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

The use of remdesivir has been associated to contradictory virological and clinical results in the past months. Here, we analyzed its effect on viral dynamics in the DisCoVeRy trial, where 665 patients were randomized to either standard of care (SoC) or SoC + remdesivir. We used a mathematical model to reconstruct virological profiles and to estimate the antiviral efficacy of remdesivir in reducing viral production.

Using this model, we showed that remdesivir has a significant antiviral activity, reducing the amount of viral particles released by infected cells by a 2-fold factor on average. Remdesivir had a larger impact in patients with high viral load at randomization, reducing viral production by 5-fold on average.

In conclusion our results reconciliate the contradictory findings of the literature, demonstrating that remdesivir has an antiviral activity, albeit too limited to generate, as a monotherapy, a clinical effect.

Link to the article published in the Journal of Antimicrobial Chemotherapy :

https://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkac048/6540540?searchresult=1

Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial

Data from 832 patients hospitalized between March 2020 and January 2021, recruited in 5 European countries (418 patients receiving standard of care and 414 additionally receiving remdesivir), were analyzed. The analysis has shown no difference between the two groups in patient clinical status 15 and 29 days after receipt of the first remdesivir dose, in time to discharge from hospital, and in death rate on Day 28. There was also no demonstrated difference between the groups in terms of speed of elimination of the virus at nasopharyngeal level. Severe side effects were distributed similarly between the two groups. These data support those of the Solidarity trial conducted by the WHO, in particular by providing results on a larger number of endpoints.

Link to the article published in the The Lancet Infectious Diseases :

https://doi.org/10.1016/S1473-3099(21)00485-0

Remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1 have finally little or no effect on hospitalized patients with Covid-19 and are not recommended in severe forms of the disease.

They don’t decrease the risk of mortality, the need of ventilation, and the duration of hospital stay. Those conclusions are issued after data analysis of 11,330 adults included in the Solidarity trial (including Discovery trial). They were hospitalized in 405 different hospitals in 30 countries.

In total, 1253 deaths were reported between 4 to 14 days after randomisation with a 11,8% rate of mortality at 28 days. This risk depended on several factors, particularly age (20.4% if ≥70 years and 6.2% if <50 years) and ventilation status (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise).
Compared with the group with no trial drugs, the ones receiving remdesivir, hydroxychloroquine, lopinavir or interferon didn’t show any improvement regarding mortality or initiation of ventilation. They neither reduced the duration of hospital stay, which suggests that none of the four treatments has a pharmacologic effect to substantially reduce time to recovery. Those results were consistent overall or in any particular subgroup of age, sex, or health condition.
This trial proves the lack of efficacy for those four repurposed antivirals in reducing COVID-19 mortality, refuting early hopes for those treatments, initially based on smaller or nonrandomized studies.

Articles:

Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results
NEJM DOI: 10.1056/NEJMoa2023184

Antiviral drugs in hospitalized patients with COVID-19 – the DisCoVeRy trial
doi: https://doi.org/10.1101/2021.01.08.20248149