What is the role of remdesivir in patients with COVID-19?

PURPOSE OF REVIEW: COVID-19 represents an unprecedented public health crisis caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The antiviral remdesivir is one component of treating COVID-19. Unfortunately, the trials evaluating remdesivir have reported mixed results, leading to uncertainty on when to use remdesivir. This review discusses the trials evaluating the efficacy of remdesivir for COVID-19 and other supporting data to help inform the role of remdesivir in patients with COVID-19. RECENT FINDINGS: Since the start of the pandemic, there have been four randomized trials of remdesivir in treating patients hospitalized with COVID-19. More recently, extensive observational studies have provided supportive data. SUMMARY: The majority of trials evaluating remdesivir suggest that remdesivir is effective in the treatment of patients hospitalized with COVID-19. Although there may be a benefit in some subgroups more than others, there is insufficient data to make definitive statements about benefits or lack of benefits in particular groups. Remdesivir has demonstrated clinical benefits such as decreased time in the hospital, lower progression to mechanical ventilation, and decreased utilization of other hospital resources; it is unclear if it reduces mortality, but one randomized controlled trial suggested possible survival benefits. Based on the data available, remdesivir has been approved (or authorized for early use) in 48 countries.

Remdesivir for the Treatment of Covid-19 - Final Report.

BACKGROUND: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. RESULTS: A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%). CONCLUSIONS: Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.).

Real-life experience with remdesivir for treatment of COVID-19 among older adults: a multicentre retrospective study.

INTRODUCTION: The effect of remdesivir on COVID-19 mortality remains conflicting. Elderly individuals are at risk for poor COVID-19 outcomes. We aimed to assess the effect of remdesivir on COVID-19 mortality among elderly individuals, using real-world data. METHODS: Retrospective multinational cohort of individuals aged ≥65 years, hospitalized with COVID-19 in six medical centres between January 2020 and May 2021. Associations with in-hospital mortality were evaluated using a multivariable logistic regression model with propensity score adjustment for remdesivir therapy and while implementing generalized estimating equations to control for centre effect. Sensitivity analysis was performed by stratification according to the degree of respiratory support. RESULTS: Of 3010 individuals included, 2788 individuals required either oxygen supplementation or non-invasive/invasive mechanical ventilation, 489 (16%) were treated with remdesivir, and 836 (28%) died. Median age was 77 (IQR 70-84) years and 42% were women. Remdesivir was the only therapeutic intervention associated with decreased mortality [adjusted OR (aOR) 0.49, 95% CI 0.37-0.66, P < 0.001]. This protective effect was shown for individuals requiring oxygen support and non-invasive mechanical ventilation, while no association was found among individuals necessitating invasive mechanical ventilation.Risk factors for mortality included invasive ventilation (aOR 5.18, 95% CI 2.46-10.91, P < 0.001), higher serum creatinine (aOR 1.25, 95% CI 1.09-1.43, P = 0.001) and dyspnoea (aOR 1.40, 95% CI 1.07-1.84, P = 0.015) on presentation, and other non-modifiable factors, such as comorbidities. CONCLUSIONS: Among elderly individuals hospitalized with COVID-19, remdesivir carries survival benefit for those with moderate to severe disease. Its role among individuals with critical illness should be further assessed.

Coronavirus disease 2019 management.

PURPOSE OF REVIEW: Coronavirus disease 2019 (COVID-19) is an acute multisystem disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Investigations are ongoing in the search for effective therapeutics, with clinical approaches evolving based upon such evidence. RECENT FINDINGS: The antiviral agent, remdesivir, and the immunomodulator, dexamethasone, are the first therapeutics for which there is evidence of efficacy from randomized trials. Subgroup analyses suggest remdesivir is beneficial in hospitalized patients whose severity of illness falls at the lower end of the spectrum, while dexamethasone is more beneficial in hospitalized patients whose severity of illness falls at the higher end of the spectrum. We recommend that inpatients who require supplemental oxygen but are not mechanically ventilated receive both remdesivir and dexamethasone, and inpatients who require mechanical ventilation receive dexamethasone monotherapy. Additional evidence regarding anti-SARS-CoV-2 antibodies, convalescent plasma, and a variety of antiinterleukin therapies is forthcoming. SUMMARY: The body of evidence related to COVID-19 therapeutics continues to evolve and, as a result, management is likely to change with time. As new evidence is generated and published, the optimal approach to managing patients with COVID-19 should be reconsidered.

USA stockpiling of remdesivir: How should the world respond?

The race to find an effective treatment for coronavirus disease 2019 (COVID-19) is still on, with only two treatment options currently authorized for emergency use and/or recommended for patients hospitalized with severe respiratory symptoms: low-dose dexamethasone and remdesivir. The USA decision to stockpile the latter has resulted in widespread condemnation and in similar action being taken by some other countries. In this commentary we discuss whether stockpiling remdesivir is justified in light of the currently available evidence.

Remdesivir and corticosteroids in the treatment of hospitalized COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is a pandemic infection caused by the newly discovered severe acute respiratory syndrome coronavirus 2. Remdesivir (RDV) and corticosteroids are used mainly in COVID-19 patients with acute respiratory failure. The main objective of the study was to assess the effectiveness of remdesivir with and without corticosteroids in the treatment of COVID-19 patients. We conducted a prospective observational study, including adult patients consecutively hospitalized with confirmed COVID-19 and acute respiratory failure. Patients were divided according to treatment strategy: RDV alone versus RDV with corticosteroids. The primary outcome was the time to recovery in both treatment groups. We included 374 COVID-19 adult patients, 184 were treated with RDV, and 190 were treated with RDV and corticosteroid. Patients in the RDV group had a shorter time to recovery in comparison with patients in the RDV plus corticosteroids group at 28 days after admission [11 vs. 16 days (95% confidence Interval 9.7-12.8; 14.9-17.1; p = .016)]. Patients treated with RDV alone had a shorter length of hospital stay. The use of corticosteroids as adjunctive therapy of RDV was not associated with improvement in mortality of COVID-19 patients.

Enhanced Remdesivir Analogues to Target SARS-CoV-2.

We report the short synthesis of novel C-nucleoside Remdesivir analogues, their cytotoxicity and an in vitro evaluation against SARS-CoV-2 (CoV2). The described compounds are nucleoside analogues bearing a nitrogen heterocycle as purine analogues. The hybrid structures described herein are designed to enhance the anti-CoV2 activity of Remdesivir. The compounds were evaluated for their cytotoxicity and their anti-CoV2 effect. We discuss the impact of combining both sugar and base modifications on the biological activities of these compounds, their lack of cytotoxicity and their antiviral efficacy.

Early administration of remdesivir plus convalescent plasma therapy is effective to treat COVID-19 pneumonia in B-cell depleted patients with hematological malignancies.

Patients with hematological malignancies (HMs) are at a higher risk of developing severe form and protracted course of COVID-19 disease. We investigated whether the combination of viral replication inhibition with remdesivir and administration of anti-SARS-CoV-2 immunoglobulins with convalescent plasma (CP) therapy might be sufficient to treat B-cell-depleted patients with COVID-19. We enrolled 20 consecutive patients with various HMs with profound B-cell lymphopenia and COVID-19 pneumonia between December 2020 and May 2021. All patients demonstrated undetectable baseline anti-SARS-CoV-2 immunoglobulin levels before CP. Each patient received at least a complete course of remdesivir and at least one unit of CP. Previous anti-CD20 therapy resulted in a more prolonged SARS-CoV-2 PCR positivity compared to other causes of B-cell lymphopenia (p = 0.004). Timing of CP therapy showed a significant impact on the clinical outcome. Simultaneous use of remdesivir and CP reduced time period for oxygen weaning after diagnosis (p = 0.017), length of hospital stay (p = 0.007), and PCR positivity (p = 0.012) compared to patients who received remdesivir and CP consecutively. In addition, time from the diagnosis to CP therapy affected the length of oxygen dependency (p < 0.001) and hospital stay (p < 0.0001). In those cases where there were at least 10 days from the diagnosis to plasma administration, oxygen dependency was prolonged vs. patients with shorter interval (p = 0.006). In conclusion, the combination of inhibition of viral replication with passive immunization was proved to be efficient and safe. Our results suggest the clear benefit of early, combined administration of remdesivir and CP to avoid protracted COVID-19 disease among patients with HMs and B-cell lymphopenia.

Safety of Remdesivir in 20 Children with COVID-19-Case Series-

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) virus, has spread worldwide since 2019. Several studies report that adult patients hospitalized with severe COVID-19 can be treated successfully with remdesivir (RDV). However, few studies report the safety and efficacy of RDV for children. This study included 20 hospitalized patients who were diagnosed with COVID-19 and received RDV at Kobe Children's Hospital, Japan, between February and June, 2022. The median age was 2 years (IQR, 1-11 years; range, 5 months to 19 years). Twelve (60%) patients were male. Three (15%) patients were previously healthy, whereas the other 17 had at least one underlying medical condition: five (25%) patients had respiratory disease, four (20%) had cardiac disease, three (15%) had central nervous system disease, four (20%) had hematologic or oncologic disease, and two (10%) had a chromosomal abnormal. All patients recovered without any sequelae, and no serious adverse events were reported. The adverse events were elevated liver enzymes in 4 children (20%), leukopenia (5%), neutropenia (5%), and hypokalemia (5%). Our study may show that the use of RDV for COVID-19 in children led to no serious adverse events.

Remdésivir chez les patients hospitalisés pour la COVID-19 au Canada: essai clinique randomisé et contrôlé.

CONTEXTE: Le rôle du remdésivir dans le traitement des patients hospitalisés pour la COVID-19 reste imprécis dans un contexte international. L'essai randomisé et contrôlé (ERC) Solidarity de l'Organisation mondiale de la Santé a évalué le remdésivir chez des patients de nombreux pays; le Canada a inscrit des patients dans un protocole élargi de collecte de données: l'essai CATCO (Canadian Treatments for COVID-19). Nous faisons état des observations canadiennes, des données démographiques, des caractéristiques et des indicateurs cliniques qui témoignent de la variabilité des effets d'un système de santé à l'autre. MÉTHODES: Nous avons procédé à un ERC pragmatique à étiquetage en clair dans les hôpitaux canadiens, en collaboration avec l'essai Solidarity. Nous avons procédé à une attribution aléatoire des patients à 10 jours au remdésivir (200 mg par voie intraveineuse [IV] au jour 0, suivis de 100 mg IV par jour) en plus du traitement standard, ou au traitement standard seulement. L'indicateur principal était la mortalité perhospitalière. Les indicateurs secondaires incluaient les modifications de la gravité de l'état clinique, le nombre de jours sans oxygénothérapie et sans ventilation (à 28 jours), l'incidence d'un nouveau recours à l'oxygénothérapie et à la ventilation mécanique, la durée du séjour hospitalier et les taux d'effets indésirables. Nous avons effectué des analyses de sous-groupes préspécifiés selon la durée des symptômes avant le recrutement, l'âge, le sexe, et la gravité des symptômes à l'arrivée. RÉSULTATS: Parmi 52 hôpitaux canadiens, entre le 14 août 2020 et le 1er avril 2021, nous avons procédé à une attribution aléatoire de 1282 patients au remdésivir (n = 634) ou au traitement standard (n = 648). Parmi ces patients, 15 ont retiré leur consentement ou étaient encore hospitalisés, pour un échantillon total de 1267 patients. Parmi les patients auxquels on a attribué le remdésivir, la mortalité perhospitalière a été de 18,7 %, contre 22,6 % chez les patients sous traitement standard (risque relatif [RR] 0,83, intervalle de confiance [IC] de 95 % 0,67­1,03 et la mortalité à 60 jours a été de 24,8 % et 28,2 %, respectivement (IC de 95 % 0,72­1,07). Pour les patients non ventilés mécaniquement au départ; le recours à la ventilation mécanique a été de 8,0 % chez les patients qui recevaient le remdésivir et de 15,0 % chez ceux sous traitement standard (RR 0,53, IC de 95 % 0,38­0,75). Le nombre moyen de jours sans oxygénothérapie ni ventilation au jour 28 étaient de 15,9 (± écart-type [É.T.] 10,5) et 21,4 (± É.-T. 11,3) chez les patients sous remdésivir et de 14,2 (± É.-T. 11) et 19,5 (± É.-T. 12,3) chez les patients sous traitement standard (p = 0,006 et 0,007, respectivement). On n'a noté aucune différence quant à l'innocuité (p. ex., recours à la dialyse, changement du taux de créatinine, ou nouveaux cas d'insuffisance hépatique) entre les 2 groupes. INTERPRÉTATION: Comparativement au traitement standard, le remdésivir a eu un effet modeste, mais significatif sur certains indicateurs importants pour les patients et pour les systèmes de santé, tels que le recours à la ventilation mécanique. NUMÉRO D'ENREGISTREMENT DE LA RECHERCHE: ClinicalTrials.gov, no. NCT04330690.

Effect of remdesivir on mortality and the need for mechanical ventilation among hospitalized patients with COVID-19: real-world data from a resource-limited country.

OBJECTIVES: Georgia introduced remdesivir for the treatment of COVID-19 in December 2020. We evaluated the real-world effect of remdesivir on mortality and the need for mechanical ventilation among inpatients with COVID-19. METHODS: The study included 346 remdesivir recipients and 346 controls not receiving remdesivir selected through propensity score matching based on age, gender, presence of any chronic comorbid condition, and oxygen saturation at admission. Factors associated with in-hospital mortality and the need for mechanical ventilation were assessed in a multivariable logistic regression model. RESULTS: The groups were comparable by age, gender, comorbidities, and baseline oxygen saturation. Among 346 remdesivir recipients, 265 (76.6%) received a generic formulation of the drug. Eight (2.3%) patients died in the remdesivir group and 18 (5.2%) in the control group (P = 0.046). In the multivariable analysis, remdesivir was associated with non-statistically significant reduced odds of death (odds ratio: 0.39, 95% confidence interval: 0.14-1.04, P = 0.06). Significantly fewer patients in the remdesivir group required mechanical ventilation compared to controls: 2.9% vs 6.4% (P = 0.03). Statistically significant difference was maintained in multivariable analysis (odds ratio: 0.40, 95% confidence interval: 1.04-5.60, P = 0.04). CONCLUSION: Borderline reduction in the odds of death and statistically significant decrease in the need for mechanical ventilation support use of remdesivir in hospitalized patients with COVID-19.

Dual effects of NV-CoV-2 biomimetic polymer: An antiviral regimen against COVID-19.

Remdesivir (RDV) is the only antiviral drug approved for COVID-19 therapy by the FDA. Another drug LAGEVRIO™ (molnupiravir) though has not been approved yet by FDA but has been authorized on December 23, 2021, for emergency use to treat adults with mild-to moderate COVID-19 symptoms and for whom alternative COVID-19 treatment options are not clinically appropriate. The fact is that the efficacy of RDV is, however, limited in vivo though it is highly promising in vitro against SARS-CoV-2 virus. In this paper we are focusing on the action mechanism of RDV and how it can be improved in vivo. The stability of RDV alone and on encapsulation with our platform technology based polymer NV-387 (NV-CoV-2), were compared in presence of plasma in vitro and in vivo. Furthermore, a non-clinical pharmacology study of NV-CoV-2 (Polymer) and NV CoV-2 (Polymer encapsulated Remdesivir) in both NL-63 infected and uninfected rats was done. In addition, the antiviral activity of NV-CoV-2 and NV-CoV-2-R was compared with RDV in a cell culture study. The results are (i) NV-CoV-2 polymer encapsulation protects RDV from plasma-mediated catabolism in both in vitro and in vivo, studies; (ii) Body weight measurements of the normal (uninfected) rats after administration of the test materials (NV-CoV-2 and NV-CoV-2-R) showed no toxic effects. (iii) Body weight measurements and survival rates of the NL-63 infected rats were similar to the uninfected rats after treatment with NV-CoV-2 and NV-CoV-2-R. Overall, the efficacy as an antiviral regimens were found in this order as below; NV-CoV-2-R > NV-CoV-2 > RDV. Our platform technology based NV-387-encapsulated-RDV (NV-CoV-2-R) drug has a dual effect against different variants of the coronaviruses. First, NV-CoV-2 is an antiviral regimen. Secondly, RDV is protected from plasma-mediated degradation in transit. All together, NV-CoV-2-R is the safest and efficient regimen against COVID-19.

Remdesivir Plus Dexamethasone Versus Dexamethasone Alone for the Treatment of Coronavirus Disease 2019 (COVID-19) Patients Requiring Supplemental O2 Therapy: A Prospective Controlled Nonrandomized Study.

BACKGROUND: Remdesivir is an antiviral used to treat coronavirus disease 2019 (COVID-19), which improves some clinical outcomes. Dexamethasone has been shown to be effective in reducing mortality. It has been hypothesized that combination of these two drugs can improve mortality. We evaluated the effect of combination on mortality of COVID-19 patients requiring O2 therapy. METHODS: A prospective quasi-experimental study, including two independent, sequential controlled cohorts, one received remdesivir-dexamethasone and the other dexamethasone alone, was designed. All COVID-19 patients requiring supplemental O2 therapy were enrolled consecutively. The sample size to power mortality was a priori calculated. The primary endpoints were 30-day mortality and viral clearance differences. Secondary endpoints were differences in hospitalization times, improvement in respiratory failure (PO2/FiO2) and inflammatory indices (fibrinogen, CRP, neutrophil/lymphocyte ratio, D-Dimer). Kaplan-Meier curves and the log-rank test were used to evaluate significant differences in mortality between groups. RESULTS: In total, 151 COVID-19 patients were enrolled (remdesivir/dexamethasone group, 76, and dexamethasone alone, 75). No differences in demographic, clinical, and laboratory characteristics were observed between the 2 groups at baseline. Faster viral clearance occurred in the remdesivir/dexamethasone group compared to dexamethasone alone (median 6 vs 16 days; P < .001). The 30-day mortality in the remdesivir/dexamethasone group was 1.3%, whereas in dexamethasone alone was 16% (P < .005). In the remdesivir/dexamethasone group compared to dexamethasone alone there was a reduction in hospitalization days (P < .0001) and a faster improvement in both respiratory function and inflammatory markers. CONCLUSIONS: Remdesivir/dexamethasone treatment is associated with significant reduction in mortality, length of hospitalization, and faster SARS-CoV-2 clearance, compared to dexamethasone alone.

Early Stage Combination Treatment with Methylprednisolone Pulse and Remdesivir for Severe COVID-19 Pneumonia.

BACKGROUND: This study evaluated the clinical outcomes of patients with severe COVID-19 pneumonia treated with remdesivir plus standard corticosteroid treatment (SCT) or with remdesivir plus high-dose corticosteroid pulse therapy (HDCPT). METHODS: One hundred and two patients with severe COVID-19 pneumonia and respiratory failure were included. The patients were divided into two cohorts. The first comprised patients who received remdesivir and SCT, consisting of 6 mg dexamethasone daily for up to 10 days or until hospital discharge. The second included patients who received remdesivir and HDCPT, composed of 250 mg iv of methylprednisolone for three days, followed by a slow reduction in the dose of steroids. The severity of hypoxemia was assessed using the SaO2/FiO2 peripheral oxygen saturation index. RESULTS: 55 received remdesivir plus HDCPT, and 47 received remdesivir plus SCT. Mortality at 30 days was significantly lower among patients who received remdesivir plus HDCPT (4/55) than among those who did not (15/47). In patients who received remdesivir plus HDCPT, 7.3% required invasive mechanical ventilation and admission to the ICU and 36.4% non-invasive ventilation versus 29.8% and 61.7%, respectively, among those treated with remdesivir plus SCT. Remdesivir plus HDCPT induced a significantly faster improvement in the SaO2/FiO2 index. CONCLUSION: Early combination treatment with remdesivir plus HDCPT reduced in-hospital mortality and the need for admission to the ICU. Furthermore, it improved the SaO2/FiO2 index faster in patients with severe COVID-19 pneumonia.

Pharmacologic Treatment of Transplant Recipients Infected With SARS-CoV-2: Considerations Regarding Therapeutic Drug Monitoring and Drug-Drug Interactions.

BACKGROUND: COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-coronavirus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs (ISDs). It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals. METHODS: This article is not intended to provide a systematic literature review on investigational treatments tested against COVID-19; rather, the authors aim to provide recommendations for therapeutic drug monitoring of ISDs in transplant recipients infected with SARS-CoV-2 based on a review of existing data in the literature. RESULTS: Management of drug-drug interactions between investigational anti-SARS-CoV-2 drugs and immunosuppressants is a complex task for the clinician. Adequate immunosuppression is necessary to prevent graft rejection while, if critically ill, the patient may benefit from pharmacotherapeutic interventions directed at limiting SARS-CoV-2 viral replication. Maintaining ISD concentrations within the desired therapeutic range requires a highly individualized approach that is complicated by the pandemic context and lack of hindsight. CONCLUSIONS: With this article, the authors inform the clinician about the potential interactions of experimental COVID-19 treatments with ISDs used in transplantation. Recommendations regarding therapeutic drug monitoring and dose adjustments in the context of COVID-19 are provided.