Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected more than 3 million patients with more than 200 000 deaths in more than 230 countries.1 COVID-19 spreads quickly from person to person,2 and is primarily an acute viral pneumonia leading to respiratory failure as reported in autopsy studies and animal models,3, 4 although cytokine storm and extrapulmonary involvements have been occasionally reported.3, 4 Besides respiratory and intensive care support to the extent of extracorporeal membrane oxygenation, no specific antiviral treatment has been recommended because of insufficient evidence from randomised trials. Many repurposed drugs have been shown to have in-vitro activity against the close relatives of SARS-CoV-2, which are all beta-coronaviruses. Lopinavir and many interferons, particularly interferon beta, have been shown to have modest activity in vitro against SARS-CoV and Middle East respiratory syndrome (MERS)-CoV, and can be used synergistically with ribavirin.5, 6 In 2003, we did an open-label trial using historical controls, and showed that a combination of lopinavir–ritonavir with ribavirin reduced the mortality and need for intensive respiratory support of patients with SARS who had been admitted to hospital.7 Moreover, lopinavir–ritonavir or interferon beta-1b has been shown to reduce viral load and improve lung pathology in a common marmoset model.8 However the viral load of SARS and MERS peaks at around day 7–10 after symptom onset, whereas the viral load of COVID-19 peaks at the time of presentation, similar to influenza.9, 10 Experience from the treatment of patients with influenza who are admitted to hospital suggested that a combination of multiple antiviral drugs is more effective than single drug treatments in this setting of patients with a high viral load at presentation.11, 12 Therefore, we did this phase 2 randomised trial to establish whether a combination of three modestly active drugs against SARS-CoV-2 can improve the viral load profile and clinical parameters in adults with COVID-19 requiring hospital admission.

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