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1.
Lancet ; 399(10339): 1941-1953, 2022 05 21.
Article in English | MEDLINE | ID: covidwho-2159958

ABSTRACT

BACKGROUND: The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-ß1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date. METHODS: Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-ß1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol-specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948. FINDINGS: Between March 22, 2020, and Jan 29, 2021, 14 304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14 221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82-1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89-1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76-0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46-1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76-0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77-1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75-0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings. INTERPRETATION: Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both). FUNDING: WHO.


Subject(s)
Antiviral Agents , COVID-19 , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adult , Alanine/analogs & derivatives , Alanine/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Hydroxychloroquine/therapeutic use , Interferon beta-1a/therapeutic use , Lopinavir/therapeutic use , Oxygen/administration & dosage , Randomized Controlled Trials as Topic , Treatment Outcome , World Health Organization
2.
Infect Dis Clin North Am ; 36(1): 1-14, 2022 03.
Article in English | MEDLINE | ID: covidwho-2130977

ABSTRACT

Although COVID-19 has impacted many children, severe disease is rare and most recover with supportive care. Manifestations are diverse and often nonrespiratory. Adolescents/children with medical comorbidities are at risk for severe respiratory compromise. The most serious manifestation in previously healthy children is a delayed multisystem inflammatory syndrome with cardiac compromise in severe cases. Anti-SARS-CoV-2 monoclonal antibodies are available for adolescents at risk of progression and not hospitalized. Therapeutic options for severe respiratory disease with hypoxia include remdesivir and glucocorticoids. Therapies for multisystem inflammatory syndrome in children include intravenous immunoglobulin and glucocorticoids. Refractory cases may benefit from additional immunomodulators.


Subject(s)
COVID-19 , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adolescent , Alanine/analogs & derivatives , Alanine/therapeutic use , COVID-19/complications , COVID-19/epidemiology , COVID-19/therapy , Child , Glucocorticoids/therapeutic use , Hospitalization , Humans , Immunoglobulins, Intravenous/therapeutic use , Systemic Inflammatory Response Syndrome
3.
PLoS One ; 17(11): e0276751, 2022.
Article in English | MEDLINE | ID: covidwho-2116658

ABSTRACT

Despite new antivirals are being approved against SARS-CoV-2 they suffer from significant constraints and are not indicated for hospitalized patients, who are left with few antiviral options. Repurposed drugs have previously shown controversial clinical results and it remains difficult to understand why certain trials delivered positive results and other trials failed. Our manuscript contributes to explaining the puzzle: this might have been caused by a suboptimal drug exposure and, consequently, an incomplete virus suppression, also because the drugs have mostly been used as add-on monotherapies. As with other viruses (e.g., HIV and HCV) identifying synergistic combinations among such drugs could overcome monotherapy-related limitations. In a cell culture model for SARS-CoV-2 infection the following stringent criteria were adopted to assess drug combinations: 1) identify robust, synergistic antiviral activity with no increase in cytotoxicity, 2) identify the lowest drug concentration inhibiting the virus by 100% (LIC100) and 3) understand whether the LIC100 could be reached in the lung at clinically indicated drug doses. Among several combinations tested, remdesivir with either azithromycin or ivermectin synergistically increased the antiviral activity with no increase in cytotoxicity, improving the therapeutic index and lowering the LIC100 of every one of the drugs to levels that are expected to be achievable and maintained in the lung for a therapeutically relevant period of time. These results are consistent with recent clinical observations showing that intensive care unit admission was significantly delayed by the combination of AZI and RDV, but not by RDV alone, and could have immediate implications for the treatment of hospitalized patients with COVID-19 as the proposed "drug cocktails" should have antiviral activity against present and future SARS-CoV-2 variants without significant overlapping toxicity, while minimizing the onset of drug resistance. Our results also provide a validated methodology to help sort out which combination of drugs are most likely to be efficacious in vivo, based on their in vitro activity, potential synergy and PK profiles.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/drug therapy , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/pharmacology , Alanine/therapeutic use , Lung , Drug Combinations
7.
PLoS Comput Biol ; 18(8): e1010443, 2022 08.
Article in English | MEDLINE | ID: covidwho-2021468

ABSTRACT

In this paper, a logical-based mathematical model of the cellular pathways involved in the COVID-19 infection has been developed to study various drug treatments (single or in combination), in different illness scenarios, providing insights into their mechanisms of action. Drug simulations suggest that the effects of single drugs are limited, or depending on the scenario counterproductive, whereas better results appear combining different treatments. Specifically, the combination of the anti-inflammatory Baricitinib and the anti-viral Remdesivir showed significant benefits while a stronger efficacy emerged from the triple combination of Baricitinib, Remdesivir, and the corticosteroid Dexamethasone. Together with a sensitivity analysis, we performed an analysis of the mechanisms of the drugs to reveal their impact on molecular pathways.


Subject(s)
COVID-19 , Adenosine Monophosphate/therapeutic use , Alanine/pharmacology , Alanine/therapeutic use , Anti-Inflammatory Agents , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , SARS-CoV-2
10.
J Formos Med Assoc ; 120 Suppl 1: S77-S85, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1972179

ABSTRACT

BACKGROUND/PURPOSE: A synthesis design and multistate analysis is required for assessing the clinical efficacy of antiviral therapy on dynamics of multistate disease progression and in reducing the mortality and enhancing the recovery of patients with COVID-19. A case study on remdesivir was illustrated for the clinical application of such a novel design and analysis. METHODS: A Bayesian synthesis design was applied to integrating the empirical evidence on the one-arm compassion study and the two-arm ACTT-1 trial for COVID-19 patients treated with remdesivir. A multistate model was developed to model the dynamics of hospitalized COVID-19 patients from three transient states of low, medium-, and high-risk until the two outcomes of recovery and death. The outcome measures for clinical efficacy comprised high-risk state, death, and discharge. RESULTS: The efficacy of remdesivir in reducing the risk of death and enhancing the odds of recovery were estimated as 31% (95% CI, 18-44%) and 10% (95% CI, 1-18%), respectively. Remdesivir therapy for patients with low-risk state showed the efficacy in reducing subsequent progression to high-risk state and death by 26% (relative rate (RR), 0.74; 95% CI, 0.55-0.93) and 62% (RR, 0.38; 95% CI, 0.29-0.48), respectively. Less but still statistically significant efficacy in mortality reduction was noted for the medium- and high-risk patients. Remdesivir treated patients had a significantly shorter period of hospitalization (9.9 days) compared with standard care group (12.9 days). CONCLUSION: The clinical efficacy of remdesvir therapy in reducing mortality and accelerating discharge has been proved by the Bayesian synthesis design and multistate analysis.


Subject(s)
Adenosine Monophosphate/therapeutic use , Alanine/therapeutic use , Antiviral Agents , COVID-19 , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Bayes Theorem , COVID-19/drug therapy , Humans , SARS-CoV-2 , Treatment Outcome
12.
Eur J Intern Med ; 102: 17-23, 2022 08.
Article in English | MEDLINE | ID: covidwho-1944876

ABSTRACT

The clinical progression of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to critical illness is associated with a systemic and uncontrolled inflammatory response of the innate and adaptive immunity with the release of a plethora of proinflammatory cytokines termed "cytokine storm". In the absence of an effective treatment, many off-label agents from the armamentarium of rheumatology are used. Here, from the perspective of a rheumatologist, we will discuss the current therapeutic strategies in critically ill patients with SARS-CoV-2 pneumonia. Thus, we will discuss the agents that aim to target viral entry and its replication into the host cell and those focusing and targeting the inflammatory response. In this setting, many agents have been used with promising results but, not all have been approved by the International Authorities and Institutions. In the first step (viral entry), SARS-CoV-2 monoclonal antibodies and remdesivir have been approved to be used and, in the second step, corticosteroids along with interleukin-6 inhibitors, or Janus Kinase inhibitors are currently used.


Subject(s)
COVID-19 , Rheumatology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adrenal Cortex Hormones/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Antibodies, Monoclonal/therapeutic use , COVID-19/drug therapy , Critical Illness , Cytokine Release Syndrome , Cytokines , Humans , SARS-CoV-2
13.
Sci Rep ; 12(1): 9622, 2022 06 10.
Article in English | MEDLINE | ID: covidwho-1947488

ABSTRACT

This network meta-analysis (NMA) assessed the efficacy of remdesivir in hospitalized patients with COVID-19 requiring supplemental oxygen. Randomized controlled trials of hospitalized patients with COVID-19, where patients were receiving supplemental oxygen at baseline and at least one arm received treatment with remdesivir, were identified. Outcomes included mortality, recovery, and no longer requiring supplemental oxygen. NMAs were performed for low-flow oxygen (LFO2); high-flow oxygen (HFO2), including NIV (non-invasive ventilation); or oxygen at any flow (AnyO2) at early (day 14/15) and late (day 28/29) time points. Six studies were included (N = 5245 patients) in the NMA. Remdesivir lowered early and late mortality among AnyO2 patients (risk ratio (RR) 0.52, 95% credible interval (CrI) 0.34-0.79; RR 0.81, 95%CrI 0.69-0.95) and LFO2 patients (RR 0.21, 95%CrI 0.09-0.46; RR 0.24, 95%CrI 0.11-0.48); no improvement was observed among HFO2 patients. Improved early and late recovery was observed among LFO2 patients (RR 1.22, 95%CrI 1.09-1.38; RR 1.17, 95%CrI 1.09-1.28). Remdesivir also lowered the requirement for oxygen support among all patient subgroups. Among hospitalized patients with COVID-19 requiring supplemental oxygen at baseline, use of remdesivir compared to best supportive care is likely to improve the risk of mortality, recovery and need for oxygen support in AnyO2 and LFO2 patients.


Subject(s)
COVID-19 , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , COVID-19/drug therapy , Humans , Oxygen/therapeutic use , Randomized Controlled Trials as Topic , Treatment Outcome
15.
Antimicrob Agents Chemother ; 66(6): e0025422, 2022 06 21.
Article in English | MEDLINE | ID: covidwho-1874495

ABSTRACT

The objective of this study was to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalized coronavirus disease 2019 (COVID-19) patients. A prospective observational pharmacokinetic study was performed in non-critically ill hospitalized COVID-19 patients with hypoxemia. For evaluation of the plasma concentrations of remdesivir and its metabolite GS-441524, samples were collected on the first day of therapy. A nonlinear mixed-effects model was developed to describe the pharmacokinetics and identify potential covariates that explain variability. Alternative dosing regimens were evaluated using Monte Carlo simulations. Seventeen patients were included. Remdesivir and GS-441524 pharmacokinetics were best described by a one-compartment model. The estimated glomerular filtration rate (eGFR) on GS-441524 clearance was identified as a clinically relevant covariate. The interindividual variability in clearance and volume of distribution for both remdesivir and GS-441524 was high (remdesivir, 38.9% and 47.9%, respectively; GS-441525, 47.4% and 42.9%, respectively). The estimated elimination half-life for remdesivir was 0.48 h, and that for GS-441524 was 26.6 h. The probability of target attainment (PTA) of the in vitro 50% effective concentration (EC50) for GS-441524 in plasma can be improved by shortening the dose interval of remdesivir and thereby increasing the total daily dose (PTA, 51.4% versus 94.7%). In patients with reduced renal function, the metabolite GS-441524 accumulates. A population pharmacokinetic model for remdesivir and GS-441524 in COVID-19 patients was developed. Remdesivir showed highly variable pharmacokinetics. The elimination half-life of remdesivir in COVID-19 patients is short, and the clearance of GS-441524 is dependent on the eGFR. Alternative dosing regimens aimed at optimizing the remdesivir and GS-441524 concentrations may improve the effectiveness of remdesivir treatment in COVID-19 patients.


Subject(s)
COVID-19 , Adenosine/analogs & derivatives , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Anti-Bacterial Agents/pharmacokinetics , COVID-19/drug therapy , Critical Illness/therapy , Furans , Humans , Monte Carlo Method , Triazines
16.
J Hematol Oncol ; 14(1): 163, 2021 10 11.
Article in English | MEDLINE | ID: covidwho-1869090

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently constitutes the leading and overwhelming health issue worldwide. In comparison with adults, children present milder symptoms, with most having an asymptomatic course. We hypothesized that COVID-19 infection has a negative impact on the continuation of chemotherapy and increases nonrelapse mortality. MATERIAL AND METHODS: This study was performed to assess the course of SARS-CoV-2 among children with hematological or oncological malignancies and its impact on cancer therapy. Records of SARS-CoV-2 infection in 155 children with malignancies from 14 Polish centers for pediatric hematology and oncology were collected and analyzed. RESULTS: SARS-CoV-2 replication was observed in 155 patients. Forty-nine patients were symptomatic, with the following being the most common manifestations: fever (31 patients), gastrointestinal symptoms (10), coryza (13), cough (13) and headache (8). In children who were retested, the median time of a positive PCR result was 16 days (range 1-70 days), but 12.7% of patients were positive beyond day + 20. The length of viral PCR positivity correlated with the absolute neutrophil count at diagnosis. Seventy-six patients did not undergo further SARS-CoV-2 testing and were considered convalescents after completion of isolation. Antibiotic therapy was administered in 15 children, remdesivir in 6, convalescent plasma in 4, oxygen therapy in 3 (1-mechanical ventilation), steroids in 2, intravenous immunoglobulins in 2, and heparin in 4. Eighty patients were treated with chemotherapy within 30 days after SARS-CoV-2 infection diagnosis or were diagnosed with SARS-CoV-2 infection during 30 days of chemotherapy administration. Respiratory symptoms associated with COVID-19 and associated with oxygen therapy were present in 4 patients in the study population, and four deaths were recorded (2 due to COVID-19 and 2 due to progressive malignancy). The probability of 100-day overall survival was 97.3% (95% CI 92.9-99%). Delay in the next chemotherapy cycle occurred in 91 of 156 cases, with a median of 14 days (range 2-105 days). CONCLUSIONS: For the majority of pediatric cancer patients, SARS-CoV-2 infection does not result in a severe, life-threatening course. Our data show that interruptions in therapy are common and can result in suboptimal therapy.


Subject(s)
COVID-19/complications , COVID-19/therapy , Hematologic Neoplasms/complications , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adolescent , Alanine/analogs & derivatives , Alanine/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/diagnosis , COVID-19/epidemiology , Child , Child, Preschool , Disease Management , Female , Hematologic Neoplasms/drug therapy , Humans , Immunization, Passive , Infant , Male , Poland/epidemiology , SARS-CoV-2/isolation & purification
19.
Arch Toxicol ; 96(8): 2341-2360, 2022 08.
Article in English | MEDLINE | ID: covidwho-1844345

ABSTRACT

Remdesivir is a prodrug of a nucleoside analog and the first antiviral therapeutic approved for coronavirus disease. Recent cardiac safety concerns and reports on remdesivir-related acute kidney injury call for a better characterization of remdesivir toxicity and understanding of the underlying mechanisms. Here, we performed an in vitro toxicity assessment of remdesivir around clinically relevant concentrations (Cmax 9 µM) using H9c2 rat cardiomyoblasts, neonatal mouse cardiomyocytes (NMCM), rat NRK-52E and human RPTEC/TERT1 cells as cell models for the assessment of cardiotoxicity or nephrotoxicity, respectively. Due to the known potential of nucleoside analogs for the induction of mitochondrial toxicity, we assessed mitochondrial function in response to remdesivir treatment, early proteomic changes in NMCM and RPTEC/TERT1 cells and the contractile function of NMCM. Short-term treatments (24 h) of H9c2 and NRK-52E cells with remdesivir adversely affected cell viability by inhibition of proliferation as determined by significantly decreased 3H-thymidine uptake. Mitochondrial toxicity of remdesivir (1.6-3.1 µM) in cardiac cells was evident by a significant decrease in oxygen consumption, a collapse of mitochondrial membrane potential and an increase in lactate secretion after a 24-48-h treatment. This was supported by early proteomic changes of respiratory chain proteins and intermediate filaments that are typically involved in mitochondrial reorganization. Functionally, an impedance-based analysis showed that remdesivir (6.25 µM) affected the beat rate and contractility of NMCM. In conclusion, we identified adverse effects of remdesivir in cardiac and kidney cells at clinically relevant concentrations, suggesting a careful evaluation of therapeutic use in patients at risk for cardiovascular or kidney disease.


Subject(s)
Antiviral Agents , Proteomics , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Animals , Antiviral Agents/toxicity , Cell Proliferation , Humans , Kidney , Mice , Rats
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