Early triple antiviral therapy for COVID-19 - Authors' reply.

We thank Nelson Lee and colleagues for the important questions. We agree that there are limitations to our study, including the absence of a placebo and no intervention group, which was mentioned in the discussion section of our Article.

As explained in the methods section of the Article, a placebo group was not accepted in Chinese culture and therefore, we had to use lopinavir–ritonavir as a control. We also agree that the efficacy of lopinavir–ritonavir and ribavirin might be weak. Nevertheless, our study was designed in January, 2020, and commenced in early February, 2020, and it was based on results from our previous in-vitro and in-vivo studies,3, 4in which we found that lopinavir–ritonavir and ribavirin are active against severe acute respiratory syndrome and Middle East respiratory syndrome coronavirus (MERS-CoV). This work was done well before the lopinavir–ritonavir trial was completed and published online in March, 2020. Additionally, most of the trials listed by Lee and colleagues were non-randomised studies on COVID-19 and MERS-CoV. Although 40% of the combination group was not given interferon beta-1b due to late presentation, both the group and subgroup analyses showed high statistical significance, with clinical (national early warning score 2 and sequential organ failure assessment scores) and virological improvement in the combination group. Despite a mild to moderate illness, all patients were symptomatic, and 96 (76%) of 127 patients had pneumonia at baseline. Most patients were admitted to hospital within the first week of symptom onset, and early antiviral treatment probably prevented a substantial proportion of these patients from further deterioration by rapidly reducing viral load and by cytokine suppression. These patients would otherwise have needed a ventilator and intensive care support. The discharge policy was based on two consecutive negative PCR results at least 24 h apart, and all patients were afebrile for 48 h. The 2-week low-dose ribavirin treatment was safe with negligible side-effects, and none of the patients in our study had any harmful drug effects. Overall, our work showed that early interferon-based combination therapy resulted in both clinical and virological improvement in patients with mild to moderate COVID-19. In the future, larger and high-powered studies on interferon-based combination therapy are needed.