Triple antiviral therapy shows promise in mild-to-moderate COVID-19 in HK study

A triple antiviral regimen of interferon (IFN) beta-1b, lopinavir-ritonavir and ribavirin, given within 7 days of symptom onset, is superior to lopinavir-ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild-to-moderate coronavirus disease 2019 (COVID-19), a prospective open-label phase II study in Hong Kong has shown.

In the study, 127 adult patients (median age, 52 years; 54 percent male) with laboratory-confirmed COVID-19 admitted to one of six public hospitals in Hong Kong between 10 February and 20 March 2020 were randomized to receive 14 days of lopinavir-ritonavir (400/100 mg every 12 hours) alone (control group; n=41) or in combination with ribavirin (400 mg every 12 hours) and up to three doses of IFN beta-1b (1 mL [8 million IU] on alternate days) (combination therapy group; n=86). In the combination therapy group, IFN beta-1b was omitted in 34 patients recruited and treated at 7–14 days from symptom onset to avoid its proinflammatory effects. [Lancet 2020, doi: 10.1016/ S0140-6736(20)31042-4]

All patients in the study received standard care, including ventilation support, dialysis support, antibiotics and corticosteroids. The median time from symptom onset to start of study treatment was 5 days.

The combination therapy was associated with a significantly shorter time to negative nasopharyngeal swab than lopinavir-ritonavir alone (median, 7 days vs 12 days; hazard ratio [HR], 4.37; 95 percent confidence interval [CI], 1.86 to 10.24; p=0.001).

Time to negative viral load was also significantly shorter in the combination therapy vs control group in all specimens when assessed individually (posterior oropharyngeal saliva, 6 days vs 8 days; p=0.044) (throat swab, 4.5 days vs 7 days; p=0.039) (stool, 5 days vs 7 days; p=0.03), and in all specimens combined (8 days vs 13 days; p=0.001).

“Most patients treated with the triple combination regimen tested negative on real-time polymerase chain reaction [RT-PCR] in all specimens by day 8,” the investigators noted.

Clinically, patients in the combination therapy group achieved complete alleviation of symptoms (4 days vs 8 days; HR, 3.92; 95 percent CI, 1.66 to 9.23; p<0.0001) and a Sequential Organ Failure Assessment (SOFA) score of 0 (3 days vs 8 days; HR, 1.89; 95 percent CI, 1.03 to 3.49; p=0.041) significantly earlier than those in the control group.

These improvements in virological and clinical responses led to significantly shorter hospital stay in the combination therapy vs control group (median, 9 days vs 14.5 days; HR, 2.72; 95 percent CI, 1.2 to 6.13; p=0.016).

In a post-hoc subgroup comparison, patients who started treatment <7 days after symptom onset were found to have better virological and clinical outcomes with triple antiviral therapy vs lopinavir-ritonavir alone. However, no significant between-group differences in outcomes were found in those treated ≥7 days after symptom onset.

Adverse events included self-limiting nausea and diarrhoea, with no significant differences between the two groups.

“Our trial demonstrates that early treatment of mild-to-moderate COVID-19 with a triple combination of antiviral drugs may rapidly suppress the virus, relieve symptoms, and reduce the risk to healthcare workers by reducing the duration and quantity of viral shedding. The combination treatment appeared safe and well tolerated,” said principal investigator Professor Kwok-Yung Yuen of the University of Hong Kong.

Noting that the findings may be confounded by the subgroup of 34 patients in the combination therapy group who were not given IFN beta-1b, the investigators suggested that a phase III trial with IFN beta-1b as a backbone treatment with a placebo control group should be considered.