Among the explored options by the scientific community against the SARS-CoV-2 virus (COVID-19), drugs with antiviral activity stand out. This report assesses the scientific evidence shown by remdesivir (RDV) so far, in the context of the current pandemic.
RDV has been the subject of controversy when it was first granted an orphan drug status by the US FDA. Based on this designation, the manufacturing company was entitled to tax benefits and other rights. Eventually the FDA cancelled this decision at the manufacturer’s own request (1).
The Spanish Agency for Medicines and Healthcare Products (AEMPS) has issued a document where it provides a brief analysis on the most representative pharmacological alternatives against COVID-19, describing several aspects of interest for each drug (2).
The RDV section provides information about dosage, adverse effects and how to reconstitute the drug prior to intravenous administration. In Spain, patients can access the drug mainly through five active clinical trials.
RDV is a prodrug of a nucleoside analogue, which disrupts viral replication by inhibiting the enzyme RNA polymerase in the virus (3). It is an investigational product for which the US FDA has issued an emergency use authorization for hospitalized patients with severe VOC-19 (4). It was initially developed as a therapy against the Ebola virus, though in a clinical trial it registered higher mortality than other monoclonal antibody therapies (5). It has been shown to be active against COVID-19 and other coronaviruses (SARS-CoV and MERS-CoV) in in vitro studies and animal models. However, data are still very limited regarding the use of RDV in COVID-19 patients (6).
A CRITICAL APPRAISAL OF THE CLINICAL EVIDENCE
The ClinicalTrials.gov website (https://clinicaltrials.gov) informs about 7 active controlled clinical trials initiated with RDV. One of the most ambitious projects underway is the SOLIDARITY trial, sponsored by the World Health Organization, in which several Spanish centers are expecting to participate (7). A study protocol synopsis can be consulted in the Spanish Clinical Trials Registry (https://reec.aemps.es). It will compare 5 treatment strategies against COVID-19: Lopinavir/ritonavir, remdesivir, Lopinavir/ritonavir + interferon β, chloroquine / hydroxychloroquine and standard care. The primary variable is all-cause mortality, stratified by severity of disease at the time of randomization.
There are currently two clinical trials with available results on the use of RDV in COVID- 19 patients.
A preliminary report of this project sponsored by the US National Institute of Allergy and Infectious Diseases (NIAID), known as the ACTT-1 Study, has finally been published after being announced as a press release (8). The clinical trial has an adaptive design, in which several treatments can be evaluated at the same time and, by means of interim analyses, drugs can be either ruled out or introduced. The main variable is time to recovery, which is defined as the first day to reach categories 1, 2 or 3 (on an 8-category scale): 1, not hospitalized, no activity limitation; 2, not hospitalized, activity limitation and/or oxygen requirement; 3, hospitalized, no oxygen requirement, no medical care required. Preliminary results would indicate a shorter time to recovery in patients assigned to the RVD group [median 11 days, CI95% (9-12)] compared to the placebo group [median 15 days, CI95% (13-19)] with no statistically significant differences in mortality [Hazard Ratio 0.70 CI95% (0.47-1.04)]. The proportion of serious adverse events in the RDV group was 21.1% and 27.0% in the placebo group. After the analysis of published data, which include the main report, protocol, supplemental material and conflict of interest statement, several comments can be made:
• The non-definite condition of the report implies that its results and conclusions are also preliminary until the full trial is completed and reported.
• COVID-19 is a non-chronic disease whose main outcome to be avoided is patient’s death. In the present trial mortality was defined as a secondary variable without statistical adjustment for multiple comparisons, which can only generate hypotheses. In any case, results on mortality lacked of significant differences in light of the current data.
• The main outcome ‘time to recovery’ has a subjective character established on the basis of the hospitalization situation and oxygen therapy requirement, not on clinical parameters or severity scales. Thus, any decision made by clinicians has a great influence on the clinical severity category assigned to each patient. In this context, the importance of blinding to avoid bias is vital. Unfortunately, very little information has been facilitated on this aspect and the data provided is not reassuring. For example, in the face of a shortage of placebos, opaque bags were sometimes used to conceal the treatment given. It is also indicated in the protocol that nurses in charge of giving the medication were not blinded, without detailing any measure taken to prevent other clinicians linked to the trial from having access to this sensitive information.
• No information is provided on concomitant medication received by the patients, either at baseline or throughout the trial. Since standard care was allowed and this could even include other antivirals, this information would be of great relevance to attribute or not to RDV, and to what extent, the improvement in time to recovery.
• The benefit of RDV in the ‘time to recovery’ outcome is not related to the most severe patients but in those who received oxygen supply without other extraordinary measures. The study authors have interpreted this finding by stressing the need to start antiviral treatment at an earlier stage, which would involve a large population of patients. However, it should be remembered that the main objective is cure. Bearing in mind that, with the available data, RDV has not been shown to reduce mortality, its real benefit should be weighed against the potential savings from shorter hospitalizations as opposed to the cost of the drug.
• Fifteen percent of the 40 principal investigators who signed the paper are reporting some economic link to Gilead. Also, although the protocol states that members of the Data and Safety Monitoring Board (DSMB) should not have conflicts of interest in relation to the trial, one of the five members (Nina Singh) received $5,800 from Gilead in 2017 for consulting and other expenses. In addition, unlike what usually happens in traditionally designed clinical trials, in this case there were no pre-specified rules for altering the course of the study for efficacy or safety reasons, leaving it to the DSMB judgement to recommend these measures, as finally happened.
• Finally, the study authors concluded that data supported the use of RDV in patients with COVID-19 but, at the same time, acknowledged that treatment with an antiviral in monotherapy was likely not sufficient. This call for the evaluation of combination strategies might be interpreted as an attempt to establish RDV as the standard treatment for COVID-19, a claim that is far from fully justified at this time.
This randomized 2:1, double-blind, multicenter, placebo-controlled study was terminated prematurely due to recruitment difficulties. The 237 patients included had severe COVID-19 infection, with confirmed pneumonia and oxygen saturation <95% or PaO2/FiO2 ≤300 mmHg (9). They were randomized to receive RDV 200 mg on day 1 followed by 100 mg on days 2-10, for 10 days, or placebo. Other antiviral drugs, interferon and corticoids were allowed in both groups. The main outcome was time to clinical improvement within 28 days. No differences were found between RVD and placebo for the main [Hazard Ratio 1.23 CI95% (0.87-1.75)] or secondary outcomes, including mortality. The rate of adverse effects was similar in both groups, although treatment discontinuation was more frequent in patients with RVD (12%) than in the placebo group (5%).
These data contrast with the statement made by Gilead, maker of RVD, about other study results on patients with severe COVID-19 (10). In the absence of publication, the company’s statement claims that patients who received RVD for 5 days improved their clinical status to the same extent as those who received RVD for 10 days. However, as the study did not have a control group, nothing can be concluded about the potential role of RVD in the claimed improvement.
Finally, it is worth mentioning the case report described by Grein et al (11). This non- controlled study provides information on 53 COVID-19 confirmed patients who had an oxygen saturation < 95% or had a need for oxygen support. All received RDV through the compassionate use program for a maximum of 10 days, consisting of a loading dose of 200 mg on day 1, plus 100 mg daily for the following 9 days. Follow-up was to continue through at least 28 days after the beginning of treatment with RDV or until discharge or death. As for the results, 68% of patients improved in their need for oxygen and 15% got worse. Improvement was seen more often in those patients with less severity. Around 13% of the participants died after completing RDV treatment, with those over 70 years old, higher serum creatinine and requiring invasive ventilation having the greatest risk. The most frequent adverse effects with RDV were increased liver enzymes, diarrhea, rash, renal failure, and hypotension. Four patients (8%) discontinued RDV treatment prematurely. There are important study limitations, such as the poor methodological quality derived from a non-controlled cohort. Other noteworthy features are the small sample size, short duration of follow-up, absence of information on viral load and the lack of knowledge about 8 initially treated patients without additional information.
RISK OF ADVERSE EVENTS WITH REMDESIVIR
As RDV is still an experimental drug, the adverse effect profile is not known in detail yet. Up to now, the most characteristic adverse event seems to be increased liver enzymes (ALT, AST). For that reason it is recommended to estimate their levels before the treatment is started. RDV should be suspended or not initiated when ALT > 5 x upper limit of normal were confirmed. Regarding the renal function, RDV should not be used with a glomerular filtration rate <30 mL/min (6).
As far as potential interactions with other drugs are concerned, no major contraindications have been identified so far, except for the precaution of using them together with other drugs with proven hepatotoxicity, as rifampicin (6). On the basis of their rapid distribution, metabolism and excretion pharmacokinetics, the probability of clinically relevant interactions seems low (monitoring is recommended when used concomitantly with metamizole). RDV does not cause alterations in the QTc interval (12).
CONFLICT OF INTEREST
The author declares no conflict of interest.
To Leire Leache, Marta Gutiérrez-Valencia and Juan Erviti, for their valuable suggestions to this report.
1. Mahase E. Covid-19: what treatments are being investigated? BMJ 2020;368:m1252 doi: 10.1136/bmj.m1252
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7. World Health Organization. “Solidarity” clinical trial for COVID-19 treatments. Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel- coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
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10. Gilead announces results from Phase 3 trial of investigational antiviral remdesivir in patients with severe COVID-19. Available at: https://www.gilead.com/news-and-press/press-room/press- releases/2020/4/gilead-announces-results-from-phase-3-trial-of-investigational-antiviral-remdesivir- in-patients-with-severe-covid-19
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12. Liverpool Drug Interactions Group. Interactions with experimental COVID-19 therapies. 12/05/2020. Available at: https://cutt.ly/dyP1Arb