running-list-of-studies-showing-remdesivir-is-harmful-and-not-effective

Running List of Studies Showing Remdesivir Is Harmful and Not Effective


Here is a running list of studies and other scientific evidence showing Remdesivir, a Gilead antiviral drug, is not safe for the treatment of COVID-19. The WHO advises *against* the use of Remdesivir for COVID-19, and, according to large amounts of data, the drug has serious side effects including acute liver failure.


SUMMARY

According to the U.S. Government Accountability Office (GAO) Remdesivir, a broad-spectrum antiviral drug (BSA), began its development at Gilead—a research-based biopharmaceutical company with a market cap of approximately $75 billion as of this writing—in 2009. Between then and 2014 “Gilead had synthesized the remdesivir compound, conducted and funded preclinical research that first identified and confirmed the antiviral activity of remdesivir and its parent compound against coronaviruses and other viruses, and had begun patenting the compounds.”

Between 2013 and 2020, the Centers for Disease Control and Prevention (CDC), the Department of Defense (DOD), and the National Institutes of Health (NIH), conducted and funded preclinical research collaborations with Gilead that “helped to demonstrate remdesivir’s antiviral properties against multiple viruses.”

GAO says that as of December 2020, federal funding for preclinical studies and clinical trials involving remdesivir totaled approximately $162 million; with $109.2 million of that coming from the NIH. The NIH also notes that “NIAID-supported investigators” have helped to develop remdesivir.

Despite its extensive development history, remdesivir has failed as a treatment in general, and as one for COVID-19 in particular. This is unequivocal. The World Health Organization (WHO) literally advises against the use of remdesivir. “WHO has issued a conditional recommendation against the use of remdesivir in hospitalized [COVID-19] patients, regardless of disease severity, as there is currently no evidence that remdesivir improves survival and other outcomes in these patients.,” the organization says on its website.  And while the organization has qualified its recommendation with claims that new evidence shows Remdesivir is actually useful (updated April 22, 2022), note the WHO still left up its original recommendation. And, more importantly, that there is robust evidence showing Remdesivir is dangerous.

WHO’s conditional recommendation against the use of remdesivir for treating COVID-19 comes from data collected from over 7,000 patients across four trials. “The evidence [suggests] no important effect on mortality, need for mechanical ventilation, time to clinical improvement, and other patient-important outcomes,” the organization says.

Not only does the WHO advise against the use of remdesivir for COVID-19, but there is an overwhelming amount of evidence that it is harmful for patients. Beginning with its effects in vitro.

In a preprint posted in August 2020, Akicini et al. wrote that remdesivir treatment leads to a repression of mitochondrial respiratory activity and that “biochemical studies combined with our findings of remdesivir-induced mitochondrial dysfunction” show that remdesivir is cytotoxic—that is, toxic to cells. A study published on March 8, 2021 in Baylor University Medical Center Proceedings, which performed a literature review on remdesivir, notes that “On a cellular level, remdesivir has been demonstrated to be toxic to human hepatocytes, and the FDA has cautioned about the incidence of elevated liver enzymes in patients treated with remdesivir, indicating potential drug-induced liver injury.

The same Baylor Proceedings study, authored by Aleem et al., also notes that “Our observation supports previous findingssuggesting this antiviral may cause hepatocellular injury” and that remdesivir plays “a direct role” in hepatocellular toxicity. The researchers also say they noticed a “a clear trend of bilirubin elevation with LPV/r and ALT/AST elevation with” remdesivir.

In a study published in the Journal of Nephropathology in April 2021, Rahimi et al. write that “Remdesivir can…lead to renal dysfunction or liver involvement during medical treatment of COVID-19.” The authors add that prescribing drugs such as remdesivir should proceed with extreme caution…[especially with patients] who had liver disease or who undergo continuous or intermittent dialysis…as [it] may not be the safe candidates to receive remdesivir.

In a study published in the of Biomedicine & Pharmacotherapy in July 22, 2020, Fan et al. note that with increasing application, adverse effects of remdesivir have been detected and become a concern of clinicians. The authors, who performed a literature review, also say that “Based on a RCT [randomized controlled trial] in China, a higher proportion of remdesivir recipients than placebo recipients had dosing prematurely stopped because of anorexia, nausea, and vomiting.” Along with other concerning findings, the authors also found that remdesivir had an “effect on fertility parameters in female rats” and that “it is not recommended to use in pregnant women.”

Along with literature reviews and randomized controlled trials, there are also numerous case reports outlining liver failure and other serious adverse events (including death) in those “treated” with remdesivir.

In a paper published on June 28, 2020 in Clinical Infectious Diseases, Leegwater et al. outline a case report of s COVID-19 patient who suffered from “drug-induced liver injury most likely caused by remdesivir.” In a paper published in Pharmacotherapy on October 27, 2020, study authors outline two case reports of acute liver failure (ALF) in which “liver function abnormalities appears to point to remdesivir as a possible contributing cause .” The study concludes that “The use of the novel antiviral remdesivir in the treatment of COVID-19 pneumonia may put patients at risk of drug-associated acute liver failure.

Along with the WHO’s recommendation not to use remdesivir in the treatment of COVID-19 patients, as well as the body of literature, literature reviews, and case reports evincing its inefficacy and serious downsides, the study used to support remdesivir’s efficacy in treating COVID-19 itself showed the drug is highly toxic.

A total of 32 patients (60%) reported adverse events during follow-up,” Grein et al. reported in a study published in The New England Journal of Medicine on June 11, 2020. “A total of 12 patients (23%) had serious adverse events. The most common serious adverse events — multiple-organ-dysfunction syndrome, septic shock, acute kidney injury, and hypotension — were reported in patients who were receiving invasive ventilation at baseline.” The authors added that “Four patients (8%) discontinued remdesivir treatment prematurely: one because of worsening of preexisting renal failure, one because of multiple organ failure, and two because of elevated aminotransferases, including one patient with a maculopapular rash.”

On top of that, the study supposedly used to demonstrate remdesivir’s efficacy in treating Ebola—a touted benefit used to support the use of the drug in treating COVID-19—also shows it’s not safe for humans. In fact, in that study remdesivir proved to be—literally—the most dangerous treatment option in the trial.

A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial” Mulangu et al. write in their study published in The New England Journal of Medicine on December 12, 2019. The authors compared remdesivir against other treatment options for Ebola infections, but discontinued remdesivir after finding it had the highest mortality rate.

Studies evincing other dangerous side effects associated with the use of remdesivir—including serious adverse cardiovascular problems—are in the list below as well. Immediately below this summary is WHO’s guidance on remdesivir, verbatim. Beneath that is an interview with Dr. Bryan Ardis. Ardis, co-founder of TruLabs LLC, creator of the Ardis Healing Center, and host of “The Dr. Ardis Show,” gives his rundown of the dangers of remdesivir. As well as the regulatory abuses that have taken place in order to get it authorized, and then approved for use in COVID-19.

WORLD HEALTH ORGANIZATION GUIDANCE:

“WHO has issued a conditional recommendation against the use of remdesivir in hospitalized patients, regardless of disease severity, as there is currently no evidence that remdesivir improves survival and other outcomes in these patients.

“This recommendation, released on 20 November, is part of a living guideline on clinical care for COVID-19. It was developed by an international guideline development group, which includes 28 clinical care experts, 4 patient-partners and one ethicist.

“The guidelines were developed in collaboration with the non-profit Magic Evidence Ecosystem Foundation (MAGIC), which provided methodologic support. The guidelines are an innovation, matching scientific standards with the speed required to respond to an ongoing pandemic.

“Work on this began on 15 October when the WHO Solidarity Trial published its interim results. Data reviewed by the panel included results from this trial, as well as 3 other randomized controlled trials. In all, data from over 7000 patients across the 4 trials were considered.

“The evidence suggested no important effect on mortality, need for mechanical ventilation, time to clinical improvement, and other patient-important outcomes.

“The guideline development group recognized that more research is needed, especially to provide higher certainty of evidence for specific groups of patients. They supported continued enrollment in trials evaluating remdesivir.

“Updated 20 November 2020
* A conditional recommendation is issued when the evidence around the benefits and risks of an intervention are less certain.  In this case, there is a conditional recommendation against the use of remdesivir.  This means that there isn’t enough evidence to support its use.


REINER FUELLMICH INTERVIEW WITH BRYAN ARDIS


LIST OF STUDIES

1. Baylor University Medical Center Proceedings (Published March 8, 2021)

TITLE: Hepatic manifestations of COVID-19 and effect of remdesivir on liver function in patients with COVID-19 illness

METHODS: “Through a literature search, we identified five randomized controlled trials, two case reports, and one case series, including a total of 2375 patients.”

EXCERPTS FROM CONCLUSION:

1. “Although mild transaminase elevation has been reported as a feature of COVID-19, there has been a concern of hepatotoxicity associated with the use of remdesivir. Based on the limited available data regarding the adverse effects of remdesivir on hepatic function, it is prudent to exercise caution by evaluating baseline liver function, avoiding the use of potentially hepatotoxic drugs, and closely monitoring liver function when using remdesivir in patients hospitalized with COVID-19.

2. “The route of elimination, pharmacokinetics, drug-drug interactions, and safety of remdesivir in children and in women who are pregnant or breastfeeding is mostly unknown due to the absence of long-term studies. However, given the limited data available regarding the safety profile of remdesivir, clinicians should consider laboratory monitoring such as baseline renal function, hepatic function, and coagulation (prothrombin time) parameters before and after the initiation of remdesivir and closely monitor for any acute changes in clinical status and drug-drug reactions.”

3. “Data regarding the potential hepatotoxicity of remdesivir is currently limited, and there are no specific studies conducted with its use in patients with hepatic impairment. On a cellular level, remdesivir has been demonstrated to be toxic to human hepatocytes, and the FDA has cautioned about the incidence of elevated liver enzymes in patients treated with remdesivir, indicating potential drug-induced liver injury. Given the increase in the frequency of liver dysfunction in patients with COVID-19, the attribution of hepatotoxicity to remdesivir is indeed challenging. Mild (Grade 1) to moderate (Grade 2) transaminasemia was observed in healthy volunteers who received remdesivir, with resolution upon discontinuation of remdesivir.

4. “In conclusion, the use of remdesivir in hospitalized patients with COVID-19 is associated with transient mild to moderate elevation in liver biochemistries with low discontinuation rates. It is prudent to perform baseline hepatic function testing in all patients before initiation of remdesivir, closely monitor liver function tests daily while on remdesivir therapy, and avoid using other potentially hepatotoxic drugs that can worsen liver function in patients hospitalized with COVID-19. The discontinuation of remdesivir infusions in de novo elevations in ALT or AST above 10 times the upper limit of normal should be considered.”

LINK TO STUDY


2. Hepatology International (Published July 28, 2020)

TITLE: Liver injury in remdesivir-treated COVID-19 patients

METHODS: “Treatment was given in a compassionate use program (CPU) approved by our Ethics Committee.”

CONCLUSION: Our observation supports previous findings obtained in healthy volunteers (Gilead Sciences, data on file) and COVID-19 patients treated with RDV [remdesivir], suggesting this antiviral may cause hepatocellular injury. In our patients, this adverse effect neither progressed to severe liver damage nor induced liver failure, although none had a prior chronic liver disease. Although SARS-CoV-2 infection can cause aminotransferase elevation per se, 4 of our 5 patients had normal or slightly elevated AST/ALT levels at RDV treatment start, suggesting a direct role of RDV in hepatocellular toxicity. Despite the overall low number of patients treated, we observed a clear trend of bilirubin elevation with LPV/r and ALT/AST elevation with RDV. Our observation suggests RDV can be used with close monitoring of liver function tests and with caution in subjects with prior liver disease.”

LINK TO STUDY


3. Journal of Nephropathology (Published April 2021)

TITLE: Renal and liver injury following the treatment of COVID-19 by remdesivir

METHODS: “In this mini-review, international databases including PubMed, Web of Science and Scopus were considered for search of English articles from 31 December 2019 to 15 August 2020. All type of articles was included. Keywords were COVID-19, novel coronavirus, 2019-nCoV, coronavirus disease 2019, renal involvement, renal injury, renal failure, kidney injury, kidney failure, kidney involvement, remdesivir, veklury, GS-5734, liver injury, and liver involvement. After collection of articles of interest, references imported to Endnote software and removed duplicate titles. The selected studies were performed on humans and published in English.”

CONCLUSION: “Nephropathy and liver involvement may occur due to direct inflammatory effect of cytokines following COVID-19. Both liver and renal dysfunctions are prognostic factors in the mortality rate of COVID-19 and usually happen in severely ill patients. Remdesivir can also lead to renal dysfunction or liver involvement during medical treatment of COVID-19. Therefore, prescribing drugs such as remdesivir should proceed with extreme caution. Patients who had liver disease or who undergo continuous or intermittent dialysis or those with transient AKI may not be the safe candidates to receive remdesivir. Therapy assessment in patients with COVID-19 who have AKI or end-stage renal disease is fundamental in which needs primary assessments of the pros and cons, while the patients with COVID-19 are at high risk for suffering from lots of morbidity and mortality. In the patients taking remdesivir, liver function tests must be monitored daily, and remdesivir should be held in patients with high ALT level more than five times the allowable limit”

LINK TO STUDY


4. Clinical Infectious Diseases (Published June 28, 2020)

TITLE: Drug-induced Liver Injury in a Patient With Coronavirus Disease 2019: Potential Interaction of Remdesivir With P-Glycoprotein Inhibitors 

METHODS: “We report a case of a man with COVID-19 who developed acute hepatotoxicity related to remdesivir with probable interaction of P-glycoprotein (P-gp) inhibitors. Until further details on this interaction become available, we recommend physicians to be cautious with the prescription of P-gp inhibitors in patients receiving remdesivir therapy.”

EXCERPTS FROM DISCUSSION: We presented a case of drug-induced liver injury most likely caused by remdesivir. Remdesivir toxicity was suspected based on the time relation, the positive dechallenge, the known in vitro toxicity of remdesivir, and the absence of alternative causes of hepatotoxicity. COVID-19 has also been found to be associated with elevated liver enzymes. COVID-19 could therefore be the cause of elevated ALT seen in the period prior to remdesivir therapy. However, the sudden ALT peak occurred 27 days after the first onset of symptoms, making viral replication of SARS-CoV-2 as a cause of acute hepatotoxicity very unlikely. Amiodarone-induced liver toxicity was considered less likely, since acute amiodarone toxicity has an early onset (within 24 hours) and the given cumulative dose was low. Furthermore, given amiodarone’s very long half-life (26–107 days), the rapid resolution that was seen after the initial elevation of ALT makes a causative role of amiodarone unlikely.”

“To summarize, we present a case of hepatotoxicity most likely related to remdesivir. Therefore, we urge the need for consistent monitoring for hepatotoxicity in patients receiving remdesivir. Additionally, we propose a mechanism for a drug–drug interaction between remdesivir and P-gp inhibitors. More research is needed to verify this mechanism, but we recommend that physicians be cautious with the prescription of P-gp inhibitors in patients receiving remdesivir therapy.”

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5. Journal of Biomedicine & Pharmacotherapy (Published online July 22, 2020)

TITLE: Safety profile of the antiviral drug remdesivir: An update

METHODS: “The expanding epidemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed a serious threat to the global public health. There is an urgent demand for safe and effective therapeutics. Remdesivir, a broad-spectrum antiviral drug, emerges as a potential candidate for fighting against COVID-19 because of its potent in vitro anti-SARS-CoV-2 activity and encouraging benefits for the infected patients. However, with increasing application, adverse effects of remdesivir have been detected and become a concern of clinicians. Since current safety data about remdesivir is fragmented and limited, we reviewed published studies and official documents regarding remdesivir treatment and summarize the up-to-date safety information, especially in COVID-19 patients, to provide evidence for clinical practices.”

EXCERPTS FROM CONCLUSION:

Re: Gastrointestinal symptoms: “According to a case series in which three COVID-19 patients were treated with remdesivir, two had nausea and one suffered from gastroparesis after the treatment initiation. Diarrhea was observed in 9 % of the remdesivir recipients in Grein et al.’s study. Based on a RCT in China, a higher proportion of remdesivir recipients than placebo recipients had dosing prematurely stopped because of anorexia, nausea, and vomiting.

Re: Respiratory toxicity: “Safety studies of remdesivir in animals showed no adverse effects on respiration except for transiently increased respiration rates. However, acute respiratory distress syndrome (4 %) and pneumothorax (4 %) were reported after the infusion of remdesivir in Grein et al.’s study. Based on the findings from a RCT in China, more patients in the remdesivir group than the placebo group suffered from respiratory failure or acute respiratory distress syndrome (10 % versus 8 %) and therefore discontinued the study drug (5 % versus 1 %).”

Re: Reproductive toxicity: “Reproductive and development toxicity studies in animals revealed remdesivir had no effect on reproductive functions in males or on embryo-fetal and peri-postnatal development, but effect on fertility parameters in female rats were notably found. Although it is not recommended to use in pregnant women, remdesivir treatment is necessary in some cases after weighing the pros and cons. Based on previous application against Ebola, remdesivir appears to be safe in human pregnancies. However, the safety of remdesivir in this special group of patients needs to be further evaluated by therapeutic trials which include pregnant women of COVID-19.”

Cardiovascular toxicity. “No side effect of remdesivir on cardiovascular parameters was observed in safety studies on monkeys. However, one case of hypotension was judged to be potentially related to remdesivir in a RCT of experimental therapies against Ebola. In Grein et al.’s study, hypotension (8 %), atrial fibrillation (6 %) and hypernatremia (6 %) were observed in COVID-19 patients treated with remdesivir. What is more, one case of cardiac arrest was reported in remdesivir group in a RCT in China.”

LINK TO STUDY


6. Pharmacotherapy (Published October 27, 2020)

TITLE: Acetylcysteine for the Treatment of Suspected Remdesivir-Associated Acute Liver Failure in COVID-19: A Case Series

METHODS: “Here, we present two cases of suspected remdesivir-associated acute liver failure (ALF) in which the liver failure improved after continuous infusion acetylcysteine and withdrawal of remdesivir.”

“In the two cases we present, the time course of COVID-19 infection, remdesivir administration, and liver function abnormalities appears to point to remdesivir as a possible contributing cause of ALF. When utilizing the Naranjo algorithm to determine the possibility of a drug-induced effect, both cases scored as a “probable” adverse drug reaction with a score of 6 each.13 In the first case presented, ALF was noted on day 3 of remdesivir therapy.”

CONCLUSION:

The use of the novel antiviral remdesivir in the treatment of COVID-19 pneumonia may put patients at risk of drug-associated acute liver failure. In the two cases presented, the liver failure experienced improved with the administration of acetylcysteine and discontinuation of potentially hepatotoxic medications. More data on the risk of remdesivir-associated acute liver failure and its management with acetylcysteine is needed.”

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7. Preprint, not yet published (Posted August 28, 2020)

TITLE: Elucidation of remdesivir cytotoxicity pathways through genome-wide CRISPR-Cas9 screening and transcriptomics

METHODS: “In order to better understand the mechanisms by which remdesivir affects host cells and induces cytotoxicity, we have performed RNA-sequencing (RNA-seq) and genomewide CRISPR-Cas9 screening on liver and intestinal cell lines treated with remdesivir. RNA-seq has been employed previously to characterize drug mechanisms, which include cytotoxicity15,16. CRISPR-Cas9 screening has been used to identify genetic pathways driving cancer drug resistance17. To our knowledge, neither approach has been used to characterize the effects of remdesivir.”

CONCLUSION: “Through genome-wide CRISPRCas9 screening and RNA sequencing, we show that remdesivir treatment leads to a repression of mitochondrial respiratory activity, and we identify five genes whose loss significantly reduces remdesivir cytotoxicity.”

“Once formed, remdesivir-triphosphate restricts viral replication in the cytoplasm, while biochemical studies combined with our findings of remdesivir-induced mitochondrial dysfunction suggest that cytotoxicity predominantly occurs through its inhibition of mitochondrial RNA polymerase in the mitochondrial matrix.”

LINK TO STUDY


8. Cureus Journal of Medical Science (Published October 24, 2020)

TITLE: Cardiac Adverse Events With Remdesivir in COVID-19 Infection

METHODS: Since December 2019, coronavirus has gradually progressed to a pandemic with no efficacious treatment. Remdesivir is an antiviral medication and inhibitor of viral RNA dependent RNA polymerase with inhibitory action against SARS-CoV virus. Two patients diagnosed with coronavirus infection with worsening respiratory status were initiated with multimodality therapy with antibiotics, steroids and remdesivir. After initiation of remdesivir, the patients’ developed bradycardia, with one of the two also showing signs of worsening QT interval. This reverted upon stopping remdesvir therapy. The prevalence of bradycardia with prolonged QT interval is not well-known yet with this medication.

EXCERPTS FROM DISCUSSION: “Adverse effects are common with remdesivir, but few studies exist that focus on remdesivir and its effects on the cardiovascular system. Out of a study of 53 patients receiving remdesivir, 32 patients (60%) experienced adverse events during follow-up. These adverse events were increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension. Adverse events were more common for those on mechanical ventilation compared to those that were not. Bradycardia or EKG changes were mentioned in this cohort study which would pertain to our findings in this case report and neither of the patients in our study progressed to mechanical ventilation. One study evaluating cardiovascular safety reports a decreased potassium level in patients with COVID-19 which may be contributing to a prolongation of the QT interval on EKG. However, our 26 year old patient who experienced a QT interval prolongation had a potassium within the normal range, indicating potassium is less likely to have played a significant role. It is important to note that this patient was on azithromycin the day prior to discontinuation of remdesivir which is well known to prolong the QT interval. It is possible that it contributed to the prolongation of the QT interval in this patient despite having been discontinued shortly before remdesivir initiation. Remdesivir itself has been mentioned in its own right to have an effect on the QT interval, but more studies are needed to support a causality. Cardiac disturbances in COVID-19 patients receiving remdesivir seem to be primarily due to bradycardia or hypotension in the studies found and less commonly being due to QT prolongation.”

CONCLUSION: “Some SARS-CoV-2 patients on remdesivir develop sinus bradycardia and a prolonged QT interval. Appropriate caution and continuous EKG monitoring should be utilized in all patients participating in ongoing trials for COVID-19 as the safety of remdesivir remains largely uncertain. Even closer surveillance for patients with pre-existing heart disease is warranted when using remdesivir. There remains the need for more high quality evidence from randomized controlled trials presently underway. Attention to additive cardiovascular adverse effects from other drug classes remains crucial to ensure positive patient outcomes and to minimize risk of potential fatal arrhythmias or cardiac arrest.”

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9. The Lancet (Published May 16, 2020)

TITLE: Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

METHODS: “We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656.”

CONCLUSION: “In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies.”

“Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87-1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95-2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early.”

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10. The American Journal of Gastroenterology (Published October 2021)

TITLE: A Case of Acute Liver Failure Secondary to Remdesivir in the Treatment of SARS-CoV-2

CASE DESCRIPTION: “An 83-year-old obese male with chronic kidney and cardiac disease presented with cough and diarrhea for one week and was diagnosed with SARS-CoV-2. Due to hypoxemia, he was started on remdesivir and dexamethasone on hospital day 1. Compared to normal transaminases on admission, on hospital day 6, the patient had an acute elevation of his aspartate aminotransferase (AST) to 3539, alanine aminotransferase (ALT) to 2246, international normalized ratio (INR) to 4.77 and mild elevations in alkaline phosphatase (ALP) to 207 and total bilirubin to 2.9. This was consistent with a hepatocellular pattern of injury. He concurrently developed altered mental status with no asterixis. Acute viral hepatitis serologies and autoimmune markers were negative and liver ultrasound demonstrated a patent portal vein and normal biliary ducts. Remdesivir and dexamethasone were discontinued. Intravenous vitamin K was administered to reverse his coagulopathy and a 5-day course of NAC was completed. The patient had significant improvement in his mental status, AST, ALT, and INR within 24 hours of NAC initiation, with continued improvement over the next two weeks of hospitalization.”

DISCUSSION: “Transaminase elevation [an indicator of liver dysfunction] is a known side effect of remdesivir, and close monitoring of liver tests is recommended. However, ALF [acute liver failure] is a rare complication with only two other published cases and with no approved therapy. In our case of an elderly gentleman with SARS-CoV-2 who developed ALF with grade 1 encephalopathy 6 days after initiation of remdesivir, the discontinuation of the drug along with NAC treatment was successful in reversing the ALF. Furthermore, this patient’s obesity may have increased his risk of Remdesivir hepatotoxicity through impaired cytochrome P450 metabolism. While seemingly rare, more research on the mechanism and risk profile of remdesivir hepatotoxicity is needed as this drug becomes more commonly used in the treatment of SARS-CoV-2.”

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11. The New England Journal of Medicine (Published December 12, 2019)

TITLE: A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics

METHODS: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase–polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days.

CONCLUSION: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P=0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P=0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs.”

LINK TO STUDY (NOTE: The study was funded by the NIAID.)


12. The New England Journal of Medicine (Published June 11, 2020)

TITLE: Compassionate Use of Remdesivir for Patients with Severe Covid-19

METHODS: “We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day.”

CONCLUSION/SAFETY: A total of 32 patients (60%) reported adverse events during follow-up. The most common adverse events were increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension. In general, adverse events were more common in patients receiving invasive ventilation. A total of 12 patients (23%) had serious adverse events. The most common serious adverse events — multiple-organ-dysfunction syndrome, septic shock, acute kidney injury, and hypotension — were reported in patients who were receiving invasive ventilation at baseline.

“Four patients (8%) discontinued remdesivir treatment prematurely: one because of worsening of preexisting renal failure, one because of multiple organ failure, and two because of elevated aminotransferases, including one patient with a maculopapular rash.”

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13. International Journal of Infectious Diseases (Published June 30, 2020)

TITLE: Case report study of the first five COVID-19 patients treated with remdesivir in France

METHODS: “Five patients were treated with compassionate-use remdesivir in our centre in Paris, France. Early findings in two of these patients have been described previously. Here we describe the complete follow-up, drug tolerance, and virological monitoring of these five patients.

“All patients admitted to the Bichat-Claude Bernard University Hospital, Paris, France, between January 24 and March 1, 2020, diagnosed with COVID-19 and treated with remdesivir (Gilead Sciences), were enrolled. The indication criteria for compassionate-use remdesivir were defined by the French national regulatory authorities and French Ministry of Health: signs of severe illness at diagnosis or subsequent clinical worsening (respiratory symptoms or general signs). Since March 22, all patients requiring antiviral treatment have been enrolled in the Discovery Study (2020-000936-23). The Institutional Review Board of Bichat-Claude Bernard University Hospital approved this report and waived the need for informed consent from individual patients, due to the retrospective chart review design and absence of identifying images or personal/clinical details that could compromise anonymity.”

DISCUSSION/ABSTRACT: “Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as the virus responsible for the coronavirus disease 2019 (COVID-19) outbreak worldwide. Data on treatment are scare and parallels have been made between SARS-CoV-2 and other coronaviruses. Remdesivir is a broad-spectrum antiviral with efficient in vitro activity against SARS-CoV-2. Evidence of clinical improvement in patients with severe COVID-19 treated with remdesivir is controversial. The aim of this study was to describe the clinical outcomes and virological monitoring of the first five COVID-19 patients admitted to the intensive care unit of Bichat-Claude Bernard University Hospital, Paris, France, for severe pneumonia related to SARS-CoV-2 and treated with remdesivir. Quantitative reverse transcription PCR was used to monitor SARS-CoV-2 in blood plasma and the lower and upper respiratory tract. Among the five patients treated, two needed mechanical ventilation and one needed high-flow cannula oxygen. A significant decrease in SARS-CoV-2 viral load in the upper respiratory tract was observed in most cases, but two patients died with active SARS-CoV-2 replication in the lower respiratory tract. Plasma samples were positive for SARS-CoV-2 in only one patient. Remdesivir was interrupted before the initialy planned duration in four patients, two because of alanine aminotransferase elevations (3 to 5 normal range) and two because of renal failure requiring renal replacement. This case series of five COVID-19 patients requiring intensive care unit treatment for respiratory distress and treated with remdesivir, highlights the complexity of remdesivir use in such critically ill patients.”

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14. Clinical Pharmacology & Therapeutics (Published January 16, 2021)

TITLE: Remdesivir and Acute Renal Failure: A Potential Safety Signal From Disproportionality Analysis of the WHO Safety Database

METHODS: “Since 1978, Uppsala Monitoring Centre (UMC) monitors drug safety on the behalf of the World Health Organization (WHO). UMC gathers pharmacovigilance data from the national pharmacovigilance networks (130 member states). Each local pharmacovigilance organization relies on spontaneous notifications then collected into VigiBase, respecting the anonymity of patients and notifiers. Individual patient data collected included sociodemographic characteristics (age, sex, and notifier’s country), and the reported effect (suspected and concomitant drugs, ADRs, date of occurrence, and seriousness). We queried VigiBase for notified cases of ARF with remdesivir suspected and sought a potential pharmacovigilance signal relying on two different disproportionality approaches.”

CONCLUSION: “The combination of the terms ‘acute renal failure’ and ‘remdesivir’ yielded a statistically significant disproportionality signal with 138 observed cases instead of the 9 expected. ROR of ARF with remdesivir was 20-fold (20.3; confidence interval 0.95 [15.7–26.3], P < 0.0001]) that of comparative drugs. Based on ARF cases reported in VigiBase, and despite the caveats inherent to COVID-19 circumstances, we detected a statistically significant pharmacovigilance signal of nephrotoxicity associated with remdesivir, deserving a thorough qualitative assessment of all available data. Meanwhile, as recommended in its Summary of Product Characteristics, assessment of patients with COVID-19 renal function should prevail before and during treatment with remdesivir in COVID-19.

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15. The Cardiovascular Toxicology Journal (Published October 13, 2021)

TITLE: Potential Cardiotoxic Effects of Remdesivir on Cardiovascular System: A Literature Review

METHODS: Literature review.

CONCLUSION/ABSTRACT: “Corona disease 2019 (COVID-19) pandemic continues to spread around the world with no efficacious treatment. Intravenous remdesivir is the only authorized drug for treatment of COVID-19 disease under an Emergency Use Authorization. Remdesivir is a 1′-cyano-substituted adenosine nucleotide prodrug which inhibits viral RNA synthesis. This metabolite is an adenosine analog but with a significantly longer half-life than adenosine. Adenosine is a powerful vasodilator that can cause profound hypotension which is followed by the compensatory release of catecholamines. It can also shorten atrial action potential and refractoriness and lead to atrial fibrillation (AF). These effects may also occur in ventricular cells and predispose patients to ventricular fibrillation. Remdesivir can also induce significant cytotoxic effects in cardiomyocytes that is considerably worse than chloroquine cardiotoxic effects. Remdesivir-induced cardiotoxicity is due to its binding to human mitochondrial RNA polymerase. On the other hand, remdesivir can increase field potential duration with decreased Na+ peak amplitudes and spontaneous beating rates in a dose-dependent manner that might induce prolonged QT interval and torsade de point. There are some reports of sinus bradycardia, hypotension, T-wave abnormalities, AF, and a prolonged QT interval and few cases of cardiac arrest and complete heat block following remdesivir infusion. It seems remdesivir have some cardiotoxic and proarrhythmic effects that are especially more pronounced in patients with previous cardiovascular diseases. The current safety profile of remdesivir is still not completely known and further prospective clinical trials are needed to assess its safety profile and potential adverse cardiovascular effects.”

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Feature image: Jernej Furman

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