RECOVERY trial shoots down possibility of lopinavir-ritonavir as Covid treatment

Researchers at the Oxford University conducting the RECOVERY trial said the drug combination did not show any significant benefit in reducing Covid mortality.

A medic collects samples during door-to-door serological survey to analyse the spread of Covid-19, at Paharganj in New Delhi | PTI

New Delhi: Yet another drug seems to have bitten the dust as a treatment option for the novel coronavirus disease.

Researchers in the RECOVERY trial at the University of Oxford have reported that HIV drugs lopinavir and ritonavir ⁠— India’s drugs of choice against Covid-19 for a brief period ⁠— do not show any significant benefit in reducing mortality of Covid patients.

“Today, 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 … These data convincingly rule out any meaningful mortality benefit of lopinavir-ritonavir in the hospitalised Covid-19 patients we studied,” the researchers said in a statement Thursday night.

“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,” the statement added.

This follows an earlier negative finding in the same trial about hydroxychloroquine (HCQ) which is used against malaria and auto immune disorders and still among the drugs India is using for Covid-19 cases. The trial, however, did come up with a positive finding for the glucocorticoid dexamethasone.

Trial results

In the lopinavir-ritonavir arm of the trial, 1,596 patients were randomly assigned to be administered the drug. The outcomes in these patients were compared with 3,376 patients randomly assigned to get only standard care.

Of these patients, 4 per cent required invasive mechanical ventilation when they entered the trial while 70 per cent required oxygen alone and 26 per cent did not require any respiratory intervention.

“There was no significant difference in the primary endpoint of 28-day mortality (22.1 per cent lopinavir-ritonavir vs. 21.3 per cent usual care…) 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,” explained the statement. The data was reviewed last Thursday by the trial steering committee after which a decision was taken to release the findings.

Peter Horby, professor of Emerging Infectious Diseases and Global Health in the Nuffield Department of Medicine, 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.”

Lopinavir-ritonavir showed early signs of promise

Lopinavir and ritonavir are normally used as second line anti-HIV drugs. India manufactures the drugs mostly for export. In February this year, the Indian Council of Medical Research (ICMR) had obtained clearance for using the drugs in case of a Covid-related public health emergency. The drugs were also used in some Covid patients early in March, including at the Sawai Man Singh Hospital in Jaipur where doctors treated two Italian patients and later announced they tested negative for SARS-CoV-2.

However, even as India was using the drugs, the results of a 199-subject trial from China reported no benefits of the drug combination. The trial results, published in the New England Journal of Medicine, reported a mortality rate of 22.1 per cent in patients who were administered the drug ⁠— higher than the 11 per cent to 14.5 per cent mortality otherwise reported.

“In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit,” researchers from the National Clinical Research Center for Respiratory Diseases and other Chinese institutes had reported in the medical journal.

Soon afterwards, India revised its clinical management protocol for Covid-19 to exclude the two drugs.

RECOVERY trial still looking for Covid treatment

RECOVERY is currently the world’s largest trial exploring possible treatments for Covid-19. Over 11,800 patients have been randomised to various arms to find out the efficacy of various drugs.

Apart from lopinavir-ritonavir, they include low-dose dexamethasone (has now been stopped in adults after clear positive results), HCQ (stopped due to lack of efficacy), azithromycin (a commonly used antibiotic), tocilizumab (an anti-inflammatory treatment given by injection), convalescent plasma therapy (collected from donors who have recovered from Covid-19 and contains antibodies against the SARS-CoV-2 virus).

The trial, which reported the negative findings on HCQ, also reported that low-dose dexamethasone reduces the risk of death by about one-third among patients receiving ventilation and by one-fifth in those requiring oxygen alone. However, there was no benefit among those patients who did not require respiratory support.

The trial continues to enrol patients to study the efficacy of azithromycin, tocilizumab, and convalescent plasma. It is being conducted in 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 Centre, Wellcome, 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.