Open-label RCT of triple combination (LPV/r, Ribavirin, Interferon) on SARS-CoV2


This study is generating a lot of discussion at the moment. The reported effect sizes are larger than prior sars-cov2 studies, but their are also many questions among clinicians regarding the validity of the statistical analysis.



Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir–ritonavir, and ribavirin for treating patients with COVID-19.


This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population. The study is registered with, NCT04276688.


Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3–7). The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days [IQR 5–11]) than the control group (12 days [8–15]; hazard ratio 4·37 [95% CI 1·86–10·24], p=0·0010). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir–ritonavir because of biochemical hepatitis. No patients died during the study.


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 COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted.


  1. The study was designed based on power-analysis assuming 26.4% difference in the 21-day mortality or acute respiratory distress syndrome rate. However, the primary outcome was time to achieve a negative RT-PCR result. How common is it to have a power analysis for something other than the primary outcome? Should this be a reason for concern? The authors note that when the study was designed, little was known about sar-cov2.

  2. The combined intervention had an unusual design, where all patients received LPV/r & Ribavirin on recruitment, but only Interferon if symptoms duration was <7 days on recruitment. Does this wrinkle of 7-days in effect create another group? Is it now 2 different intervention groups and 1 control? Or maybe its 2x2 groups? Does this change how the study should be analyzed? Since the study did not do stratified randomization based on 7-day symptoms history at recruitment, I dont think a 2x2 group, or 3 group analysis would be appropriate. But many clinicians are concerned that lumping the intervention group together might also create bias, and invalidate the primary outcome (time to negative PCR). The protocols from the paper are quoted below:

“In the combination group, patients who were recruited and treated less than 7 days from symptom onset received a triple combination of 14 days of oral lopinavir–ritonavir (lopinavir 400 mg and ritonavir 100 mg) every 12 h (via nasogastric tube to intubated patients), ribavirin 400 mg every 12 h, and subcutaneous injection of one to three doses of interferon beta-1b 1 mL (8 million international units [IU]) on alternate days depending on the day of drug commencement (if commenced on day 1–2 from symptom onset, the patient received all three doses of interferon beta-1b; if commenced on day 3–4, the patient received two doses; if commenced on day 5–6, the patient received one dose). For those recruited and treated between days 7 and 14, interferon beta-1b injection was omitted to avoid its proinflammatory effects. Patients assigned to the control group received only oral lopinavir–ritonavir (lopinavir 400 mg and ritonavir 100 mg) every 12 h for 14 days.”

Thanks to all for your help!


What am I missing?

Unless the control group is a proven standard of care, it seems possible that the each intervention is worse than supportive care in respect to recovery rates.

Shortening the duration of viral shedding (a surrogate for benefit) could be offset by the toxicities of the interventions - particularly for a disease that is thought to kill indirectly - by a overly exuberant immune response.

1 Like