Preliminary trial results find antiviral drug lopinavir/ritonavir does not reduce death in hospitalised patients with COVID-19


01-07-2020

The ‘RECOVERY’ trial has released preliminary results showing lopinavir/ritonavir, an antiviral drug commonly used to treat HIV, had no significant mortality benefit in hospitalised COVID-19 patients.

The RECOVERY trial (which stands for ‘Randomised Evaluation of COVid-19 thERapY’) was funded by UKRI as part of the UKRI/DHSC/NIHR COVID-19 rapid research response.

To provide real-time information in the pandemic, the results have been announced as quickly as possible, so it should be noted that the findings have not yet been peer-reviewed and accepted in a journal.

A range of potential treatments have been suggested for COVID-19 but nobody knows if any of them will turn out to be more effective in improving survival than the usual standard of hospital care which all patients will receive.

The RECOVERY trial has also recently announced preliminary results showing: low-cost dexamethasone reduced death by up to one third in hospitalised patients with severe respiratory complications of COVID-19; and no effect on mortality from the use of hydroxychloroquine in patients admitted to hospital with COVID-19.

Lopinavir is an HIV protease inhibitor, which is combined with ritonavir to increase lopinavir’s plasma half-life. Lopinavir/ritonavir had shown promising activity against SARS and MERS coronaviruses.

Professor Peter Horby, University of Oxford, and Chief Investigator for the trial, said: “Today we release the third set of results from the RECOVERY trial. These preliminary results show that for patients hospitalised with COVID-19 and not on a ventilator, lopinavir-ritonavir is not an effective treatment. In 100 days, the RECOVERY trial has provided results enabling change in global practice three times. This extraordinary national effort has shown that two drugs used to treat hospitalised COVID patients throughout the world, hydroxychloroquine and lopinavir-ritonavir, do not improve survival, whilst one drug that was not recommended, dexamethasone, saves lives.”

Professor Fiona Watt, Executive Chair of the Medical Research Council, which helped fund the trial, said: ‘It is very important that we test potential therapies in randomised clinical trials so that we can find out whether re-purposed drugs work or not. The UK’s RECOVERY trial is the world’s largest randomised trial of potential COVID-19 treatments and has worked with unprecedented speed to start delivering the answers we need. Whilst it is disappointing that lopinavir/ritonavir, like hydroxychloroquine, has been found to be ineffective, the earlier findings with dexamethasone were positive. Researchers and health professionals are now focusing their efforts, and patient care, on other promising drugs.’

On the latest findings for lopinavir/ritonavir, Professor Peter Horby and Professor Martin Landray, chief investigators of the trial, said in a statement: ‘In March 2020, the RECOVERY trial was established as a randomised clinical trial to test a range of potential treatments for COVID-19, including lopinavir-ritonavir (an antiviral treatment commonly used to treat HIV). Over 11,800 patients have been enrolled from 176 NHS hospitals in the UK.

‘On Thursday 25 June, the independent Data Monitoring Committee conducted a routine review of the emerging data and recommended that the chief investigators be unblinded to the results for the lopinavir-ritonavir arm.

‘[On Tuesday 30 June], the trial Steering Committee concluded that there is no beneficial effect of lopinavir-ritonavir in patients hospitalised with COVID-19 and closed randomisation to that treatment arm.

‘A total of 1596 patients were randomised to lopinavir-ritonavir and compared with 3376 patients randomised to usual care alone. Of these patients, 4% required invasive mechanical ventilation when they entered the trial, 70% required oxygen alone, and 26% did not require any respiratory intervention. There was no significant difference in the primary endpoint of 28-day mortality (22.1% lopinavir-ritonavir vs. 21.3% usual care; relative risk 1.04 [95% confidence interval 0.91-1.18]; p=0.58) and the results were consistent in different subgroups of patients. There was also no evidence of beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay. 

‘These data convincingly rule out any meaningful mortality benefit of lopinavir-ritonavir in the hospitalised COVID-19 patients we studied. We were unable to study a large number of patients on invasive mechanical ventilation because of difficulty administering the drug to patients on ventilators. As such, we cannot make conclusions about the effectiveness in mechanically ventilated patients. Full results will be made available as soon as possible.’

Professor Martin Landray, University of Oxford, and Deputy Chief Investigator, said: “These are clear results and once again emphasise the value of large randomised clinical trials in differentiating drugs we hope work from treatments we know do work. In many countries, current guidelines recommend lopinavir-ritonavir as a treatment for COVID-19. The results from this trial, together with those from other large randomised trials, should inform revisions to those guidelines and changes to the way individual patients are treated.”

“These results have been made possible by the huge efforts of the many doctors, nurses, and other healthcare staff that are contributing to RECOVERY – and above all the patients whose participation is driving forward our knowledge of how best to treat COVID-19.”

RECOVERY continues to enrol patients to allow the study of azithromycin, tocilizumab, and convalescent plasma. It is anticipated that other treatments will be included for study in the future.

The RECOVERY Trial is conducted by the registered clinical trials units with the Nuffield Department of Population Health in partnership with the Nuffield Department of Medicine. The trial is supported by a grant to the University of Oxford from UK Research and Innovation/National Institute for Health Research (NIHR) and by core funding provided by NIHR Oxford Biomedical Research CentreWellcome, the Bill and Melinda Gates Foundation, the Department for International Development, Health Data Research UK, the Medical Research Council Population Health Research Unit, and NIHR Clinical Trials Unit Support Funding. 

The RECOVERY trial involves many thousands of doctors, nurses, pharmacists, and research administrators at 176 hospitals across the whole of the UK, supported by staff at the NIHR Clinical Research Network, NHS DigiTrials, Public Health England, Department of Health & Social Care, the Intensive Care National Audit & Research Centre, Public Health Scotland, the Secure Anonymised Information Linkage at University of Swansea, and the NHS in England, Scotland, Wales and Northern Ireland. 

Based on content provided by the University of Oxford.

To read more information, click here.