Effect of remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial

Lingas, Guillaume; Néant, Nadège; Gaymard, Alexandre; Belhadi, Drifa; Peytavin, Gilles; Hites, Maya; Staub, Thérèse; Greil, Richard; Paiva, José-Artur; Poissy, Julien; Peiffer-Smadja, Nathan; Costagliola, Dominique; Yazdanpanah, Yazdan; Wallet, Florent; Gagneux‐Brunon, Amandine; Mentré, France; Ader, Florence; Burdet, Charles; Guedj, Jérémie; Bouscambert‐Duchamp, Maude

doi:10.1093/jac/dkac048

Cited by 30 publications

(27 citation statements)

References 30 publications

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“…In the same study, viral dynamics after hospitalization was an independent predictor of mortality (HR = 1.31, p < 10 − 3). Finally, a secondary analysis of the DISCOVERY study comparing remdesivir with the standard of care found that remdesivir use was associated with a small but signi cant increase in viral clearance (32). We can therefore postulate that the potential bene t of high-dose DXM in the in ammatory process is offset by a detrimental effect on viral clearance.…”

Section: Discussionmentioning

confidence: 99%

‘Which severe COVID-19 patients could benefit from High dose dexamethasone? A Bayesian reanalysis of a randomized clinical trial

Chevret

Bouadma²,

Dupuis

et al. 2023

Preprint

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Background: The respective benefits of high and low doses of dexamethasone (DXM) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and acute respiratory failure (ARF) are controversial, with two large triple-blind RCTs reaching opposite conclusions. In the COVIDICUS trial, we argued against any additional benefit of high-dose dexamethasone (DXM20). We aimed to explore whether some specific patient phenotypes could benefit from DXM20 compared to the standard of care dose of DXM (DXMSoC). Methods: We performed a post hoc exploratory Bayesian analysis of 473 patients who received either DXM6 or DXM20 in the COVIDICUS trial. The primary outcome was the 60-day mortality rate of DXM20 over DXMSoC, with the treatment effect measured on the posterior mean of relative risk (RR) estimated using a beta-binomial model with 95% credibility intervals (95% CrI). Bayesian measures of interaction quantified the probability of interaction (Pr Interact) that the RR of 60-day death differed across the subsets by 20%. Results: Overall, the posterior mean RR of Day 60 mortality was 1.06 with a 95% credible confidence interval (0.77 to 1.44) and a posterior probability of benefit and harm of 27.0% and 50.5%, respectively. There was some evidence of treatment by subset interaction according to age, with the benefit increasing in patients aged below 70 years (RR=0.74, 95% CrI 0.41-1.22) compared to those aged above 70 (RR=1.12, 95% CrI 0.77 to 1.60) (Pr Interact, 77%), when the time since symptoms onset was lower than 7 days (RR=0.66, 95% CrI 0. 36 to 1.09) compared to 7 days or more (RR=1.15, 95% CrI 0.76 to 1.67) (Pr Interact, 90%) and in patients receiving remdesivir (RR=0.62, 95% CrI 0.29 to 1.14) compared to those who did not (RR=1.12, 95% CrI 0.78 to 1.58) (Pr Interact, 88%). Conclusions: In this exploratory post hoc Bayesian analysis, compared with standard-of-care DXM, high-dose DXM may benefit patients aged less than 70 years with severe ARF that occurred less than 7 days after symptoms onset. The use of remdesivir may also favour the benefit of DXM20. Further analysis is needed to confirm these findings. Trial registration: NCT04344730, date of registration April 14, 2020 (https://clinicaltrials.gov/ct2/show/NCT04344730?term=NCT04344730&draw=2&rank=1); EudraCT: 2020-001457-43 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-001457-43).

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Section: Discussionmentioning

confidence: 99%

‘Which severe COVID-19 patients could benefit from High dose dexamethasone? A Bayesian reanalysis of a randomized clinical trial

Chevret

Bouadma²,

Dupuis

et al. 2023

Preprint

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“…It is also variably confounded by detection of the slower terminal virus elimination phase. An alternative is to use mechanistic models of viral kinetics but it is unclear whether this would have an advantage over robust linear regression given that the underlying viral dynamics are likely to be highly complex ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

Characterizing SARS-CoV-2 Viral Clearance Kinetics to Improve the Design of Antiviral Pharmacometric Studies

Watson

Kissler

Day

et al. 2022

Antimicrob Agents Chemother

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A consensus methodology for the pharmacometric assessment of candidate SARS-CoV-2 antiviral drugs would be useful for comparing trial results and improving trial design. The time to viral clearance, assessed by serial qPCR of nasopharyngeal swab samples, has been the most widely reported measure of virological response in clinical trials, but it has not been compared formally with other metrics, notably model-based estimates of the rate of viral clearance.

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“…Of these 490 patients, 54.7% achieved VC during hospitalization, while the remaining 45.3% reached VC during the post-discharge follow-up period. Median time to VC was 25 (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) days.…”

Section: Sars-cov-2 Clearancementioning

confidence: 99%

“…20 In addition, evidence for the effect of RDV on SARS-CoV-2 viral clearance (VC) is scarce and contradictory. Different studies 19,21,22 have shown that the use of RDV is not associated with nasopharyngeal viral load changes, while other studies 23,24 have demonstrated that RDV treatment was associated with faster viral decay. However, these studies were all characterized by small sample sizes or follow-up periods that did not exceed the hospitalization period.…”

Section: Introductionmentioning

confidence: 99%

505. Impact of Remdesivir on SARS-CoV-2 Clearance in a Real-Life Setting: A Matched-Cohort Study

Spagnuolo

Voarino

Tonelli

et al. 2021

Open Forum Infectious Diseases

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Background Evidence regarding the impact of remdesivir (RDV) on SARS-CoV-2 viral clearance (VC) is scarce. Aim of this study was to compare VC timing in COVID-19 patients who received RDV with those who did not. Methods Matched-cohort study conducted (25 February 2020-15 April 2021) at the IRCSS San Raffaele, Milan, Italy. The study enrolled hospitalized patients with pneumonia and a SARS-CoV-2 positive nasopharyngeal swab (NPS) at admission and at least one NPS during follow-up. Follow-up started at hospital admission and ended at the date of the first negative NPS (within 30 days after discharge). Patients who received RDV (cases) and patients who did not (controls) were matched based on age (±5 years), sex and PaO2/FiO2 (P/F; ±10 mmHg) values at admission. NPS were analyzed with RT-PCR. Results described as median (IQR) or frequency (%). Time to VC was estimated with Kaplan-Meier curve and compared with log-rank test. Results 648 patients were enrolled: 216 cases and 432 controls. Patients’ characteristics at admission are reported in Table 1. VC was observed in 490 patients (75.6%) in a median time of 25 (16-34) days. Overall, time to VC was similar in patients receiving or not receiving remdesivir (p=0.519). However, time to VC was different when considering both the use of RDV (yes vs no) and age (≤ or > 63 years), as shown in Figure 1A. A significant finding was also observed considering the use of RDV and P/F values at admission (≤ or > 200 mmHg), as reported in Figure 1B. Among the 490 patients who reached VC during follow-up, overall time to VC was similar in patients receiving or not receiving RDV (p=0.075; Figure 2A); however, RDV use was associated with a higher probability of VC in the subgroup of patients with P/F admission values ≤ 200mmHg (p=0.035; Figure 2B), in the age group 55-65 years (p=0.025; Figure 2C) and in patients with comorbidities (p=0.028). Time to viral clearance among the 490 patients who reached VC during follow-up. Panel A: time to VC according to RDV use. Panel B: time to VC according to RDV and P/F ratio value at admission. Panel C: time to VC according to RDV in the age group 55-65 years. Conclusion Time to viral clearance was similar in patients receiving or not receiving remdesivir; however the use of RDV was associated with a benefit on time to viral clearance in younger patients and in those with a P/F ratio at admission ≤200 mmHg. Disclosures Vincenzo Spagnuolo, MD, ViiV Healthcare (Other Financial or Material Support, Preparation of educational material) Antonella Castagna, MD, Gilead Sciences (Other Financial or Material Support, Speaking fee)Jansenn-Cilag (Other Financial or Material Support, Speaking fee)MSD (Other Financial or Material Support, Speaking fee)Theratechnologies (Other Financial or Material Support, Speaking fee)ViiV Healthcare (Other Financial or Material Support, Speaking fee)

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Effect of remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial

Cited by 30 publications

References 30 publications

‘Which severe COVID-19 patients could benefit from High dose dexamethasone? A Bayesian reanalysis of a randomized clinical trial

‘Which severe COVID-19 patients could benefit from High dose dexamethasone? A Bayesian reanalysis of a randomized clinical trial

Characterizing SARS-CoV-2 Viral Clearance Kinetics to Improve the Design of Antiviral Pharmacometric Studies

505. Impact of Remdesivir on SARS-CoV-2 Clearance in a Real-Life Setting: A Matched-Cohort Study

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