The COVID-19 pandemic began in March 2020 and has affected many countries and infected over a million people. It has had a serious impact on people's physical and mental health, daily life and the global economy. Today, many drugs show limited efficacy in the treatment of COVID-19 and studies to develop effective drugs continue. Here, we aim to the synthesise and characterise of the flavonol-3-O-glycoside derivatives, the following and evaluated molecular docking studies with antimicrobial activity, inhibition of SARS-CoV-2 main protease enzyme (3CLpro) and nuclease activity. Molecular docking simulations of the synthesized flavonol-3-O-glycoside derivatives, especially compounds 5a, 5d, 5h, 5i and 5m, showed a stronger interaction with SARS-CoV-2 3CLpro in the active site. Two compounds from the target compounds, 5h and 5m, were found to be specifically effective against M. smegmatis and yeasts. In particular, compounds 5a, 5d, 5h, 5i and 5m, which exhibited high activity against the SARS-CoV-2 main protease enzyme, were found to be effective at low concentrations. We determined the IC50 values for the compounds that showed an inhibitory effect as well as their nuclease activities, which further emphasising the potential of our results. Among these, compound 5d showed a significant competitive inhibitor of 3CLpro. Furthermore, nuclease activity studies identified compound 5d as the most potent. The above results suggest that the flavonol-3-O-glycoside derivatives could be promising new antiviral agents for the development of 3CLpro inhibitors to combat COVID-19.

SARS-CoV-2 can infect cells through endocytic uptake, a process that is targeted by inhibition of lysosomal proteases. However, clinically this approach to treat viral infections has afforded mixed results, with some studies detailing an oral regimen of hydroxychloroquine accompanied by significant off-target toxicities. We rationalized that an organelle-targeted approach will avoid toxicity while increasing the concentration of the drug at the target. Here, we describe a lysosome-targeted, mefloquine-loaded poly(glycerol monostearate-co-ε-caprolactone) nanoparticle (MFQ-NP) for pulmonary delivery via inhalation. Mefloquine is a more effective inhibitor of viral endocytosis than hydroxychloroquine in cellular models of COVID-19. MFQ-NPs are less toxic than molecular mefloquine, are 100-150 nm in diameter, and possess a negative surface charge, which facilitates uptake via endocytosis allowing inhibition of lysosomal proteases. MFQ-NPs inhibit coronavirus infection in mouse MHV-A59 and human OC43 coronavirus model systems and inhibit SARS-CoV-2 WA1 and its Omicron variant in a human lung epithelium model. Organelle-targeted delivery is an effective means to inhibit viral infection.

Remdesivir (RDV) and nirmatrelvir/ritonavir (NMVr) are among the most widely used antivirals in the treatment of COVID-19, aiming to reduce disease severity and progression. Adverse neuropsychiatric effects, such as anxiety, sleep disturbances, and movement disorders, have emerged as significant concerns associated with these treatments. To better understand the safety profiles of RDV and NMVr, this study performs a pharmacovigilance analysis of individual case safety reports (ICSRs) from the EudraVigilance (EV) database. Objectives: This study evaluates the risk of neuropsychiatric adverse events associated with RDV and NMVr. Comparisons with other antiviral drugs, including darunavir, sofosbuvir, ribavirin, tenofovir, ritonavir, and sotrovimab, are also performed to develop a comprehensive understanding of the safety profiles. Methods: A retrospective analysis of ICSRs submitted to EV until 7 July 2024, with data extraction on 12 July 2024, was conducted. Demographic characteristics (age, sex, geographic region, and reporter type) and case severity were included in the descriptive analysis. Disproportionality analysis using reporting odds ratio (ROR) and 95% confidence intervals (CI) was performed to compare adverse drug reaction (ADRs) frequencies across 27 system organ classes (SOCs), with emphasis on "Nervous system disorders" and "Psychiatric disorders. Results: The total number of ICSRs was significantly higher for NMVr (n = 8078) compared to RDV (n = 3934). Nervous system disorders accounted for 3.07% of the total RDV reports and for 17.31% of NMVr reports, while psychiatric disorders represented 0.92% of the total ADRs reported for RDV (n = 60) and 3.61% for NMVr (n = 672). On the other hand, RDV showed a significantly lower frequency of reporting headache compared to NMVr (ROR: 0.1057; 95% CI: 0.0676-0.1653). Conclusions: NMVr presents a higher risk of neuropsychiatric ADRs than RDV, underscoring the need for enhanced monitoring, particularly in patients with preexisting central nervous system (CNS) conditions. These findings contribute to optimizing antiviral safety and informing clinical decision making.

Background/Objective: Millions of children were infected with SARS-CoV-2, and a small proportion progressed to severe disease, especially those with underlying risk factors. Adult COVID-19 studies showed mortality benefits with Remdesivir. Data on Remdesivir use in pediatrics are limited. We report on the safety and tolerability of Remdesivir in pediatric patients seen at our institution. Methods: This was a retrospective cohort study of patients <19 years old with acute SARS-CoV-2 infection who received at least one dose of Remdesivir. Patients followed strict institutional guidelines for safety monitoring including standard clinical and laboratory daily observations. Demographics and underlying conditions were reported as averages; for laboratory values, linear regression was applied within a generalized linear mixed-effects model framework to evaluate the significance of changes in average levels over time. Results: We enrolled 318 patients with acute SARS-CoV2 infection from May 2020 to December 2022. In total, 53% were male, and the age range was distributed broadly. In total, 61% were school-aged children (28% 5-11 and 33% 12-18 years of age). In total, 62% of cases were Hispanic. The most common reasons for Remdesivir treatment included respiratory distress (201; 63%) and having high-risk underlying conditions (109; 34%). Therapy was completed as planned in 91% and discontinued early in 9%. Mean baseline, peak, and end of treatment values for AST were 57 (95% CI 53, 61), 79 (95% CI 73, 84) (p < 0.001), and 55 (51, 59) (p = 0.479); for ALT, they were 42 (38, 47), 59 (95% CI 52, 66) (p < 0.001), and 46 (95% CI 41, 52) (p = 0.054); and for bilirubin, they were 0.56 (95% CI 0.50, 0.62), 0.67 (95% CI 0.61, 0.74) (p < 0.001), and 0.44 (95% CI 0.40, 0.48) (p < 0.001), respectively. During Remdesivir treatment, we did not observe marrow suppression or renal toxicity. Conclusions: No clinically significant hematological or renal toxicity was noted. Mean liver enzymes increased modestly and returned to baseline without interrupting treatment. Remdesivir was well tolerated in patients <19 years old.

Since the COVID-19 pandemic, it has caused a great threat to the global economy and public health, initiatives have been launched to control the spread of the virus. To explore the efficacy of drugs, a large number of clinical trials have been carried out, with the purpose of providing guidelines based on high-quality evidence for clinicians. We mainly discuss therapeutic agents for COVID-19 and explain the mechanism, including antiviral agents, tocilizumab, Janus kinase (JAK) inhibitors, neutralizing antibody therapies and corticosteroids. In addition, the COVID-19 vaccine has been proven to be efficacious in preventing SARS-CoV-2 infection. We systematically analyzed four mainstream vaccine platforms: messenger RNA (mRNA) vaccines, viral vector vaccines, inactivated vaccines and protein subunit vaccines. We evaluated the therapeutic effects of drugs and vaccines through enumerating the most typical clinical trials. However, the emergence of novel variants has further complicated the interpretation of the available clinical data, especially vaccines and antibody therapies. In the post-epidemic era, therapeutic agents are still the first choice for controlling the progression of disease, whereas the protective effect of vaccines against different strains should be assessed comprehensively.

Since the first cases of the COVID-19 pandemic, caused by the SARS-CoV-2 virus, described in 2019, numerous drugs have been proposed for the treatment of the disease. However, studies have given contradictory or inconclusive results, making it difficult to determine which treatments are truly effective. The objective was to carry out a systematic review of the literature analyzing the effectiveness (mortality, hospitalization and clinical improvement) of COVID-19 treatments initially proposed and finally authorized in the European Union.

PubMed and other electronic databases were systematically searched for meta-analyses published between January 2020 and December 2022, as well as two additional searches: one of individual clinical studies published until October 2023 and another of those drugs that were considered at the beginning and that were discarded early because the clinical results were unfavorable.

In the synthesis, 85 meta-analyses and 19 additional clinical studies were included (base case). All medications indicated in the treatment of COVID-19 have favorable efficacy results (mortality, hospitalization rate, clinical improvement) but these results were not confirmed in all studies carried out, being frequently contradictory (confirming or not confirming the impact of treatment on mortality). According to meta-analysis with the largest sample size, the drugs with the greatest evidence of effectiveness in reducing mortality are remdesivir (HR= 0.79; 95% CI 0.73-0.85) and tocilizumab (OR= 0.73; 95% CI 0.56-0.93). Regarding the composite of Covid-19-related hospitalization or death from any cause, the drugs with the greatest evidence of efficacy are remdesivir, nirmatrelvir/ritonavir and sotrovimab (although, currently the effectiveness of monoclonal antibodies against the new variants of the virus has not been demonstrated).

According to this systematic review, the treatments with the greatest evidence of reducing mortality in patients with COVID-19 are remdesivir and tocilizumab.

Tick-borne encephalitis (TBE) is a neurological disease caused by the tick-borne encephalitis virus (TBEV). Despite available vaccines, breakthrough infections occur, some fatal.

As no antiviral therapy for TBE is currently approved, this study evaluated the in vitro activity of already licenced remdesivir (RDV) and sofosbuvir (SOF) for possible drug repurposing against TBEV.

TBEV was cultured in A549 cells, and the inhibitory effects of RDV (GS-5734), its parent nucleotide GS-441524, and SOF (GS-7977) were assessed.

After 78 h, RDV demonstrated significantly lower EC50 values than SOF (0.14 vs. 11 µM) based on TBEV RNA levels measured by RT-qPCR. RDV also had a lower mean EC50 (0.55 µM) compared to GS-441524 and SOF (>8.9 and 13.1 µM, respectively) using crystal violet staining after 5 days. After 11 passages of TBEV in the presence of RDV, emergence of virus with a higher EC50 (1.32 vs. 0.55 µM) was detected with two mutations (L3122F and Y3278F) in NS5, the viral RNA-dependent RNA polymerase (RdRp), and one substitution in envelope (E) protein (E402G). Similarly, SOF resistance appeared after 20 passages, increasing EC50 values (35.5 vs. 10 µM).

RDV exhibits potent in vitro antiviral activity against TBEV via specific targeting of the viral RdRp as confirmed by the emergence of resistance-associated double NS5 substitutions in vitro in the presence of RDV. While the potential in vivo implications of the observed RDV resistance remain to be determined, these in vitro data support further assessment of RDV for the treatment of TBEV infection.

Acute respiratory infections (ARIs) caused by viruses such as SARS-CoV-2, influenza viruses, and respiratory syncytial virus (RSV), pose significant global health challenges, particularly for the elderly and immunocompromised individuals. Substantial evidence indicates that acute viral infections can manipulate the host's epigenome through mechanisms like DNA methylation and histone modifications as part of the immune response. These epigenetic alterations can persist beyond the acute phase, influencing long-term immunity and susceptibility to subsequent infections. Post-infection modulation of the host epigenome may help distinguish infected from uninfected individuals and predict disease severity. Understanding these interactions is crucial for developing effective treatments and preventive strategies for viral ARIs. This review highlights the critical role of epigenetic modifications following viral ARIs in regulating the host's innate immune defense mechanisms. We discuss the implications of these modifications for diagnosing, preventing, and treating viral infections, contributing to the advancement of precision medicine. Recent studies have identified specific epigenetic changes, such as hypermethylation of interferon-stimulated genes in severe COVID-19 cases, which could serve as biomarkers for early detection and disease progression. Additionally, epigenetic therapies, including inhibitors of DNA methyltransferases and histone deacetylases, show promise in modulating the immune response and improving patient outcomes. Overall, this review provides valuable insights into the epigenetic landscape of viral ARIs, extending beyond traditional genetic perspectives. These insights are essential for advancing diagnostic techniques and developing innovative treatments to address the growing threat of emerging viruses causing ARIs globally.

The impact of remdesivir on SARS-CoV-2 diversity and evolution in vivo has remained unclear. In this single-center, retrospective cohort study, we assessed SARS-CoV-2 diversification and diversity over time in a cohort of hospitalized patients who did or did not receive remdesivir. Whole-genome sequencing was performed on 98 paired specimens collected from 49 patients before and after remdesivir administration. The genetic divergence between paired specimens was not significantly different in this cohort compared with that in a control group of patients who did not receive the drug. However, when we focused on minority variants, several positions showed preferential diversification after remdesivir treatment, some of which were associated with specific variants of concern. Most notably, remdesivir administration resulted in strong selection for a nonsynonymous mutation in nsp12, G671S, previously associated with enhanced viral fitness. This same mutation was found to be enriched in a second cohort of 143 inpatients with specimens collected after remdesivir administration compared with controls. Only one other mutation previously implicated in remdesivir resistance (nsp12:V792I) was found to be preferentially selected for after remdesivir administration. These data suggest that SARS-CoV-2 variants with enhanced replicative fitness may be selected for in the presence of antiviral therapy as an indirect means to overcome this selective pressure.

Racial and ethnic minorities have been disproportionally burdened by hospitalization and death due to COVID-19. Participation of individuals of diverse races and ethnicities in clinical trials, according to study-level characteristics of randomized controlled trials (RCTs) that test effectiveness of COVID-19 drugs, could be insightful for future researchers. Our objective for this scoping review was to describe the frequency of race and ethnicity reported as demographic variables and specific reporting of race and ethnicity according to COVID-19 RCT characteristics. We conducted comprehensive searches in PubMed, ProQuest, World Health Organization Database, and Cochrane Central Register of Controlled Trials, and gray literature via preprint servers from January 1, 2020, to May 4, 2022. We included RCTs on emergency- or conditionally approved COVID-19 drug interventions (remdesivir, baricitinib, and molnupiravir) with or without comparators. Self-reported race as American Indian/Pacific Islander, Asian, Black/African American, or White, ethnicity as Hispanic/Latinx, study design characteristics, and participant-relevant data were collected. In total, 17 RCTs with 17 935 participants were included. Most (n = 13; 76%) reported at least 1 race and ethnicity and were US-based, industry-funded RCTs. Asian, Black, Latinx, and White participants were mostly enrolled in RCTs that studied remdesivir. Native American and Hawaiian participants were mostly assessed for progression to high-flow oxygen/noninvasive ventilation. Time to recovery was assessed predominantly in Black and White participants, whereas hospitalization or death was mostly assessed in Asian, Latinx, and multirace participants. Trialists should be aware of RCT-level factors and characteristics that may be associated with low participation of racial and ethnic minorities, which could inform evidence-based interventions to increase minority participation.

Reducing hospital readmission offer potential benefits for patients, providers, payers, and policymakers to improve quality of healthcare, reduce cost, and improve patient experience. We investigated effectiveness of remdesivir in reducing 30-day coronavirus disease 2019 (COVID-19)-related readmission during the Omicron era, including older adults and those with underlying immunocompromising conditions.

This retrospective study utilized the US PINC AI Healthcare Database to identify adult patients discharged alive from an index COVID-19 hospitalization between December 2021 and February 2024. Odds of 30-day COVID-19-related readmission to the same hospital were compared between patients who received remdesivir vs those who did not, after balancing characteristics of the two groups using inverse probability of treatment weighting (IPTW). Analyses were stratified by maximum supplemental oxygen requirement during index hospitalization.

Of 326 033 patients hospitalized for COVID-19 during study period, 210 586 patients met the eligibility criteria. Of these, 109 551 (52%) patients were treated with remdesivir. After IPTW, lower odds of 30-day COVID-19-related readmission were observed in patients who received remdesivir vs those who did not, in the overall population (3.3% vs 4.2%, respectively; odds ratio [95% confidence interval {CI}]: 0.78 [.75-.80]), elderly population (3.7% vs 4.7%, respectively; 0.78 [.75-.81]), and those with underlying immunocompromising conditions (5.3% vs 6.2%, respectively; 0.86 [.80-.92]). These results were consistent irrespective of supplemental oxygen requirements.

Treating patients hospitalized for COVID-19 with remdesivir was associated with a significantly lower likelihood of 30-day COVID-19-related readmission across all patients discharged alive from the initial COVID-19 hospitalization, including older adults and those with underlying immunocompromising conditions.

Low levels and function of natural killer (NK) cells are associated with increased coronavirus disease 2019 (COVID-19) severity. NK cell immunotherapy may improve immune function to reduce infection severity. We conducted a first-in-human, open-label, phase 1, dose-escalating (100 × 106, 300 × 106, or 900 × 106 cells) study of a single dose of DVX201, a cord-blood-derived allogeneic NK cell therapy, in hospitalized patients with COVID-19. Participants were followed for 28 days. The maximum allowed steroid dose for eligibility was up to 0.5 mg/kg prednisone (or equivalent) daily. We enrolled nine participants, 3 per dose level. Eight participants had ≥1 comorbidity associated with increased COVID-19 severity, three of whom had a hematologic malignancy. Infusions were well tolerated, with no treatment-related adverse events. There was no evidence of inflammatory complications related to infusions. Peripheral blood NK cells generally increased after infusion, peaking by day 7. The median time from infusion to discharge was 2 days (range: 1-13). Two patients (both with acute lymphoblastic leukemia) were readmitted with recurrent COVID-19. This trial demonstrates the safety of allogeneic NK cell immunotherapy as a potential antiviral. Larger controlled trials are needed to establish efficacy.

The coronavirus-induced disease 19 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections, has had a devastating impact on millions of lives globally, with severe mortality rates and catastrophic social implications. Developing tools for effective vaccine strategies and platforms is essential for controlling and preventing the recurrence of such pandemics. Moreover, molecular virology tools that facilitate the study of viral pathogens, impact of viral mutations, and interactions with various host proteins are essential. Viral replicon- and virus-like particle (VLP)-based systems are excellent examples of such tools. This review outlines the importance, advantages, and disadvantages of both the replicon- and VLP-based systems that have been developed for SARS-CoV-2 and have helped the scientific community in dimming the intensity of the COVID-19 pandemic.

A 69-year-old Japanese male with follicular lymphoma and renal pelvic carcinoma presented with fever and cough, testing positive for SARS-CoV-2 via PCR. Chest CT revealed ground-glass opacities. Initially, his symptoms improved with a 10-day course of remdesivir (RDV), but they recurred. On day 42, a second 10-day course of RDV combined with dexamethasone was initiated; however, symptoms persisted, and his SARS-CoV-2 PCR test remained positive on day 72. Subsequently, a successful treatment regimen of 10 days of RDV followed by five days of molnupiravir (MOL) was administered. This study represents the first reported case of persistent SARS-CoV-2 infection successfully treated with sequential therapy transitioning from RDV to MOL, without extending the treatment duration.

Few antiviral therapies have been studied in patients with coronavirus disease 2019 (COVID-19) and kidney impairment. Herein, the efficacy, safety, and pharmacokinetics of remdesivir, its metabolites, and sulfobutylether-β-cyclodextrin excipient were evaluated in hospitalized patients with COVID-19 and severe kidney impairment.

In REDPINE, a phase 3, randomized, double-blind, placebo-controlled study, participants aged ≥12 years hospitalized for COVID-19 pneumonia with acute kidney injury, chronic kidney disease, or kidney failure were randomized 2:1 to receive intravenous remdesivir (200 mg on day 1; 100 mg daily up to day 5) or placebo (enrollment from March 2021 to March 2022). The primary efficacy end point was the composite of the all-cause mortality rate or invasive mechanical ventilation rate through day 29. Safety was evaluated through day 60.

Although enrollment concluded early, 243 participants were enrolled and treated (remdesivir, n = 163; placebo, n = 80). At baseline, 90 participants (37.0%) had acute kidney injury (remdesivir, n = 60; placebo, n = 30), 64 (26.3%) had chronic kidney disease (remdesivir, n = 44; placebo, n = 20), and 89 (36.6%) had kidney failure (remdesivir, n = 59; placebo, n = 30); and 31 (12.8%) were vaccinated against COVID-19. Composite all-cause mortality or invasive mechanical ventilation rates through day 29 were 29.4% and 32.5% in the remdesivir and placebo group, respectively (P = .61). Treatment-emergent adverse events were reported in 80.4% for remdesivir versus 77.5% for placebo, and serious adverse events in 50.3% versus 50.0%, respectively. Pharmacokinetic plasma exposure to remdesivir was not affected by kidney function.

Although the study was underpowered, no significant difference in efficacy was observed between treatment groups. REDPINE demonstrated that remdesivir is safe in patients with COVID-19 and severe kidney impairment.

EudraCT 2020-005416-22; Clinical Trials.gov NCT04745351.

Remdesivir, an RNA-polymerase prodrug inhibitor approved for treatment of coronavirus disease 2019 (COVID-19), shortens recovery time and improves clinical outcomes. This prespecified analysis compared remdesivir plus standard of care (SOC) with SOC alone in adults hospitalized with COVID-19 requiring oxygen support in the early stage of the pandemic.

Data for 10-day remdesivir treatment plus SOC from the extension phase of an open-label study (NCT04292899) were compared with real-world, retrospective data on SOC alone (EUPAS34303). Both studies included patients aged ≥18 years hospitalized with severe acute respiratory syndrome coronavirus 2 up to 30 May 2020, with oxygen saturation ≤94% on room air or supplemental oxygen (all forms), and with pulmonary infiltrates. Propensity score weighting was used to balance patient demographics and clinical characteristics across treatment groups. The primary endpoint was time to all-cause mortality or end of study (day 28). Time to discharge, with a 10-day landmark to account for duration of remdesivir treatment, was a secondary endpoint.

A total of 1974 patients treated with remdesivir plus SOC, and 1426 with SOC alone, were included after weighting. Remdesivir significantly reduced mortality versus SOC (hazard ratio [HR], 0.46; 95% confidence interval, .39-.54). This association was observed at each oxygen support level, with the lowest HR for patients on low-flow oxygen. Remdesivir significantly increased the likelihood of discharge at day 28 versus SOC in the 10-day landmark analysis (HR, 1.64; 95% confidence interval: 1.43-1.87).

Remdesivir plus early-2020 SOC was associated with a 54% lower mortality risk and shorter hospital stays compared with SOC alone in patients hospitalized with COVID-19 requiring oxygen support. Clinical Trials Registration.  ClinicalTrials.gov NCT04292899 and EUPAS34303.

Early in the course of the SARS-CoV-2 pandemic it was hypothesised that host genetics played a role in the pathophysiology of COVID-19 including a suggestion that the CCR5-Δ32 mutation may be protective in SARS-CoV-2 infection. Leronlimab is an investigational CCR5-specific humanized IgG4 monoclonal antibody currently in development for HIV-1 infection. We aimed to explore the impact of leronlimab on the severity of disease symptoms among participants with mild-to-moderate COVID-19.

The TEMPEST trial was a randomized, double-blind, placebo-controlled study in participants with mild-to-moderate COVID-19. Participants were randomly assigned in a 2:1 ratio to receive subcutaneous leronlimab (700 mg) or placebo on days 0 and 7. The primary efficacy endpoint was assessed by change in total symptom score based on fever, myalgia, dyspnea, and cough, at end of treatment (day 14).

Overall, 84 participants were randomized and treated with leronlimab (n = 56) or placebo (n = 28). No difference was observed in change in total symptom score (P = 0.8184) or other pre-specified secondary endpoints between treatments. However, in a post hoc analysis, 50.0% of participants treated with leronlimab demonstrated improvements from baseline in National Early Warning Score 2 (NEWS2) at day 14, compared with 20·8% of participants in the placebo group (post hoc; p = 0.0223). Among participants in this trial with mild-to-moderate COVID-19 adverse events rates were numerically but not statistically significantly lower in leronlimab participants (33.9%) compared with placebo participants (50.0%).

At the time the TEMPEST trial was designed although CCR5 was known to be implicated in COVID-19 disease severity the exact pathophysiology of SARS-CoV-2 infection was poorly understood. Today it is well accepted that SARS-CoV-2 infection in asymptomatic-to-mild cases is primarily characterized by viral replication, with a heightened immune response, accompanied by diminished viral replication in moderate-to-severe disease and a peak in inflammatory responses with excessive production of pro-inflammatory cytokines in critical disease. It is therefore perhaps not surprising that no differences between treatments were observed in the primary endpoint or in pre-specified secondary endpoints among participants with mild-to-moderate COVID-19. However, the results of the exploratory post hoc analysis showing that participants in the leronlimab group had greater improvement in NEWS2 assessment compared to placebo provided a suggestion that leronlimab may be associated with a lower likelihood of people with mild-to-moderate COVID-19 progressing to more severe disease and needs to be confirmed in other appropriately designed clinical trials.

gov number, NCT04343651 https://classic.

gov/ct2/show/NCT04343651.

Evidence on the effectiveness of remdesivir when used in real-life clinical practice is controversial. This study aims to analyse its effectiveness and the factors associated with increased mortality in non-critically ill patients with COVID-19 pneumonia who require supplemental low-flow oxygen and received remdesivir.

A retrospective cohort study was conducted at Ramón y Cajal University Hospital (Madrid, Spain) which included all patients treated with remdesivir in our institution during the second pandemic breakout in Spain, from August to November 2020. Treatment with remdesivir was limited to non-critically ill patients with COVID-19 pneumonia requiring low-flow supplemental oxygen, with a treatment duration of 5 days.

A total of 1757 patients were admitted with COVID-19 pneumonia during the study period, of which 281 non-critically ill patients were treated with remdesivir and included in the analysis. Mortality at 28 days after initiation of treatment was 17.1%. The median (IQR) time to recovery was 9 days (6-15). 104 (37.0%) patients had complications during hospitalisation, with renal failure being the most frequent (31 patients; 36.5%). After adjustment for confounding factors, high-flow oxygen therapy was associated with increased 28-day mortality (HR 2.77; 95% CI 1.39 to 5.53; p=0.004) and decreased 28-day clinical improvement (HR 0.54; 95% CI 0.35 to 0.85; p=0.008). A significant difference in survival and clinical improvement was identified between patients treated with high and low-flow oxygen.

The 28-day mortality rate in patients treated with remdesivir needing low-flow oxygen therapy was higher than that published in clinical trials. Age and increased oxygen therapy needed after the beginning of treatment were the main risk factors associated with mortality.

In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in adults with pneumonia in Wuhan, China.

It is now believed that several billion humans have been infected with SARS-CoV-2 and more than ten million have died from coronavirus disease 2019 (COVID-19), the disease caused by SARS-CoV-2.

The first five years of the SARS-CoV-2 pandemic have been marked by unfathomable suffering as well as remarkable scientific progress. This manuscript examines what has been learned about the treatment of inpatients with COVID-19 and explores how the therapeutic approach may evolve in the years ahead.

The extent of the SARS-CoV-2 short-term evolution under Remdesivir (RDV) exposure and whether it varies across different upper respiratory compartments are not fully understood.

Patients hospitalized for COVID-19, with or without RDV therapy, were enrolled and completed up to three visits, in which they provided specimens from four respiratory compartments. Near full-length genome SARS-CoV-2 sequences were obtained from viral RNA, standard lineage and variant assignments were performed, and viral mutations in the RNA-dependent RNA polymerase (RdRp) region-the RDV target gene-were detected and compared between participants with and without RDV, across the four compartments, within participants across visits, and versus a larger sequence dataset. The statistical analysis used a generalized linear mixed-effects model.

A total of 139 sequences were obtained from 37 out of the 44 (84%) enrolled participants. The genotyping success varied across respiratory compartments, which ranged from 42% with oropharyngeal specimens to 67% with nasopharyngeal specimens and showed improvement with higher viral loads. No RdRp mutations known to be associated with RDV resistance were identified, and for 34 detected mutations at 32 amino acid positions that are not known as RDV-associated, there was no evidence of any associations with the RDV exposure, respiratory compartment, or time. At least 1 of these 34 mutations were detected in all participants, and some differed from the larger sequence dataset.

This study highlighted the SARS-CoV-2 short-term genomic stability within hosts and across upper respiratory compartments, which suggests a lack of evolution of RDV resistance over time. This contributes to our understanding of SARS-CoV-2 genomic dynamics.

CT-scan and inflammatory and coagulation biomarkers could help in prognostication of COVID-19 in patients on ICU admission.

The objectives of this study were to measure the prognostic value of the extent of lung parenchymal lesions on computed tomography (CT) and of several coagulation and inflammatory biomarkers, and to explore the characteristics of the patients depending on the extent of lung parenchymal lesions.

Retrospective monocentric observational study achieved on a dataset collected prospectively.

Medical ICU of the university hospital of Clermont-Ferrand, France.

All consecutive adult patients aged ≥18 years admitted between 20 March, 2020 and 31 August, 2021 for COVID-19 pneumonia.

Characteristics at baseline and during ICU stay, and outcomes at day 60 were recorded. The extent of lung parenchyma lesions observed on the chest CT performed on admission was established by artificial intelligence software.

Several clinical characteristics and laboratory features were collected on admission including plasma interleukin-6, HLA-DR monocytic-expression rate (mHLA-DR), and the extent of lung parenchymal lesions. Factors associated with day-60 mortality were investigated by uni- and multivariate survival analyses.

270 patients were included. Inflammation biomarkers including the levels of neutrophils, CRP, ferritin and Il10 were the indices the most associated with the severity of the extent of the lung lesions. Patients with more extensive lung parenchymal lesions (≥ 75%) on admission had higher CRP serum levels. The extent of lung parenchymal lesions was associated with a decrease in the PaO2/FiO2 ratio(p<0.01), fewer ventilatory-free days (p = 0.03), and a higher death rate at day 60(p = 0.01). Extent of the lesion of more than 75% was independently associated with day-60 mortality (aHR = 1.72[1.06; 2.78], p = 0.03). The prediction of death at day 60 was improved when considering simultaneously biological and radiological markers obtained on ICU admission (AUC = 0.78).

The extent of lung parenchyma lesions on CT was associated with inflammation, and the combination of coagulation and inflammatory biomarkers and the extent of the lesions predicted the poorest outcomes.

Transaminase and creatinine elevations have been well described in adults treated with remdesivir for COVID-19. It is hypothesized that a similar safety profile exists in children with COVID-19 treated with remdesivir, but available data are limited, especially in children < 12 months. The primary aim of this study was to determine the prevalence and timing of elevations in transaminases and creatinine in children with COVID-19 who were treated with remdesivir.

This was a retrospective, observational cohort study including all pediatric patients admitted to a single, freestanding children's hospital who were positive for COVID-19 and received at least 1 dose of remdesivir between 1/1/2020 and 5/31/2022. Available baseline and peak transaminase and creatinine concentrations were evaluated. Multivariable logistic regression analysis was performed to identify risk factors for transaminase elevation.

A total of 180 patients met inclusion criteria. Creatinine elevation of any grade was noted in 16% and remained elevated only in those with underlying chronic kidney disease. Transaminase elevation of any grade was noted in 58% of patients and remained elevated in only 1%. Older age and critical respiratory disease were associated with higher risk of significant transaminase elevation, whereas non-Hispanic ethnicity was strongly associated with protection against significant transaminase elevation.

In our cohort of hospitalized children with COVID-19 who were treated with remdesivir, most patients experienced only mild transaminitis and normal creatinine concentrations. A limited number of patients experienced laboratory abnormalities which were transient, suggesting a favorable safety profile for remdesivir use in pediatrics.

Acute kidney injury (AKI) is common after coronavirus 2 infection (COVID-19), leading to higher morbidity and mortality. There is little prospective data from India regarding the incidence, risk factors, and outcome of AKI in COVID-19.

This study was conducted prospectively in adult patients between September and December 2020 in a tertiary care hospital in the national capital region of Delhi. A total of 856 patients with COVID-19 infection were enrolled in the study. Survivors were followed for 3 months after discharge.

Out of 856 patients, 207 (24%) developed AKI. AKI was significantly higher in those with severe disease as compared to mild-moderate disease (88% vs. 12%, P = 0.04). Out of all AKI, 3.4% had stage 1, 9.2% had stage 2, and the rest 87.4% had stage 3 AKI. 183/207 (88%) patients were on mechanical ventilators, 133 (64%) required inotropic support, and 137/207 (83.6%) patients required kidney replacement therapy. Out of 207 AKI patients, 74% (153) died as compared to 4% (27) in non-AKI group (P = 0.0001). After 3 months, chronic kidney disease (CKD) developed in 10/54 (18.5%) patients. On multivariable analysis, the presence of diabetes mellitus, severe COVID-19 disease, high levels of C reactive protein, lactate dehydrogenase, D-Dimer, and use of intravenous steroids, tocilizumab and remdesivir, were found to be significant predictors of AKI.

AKI is common after COVID-19 infection and it is a significant risk factor for mortality in COVID-19. Patients with diabetes and high levels of inflammatory markers have higher mortality. CKD may develop in many patients after discharge.

We aimed to evaluate the cardiac adverse events (AEs) in hospitalized patients with coronavirus disease 2019 (COVID-19) who received remdesivir plus standard of care (SoC) compared with SoC alone (control), as an association was noted in some cohort studies and disproportionality analyses of safety databases.

This post hoc safety analysis is based on data from the multicenter, randomized, open-label, controlled DisCoVeRy trial in hospitalized patients with COVID-19. Any first AE that occurred between randomization and day 29 in the modified intention-to-treat (mITT) population randomized to either remdesivir or control group was considered. Analysis was performed using Kaplan-Meier survival curves, and Kaplan-Meier estimates were calculated for event rates.

Cardiac AEs were reported in 46 (11.2%) of 410 and 48 (11.3%) of 423 patients in the mITT population (n = 833) enrolled in the remdesivir and control groups, respectively. The difference between both groups was not significant (hazard ratio [HR], 1.0; 95% confidence interval [CI], .7-1.5; P = .98), even when serious and nonserious cardiac AEs were evaluated separately. The majority of reports in both groups were of arrhythmic nature (remdesivir, 84.8%; control, 83.3%) and were associated with a favorable outcome. There was no significant difference between the two groups in the occurrence of cardiac AE subclasses, including arrhythmic events (HR, 1.1; 95% CI, .7-1.7; P = .68).

Remdesivir treatment was not associated with an increased risk of cardiac AEs compared with control in patients hospitalized with moderate or severe COVID-19. These results are consistent with other randomized, controlled trials and meta-analyses. Clinical Trials Registration. NCT04315948; EudraCT 2020-000936-23.

Efficacy of remdesivir for COVID-19 remains unclear. We updated our published systematic review to better inform on the use of remdesivir for COVID-19.

We searched for randomized controlled trials (RCTs) among hospitalized COVID-19 patients. Meta-analysis was conducted using an inverse variance, random-effects model, presenting relative risk (RR) or mean difference (MD) and their associated 95% confidence intervals (CIs). Statistical heterogeneity was calculated using the I2 statistic. In addition, we conducted trial sequential analysis (TSA). Outcomes with additional data were clinical progression, hospitalization days, and all-cause mortality.

We included nine RCTs (12,876 individuals). Three trials each were of a low, unclear, and a high risk of bias. Compared with no treatment/placebo, remdesivir (100 mg daily, over 10 days) significantly improved clinical progression (RR 1.06, CI 1.02-1.11), but did not significantly reduce hospitalization days (MD -0.48, CI -2.18-1.21) and all-cause mortality (RR 0.92, CI 0.84-1.01). TSA suggested that further information is not required to conclude on the efficacy of remdesivir in improving clinical progression, and that, while more information is required for hospitalization days and all-cause mortality, further RCTs to prove fewer hospitalization days may be futile, as efficacy of remdesivir for this outcome is unlikely.

Remdesivir appeared promising for COVID-19, but there is insufficient evidence of its efficacy. High quality RCTs are needed for a stronger evidence base.

To illustrate the challenges encountered when gathering rapidly synthesized evidence in response to the coronavirus disease 2019 (COVID-19) pandemic.

In this article, we describe the challenges encountered when we performed a systematic literature review (SLR) of randomized controlled trials (RCTs) on the efficacy and safety of treatments for severe COVID-19. The methods of the SLR are described in full, to show the context of our objectives. Then we use the results of the SLR to demonstrate the problems of producing synthesized evidence in this setting.

Various challenges were identified during this SLR. These were primarily a result of heterogeneity in the study methodology of eligible studies. Definitions of the patient populations and outcome measurements were highly variable and the majority of studies demonstrated a high risk of bias, preventing quantitative synthesis of the collated evidence.

Consolidating evidence from RCTs evaluating COVID-19 interventions was problematic. Guidance is needed for scenarios with high rapid output in primary research.

We aimed to validate and, if performance was unsatisfactory, update the previously published prognostic model to predict clinical deterioration in patients hospitalized for COVID-19, using data following vaccine availability.

Using electronic health records of patients ≥18 years, with laboratory-confirmed COVID-19, from a large care-delivery network in Massachusetts, USA, from March 2020 to November 2021, we tested the performance of the previously developed prediction model and updated the prediction model by incorporating data after availability of COVID-19 vaccines. We randomly divided data into development (70%) and validation (30%) cohorts. We built a model predicting worsening in a published severity scale in 24 h by LASSO regression and evaluated performance by c-statistic and Brier score.

Our study cohort consisted of 8185 patients (Development: 5730 patients [mean age: 62; 44% female] and Validation: 2455 patients [mean age: 62; 45% female]). The previously published model had suboptimal performance using data after November 2020 (N = 4973, c-statistic = 0.60. Brier score = 0.11). After retraining with the new data, the updated model included 38 predictors including 18 changing biomarkers. Patients hospitalized after Jun 1st, 2021 (when COVID-19 vaccines became widely available in Massachusetts) were younger and had fewer comorbidities than those hospitalized before. The c-statistic and Brier score were 0.77 and 0.13 in the development cohort, and 0.73 and 0.14 in the validation cohort.

The characteristics of patients hospitalized for COVID-19 differed substantially over time. We developed a new dynamic model for rapid progression with satisfactory performance in the validation set.

The number of severe cases of coronavirus disease 2019 (COVID-19) has been decreasing since the emergence of the Omicron variant at the end of 2021. COVID-19 has become a common infectious disease in Japan and was downgraded to a category five infectious disease on May 8, 2023. This study aimed to compare the impact of diabetes mellitus on in-hospital mortality in COVID-19 patients since COVID-19 became a common infectious disease.

We conducted a retrospective observational study using data from an advanced critical care center in Osaka, Japan. The study included 1,381 patients of COVID-19 admitted to the center between March 1, 2020, and May 7, 2023, before COVID-19 became a category five infectious disease in Japan. Individuals younger than 18 years and pregnant women were excluded. We divided the patients into two groups: pre- and post-Omicron epidemic groups. The primary endpoint of the study was the in-hospital mortality, and the prognostic impact of diabetes mellitus was compared between the groups.

The Kaplan-Meier curve showed a significantly lower rate of in-hospital mortality in the post-Omicron epidemic group than in the pre-Omicron epidemic group. The hazard ratio (HR) was 1.83 (95% CI, 1.36-2.50; p < 0.0001). Patients with diabetes mellitus had higher in-hospital mortality in both the pre- and post-Omicron epidemic groups; their HRs were 1.39 (95% CI, 1.21-1.59; p < 0.0001) and 1.45 (95% CI, 1.15-1.83; p = 0.0012), respectively. Diabetes mellitus had no significant interaction effect on the association between the post-Omicron epidemic and in-hospital mortality (p for interaction = 0.2154).

Diabetes mellitus may continue contributing to COVID-19 in-hospital mortality in the future, as the Omicron sub-strain may still be prevalent.

Camostat mesylate, an oral serine protease inhibitor, is a powerful TMPRSS2 inhibitor and has been reported as a possible antiviral treatment against COVID-19. Therefore, we aim to assess the safety and efficacy of camostat mesylate for COVID-19 treatment.

A systematic review and meta-analysis synthesizing randomized controlled trials from PubMed, Scopus, Embase, Cochrane, Web of Science, clinical trials.gov, and medrxiv until June 2023. The outcomes were pooled using Mean difference (MD) for continuous outcomes and risk ratio (RR) for dichotomous outcomes. The protocol is registered in PROSPERO with ID CRD42023439633.

Nine RCTs, including 1,623 patients, were included in this analysis. There was no difference between camostat mesylate and placebo in producing negative PCR test results at 1-7 days (RR: 0.76, 95% CI: [0.54, 1.06] P = 0.1), 8-14 days (RR: 1.02, 95% CI: [0.84, 1.23] P = 0.87), or 15-21 days (RR: 0.99, 95% CI: [0.82, 1.19] P = 0.90); clinical resolution of symptoms at 1-7 days (RR: 0.94 (95% CI: 0.58, 1.53) P = 0.81), 8-14 days (RR: 0.91, 95% CI: [0.74, 1.11] P = 0.33, ), or 15-21 days (RR: 0.77, 95% CI: [0.40, 1.51] P = 0.45); and time to symptom improvement (MD:-0.38 weeks (95% CI: [-1.42, 0.66] P = 0.47, I2 = 85%).

Camostat mesylate did not improve clinical outcomes in patients with COVID-19, compared to placebo.

COVID-19 has affected millions worldwide, causing significant morbidity and mortality. While predominantly involving the respiratory tract, SARS-CoV-2 has also caused systemic illnesses involving other sites. Liver injury due to COVID-19 has been variably reported in observational studies. It has been postulated that liver damage may be due to direct damage by the SARS-CoV-2 virus or multifactorial secondary to hepatotoxic therapeutic options, as well as cytokine release syndrome and sepsis-induced multiorgan dysfunction. The approach to a COVID-19 patient with liver injury requires a thorough evaluation of the pattern of hepatocellular injury, along with the presence of underlying chronic liver disease and concurrent medications which may cause drug-induced liver injury. While studies have shown uneventful recovery in the majority of mildly affected patients, severe COVID-19 associated liver injury has been associated with higher mortality, prolonged hospitalization, and greater morbidity in survivors. Furthermore, its impact on long-term outcomes remains to be ascertained as recent studies report an association with metabolic-fatty liver disease. This present review provides insight into the subject by describing the postulated mechanism of liver injury, its impact in the presence of pre-existing liver disease, and its short- and long-term clinical implications.

The use of remdesivir in patients with coronavirus disease 2019 (COVID-19) and severe renal impairment has been approved; however, limited clinical data exist. Accordingly, we aimed to compare outcomes and adverse events associated with remdesivir in hospitalized patients with COVID-19, with and without severe renal impairment.

Hospitalized patients with COVID-19 undergoing a 5-day remdesivir course at Taipei Veterans General Hospital from April 1 to July 31, 2022, were enrolled. Comparative analysis of outcomes and safety between patients with or without severe renal impairment (estimated glomerular filtration rate of < 30 mL/min per 1.73 m2) were conducted. Prognostic factors associated with 28-day mortality in patients with severe renal impairment were investigated using logistic regression analysis.

A total of 671 hospitalized patients, including 132 patients with severe renal impairment, who received a 5-day course of remdesivir were analyzed. The 28-day mortality was higher in patients with severe renal impairment than in patients without severe renal impairment (15.2% vs. 7.8%). The proportion of patients with acute kidney injury (AKI) and deteriorated liver function after completing remdesivir therapy was similar between the patients with and without severe renal impairment, and the recovery rate of AKI was similar in both groups. The sequential organ failure assessment score was an independent factor associated with 28-day mortality in patients with severe renal impairment.

Remdesivir was well-tolerated in hospitalized patients with COVID-19, regardless of renal function. Our findings support the recent recommendation to administer remdesivir in patients with severe renal impairment.