Phase 2 Trial Suggests Combination Antiviral Therapy Speeds Recovery in COVID-19

Triple antiviral therapy of interferon beta-1b, lopinavir-ritonavir, and ribavirin is safe and appears to be superior to lopinavir-ritonavir monotherapy in patients with early coronavirus disease 2019 (COVID-19), according to new research.

Investigators from Queen Elizabeth Hospital and Princess Margaret Hospital, both in Hong Kong, wanted to build upon knowledge of the use of antivirals in patients with respiratory diseases like COVID-19. Back in 2003, the same group looked at the combination of lopinavir-ritonavir and ribavirin in patients with Severe Acute Respiratory Disease (SARS), and found that the combination reduced mortality and the need for intensive respiratory support.

COVID-19 is similar to SARS in many ways, but it is more like influenza in the sense that the viral load tends to be highest at onset. Investigators wondered whether using a similar combination in COVID-19 might improve viral load parameters and clinical outcomes. They published their findings in The Lancet.

The team constructed an open-label, prospective, phase 2 study of adults with COVID-19 at 6 hospitals in Hong Kong. The patients were assigned to one of 2 groups. The first group was given 14 days of a combination of lopinavir (400 mg) and ritonavir (100 mg) every 12 hours, 400 mg of ribavirin every 12 hours, and 3 doses of 8 million international units of interferon beta-1B on alternate days. The control group, meanwhile, was given 14 days of just lopinavir and ritonavir, at the same dosage and frequency of the combination group.

The study included a total of 127 patients; 86 were given the combination therapy and 41 were placed in the control group. The median time from symptom onset to treatment was 5 days.

The combination group had a significantly shorter median time from the start of treatment to negative nasopharyngeal swab for SARS-CoV-2. Those receiving the combination therapy had a median time to negative swab of 7 days, versus 12 days in the control group.

Adverse events were limited, and did not vary between the two groups. One patient in the control group dropped out of the study due to biochemical hepatitis. There were no deaths in either group.

Corresponding author Kwok-Yung Yuen, MBBS, MD, and colleagues noted that it is a lengthy process to develop new antiviral therapies to treat emerging infectious diseases.

“Therefore, drug repurposing by testing existing broad-spectrum antiviral drugs that have been used to treat other viral infections is the most feasible approach in a pandemic,” they wrote.

Furthermore, the authors wrote that the therapy can be initiated immediately upon diagnosis, since unlike SARS the viral load comes early.

“Early treatment with a triple combination of modestly active antivirals is appropriate for the treatment of COVID-19 because the viral load of SARS-CoV-2 peaks at around the time of symptom onset,” they wrote.

Investigators noted some limitations. Among them, the trial was open-label. Also, their cohort did not have any critically ill patients, thus making it impossible to extrapolate implications for patients with severe disease.

Still, they said their findings suggest further study of the combination therapy is warranted.