Lopinavir-ritonavir fails to reduce mortality risk in patients hospitalized with COVID-19

The antiviral combination of lopinavir and ritonavir does not reduce the risk of death among patients hospitalized with COVID-19, according to results of the UK-based RECOVERY* trial.

“Treatment of COVID-19 with the drug combination lopinavir-ritonavir has been recommended in many countries. However, results from this trial show that it is not an effective treatment for patients admitted to hospital with COVID-19,” said co-lead author Professor Martin Landray from the Nuffield Department of Population Health, University of Oxford, Oxford, UK.

In this multicentre (176 hospitals), open-label trial, eligible patients hospitalized with COVID-19 (mean age 66.2 years) were randomized to receive usual standard of care (SoC) alone (n=3,424) or in addition to oral lopinavir (400 mg) plus ritonavir (100 mg; n=1,616) every 12 hours for 10 days or until discharge or receipt of another RECOVERY** treatment. Patients were treated for a median 5 days.

At 28 days, all-cause mortality did not significantly differ between patients in the SoC-alone and lopinavir-ritonavir groups (22 percent vs 23 percent; rate ratio [RR], 1.03, 95 percent confidence interval [CI], 0.91–1.17; p=0.60). [Lancet 2020;doi:10.1016/S0140-6736(20)32013-4]

The results were consistent across the prespecified subgroups of age, sex, ethnicity, number of days since symptom onset, receipt of respiratory support at randomization, and baseline predicted risk of death.

Time to discharge alive from hospital did not differ between the SoC-alone and lopinavir-ritonavir groups (median 11 days for both), nor did proportion of patients who were discharged alive at 28 days (70 percent vs 69 percent; RR, 0.98, 95 percent CI, 0.91–1.05; p=0.53).

Among those not on mechanical ventilation at baseline, risk of progressing to invasive mechanical ventilation or death was also similar between the SoC and lopinavir-ritonavir groups (27 percent vs 29 percent; risk ratio, 1.09, 95 percent CI, 0.99–1.20; p=0.092).

One serious adverse event (AE) of elevated alanine aminotransferase was thought to be attributable to lopinavir-ritonavir and resolved after treatment cessation.

No role for lopinavir-ritonavir

“The result from the RECOVERY trial is clear. When combined with findings from an earlier, smaller trial and with the World Health Organization (WHO) interim results, [N Engl J Med 2020;382:1787-1799; https://www.who.int/news/item/04-07-2020-who-discontinues-hydroxychloroquine-and-lopinavir-ritonavir-treatment-arms-for-covid-19, accessed 23 October 2020] this provides strong evidence that lopinavir-ritonavir is not an effective treatment for patients hospitalized with COVID-19,” confirmed co-chief investigator Professor Peter Horby, also from the Nuffield Department of Medicine.

“Whilst it is disappointing … these findings have allowed us to focus our efforts on other promising treatments and have informed the way in which individual patients are treated,” he added.

Few patients in this study were intubated. As such, the effect of lopinavir-ritonavir in this setting could not be determined, the researchers added.

The results of the three studies, in addition to the AEs and drug interactions with lopinavir-ritonavir, “have led to updating of clinical management guidelines for COVID-19 to discourage use of lopinavir-ritonavir in patients admitted to hospital with COVID-19 outside of clinical trials,” said Drs Bin Cao from the China-Japan Friendship Hospital, Beijing, China, and Frederick Hayden from the University of Virginia School of Medicine, Charlottesville, Virginia, US, in a commentary. [Lancet 2020;doi:10.1016/S0140-6736(20)32078-X]

However, whether early antiviral initiation in mild COVID-19 or as postexposure prophylaxis in high-risk populations would be beneficial is uncertain, they said.