 - PRISMA Checklist).

A protocol stating the shared objectives and methodology of multiple evidence syntheses (systematic reviews and overviews of systematic reviews) to be conducted in parallel for different questions relevant to COVID-19 was published elsewhere[15]. The review was registered in PROSPERO with the number CRD42020183384, and a full protocol was made available[16].

Search strategies

Electronic searches

We used the search strategies already developed in the L·OVE (Living OVerview of Evidence) platform, a system that maps the evidence to different research questions. The full methods to maintain L·OVE are described in the website, but the process to devise the search strategies can be briefly described as:

●      Identification of terms relevant to the population and intervention components of the search strategy, applying Word2vec technology[17] to the corpus of documents available in Epistemonikos Database.

●      Discussion of terms with content and methods experts to identify relevant, irrelevant and missing terms.

●      Creation of a sensitive boolean strategy encompassing all the relevant terms.

●      Iterative analysis of articles missed by the boolean strategy, and refinement of the strategy accordingly.

All the information in the L·OVE platform comes from a repository developed and maintained by Epistemonikos Foundation through the screening of different sources relevant to COVID-19. At the time of releasing this article, this repository included more than 66 989 articles relevant to the Coronavirus disease, coming from the following databases, trial registries, preprint servers and websites relevant to COVID-19: Epistemonikos database, Pubmed, EMBASE, ICTRP Search Portal, Clinicaltrials.gov, ISRCTN registry, Chinese Clinical Trial Registry, IRCT - Iranian Registry of Clinical Trials, EU Clinical Trials Register: Clinical trials for covid-19, NIPH Clinical Trials Search (Japan) - Japan Primary Registries Network (JPRN) (JapicCTI, JMACCT CTR, jRCT, UMIN CTR), UMIN-CTR - UMIN Clinical Trials Registry, JRCT - Japan Registry of Clinical Trials, JAPIC Clinical Trials Information, Clinical Research Information Service (CRiS), Republic of Korea, ANZCTR - Australian New Zealand Clinical Trials Registry, ReBec - Brazilian Clinical Trials Registry, CTRI - Clinical Trials Registry - India, DRKS - German Clinical Trials Register, LBCTR - Lebanese Clinical Trials Registry, TCTR - Thai Clinical Trials Registry, NTR - The Netherlands National Trial Register,PACTR - Pan African Clinical Trial Registry, REPEC - Peruvian Clinical Trial Registry,SLCTR - Sri Lanka Clinical Trials Registry, medRxiv Preprints, bioRxiv Preprints, SSRN Preprints, WHO COVID-19 database.

The last version of the methods, the total number of sources screened, and a living flow diagram and report of the project is updated regularly on the website[18].

The repository is continuously updated[18], and the information is transmitted in real time to the L·OVE platform; however, it was last checked for this review the day before release on 25 August 2020. The searches covered the period from the inception date of each database, and no study design, publication status, or language restriction was applied.

The following strategy was used to retrieve from the repository the articles potentially eligible for this review: coronavir* OR coronovirus* OR betacoronavir* OR "beta-coronavirus" OR "beta-coronaviruses" OR "corona virus" OR "virus corona" OR "corono virus" OR "virus corono" OR hcov* OR covid* OR "2019-ncov" OR cv19* OR "cv-19" OR "cv 19" OR "n-cov" OR ncov* OR (wuhan* and (virus OR viruses OR viral)) OR sars* OR sari OR "severe acute respiratory syndrome" OR mers* OR "middle east respiratory syndrome" OR "middle-east respiratory syndrome" OR "2019-ncov-related" OR "cv-19-related" OR "n-cov-related" AND (remdesivir* OR "GS-5734" OR "GS 5734" OR GS5734*)

Other sources

In order to identify articles that might have been missed in the electronic searches, we proceeded as follows:

●      Screened the reference lists of other systematic reviews.

●      Scanned the reference lists of selected guidelines, narrative reviews, and other documents.

Eligibility criteria

We included randomized controlled trials evaluating patients infected with SARS-CoV-2 of any severity. The intervention of interest was remdesivir at any dosage, duration, timing or route of administration. The comparison of interest was a placebo (remdesivir plus standard of care versus placebo plus standard of care) or no treatment (remdesivir plus standard of care versus standard of care).

Our primary outcome of interest was all-cause mortality at longest follow-up. Secondary outcomes were invasive mechanical ventilation and adverse effects leading to discontinuation. We also extracted information on the following outcomes: time to viral clearance, length of hospital stay, and serious adverse effects.

We did not consider the outcomes as an inclusion criterion during the selection process. Any article meeting all the criteria except for the outcome criterion was preliminarily included and assessed in full text.

Selection of studies

The results of the searches in the individual sources were de-duplicated by an algorithm that compares unique identifiers (database ID, DOI, trial registry ID), and citation details (i.e. author names, journal, year of publication, volume, number, pages, article title, and article abstract). Then, the information matching the search strategy was sent in real-time to the classification tab in the L·OVE platform where at least two authors independently screened the titles and abstracts yielded against the inclusion criteria (Appendix 2). We obtained the full reports for all titles that appeared to meet the inclusion criteria or required further analysis and then decided about their inclusion.

We recorded the reasons for excluding trials in any stage of the search and outlined the study selection process in a PRISMA flow diagram that we adapted for the purpose of this project.

Extraction and management of data

Using standardized forms, two reviewers independently extracted the following data from each included trial: study design, setting, participant characteristics (including disease severity and age) and study eligibility criteria; details about the administered intervention and comparison, including dose, duration and timing (i.e. the time after diagnosis); the outcomes assessed and the time they were measured; the source of funding of the study and the conflicts of interest disclosed by the investigators; the risk of bias assessment for each individual study. We resolved disagreements by discussion, with one arbiter adjudicating unresolved disagreements.

Risk of bias assessment

The risk of bias for each randomized trial was assessed by using the 'risk of bias' tool (RoB 2.0: a revised tool to assess risk of bias in randomized trials)[19], considering the following domains of bias for each outcome result of all reported outcomes and time points: bias due to (1) the randomization process, (2) deviations from intended interventions (effects of assignment to interventions at baseline), (3) missing outcome data, (4) measurement of the outcome, and (5) selection of reported results.

Discrepancies between review authors were resolved by discussion to reach a consensus. If necessary, a third review author was consulted to achieve a decision.

Measures of treatment effect

For dichotomous outcomes, we expressed the estimate of the treatment effect of an intervention as risk ratios (RR) along with 95% confidence intervals (CI).

For continuous outcomes, we used the mean difference and standard deviation to summarize the data along with a 95% confidence interval. For continuous outcomes reported using different scales, the treatment effect was expressed as a standardized mean difference with 95% confidence interval.

Strategy for data synthesis

The results of the search and the selection of the studies is presented in the corresponding flow chart, according to recommendations of the PRISMA statement[14]. For any outcomes where it was not possible to calculate an effect estimate, a narrative synthesis is presented, describing the studies in terms of the direction and the size of effects, and any available measure of precision.

For any outcomes where data were available from more than one trial, we conducted a formal quantitative synthesis (meta-analysis) for studies clinically homogeneous using RevMan 5[20] and using the inverse variance method with the random-effects model. We assessed inconsistency by visual inspection of the forest plots and using the I² index.

Subgroup and sensitivity analysis

As few trials were found, we did not perform sensitivity or subgroup analysis.

Assessment of certainty of the evidence

The certainty of the evidence for all outcomes was judged using the Grading of Recommendations Assessment, Development and Evaluation working group methodology (GRADE Working Group)[21], across the domains of risk of bias, consistency, directness, precision and reporting bias. For the main comparisons and outcomes, we prepared a Summary of Findings (SoF) tables[22],[23].

Living evidence synthesis

An artificial intelligence algorithm deployed in the Coronavirus/COVID-19 topic of the L·OVE platform provides instant notification of articles with a high likelihood of being eligible. The authors review them, decide upon inclusion, and update the living web version of the review accordingly.

This review is part of a larger project set up to produce multiple parallel systematic reviews relevant to COVID-19[15].

Figure 1. PRISMA Flowchart (prepared by the authors from the study data).

Table 1. Inclusion criteria of the studies.

Table 2. Characteristics of the intervention.

Table 3. Baseline characteristics of the participants.

Table 4. Risk of bias in the included studies assessed by ROB-2 tool.

Figure 2. Relative risk for all-cause mortality for remdesivir versus standard care (prepared by the authors from the study data).

Figure 3. The relative risk for invasive mechanical ventilation for remdesivir versus standard care (prepared by the authors from the study data).

Figure 4. The relative risk for adverse effects leading to discontinuation for remdesivir versus standard care (prepared by the authors from the study data).

Figure 5. The relative risk for the length of hospital stay for remdesivir versus standard care (prepared by the authors from the study data).

Figure 6. Relative risk for serious adverse effects for remdesivir versus standard care (prepared by the authors from the study data).

Discussion

We conducted a systematic review and identified three randomized trials that reported data on the effect of remdesivir in patients with COVID-19[24],[25],[26]. Even though remdesivir appears to be safe, the evidence is very uncertain about the impact on the outcomes critical for decision-making in moderate and severe patients—the more relevant clinical scenario for this drug, such as mortality and need of mechanical ventilation.

It is unfortunate not knowing yet if one of the pharmaceutical interventions that have sparked more interest is effective or not. One of the limitations comes from the lack of precision of the result for the main outcomes. The early termination of the ACTT-1 trial can be seen as a missed opportunity in this regard[25]. In addition, all the trials concluded enrollment before the release of the RECOVERY trial, which showed a mortality reduction with dexamethasone[27]. It is not clear if this factor would modify the effect, if any, of remdesivir.

By now, clinicians and other decision-makers are in a difficult position. The pressure to act is high, particularly after the US Food and Drug Administration issued an emergency use authorization of remdesivir for the treatment of COVID-19[12]. We anticipate that the range of recommendations from different organizations should range between a suggestion against its use and a weak recommendation for its use in severe cases, especially in settings without resource constraints.

There are at least 46 ongoing trials that we expect will provide data in the near future. Making sense of this information is not going to be an easy task. Systematic reviews are considered the gold standard to make sense of multiple trials addressing a similar scientific question, but the traditional model for conducting reviews has several limitations, including high demand for time and resources[28] and rapid obsolescence[29]. Amid the COVID-19 crisis, researchers should make their best effort to answer the urgent needs of health decision-makers without giving up scientific accuracy. Information is being produced at a vertiginous speed[30], so alternative models are needed.

One potential solution to these shortfalls is rapid reviews, a form of knowledge synthesis that streamlines or omits specific methods of a traditional systematic review in order to move faster. Unfortunately, in many cases, this speed comes at the cost of quality[31]. Furthermore, they do not solve the issue of obsolescence. Living systematic reviews do address that issue[32]. They are continually updated by incorporating relevant new evidence as it becomes available, at a substantial effort. So, an approach combining these two models might prove more successful in providing the scientific community and other interested parties with evidence that is actionable, rapidly and efficiently produced, up to date, and of the highest quality[33].

This review is part of a larger project set up to put such an approach into practice. The project aims to produce multiple parallel living systematic reviews relevant to COVID-19 following the higher standards of quality in evidence synthesis production[15]. We believe that our methods are well suited to handle the abundance of evidence that is to come, including evidence on the role of lopinavir/ritonavir for COVID-19.

During the COVID-19 pandemic, we will maintain the search and selection of evidence for this review continuously updated, as well as an update when conclusions change or whenever there are substantial updates. Our systematic review aims to provide a high-quality, up-to-date synthesis of the evidence that is useful for clinicians and other decision-makers.

Notes

Authorship contributions
All the review authors drafted and revised the manuscript, conducted article screening and data collection, and drafted and revised the review.
The COVID-19 L·OVE Working Group was created by Epistemonikos and a number of expert teams in order to provide decision-makers with the best evidence related to COVID-19. Up-to-date information about the group and its member organizations is available here: epistemonikos.cl/working-group

Acknowledgements
The members of the COVID-19 L·OVE Working Group and Epistemonikos Foundation have made it possible to build the systems and compile the information needed by this project. Epistemonikos is a collaborative effort, based on the ongoing volunteer work of over a thousand contributors since 2012.

Competing interests
All authors declare no financial relationships with any organization that might have a real or perceived interest in this work. There are no other relationships or activities that might have influenced the submitted work.

Funding
This project was not commissioned by any organization and did not receive external funding.
Epistemonikos Foundation is providing training, support and tools at no cost for all the members of the COVID-19 L·OVE Working Group.

Ethics 
As researchers will not access information that could lead to the identification of an individual participant, obtaining ethical approval was waived.

Data sharing
All data related to the project will be available. Epistemonikos Foundation will grant access to data.

PROSPERO registration number
CRD42020183384

Annexes
Annex 1.
Annex 2.
Annex 3.

Figure 1. PRISMA Flowchart (prepared by the authors from the study data).

Table 1. Inclusion criteria of the studies.

Table 2. Characteristics of the intervention.

Table 3. Baseline characteristics of the participants.

Table 4. Risk of bias in the included studies assessed by ROB-2 tool.

Figure 2. Relative risk for all-cause mortality for remdesivir versus standard care (prepared by the authors from the study data).

Figure 3. The relative risk for invasive mechanical ventilation for remdesivir versus standard care (prepared by the authors from the study data).

Figure 4. The relative risk for adverse effects leading to discontinuation for remdesivir versus standard care (prepared by the authors from the study data).

Figure 5. The relative risk for the length of hospital stay for remdesivir versus standard care (prepared by the authors from the study data).

Figure 6. Relative risk for serious adverse effects for remdesivir versus standard care (prepared by the authors from the study data).

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