May 11, 2020

Randomised trial shows early triple antiviral therapy superior to lopinavir/ritonavir for mild, moderate COVID-19

By Denise Baez

NEW YORK -- May 11, 2020 -- Early triple antiviral therapy was safe and 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), according to a study published in The Lancet.

Between February 10, 2020, and March 20, 2020, 127 patients with mild or moderate COVID-19 at 6 hospitals in Hong Kong were randomised to receive a 14-day combination of lopinavir 400 mg/ritonavir 100 mg (every 12 hours), ribavirin 400 mg (every 12 hours), and 3 doses of interferon beta-1b on alternate days (n= 86) or to lopinavir 400 mg/ritonavir 100 mg every 12 hours for 14 days (n = 41)

The median time from the start of treatment to a negative nasopharyngeal swab -- the primary endpoint -- was 7 days for the treatment group compared with 12 days for the control group (hazard ratio [HR] = 4.37; 95% confidence interval [CI], 1.86-10.24; P = 0.0010).

The combination group also had a significantly shorter time to complete alleviation of symptoms, defined as a national early warning score 2 (NEWS2) of 0 (4 days vs 8 days; HR = 3.92; 95% CI, 1.66-9.23; P< 0.0001) and a Sequential Organ Failure Assessment (SOFA) score of 0 (3.0 days vs 8.0 days; HR = 1.89; 95% CI, 1.03-3.49; P = 0.041).

The median hospital stay in the combination group was 9 days compared with 14.5 days in the control group (HR = 2.72; 95% CI, 1.2-6.13; P = 0.016).

Within the combination group, 52 patients were admitted to hospital <7 days from symptom onset and received the triple combination treatment, but 34 patients who were admitted ≥7 days after symptom onset received only lopinavir/ritonavir and ribavirin. A post-hoc subgroup comparison of these patients showed that those who started treatment <7 days after symptom onset had better clinical and virological outcomes.

“Treatment with the triple combination effectively suppressed viral load in all clinical specimens, including the nasopharyngeal swab, throat saliva, posterior oropharyngeal saliva, and stool in most patients 8 days from treatment commencement, which was significantly shorter than the time taken in the control group,” wrote Ivan Fan-Ngai Hung, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region (SAR), China, and colleagues. “The clinical and virological efficacy resulted in shorter hospital stays and facilitated infection control.”

“Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted,” the authors stated.

The median age of the patients was 52 years, 54% were male, and 40% had underlying diseases, the most common being hypertension in both the treatment (27%) and control (32%) groups. The median time to hospital admission from symptom onset was 5 days.

The most common adverse events were diarrhoea (41%), fever (38%), nausea (34%), and elevated alanine transaminase level (14%), which mostly resolved within 3 days after drug initiation. Sinus bradycardia was reported by 4 (3%) patients. There were no differences between incidence of any of the adverse events or durations of nausea or diarrhoea between groups.

One patient in the control group discontinued lopinavir/ritonavir because of biochemical hepatitis. No patients died during the study.

Limitations of the study included the open-label nature of the study, lack of a placebo group, the absence of critically ill patients, and the fact that, depending on time from symptom onset, some patients in the combination group did not receive interferon beta-1b.

SOURCE: The Lancet