Triple Antiviral Therapy Looks Promising for Mild to Moderate COVID-19

Treatment with interferon beta-1b in combination with lopinavir/ritonavir and ribavirin was found to be safe and superior to lopinavir/ritonavir alone for reducing the duration of viral shedding and hospital stay in adults with coronavirus disease 2019 (COVID-19).

The prospective, open-label phase 2 trial included 127 adults with mild to moderate COVID-19 who were admitted to Hong Kong hospitals between February 10 and March 20, 2020. Patients were randomized 2:1 to receive either lopinavir 400mg/ritonavir 100mg plus ribavirin 400mg every 12 hours and up to 3 doses of 8 million international units of interferon beta-1b on alternate days (n=86; combination group) or lopinavir 400mg/ritonavir 100mg every 12 hours (n=41; control group), both for 14 days. 

All patients received standard of care including ventilation support, dialysis support, antibiotics, and corticosteroids; study treatment was initiated, on average, 5 days after symptom onset. The primary end point of the study was time to a negative nasopharyngeal swab for SARS-CoV-2, the virus that causes COVID-19.

Findings showed that the median time from start of treatment to negative nasopharyngeal swab was 7 days for the combination group vs 12 days for the control group (hazard ratio [HR] 4.37; 95% CI, 1.86-10.24; P =.001). Additionally, the combination group met key secondary end points achieving significant clinical improvements, including shorter time to alleviation of symptoms (4 days vs 8 days; HR 3.92; 95% CI, 1.66-9.23; P <.0001), SOFA (sequential organ failure assessment) score of 0 (3 days vs 8 days; HR 1.89; 95% CI, 1.03-3.49; P =.041), and shorter average hospital stay (9 days vs 14.5 days; HR 2.72; 95% CI, 1.2-6.13; P =.016) vs the control group, respectively. 

With regard to safety, both treatment arms demonstrated similar adverse events including nausea, diarrhea and fever. There were no deaths reported in the study and 1 patient in the control group discontinued lopinavir/ritonavir due to biochemical hepatitis.

The study had several limitations including the open-label design that also lacked a placebo group. Moreover, the researchers noted that the findings were likely confounded by a subgroup of patients in the combination group who were admitted 7 or more days after symptom onset and who were not offered interferon beta-1b. The study also did not include critically ill COVID-19 patients.

“Our trial demonstrates that early treatment of mild to moderate COVID-19 with a triple combination of antiviral drugs may rapidly suppress the amount of virus in a patient’s body, relieve symptoms, and reduce the risk to healthcare workers by reducing the duration and quantity of viral shedding,” said Professor Kwok-Yung Yuen from the University of Hong Kong who led the research. “Despite these encouraging findings, we must confirm in larger phase 3 trials that interferon beta-1b alone or in combination with other drugs is effective in patients with more severe illness.”

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