Covid-19: Lopinavir-ritonavir does not benefit hospitalised patients, UK trial findsBMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2650 (Published 01 July 2020) Cite this as: BMJ 2020;370:m2650
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Previous experiences with other coronavirus infections, such as severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS), as well as preliminary in vitro data, provided the rationale for the investigation of lopinavir/ritonavir as a potential treatment of SARS coronavirus-2 (SARS-CoV-2) infection.  Indeed, two large scale randomized controlled clinical trials including lopinavir/ritonavir as one of the key treatment arms have rapidly started patient enrollment in March 2020--namely, the UK RECOVERY and the WHO SOLIDARITY trials.  However, experience accumulated in the weeks following the start of these two megatrials, have been disappointing.
For example, Cao and co-workers, in a prospective, randomized, open-label study reported no added benefit of lopinavir/ritonavir in hospitalized adult patients with severe COVID-19 treated with standard of care.  The latter study was the subject of fierce criticism, centered mainly on potential methodological flaws, such as inadequate patient identification, underpowered study design and wrong selection of the primary end-point.  As a result, both RECOVERY and SOLIDARITY trials have continued patient enrollment and treatment with lopinavir/ritonavir. Now, four months after the online publication of the results of the trial by Cao et al, we have heard that, according to the preliminary results released by the deputy chief investigator of the UK RECOVERY trial, lopinavir/ritonavir does not benefit hospitalized COVID-19 patients, either in terms of death rate, progression to mechanical ventilation or length of hospital stay.  We believe, and detail below, that these results could have been expected earlier.
Last April 3, Choy and coworkers reported the in vitro inhibitory activity of lopinavir against SARS-CoV-2 virus in Vero E6 cells, with an estimated 50% effective concentration (EC50) at 26 μM.  Following that publication, we have assessed the concentrations of lopinavir required to inhibit in vivo SARS-CoV-2, taking into consideration the tissue drug distribution, the drug protein binding and the plasma drug concentrations measured in patients with HIV and COVID-19 treated with the conventional lopinavir/ritonavir 400/100 mg twice daily dose.  Based on our estimations, the current dosing of lopinavir provides effective concentrations exceeding the lopinavir protein-adjusted 90% inhibitory concentrations only for HIV. Indeed, the concentrations of lopinavir required to inhibit SARS-CoV-2 replication in plasma, epithelial lining fluid and cerebrospinal fluid are, respectively, 200-fold, 20-fold and 2000-fold higher than those measured in vivo. The same findings have been consistently reported also by other independent research groups. [8,9]
Taken together, these findings provide solid evidence that the lopinavir dose necessary to inhibit SARS-CoV-2 replication is clinically unachievable (i.e., it would take a dose tens/hundreds of times greater than that currently used), clearly arguing against a role of this drug in the treatment of COVID-19. Remarkably, this information has been available in the literature for at least couple of months. Indeed, the interruption of the lopinavir/ritonavir treatment arm, if carried out immediately after the publication of the data on SARS-CoV-2 EC50 3 months ago, would have spared many patients the unpleasant experience of this drug’s side effects--namely, nausea, vomiting, liver toxicity and an elevated risk of potential drug-drug interactions.
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5. Griffin S. Covid-19: Lopinavir-ritonavir does not benefit hospitalized patients, UK trial finds. BMJ. 2020 Jul 1;370:m2650. doi: 10.1136/bmj.m2650. PMID: 32611587.
6. Choy KT, Wong AY, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 2020 Jun;178:104786. doi: 10.1016/j.antiviral.2020.104786. PMID: 32251767; PMCID: PMC7127386.
7. Cattaneo D, Corbellino M, Clementi E, Galli M, Riva A, Gervasoni C. Does lopinavir really inhibit SARS-CoV-2? Pharmacol Res. 2020 Aug;158:104898. doi: 10.1016/j.phrs.2020.104898. Epub 2020 May 11.
8. Smith PF, Dodds M, Bentley D, Yeo K, Rayner C. Dosing will be a key success factor in repurposing antivirals for COVID-19. Br J Clin Pharmacol. 2020 Apr 17. doi: 10.1111/bcp.14314. Epub ahead of print. PMID: 32304110.
9. Schoergenhofer C, Jilma B, Stimpfl T, Karolyi M, Zoufaly A. Pharmacokinetic of Lopinavir and Ritonavir in Patients Hospitalized With Coronavirus Disease 2019 (COVID-19). Ann Intern Med. 2020 May 12:M20-1550. doi: 10.7326/M20-1550. Epub ahead of print. PMID: 32422065; PMCID: PMC7236891.
Competing interests: No competing interests
We should not be surprised to see that antiviral drugs have little effect in hospitalised patients.
Antiviral drugs are relatively new (compared to antibiotics); but we have had antivirals for herpes simplex and influenza for many years now. We know that, if they are to be effective, they have to be used early in the course of the disease. Antiviral use in influenza has relatively little effect when given to somebody who is already ill. Given as chemoprophylaxis, however, they are not only given before the onset of symptoms (maximising their efficacy); but they are also effective in reducing the quantity and duration of viral shedding, and thus the infectiousness of cases. This is why they are so valuable when used in care homes, for example.
With Covid-19, we know that the severe forms of disease - the ones responsible for hospitalisation - are triggered by the infection, but are caused by an over-reaction of the immune system; and they occur at a time when most patients are no longer infectious, suggesting that by the time these reactions cause problems, the virus has already been cleared by the immune system.
If this is the case - and the virus, having triggered the immune over-reaction, is no longer present, or important in the ongoing course of the disease - it is hardly surprising that antivirals, at this point in the natural history of the disease, are of little or no value.
Competing interests: No competing interests