Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

15 octobre 2020

Source : The Lancet Published online October 5, 2020

Auteur : RECOVERY Collaborative Group


ANALYSE

Commentateur

Dr Martine Tebacher

Résumé

L’association lopinavir-ritonavir a été proposée comme traitement contre la COVID-19 sur la base de résultats in vitro, de données précliniques et d’études observationnelles. Pourtant un essai randomisé montre qu’elle n’apporte pas de bénéfice chez les patients hospitalisés pour une forme sévère de COVID-19.
L’essai a été mené dans 176 hôpitaux du Royaume-Uni et l’association a été comparée au traitement standard. Les patients volontaires inclus dans le groupe « lopinavir-ritonavir » recevaient ces deux médicaments aux doses respectives de 400 mg et 100 mg par voie orale pendant 10 jours ou jusqu’à la sortie de l’hôpital. Cet essai faisait partie du programme RECOVERY incluant d’autres groupes pour évaluer l’hydroxychloroquine, la dexamethasone, ou l’azithromycine.
Au total, 1616 patients ont reçu association lopinavir–ritonavir et 3424 les soins standards. Parmi eux, respectivement 23% et 22% des patients sont décédés dans les 28 jours (RR 1.03, 95% CI 0.91–1.17; p=0.60) sans différence entre les sous-groupes de patients.

Conclusion
Les auteurs n’ont pas non plus observé de différence sur la durée d’hospitalisation qui a été de 11 jours en médiane dans les deux groupes (5-28). Et chez les personnes n’étant pas sous ventilation artificielle au moment de l’inclusion, il n’y a pas eu non plus de différence significative sur le risque de passer en ventilation artificielle ou le risque de décès (RR 1.09, 95% CI 0.99–1.20; p=0.092).

BACKGROUND

Lopinavir–ritonavir has been proposed as a treatment for COVID-19 on the basis of in vitro activity, preclinical studies, and observational studies. Here, we report the results of a randomised trial to assess whether lopinavir–ritonavir improves outcomes in patients admitted to hospital with COVID-19.

INTRODUCTION

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of COVID-19, emerged in China in late 2019 from a zoonotic source. Most COVID-19 infections are either asymptomatic or result in only mild disease.1 However, a proportion of infected individuals develop a respiratory illness that requires hospital care, which can progress to critical illness with hypoxaemic respiratory failure that requires prolonged ventilatory support. Among patients with COVID-19 admitted to UK hospitals, the case fatality rate is over 26%, and is in excess of 37% in patients who require invasive mechanical ventilation.2 The drug combination lopinavir–ritonavir has been suggested as an antiviral treatment for COVID-19.3 Lopinavir is a HIV-1 protease inhibitor, which is combined with ritonavir to increase its plasma half-life. Lopinavir is also an inhibitor of the severe acute respiratory syndrome coronavirus (SARS-CoV) main protease, which is critical for replication and appears to be highly conserved in SARS-CoV-2.4,5 Lopinavir has in vitro inhibitory activity against SARS-CoV, SARS-CoV-2, and Middle East respiratory syndrome (MERS) coronavirus.6–9 In a marmoset model of MERS, lopinavir–ritonavir improved clinical, radiological, and pathological outcomes and reduced viral loads.10 A study of lopinavir–ritonavir in a ferret model of COVID-19 found reduced clinical symptoms in treated animals but no effect on virus titres.11 In patients with severe acute respiratory syndrome, a historically controlled study suggested that addition of lopinavir–ritonavir to ribavirin reduced the risk of adverse clinical outcomes and viral load.12 Although some observational studies in patients with COVID-19 have reported that lopinavir–ritonavir is associated with a shorter duration of viral shedding13 and fever,14 other studies have reported no such effects.15,16 A previous randomised trial of lopinavir–ritonavir among 199 patients admitted to hospital with COVID-19 showed no improvement in viral load, duration of hospital stay, or mortality.17 However, the trial was too small to rule out the possibility of clinically relevant benefits and commentators recommended larger randomised trials to confirm or refute the lack of effect.18 Here, we report the results of a randomised trial to assess whether lopinavir– ritonavir improves clinical outcomes in patients admitted to hospital with COVID-19.


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