Comparative Effectiveness and Safety of Ribavirin Plus Interferon-Alpha, Lopinavir/Ritonavir Plus Interferon-Alpha and Ribavirin Plus Lopinavir/Ritonavir Plus Interferon-Alpha in Patients with Mild to Moderate Novel Coronavirus Pneumonia: Results of a Randomized, Open-Labeled Prospective Study

Background: Currently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally, causing an unprecedented pandemic. However, there is still no specific antiviral therapy for coronavirus disease 2019 (COVID-19). Based on studies of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and the Chinese guidelines for the diagnosis and treatment of COVID-19, we conducted a clinical trial with the objective of comparing the effectiveness of three antiviral treatment regimens in patients with mild to moderate COVID-19.Methods: This was a single-center, randomized, open-labeled, prospective clinical trial. Eligible patients with mild to moderate COVID-19 were randomized into three groups: ribavirin (RBV) plus interferon-α (IFN-α), lopinavir /ritonavir (LPV/r) plus IFN-α, and ribavirin plus LPV/r plus IFN-α at a 1:1:1 ratio. Each patient was invited to participate in a 28-day follow-up after initiation of an antiviral regimen. The primary outcome was the difference in median interval to SARS-CoV-2 nucleic acid negativity among the three groups. The secondary outcomes were the differences in the rate of SARS-CoV-2 nucleic acid negativity at day 14 after antiviral treatment initiation, the mortality rate for COVID-19 patients at day 28 after antiviral treatment initiation, the rate of patients re-classified as severe cases during the study period, the rate of adverse events during the study period, and the rate of antiviral drug discontinuations due to adverse events during the study period.Findings: In total, we enrolled 101 patients in this study. Baseline clinical and laboratory characteristics of patients were comparable among the three groups. In the analysis of intention-to-treat data, the median interval from baseline to SARS-CoV-2 nucleic acid negativity was 12 days in the LPV/r+IFN-α-treated group, as compared with 13 days and 15 days in the RBV+IFN-α-treated group and in the RBV+LPV/r+ IFN-α-treated group, respectively ( p =0·23). The SARS-CoV-2 nucleic acid negativity rate in the LPV/r+IFN-α-treated group (61·1%) was higher than the RBV+ IFN-α-treated group (51·5%) and the RBV+LPV/r+IFN-α-treated group (46·9%) at day 14; however, the difference in the SARS-CoV-2 nucleic acid negativity rate between these groups was calculated to be statistically insignificant. The RBV+LPV/r+IFN-α-treated group developed a significantly higher rate of gastrointestinal adverse events than the LPV/r+ IFN-α-treated group and the RBV+ IFN-α-treated group.Interpretation: Our results indicate that there is no significant differences among the three regimens in terms of antiviral effectiveness in patients with mild to moderate COVID-19, which therefore implies that the antiviral effectiveness of LPV/r+IFN-α, RBV+IFN-α, and RBV+LPV/r+IFN-α for SARS-CoV-2 in the management of COVID-19 is questionable, although the possibility of these three regimens having similar antiviral efficacy could not be definitively excluded. Furthermore, the combination of RBV and LPV/r is associated with a significant increase in gastrointestinal adverse events, suggesting that RBV and LPV/r should not be co-administered to COVID-19 patients simultaneously.Trial Registration: Registered at the Chinese Clinical Trial Registry (ChiCTR2000029387). Funding Statement: National Science and Technology Major Project of China During the 13th Five-year Plan Period (2018ZX10302104001); and the Chongqing Special Research Project for Prevention and Control of Novel Coronavirus Pneumonia (No. cstc2020jscx-fyzx0074); and the Novel Coronavirus Infection and Prevention Emergency Research Project of Chongqing Municipal Education Commission (KYYJ202001).Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.Ethics Approval Statement: This study was approved by the Ethics Committee of Chongqing Public Health Medical Center (2020-002-01-KY).